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Morality in Pediatric ARDS: Has It Changed? 


Analgesia and Sedation for Ventilated 
Children and Infants 

Lung-Protective Strategy in Pediatric ARDS 

High-Frequency Ventilation in Pediatric ARDS 

ECMO in Pediatric Respiratory Failure 

Inhaled Nitric Oxide in Pediatric ARDS 

Future ARDS Therapies 

Management of Pediatric ARDS: A Survey 


Surfactant in Pediatric Respiratory Failure 
Partial Liquid Ventilation in Pediatric ARDS 

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A Monthly Science Journal 
Established in 1956 

The Official Journal of the 

American Association for 

Respiratory Care 


NOVEMBER 1998 / VOLUME 43 / N U 






ER 1 1 

Mark J Heulitt MD 
Little Rock, Arkansas 


Mortality for Pediatric Acute Respiratory Distress 
Syndrome in 1998: Has It Changed? 

h\ Mark J Heulitt — Little Rock. Arkansas, and James Fackler — Baltimore. Maryland 


Analgesia and Sedation for Ventilated Children and Infants 

by K J S Anand — Little Rock. Arkansas 

Lung-Protective Strategy in Pediatric Patients with 
Acute Respiratory Distress Syndrome 

by Mark J Heulitt — Little Rack. Arkansas, and Desmond Bohn— Toronto. Canada 

High-Frequency Ventilation in Pediatric ARDS 

by John H Arnold — Boston. Massaclmsetts 

Extracorporeal Life Support in Pediatric Respiratory Failure: 
Past. Present, and Future 

by Heidi J Dallon— Washington. DC and Mark J Heulitt— Little Rock. Arkansas 

Inhaled Nitric Oxide: Medical Miracle or Passing Fad? 

by Heidi J Dalton — Washington. DC 


Future ARDS Therapies 

by James Fackler — Baltimore. Maiyland 

Management of Pediatric Patients with ARDS: 
A Survey of Pediatric Intensivists 

b\ Steven M Schexna\der and Mark J Heulitt — Little Rock. Arkansas 


Surfactant in Pediatric Respiratory Failure 

by Douglas F Willson — Charlottesville. Virginia 

Partial Liquid Ventilation in Pediatric ARDS 

In- Bradley P Fuhnnan— Buffalo. Nc»- York 


Answer Key 








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190) is published monlhly by Daedalus Enterpnses Inc. at 
1 1030 Abies Lane. Dallas TX 75229-4593. for the Amer- 
ican Association for Respiratory Care. One volume is 
published per year beginning each January. Subscription 
rales are $75 per year in the US; $90 in all other countries 

The contents of the Journal are indexed in Hospital and 
Health Administration Index, Cumulative Index to Nurs- 
ing and Allied Health Literature. EMBASE/Exerpta Med- 
ica. and RNdex Library Edition, Abridged versions of 
Respiratory Care are also published in Italian, 
French, and Japanese, with permission from Daedalus En- Inc. 

Periodicals postage paid at Dallas TX and at additional 
mailing offices, POSTMASTER; Send address changes to 
RESPIRATORY CARE, Membership Office, Daedalus En- 
terprises Inc. 1 1030 Abies Lane, Dallas TX 75229-4593. 
Printed in the United States of America 
Copyright © 1998. by Daedalus Enterprises Inc. 

David J Pieison MD 

Htirhoivicw Medical Center 
Uitiver.sity tif Wu.sliington 
Seallle, Wu.shiiifilon 


Richard D Branson RRT 

University of Cincinnati 
Cincinnati, Ohio 

Charles G Durbin Jr MD 

University of Viri;inia 
Charlottesville. Viri^inia 


Dean R Hess PhD RRT 

Massachusetts General Hospital 
HaiTtiiil University 
Boston. Massachusetts 

James K Stoller MD 

The Cleveland Clinic Foundation 

Cleveland. Ohio 

Thomas A Barnes EdD RRT 

Northeastern University 
Boston. Massachusetts 

Michael J Bishop MD 
University of Washington 
Seallle. Washington 

Bartolome R CeUi MD 

Tufts Universilv 
Boston. Massachusetts 

Robert L Chatbum RRT 

University Hospitals of Cleveland 
Case Western Reseive Universin 
Cleveland. Ohio 

Luciano Gattinoni MD 

University of Milan 
Milan. Italy 

John E Heffner MD 

Medical University of South Carolina 
Charlestim. South Carolina 

Mark J HeuUtt MD 

University of Arkansas 
Little Rock. Arkansas 


Leonard D Hudson MD 

University of Wasliington 
Seattle. Washington 

Robert M Kacmarek PhD RRT 
Massachusetts General Hospital 
Harvard University 
Boston. Massachusetts 

Toshihiko Koga MD 

Koga Hospital 
Kuriime. Japan 

Marin H Kollef MD 

Washington University 
St Louis, Missouri 

Patrick Leger MD 

Clinique Medicate Edouard Rist 
Paris, France 

Neil R Maclntyre MD 

Duke University 
Durham. North Carolina 

John J Marini MD 
University of Minnesota 
St Paul, Minnesota 

Shelley C Mishoe PhD RRT 
Medical College of Georgia 
Augusta. Georgia 

Joseph L Rau PhD RRT 
Georgia State University 
Atlanta. Georgia 

Catherine SH Sassoon MD 
University of California Innne 
Long Beach. California 

Arthur S Slutsky MD 

University of Toronto 
Toronto. Ontario. Canada 

Martin J Tobin MD 

Loyola University 
Mavwood, Illinois 


Gordon D Rubenfeld MD 

University of Washington 
Seallle, Washington 

Robert R Fluck Jr MS RRT 
MS Jastremski MD 
Blood Gas Corner 

Hugh S Mathcw 
Drug Capsule 

Charles G Irvin PhD 

Gregg L Ruppel MEd RRT RPFT 

PFT Corner 

Richard D Branson RRT 
Robert S Campbell RRT 
Kitiredge 's Corner 

Jon Nilscstucn PhD RRT 
Ken Hargcll RRT 
Ruben Harwood MSA RRT 
Grapliics Corner 

Patricia Ann Doorley MS RRT 
Charles G Durbin Jr MD 
Test Your Radiologic Skill 

Barbara Wilson MEd RRT 
Jon Meliones MD 
John Palmisano RRT 
Cardiorespiratory Interactions 


Frank E Biondo RRT 
Howard J Birenhauni MD 

Donald R Ellon MD 
Ronald B George MD 

James M Hurst MD 
Michael McPcck RRT 

John Shigeoka MD 
Jeffrev J Ward MEd RRT 


Sumjiianos of PeilinenI Articles in Olher Journals 

Editorials, Commentaries, and Reviews to Note 

Tlie Physiology of Small Airways (review) — Macklem PT. Am J Respir Crit Care Med 1998; 
157(5 Pt :);.SISI-SIS3 

Assessment of Airway Inflammation in Astlima (review) — Vignola AM. Bousquet J. Chanez 
P, Gagliardo R. Merendino AM, Cliiappara G. Bonsignore G. Am J Respir Crit Care Med 
I998;157(5 Pt 2):S184-S187. 

Drug Delivery to the Small Airways (review) — Thompson PJ. Am J Respir Crit Care Med 
i99S;l.'i7(5 Pt 2);SI99-S202. 

Effects of Drugs on Small Airways— Woolcock AJ. Am J Respir Crit Care Med 1998:157(5): 

Chronobiology of Asthma (review) — Martin RJ. Banks-Schlegel S. Am J Respir Crit Care Med 

Diagnostic Techniques for Ventilator-Associated Pneumonia (letter) — Fischer JE, Janousek 
M, Nadal D. Fanconi S. Lancet 1998:352(9133):1066-lO67. 

The Long Suffering of Frederic Chopin (historical article) — Kubba AK. Young M. Chest 

The Long Suffering of Frederic Chopin, Revisited (comment) — Margolis ML. Chest 1998; 

Chopin's Malady (comment)— Carter ER. Chest 1998:1 14(2):655-656. 

Nasal Bridge Oximetry: An Alternative Site in Poor Peripheral Pulsations (letter) — Bud- 
dharaju VL. Rosen JM. Saraceno JL. 1998:1 14(2):660. 

ECRI Expert Reviews Reuse of 'Single-Use Medical Devices' (news) — Solomon RP. J Clin 
Monit Comput 1998:14(3):20.V205. 

Prognostic Value of Hypercapnia in Patients 
with Chronic Respiratory F'ailure during 
Long-Term Oxygen Therapy — Aida A, Mi- 
yamoto K, Nishimura M, Aiba M. Kira S. 
Kawakami Y. Am J Respir Crit Care Med 1 998: 

Hypercapnia ob.served in patients with chronic 
respiratory failure may not be an ominous sign 
for prognosis when they arc receiving long-lcrm 
oxygen therapy (LTOT). In this study, we se- 
lected 4.552 patients with chronic obstructive 
pulmonary disease (COPD) and 3,028 with se- 
quelae of pulmonary tuberculosis (TBsq) re- 
ceiving LTOT from 1985 to 1993 (hroughoiil 
Japan and prospectively analyzed their prog- 
noses. The hypercapnic patients (PaCO, > = 
45 min Hg) had a better prognosis than the 
normocapnic patients (35 < = PaCO, < 45 mm 

Hg) lor TBsq. but no difference was found be- 
tween the two groups with COPD. Furthermore. 
Cox's proportional hazards model revealed that 
in TBsq hypercapnia was an independent factor 
for favorable prognosis, and that the relative 
risk for mortality was 0.76 in patients with 45 
< = PaCO, < 55 mm Hg. 0.64 for those with 
55 <= PaCO, < 65 mm Hg. and 0. 49 lor 
patients with PaCO, >= 65 mm Hg against 
normocapnic patients. This favorable effect of 
hypercapnia in TBsq was particularly apparent 
in the patients without severe airway obstruc- 
tion. Even a rise of 5 mm Hg or more in PaCO, 
over the initial 6- to 18-nio follow-up period 
was not a.s.socialed with poor prognosis in TBsq. 
although it was in COPD. From these findings, 
we conclude that hypercapnia should not be 
generally considered an ominous sign for prog- 
nosis in those patients who receive l.TO'f. 

The Pressure-Volume Curve Is (Jreatly Mod- 
ified by Recruitment. A Mathematical Model 

of ARDS Lungs— Hickling KG. Am J Respir 
Crit Care Med 1998:158( 1 ):194. 

A mathematical model of the ARDS lung, with 
simulated gravitational superimposed pressure, 
evaluated the effect of varying alveolar thresh- 
old opening pressures (TOP). PEEP and peak 
inspiratory pressure (PIP) on the static pres- 
sure-volume (PV) curve. The lower inllection 
point (Pflex) was affected by SP and TOP, and 
did not accurately indicate PEEP required to 
prevent end-expiratory collapse. Reinllation of 
collapsed lung units (recruitment) continued on 
the linear portion of the PV curve, which had a 
slope at any volume greater than the total com- 
pliance of aerated alveoli. As recruitment di- 
minished, the reduced PV slope could proiluce 
an tipper Pllc\ al 20 to 30 cm H,0 pressure. An 


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iip|icr Pric\ caused b\ aUciilar civcidislcnsidil 
ciiultl he nidcliried or eliminaled by recruitment 
with high TOP. With constant PIP as PEEP 
increased, and TOP range of 5 to 60 cm H,0, 
PEEP to prevent end-expiratory collapse was 
indicated by minimum PV slope above 20 cm 
HiO. minimum hysteresis, and inaximum vol- 
ume at a pressure of 20 cm H-,0. With constant 
inflation volume as PEEP increased, the effcci 
on PV slope was unpredictable. Although m- 
creased PV slope indicated recruitment, maxi- 
mum PV slope usually underestimated PEEP 
required to prevent end-expiratory collapse. 
Therefore, with this model the PV curve did not 
reliably predict optimal ventilator settings. 

Partial l.itjuid Ventilation the In- 
flamniatorv Response in the Alveolar Envi- 
ronment of Trauma Patients — Croce MA, Fa- 
bian TC. Patton JH Jr, Mellon SM. Moore M, 
Trenlhem LL. J Trauma 1998;4_'i(2):273. 

BACKGROUND: Perflubron is a perfluorocar- 
bon with unique physical characteristics. It has 
twice the density of water, allows free diffusion 
of 02 and C02, is easily dispersed, and is in- 
soluble. Thus, it can act as 'liquid positive end- 
expiratory pressure" to recruit collapsed alveoli 
and improve oxygenation. Results of laboratory 
studies suggest that perflubron exerts an anti- 
inflammatory effect on alveolar cells. Limited 
clinical data in neonates and adults with severe 
acute respiratory distress syndrome are prom- 
ising. We present a single institution's experi- 
ence with partial liquid ventilation (PLV) in 
trauma patients compared with conventional me- 
chanical ventilation (CMV) with particular at- 
tention to the alveolar inflammatory response. 
METHODS: Ventilated patients with bilateral 
lung injury and Pa02/F102 < 300 were eligi- 
ble in this prospective mullicenter trial. Per- 
flubron was administered by means of the en- 
dotracheal lube to fill up to functional residual 
capacity (approximately 30 mL/kg), followed 
by supplemental up to 96 hours. At this 
institution, bronchoscopy with bronchoalveolar 
lavage was performed serially for white blood 
ccllcouni, protein, interleukin(lL)-l. 11,-6, II. -X. 
and 11,-10, and analyzed as e.crly (■ 4.S hours) 
and late (4S-Wi hours). Clinical response was 
deflned as a sustained \()7i increase in Pa02/ 
I-I02 at 48 hours. RESULTS: 16 patients were 
enrolled: 12 PLV patients and 4 CMV patients. 
There were no differences between groups rel- 
ative to sex. Injury Severity .Score, or initial 
Pa02/FI02. There were no inajor outcome dif- 
ferences between groups in this pilot study rel- 
ative to pneumonia (51)7, PLV and 75'1 CMV), 
deaths (one death in each group caused by mul- 
tiple organ failure), or for oxygenation after .S 
days. Eight PLV patients were rcsponders 
(PLV-R) compared with four patients who did 
not IPLV-NU). The main differences between 
these subgroups was time Irom injury to study 
(I.S days for Pl.V-K vs. .S.S lor I'LV-NR, p ■ 

0.02) and age (30 years for PLV-R vs. 42 years 
for PLV-NR, p < 0.04). Both white blood cell 
count and protein were higher in CMV, sug- 
gesting a greater inflaminatory response. Neu- 
trophils were significantly higher in CMV, de- 
spite equal IL-8 levels in both PLV and CMV. 
The inflammatory cytokines IL- 1 and IL-6 were 
greater in CMV, and the anti-inflammatory 
IL- 1 was lower in PLV. CONCLUSION: Early 
institution of partial liquid ventilation is effec- 
tive at reducing the alveolar inflammatory re- 
sponse. Perflubron exhibits an anti-inflamma- 
tory effect in the alveolar environment with 
reduction of proinflammatory IL-1 and IL-6 
(possibly removing a stimulus for lL-10), white 
blood cell count, and protein capillary leak. PLV reduces alveolar neutrophils independent 
of lL-8. Further characterization of this altered 
inflammatory response is necessary. . 

Cardiopulmonary Function after Pulmonary 
Contusion and Partial Liquid Ventilation — 

Moomey CB Jr, Fabian TC, Croce MA, Melton 
SM, Proctor KG. J Trauma 1998;45(2):283, 

PURPOSE: To compare the effects of mechan- 
ical ventilation with either positive end-expira- 
tory pressure (PEEP) or partial liquid ventila- 
tion (PLV) on cardiopulmonary function after 
severe pulmonary contusion. METHODS: Mon- 
grel pigs (32 ± 1 kg) were anesthetized, para- 
lyzed, and mechanically ventilated (8-10 niL/kg 
tidal volume; 12 breaths/min; Fi02 = 0.5). Sys- 
temic hemodynamics and pulmonary function 
were measured for 7 hours after a captive bolt 
gun delivered a blunt injury to the right chest. 
After 5 hours, Fi02 was increased to 1,0 and 
either PEEP (n = 7) in titrated increments to 25 
cm H20 or PLV with perflubron (LiquiVent, 
30 mL/kg, endotracheal) and no PEEP (n = 7) 
was administered for 2 hours. Two control 
groups received injury without treatment (n = 
6) or no injury with PLV (n = 3). Fluids were 
liberalized with PEEP versus PLV (27 ± 3 vs. 
18 ± 2 mL. kg- l.h-1 ) to maintain cardiac filling 
pressures. RESULTS: Before treatment at 5 
hours after injury, physiologic dead space frac- 
tion (30 ± 4%), pulmonary vascular resistance 
(224 ± 20% of baseline), and airway resistance 
(437 ± 1 10% of ba.seline) were all increased 
(p < 0.05). In addition, Pa02/Fi02 had de- 
creased to 112 ± 18 mm Hg, compliance was 
depressed to 1 1 ± I mL/cin H20 (36 ± }% of 
baseline), and shunt fraction was increased to 
22 ± 4% (all p < 0.05). Blood pressure and 
cardiac index remained stable relative to base- 
line, but stroke index and systeinic oxygen de- 
livery were depressed by 15 to 30% (both p < 
0.05). After 2 hours of treatment with PEEP 
versus PLV, P02/Fi02 was higher (427 ± 20 
vs. 263 ± 37) and dead .space ventilation was 
lower (4 ± 3 vs. 28 ± 1%) (both p < 0.05), 
whereas compliance tended to be higher (26 ± 
2 vs. 20 ± 2) and shunt fraction tended to be 
lower (0 ± vs. 7 ± 4). With PEEP versus 

PLV, however, cardiac index, stroke index, and 
systemic oxygen delivery were 30 to 60% lower 
(all p < 0.05). Furthermore, although contused 
lungs showed similar damage with either treat- 
ment, the secondary injury in the contralateral 
lung (as manifested by intra-alveolar hemor- 
rhage) was more severe with PEEP than with 
improved pulmonary function after severe uni- 
lateral pulmonary contusion, but negative he- 
modynamic and histologic changes were asso- 
ciated with PEEP and not with PLV. These data 
suggest that PLV is a promising novel ventila- 
tory strategy for unilateral pulmonary contu- 
sion that might ameliorate secondary injury in 
the contralateral uninjured lung. 

Outcome after Major Trauma: Discharge 
and 6-Month Follow-Up Results from the 
Trauma Recovery Project — Holbrook TL, 
Anderson JP, Sieber WJ, Browner D, Hoyt DB. 
J Trauma 1998:45(2):315. 

BACKGROUND: The study of both short-term 
and long-term outcomes after major trauma has 
become an increasingly important focus of in- 
jury research because of the improved survival 
rates attributable to the evolution of sophisti- 
cated trauma care systems. The Trauma Recov- 
ery Project (TRP) is a large prospective epide- 
miologic study designed to examine multiple 
outcomes after major trauma in adults aged 1 8 
years and older, including quality of life, func- 
tional outcome, and psychologic sequelae such 
as depression and posttraumatic stress disorder 
(PTSD). Patient outcomes were assessed at dis- 
charge and at 6, 12, and 18 months after dis- 
charge. The speciflc objectives of the present 
report are to describe functional outcomes at 
the discharge and 6-month follow-up time points 
in the TRP population and to examine the as- 
sociation of putative risk factors with functional 
outcome. METHODS: Between December 1, 
1993, and September 1, 1996, 1,048 eligible 
trauma patients triaged to four participating 
trauma center hospitals in the San Diego Re- 
gionalized Trauma System were enrolled in the 
TRP study. The admission criteria for patients 
were as follows: (1 ) age 18 years or older, (2) 
Glasgow Coma Scale score on admission of 1 2 
or greater, and (3 1 length of stay greater than 24 
hours. Functional outcome after trauma was 
measured before and after injury using the Qual- 
ity of Weil-Being (QWB) scale, a more sensi- 
tive index to the well end of the functioning 
continuum (range, = death to 1.000 = opti- 
mum functioning). Functional outcome was also 
measured using a standard activities of daily 
living (ADD scale (range, 13 = full function to 
47 = maximum dysfunction). Follow-up at 6 
months after discharge was completed lor 826 
patients (79%). RESULTS: The mean age was 
36 ± 1 4.8 years: 70% of the patients were male; 
52'.? of the patients were white, 30'X were His- 
panic, .unl IS'; were black or other. Less than 


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40% of study participants were married or liv- 
ing with a partner. The mean Injury Severity 
Score was 13 ± 8.5, with 85% bUmt injuries, 
and a mean length of stay of 7 ± 9.2 days. 
QWB scores before injury reflected the norm 
for a healthy adult population (mean, 0.810 ± 
0. 1 7 1 1. After major trauma, QWB scores at dis- 
charge showed a significant degree of functional 
limitation (mean, 0.401 ± 0.045). At 6-monlh 
follow-up, QWB scores continued to show high 
levels of functional limitation (mean. 0.633 ± 
0.122). Limitation measured using the standard 
ADL scale found only moderate dysfunction at 
discharge (mean, 30.0 ± 7.7) and at 6-month 
follow-up (mean, 15.0 ± 4.2). Postinjury de- 
pression. PTSD, serious extremity injury, and 
length of stay were significant independent pre- 
dictors of 6-month QWB outcome. CONCLU- 
SION: Postinjury functional limitation is a clin- 
ically significant complication in trauma patients 
at discharge and a 6-month follow-up. The QWB 
yields a more sensitive assessment of functional 
status than traditional ADL instruments. Postin- 
jury depression, PTSD. serious extremity in- 
jury, and length of stay are significantly asso- 
ciated with 6-month QWB outcome. 

Resolution of Experimental Pneumothorax 
in Rabbits by Graded Oxygen Therapy — En- 
gland CI. Hill RC. Timhcrlake GA. Harrah JD, 
Hill JF, Shahan YA. Billie M. J Trauma IQQS; 

BACKGROUND: Small pneumothoraces have 
been treated by observation and tube thoracos- 
tomy in asymptomatic patients. Using a rabbit 
model, we demonstrated previously that inspired 
oxygen at 609}^ Fi02 hastened the time to res- 
olution of complete pneumothoraces compared 
with room air. The present study was designed 
to evaluate the use of lower levels of inspired 
oxygen and to establish a dose-response curve 
for the treatment of experimental pneumotho- 
races. METHODS: Forty New Zealand White 
rabbits were divided randomly into four groups: 
room air (21%) and 30. 40, and 50% Fi02. 
Experimental pneumothoraces were created in 
the rabbits, and the animals were placed in cages 
with the designated level of inspired oxygen. 
Serial chest radiographs were performed until 
the pneumothoraces resolved. RESULTS: Pneu- 
mothoraces treated with room air resolved in 
61.65 ± 12.30 hours. Those treated with 30% 
Fi02 resolved in 42.90 ± 5.97 hours, with 40% 
Fi02 in 35.80 ± 4.26 hours, and with 50% 
Fi02 in 33.80 ± 4.66 hours. CONCLUSION: 
These results show a statistically significant 
(p -^ 0.01 ) dose-dependent improvement in the 
resolution of pneumothoraces with increasing 
levels of inspired oxygen. Supplemental oxy- 
gen therapy may be used to facilitate the reso- 
lution of small, uncomplicaled pneumolhora- 

A Comparison of Nebulized Budesunide, In- 
tramuscular Dexamethasone, and Placebo for 
Moderately Severe Croup — Johnson DW. Ja- 
cohson S. Edney PC. Hadfield P. Mundy ME, 
Schuh S. N Engl J Med I998:339(8):498. 

BACKGROUND: In children with croup, treat- 
ment with nebulized budesonide decreases 
symptoms, but it is uncertain how budesonide 
compares with dexamethasone, the conventional 
therapy for croup, and whether either reduces 
the rate of hospitalization. METHODS: We per- 
formed a double-blind, randomized trial involv- 
ing 144 children with moderately severe croup. 
The children were treated with racepinephrine 
and a single of 4 mg of nebulized budes- 
onide (48 children), 0.6 mg of intramuscular 
dexamethasone per kilogram of body weight 
(47 children ), or placebo (49 children ). The chil- 
dren were assessed before treatment and then 
hourly for five hours after treatment. Physicians 
who were unaware of the treatment assignments 
determined the children's need for further treat- 
ment and hospitalization. RESULTS: The char- 
acteristics of the groups were similar at base 
line, including the types of viruses identified, 
the types of croup, and the clinical severity of 
the illness. The overall rates of hospitalization 
were 71 percent in the placebo group (35 of 49 
children). 38 percent in the budesonide group 
(18 of 48 children), and 23 percent in the dexa- 
methasone group ( 1 1 of 47 children) (unadjust- 
ed P=O.OOI for the comparison of budesonide 
with placebo, P<O.OOI for the comparison of 
dexamethasone with placebo, and P=0.I8 for 
the comparison of budesonide with dexameth- 
asone). Children treated with budesonide or 
dexamethasone had a greater improvement in 
croup scores than those given placebo (P=0.03 
and P<0.00l. respectively), and those treated 
with dexamethasone had a greater improvement 
than those treated with budesonide (P=0.003). 
CONCLUSIONS: In children with moderately 
severe croup, treatment with intramuscular 
dexamethasone or nebulized budesonide re- 
sulted in more rapid clinical improvement than 
did the administration of placebo, with dexa- 
methasone offering the greatest improvement. 
Treatment with either glucocorticoid resulted in 
fewer hospitalizations. 

Long-Term Clinical Experience with Tran- 
stracheal Oxygen Catheters — Orvidas LJ, 
Kasperhauer JL, Slaats BA, Olsen KD. Mayo 
Clin Froc l9y8;7.^(S):7.W. 

OBJECTIVE: To evaluate and discuss the use 
of transtracheal oxygen catheters for Ihc treal- 
menl of chronic hypoxemia and to discuss ihe 
complicalioiis associated with the placemcnl and 
care of these devices. DESIGN: We conducted 
a retrospective study at a tertiary medical center 
and reviewed the pertinent literature. MATE- 
RIAL AND METHODS: The medical records 
1)1 56 patients who received a transtracheal o\ 

ygen catheter between January 1987 and June 
1992 at our institution were reviewed for de- 
mographic data, diagnosis leading to catheter 
placement, complications related to catheter use, 
reason for catheter removal, and duration of 
use. Follow-up results were established by doc- 
umentation in the medical records or telephone 
interview. RESULTS: During the study period. 
39 men and 1 7 women received a transtracheal 
catheter. More than half the patients (52%) had 
chronic obstructive pulmonary The du- 
ration of use of the catheter ranged from 2 days 
to more than 6 years, and the most frequent 
cause for removal of the catheter was death. Of 
the 56 patients. 42 died with the catheter in 
place, 24 within the first year after placement. 
Complications ranged from mucous plugging 
(38% of patients) to pneumothorax (4%), and 
no patient died of a catheter-related complica- 
tion. Overall, 55% of patients had their catheter 
for less than I year after placement. CONCLU- 
SION: In patients with transtracheal oxygen 
catheters, problems related to mucous plugging 
are common, but severe complications such as 
pneumothorax and pneumomediastinum are un- 
common. Although selection factors that would 
identify ideal candidates for transtracheal oxy- 
gen therapy have not been established, such a 
catheter is best placed in highly motivated pa- 
tients who can physically manage the daily care 
of this device. 

Changes in Oxygen Saturation and Transcu- 
taneous Carbon Dioxide and Oxygen Le>els 
in Patients Undergoing Fibreoptic Bronchos- 
copy — Evans EN. Ganeshalingam K, Ehdcn P. 
Respir Med I998;92(5):739. 

Patients undergoing bronchoscopy are usually 
monitored with pulse oximetry to measure ar- 
terial oxygen .saturation, but this can fail to de- 
tect hypoventilation, particulariy if added in- 
spired oxygen is used. Transcutaneous oxygen 
and carbon dioxide tensions can be measured; 
the later reflecting respiratory drive. We com- 
pared transcutaneous P02 and PC02 values with 
oxygen saturation in patients undergoing day- 
case bronchoscopy, to see if this information 
would further improve the safety of the bron- 
choscopic procedure. Twenty-two consecutive 
patients undergoing routine fibreoptic bronchos- 
copy ( 1 5 male, mean age 62.3 years; range 45-82 
years), were studied using pulse oximetry 
(Oximeter. Radiometer) and transcutaneous 
PC02/P02 monitoring (TCM3, TINA. Radi- 
ometer). We documented a statistically signif- 
icant increase in transcutaneous PC02 from 
mean (SD) stable baseline levels of 5.8 (0.3) 
kPa (range 4.2-7.9 kPa) to mean peak levels 
during bronchoscopy of 7.0 (1.0) kPa (range 
5.0-8.7 kPa). The time to first adverse change 
in transcutaneous PC02 (P = 0.046) and P02 
(P = 0.035) occurred more rapidly than reduc- 
tion in oxygen saturation in 19 of the 22 cases; 
median times for change in PC02 of 67 s (range 


Respiratory Care • N()vi:mhi:r '9S Vol 4.^ No 1 1 

From The American Respiratory 
Care Foundation 

Tedinobgy Paper Award 

Best Original Paper 

Joseph L Rau PhD RRT, 
Crystal L Dunlevy EdD RRT,& Richard L Hill 

A Comparison of Inline MDl Acliiators for Delivery of a Beta Agonist 
and a Corticosteroid with a Mechanically Ventilated Lung Model 
[RespirCare 1998;43(9):705-712] 

Richard H Kallet MS RRT, Brian M Daniel RRT, 
Michael Gropper MD, & Michael A Matthay MD 

Acute Pulmonary Edema following Upper Airway Obstruction: 
Case Reports and Brief Review 
[RespirCare 1998;43(6):476-480] 

Radiometer Awards 

Timothy R Myers BS RRT, Robert L Chatburn 
RRT, & Carolyn M Kercsmar MD 

A Pediatric Asthma Unit Staffed by Respiratory Therapists 
Demonstrates Positive Clinical and Financial Outcomes 
[RespirCare I998:43( l):22-29] 

Alexander B Adams MPH RRT, 
Robert Shapiro MD, & John J Marini MD 

Changing Prevalence of Chronically Ventilator-Assisted Individuals in 
Minnesota: Increases. Characteristics, and the Use of Noninvasive 
[Respir Care i998;43(8):643-649] 


10- 1 sou s), P02 of 120 s {ninge 26-359 s) and 
oxygen saturation of 174 s (range 43-1332 s). 
timed from administration of i.v. sedation prior 
to each bronchoscopy. Transcutaneous PC02/ 
P02 monitoring during fibreoptic bronchoscopy 
provided evidence of hypoventilation with sig- 
nificantly elevated levels of transcutaneous 
PC02. This method of monitoring provides an 
earlier indication of respiratory depression dur- 
ing fibreoptic bronchoscopy compared with 
pulse oximetry. 

Persistent Air-Leak in Spontaneous Pneumo- 
thorax — Clinical Course and Outcome — 

Chee CB. Abisheganaden J, Yeo JK. Lee P. 
Huan PY. Poh SC. Wang YT. Respir Med 1998; 

Persistent air-leak in patients with spontaneous 
pneumothorax (SP) is not uncommon and may 
present a management dilemma in who 
are unfit or unwilling for surgery. Video-as- 
sisted thoracoscopic surgery (VATS) has been 
advocated in the management of patients with 
broncho-pleural tlstulae (air-leak persisting be- 
yond 7 days): however the optimum time for 
surgical intervention remains unclear. We re- 
viewed the records of 130 episodes of SP in 
1 15 patients over a 2-year period to determine 
clinical course and outcome, particularly with 
respect to duration of air-leak. There were 90 
first episodes and 40 recurrent episodes. Eighty- 
one episodes (62%) occurred in patients with 
underlying lung disease (secondary pneumotho- 
rax). Initial management consisted of 
drainage in 104 episodes iS()'7f ) occurring in 90 
patients, percutaneous needle aspiration in five 
patients (4%) and observation in 21 episodes 
(16%) in 20 patients. In the group treated with 
chest-tube drainage, there was spontaneous res- 
olution of air leak and lung re-expansion in 90 
episodes (87%). The overall incidence of bron- 
cho-pleural fistula was 34.6%. In the primary 
SP group. 75%' of air-leaks ceased by 7 days 
and 100% by 15 days. In the secondary SP 
group, 61 % of air-leaks resolved by 7 days and 
79% by 14 days, after which time resolution of 
air-leak proceeded at a much slower rate. Five 
patients underwent surgery while nine patients 
were discharged with residual pncumothoraces. 
There were no major complications or mortal- 
ity. Based on our findings, we advocate surgery 
for patients with air-leak persisting beyond 14 
days, while favouring a conservative approach 
before this time, as the majority of air-leaks 
(especially in patients with primary pneumo- 
thorax) would resolve by 14 days. 

Vital Prognosis after Hospilali/alion for 
COPI): A .Study of a Random Population 
Sample Veslhi. .1. I'lesuill i:. I.ange P. Sch- 
nnhr P. .Icnscn Respir Med 1998;92(5):772. 

STUDY AIM: To examine .survival alter ad- 
mission due to chronic obstructive pulmonary 

disease (COPD) in a population sample over a 
time span of 15 years. DESIGN: Linkage be- 
tween a prospective population cohort and reg- 
ister information on hospitalization and mortal- 
ity. SETTING: The Copenhagen City Heart 
Study (CCHS). PARTICIPANTS: A total of 
267 men and 220 women who had participated 
in the CCHS and who were hospitalized with a 
discharge diagnosis of COPD (lCD-8 491-2). 
MAIN RESULTS: The crude 5-yr survival rate 
after a COPD admission was 45% (37% for 
men and 52% for women). Mortality risk in- 
creased with age and with decreasing forced 
expiratory volume in I s (FEV1)% predicted; 
for subjects with an FEVl < or = 40% at the 
CCHS survey. 5-yr survival after subsequent 
hospitalization was only 28%. Smoking and 
presence of chronic mucus hypersecretion at 
the examination in CCHS were not strongly 
associated with prognosis. Survival after ad- 
mis.sion due to COPD did not change signifi- 
cantly over time. CONCLUSION: Compared 
to previous studies of COPD patients, the present 
study indicates that prognosis after hospital ad- 
mission remains virtually unchanged over the 
last decades. FEV 1 is still the strongest predic- 
tor of survival in this patient group. 

An Overview of Nine Clinical Trials of Sal- 
meterol in an Asthmatic Population — Ver- 
beme AA. Fuller R. Respir Med 1998:92(5): 

In an allenipl to establish the protection afforded 
by regular salmeterol use against induced bron- 
choeonstriction in asthmatic patients, a meta- 
analysis was conducted on nine double-blind 
clinical trials that fulfilled the inclusion criteria. 
In each trial, subjects were randomly assigned 
to receive either salmeterol 50 micrograms twice 
daily or a comparator (placebo or salbutamol). 
Two hundred and twenty-five asthmatic sub- 
jects had at least one PC20 or PD20 (histamine 
or methacholine concentration or produc- 
ing 20% fall in forced expiratory volume in 1 s) 
measurement recorded within I h to 16 weeks 
after the first dose, and up to 3 1 days after the 
last dose, of medication. One hour after the first 
dose of salmeterol. there was a 3.5-fold increase 
in doubling dose compared to baseline. Within 
1 2 h of the first dose, the level of protection 
was 1.5 doubling doses, and protection was 
maintained at 0.5-1.5 doubling doses over 16 
weeks" treatment. This level of protection was 
maintained for up to 60 h afier the last dose. At 
no time during the washout period did the level 
of protection fall below zero. Salmeterol af- 
forded significantly greater protection at all time 
points during the liealment period than com- 
parator agents, but there was no significant dil- 
ference during the washout period. In conclu- 
sion, salmeterol .illoids pKileclion ,i;jainsi 
bronchoconstriclor slmiuli. and ,iii\ rcdiiclioii 
ill ihis bronchoprotective effect occurred during 
ilic fiisi tew days of treatment. During long- 

term salmeterol treatment, there was maintained 
significant protection that showed no evidence 
of attenuation after 16 weeks' treatment. Fur- 
thermore, there was no evidence of rebound 
deterioration in bronchial responsiveness after 
cessation of salmeterol treatment. 

Do Shorter-.Acting Neuromuscular Blocking 
Drugs or Opioids Associate with Reduced In- 
tensive Care Unit or Hospital Lengths of Stay 
after Coronary Artery Bypass CJrafting? — 

CABG Clinical Benchmarking Data Base Par- 
ticipants: Butterworth J, James R, Prielipp RC, 
Cerese J, Livingston J, Burnett DA. Anesthesi- 
ology 1998:88(6): 1437. 

BACKGROUND: The authors hypothesized 
that shorter-acting opioid and neuromuscular 
blocking drugs would be associated with reduc- 
tions in duration of intubation, length of stay 
(LOS) in the intensive care unit (ICU) after 
tracheal extubation, or postoperative (exclusive 
of ICU) LOS, and that shorter durations of in- 
tubation would be associated with reduced ICU 
LOS after extubation and postoperative (exclu- 
sive of ICU) LOS. METHODS: One-thousand 
ninety-four patients undergoing primary coro- 
nary artery bypass graft surgery at 40 academic 
health centers were studied. Multiple patient- 
related factors were included in multivariate 
models for hypothesis testing. RESULTS: The 
duration of tracheal intubation, ICU LOS after 
extubation, and postoperative (exclusive of ICU) 
LOS all varied significantly by site. There was 
no difference between vecuronium and pancu- 
ronium in duration of intubation, ICU LOS af- 
ter extubation, or postoperative (exclusive of 
ICU) LOS. Use of .sufentanil rathei- than fent- 
anyl was associated with a significant (P=0.045) 
reduction of 1.9 h (95% CI, 0.04 to 4.1 h) in 
duration of tracheal intubation but had no sig- 
nificant effect on ICU LOS after extubation, 
total ICU LOS, postoperative (exclusive of ICU) 
LOS, or total postoperative LOS. The authors' 
best model predicts a complex association be- 
tween increasing duration of intubation and both 
ICU LOS after tracheal extubation and postop- 
erative (exclusive of ICU) LOS, which was as- 
sociated with an increase in those measures when 
duration of intubation exceeded 7.3 or 3 h, re- 
spectively. CONCLUSIONS: The LOS mea- 
sures varied considerably among the institutions. 
Use of shorter-acting opioid and neuromuscular 
blocking drugs had no association with ICU 
LOS after tracheal extubation or with postop- 
erative (exclusive of ICU) LOS. Only when the 
duration of intubation exceeded threshold val- 
ues was it associated with increased LOS mea- 
sures. See the rehiled editorial: Fast Track Car- 
diac Surgery Pathways: I'.arly lixtiihatioii, 
I'rocess of Care, and I ost ( oiitaiiiiiieiil. Cheng 
DC. Anesthesiology I'JVS .Iun:SS(f,):l42»- 


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Early Extubation f'iillo»inj> Cardiac Surgery 
in a Veterans Population — London MJ. 
Shroyer AL. Coll JR. MaWhinney S. Fullerton 
DA. Hammemieister KE. Grover FL. Anesthe- 
siology 1998 Jun;88(6):l447. 

BACKGROUND: Early tracheal extubation is 
an importanl component of the 'fast track' car- 
diac surgery pathway. Factors associated with 
time to extubation in the Department of Veter- 
ans Affairs (DVA) population are unknown. The 
authors determined associations of preoperative and intraoperative clinical process variables 
with time to extubation in this population. 
METHODS: Three hundred four consecutive 
patients undergoing coronary artery bypass 
graft, valve surgery, or both on a fast track 
clinical pathway between October 1, 1993 and 
September 30. 1995 at a university-affiliated 
DVA medical center were studied retrospec- 
tively. After univariate screening of a battery of 
preoperative risk and intraoperative clinical pro- 
cess variables, stepwise logistic regression was 
used to determine associations with tracheal ex- 
tubation < or = 10 h (early) or > 10 h (late) 
aftersurgery. Postoperative lengths of stay, com- 
plications, and 30-day and 6-month mortality 
rates were compared between the two groups. 
RESULTS: One hundred forty-six patients 
(48.3%) were extubated early: one patient re- 
quired emergent reintubation (0.7%). Of the pre- 
operative risk variables considered, only age 
(odds ratio, 1.80 per 10-yr increment) and pre- 
operative intraaortic balloon pump (odds ratio, 
7.88) were multivariately associated with time 
to extubation (model R) ('late' association is 
indicated by an odds ratio >I.OO; 'early' asso- 
ciation is indicated by an odds ratio <1.00). 
Entry of these risk variables into a second re- 
gression model, followed by univariately sig- 
nificant intraoperative clinical process variables, 
yielded the following associations (model R-P): 
age (odds ratio, 1.86 per 10-yrincreinenl), sufen- 
tanil dose (odds ratio, 1.54 per 1-microg/kg in- 
crement), major inotrope use (odds ratio, 5.73), 
platelet transfusion (odds ratio, 10.03), use of 
an arterial graft (odds ratio, 0.32), and fentanyl 
dose (odds ratio, 1.45 per 10-microg/kg incre- 
ment). Time of arrival in the intensive care unit 
after surgery was also significant (odds ratio, 
1.42 per 1-h increment). Intraoperative clinical 
process variables added significantly to model 
performance (P < 0.001 by the likelihood ratio 
test). CONCLUSIONS: In this population, early 
tracheal extubation was accomplished in 48%' 
of patients. Intraoperative clinical process vari- 
ables are important factors to be considered in 
the timing of po.stoperative extubation after fast 
track cartliac surgery. See the reltileil ecliloriul: 
Fast Track Cardiac Sitraery Pathways: Early 
ICxtuhuliim, I'rocess nf Care, and Cost Con- 
tainmenl. Chenf; DC. Aneslliesiohf^y I<>9S 

The Use of Continuous I,V. Sedation is As- 
sociated with Prolongation of Mechanical 
Ventilation— Kollef MH, Levy NT. Ahrens TS. 
Schaiff R. Prentice D. Shennan G. Chest 1998; 

STUDY OBJECTIVE: To determine whether 
the use of continuous I.V. sedation is a.ssociated 
with prolongation of the duration of mechanical 
ventilation. DESIGN: Prospective ob.servational 
cohort study. SETTING: The medical ICU of 
Barnes-Jewish Hospital, a university-affiliated 
urban teaching hospital. PATIENTS: Two hun- 
dred forty-two consecutive ICU patients requir- 
ing mechanical ventilation. INTERVENTIONS: 
Patient surveillance and data collection. MEA- 
SUREMENTS & RESULTS: The primary out- 
come measure was the duration of mechanical 
ventilation. Secondary outcome measures in- 
cluded ICU and hospital lengths of stay, hos- 
pital mortality, and acquired organ system de- 
rangements. A total of 93 (38.4%) mechanically 
ventilated patients received continuous I.V. se- 
dation while 149 (61.6%) patients received ei- 
ther bolus administration of I.V. sedation 
(n=64) or no I.V. sedation (n = 85) following 
intubation. The duration of mechanical ventila- 
tion was significantly longer for patients re- 
ceiving continuous I.V. sedation compared with 
patients not receiving continuous I.V. sedation 
(185 ± 190 h vs 55.6 ± 75.6 h; p<0.001). 
Similariy. the lengths of intensive care (13.5 ± 
33.7 days vs 4.8 ± 4.1 days; p<0.001) and 
hospitalization (21.0 ± 25.1 days vs 12.8 ± 
14.1 days; p<0.00l) were statistically longer 
among patients receiving continuous I.V. seda- 
tion. Multiple linear regression analysis, adjust- 
ing for age, gender, severity of illness, mortal- 
ity, indication for mechanical ventilation, use 
of chemical paralysis, presence of a tracheos- 
tomy, and the number of acquired organ system 
derangements, found the adjusted duration of 
mechanical ventilation to be significantly longer 
for patients receiving continuous I.V. .sedation 
compared with patients who did not receive con- 
tinuous I.V. sedation (148 h (95% confidence 
interval: 121, 175 h) vs 78.7 h [95%' confidence 
interval: 68.9. 88.6 h); p<0.001). CONCLU- 
SION: We conclude from these preliminary ob- 
servational data that the of continuous I.V. 
sedation may be associated with the prolonga- 
tion of mechanical ventilation. This study sug- 
gests that strategies targeted at reducing the use 
of continuous I.V. .sedation could shorten the 
duration of mechanical ventilation for some pa- 
tients. Prospective randomized clinical trials, us- 
ing well-designed sedation guidelines and pro- 
tocols, are required to determine whether 
patient-specific outcomes (eg, duration of me- 
chanical ventilation, patient comfort) can be im- 
proved compared with conventional sedation 

Percutaneous Drainage of Thoracic Collec- 
tions vanSonncnhcrg H. Wittich GR. Gooda- 

ere BW. Zwischenberger JB. J Thoiac Imaging 

Various infected and noninfected thoracic fluid 
collections may be diagnosed and treated by 
interventional radiologic techniques. The core 
procedure of ultrasound-guided thoracentesis 
has been expanded to allow catheter drainage 
of empyema, bronchopleural fistula, abscesses 
in the lung, mediastinum, pericardium, and in- 
fected tumors. Tailored use of guidance meth- 
ods permits effective evacuation of most of these 
abscesses and noninfected collections. This pa- 
per details the authors' approach to each of these 
entities while highlighting the results and ex- 
pected pitfalls of these techniques. 

Percutaneous Drainage of Pleural Collec- 
tions — Patz EF Jr. Goodman PC. Erasmus JJ. 
J Thorac Imaging 1998:13(2):74. 

Pneumothorax is a frequent complication of in- 
terventional pulmonary procedures. Percutane- 
ous catheter placement enables safe and effec- 
tive drainage of pneumothoraces with rapid 
restoration of vital capacity, oxygenation, and 
lung reexpansion. 

Acute Severe Asthma Treated by Mechani- 
cal Ventilation: A Comparison of the Chang- 
ing Characteristics over a 17 Yr Period — 

Kearney SE. Graham DR. Atherton ST. Respir 
Med 1998;92(5):716. 

Recorded cases of asthma have increased in 
recent years. It is unclear, however, whether 
this apparent increase in prevalence is accom- 
panied by an increase in severity of the disor- 
der. One potential measure of asthma severity 
is the requirement for mechanical ventilation. 
This paper examines those patients ventilated 
for severe asthma in a district general hospital 
over a 1 7 yr period. Since the methods used to 
assess asthma attacks and the criteria for insti- 
tuting mechanical ventilation in this ho.spital 
did not alter between 1973 and 1992 (Jones 
criteria), it was possible to compare directly 
characteristics of all ventilated patients during 
the study period. The comparison showed that 
there was a significant increase between the 
two study periods in the number of patients 
who required mechanical ventilation. Moreover, 
in the more recent period both the subjecli\e 
speed of onset of the asthma attack and the 
objective time between admission and ventila- 
tion were significantly shorter. However, de- 
spile this increase in asthma severity the mor- 
tality and morbidity in the more recent study 
period were lower. Overall the results of this 
study support the view that, in ihe population 
served by our district general hospital, asthma 
has increa.sed in severity. This increased sever- 
ity is indicated by an increase in the number of 
patients requiring mechanical ventilation and in 
the rapidity with which attacks evolved. How- 

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ever, lor palieiUs in uhoiii vcmilallon was re- 
quired, improved care lias lowered holh mor- 
bidity and mortalily. 

Do Autopsies of Critically III Patients Reveal 
Important Findings That Were Clinically Un- 
detected? — Blosser SA. Zimmerman HE. 
StautTer JL. Crit Care Med I W8;26(S): 1.^.^2. 

OBJECTIVE; To determine if autopsies per- 
formed on patients who die in the medical in- 
tensive care unit (ICU) provide clinically im- 
portanl new information. DESIGN: 
Retrospective review. SETTING: A 16-bed 
medical-coronary ICU. PATIENTS: Patients 
who underwent autopsy during a l-yr period. 
INTERVENTIONS: Pre mortem diagnoses 
were determined froin the medical record. Au- 
topsy results were obtained from the tlnal pa- 
thology report. A panel of three physicians with 
certification of added qualifications in critical 
care medicine reviewed the findings. MEA- 
questions were asked: a) Is the primary clinical 
diagnosis confirmed? b) Are the clinical and 
pathologic causes of death the same? c) Are 
new active diagnoses revealed? and d) If the 
new findings had been known before death, 
would the clinical management have differed? 
Forty-one autopsies (31% of deaths) were done 
that showed: a) the same primary clinical diag- 
nosis and mortem diagnosis in 34 (83%) 
patients: b) the same clinical and pathologic 
cause of death in 27 (66%) patients; c) new 
active diagnoses in 37 (90%) patients; and d) 
findings that would have changed medical ICU 
therapy had the findings been known in 1 1 (27%) 
patients. CONCLUSIONS: Although the pri- 
mary clinical diagnosis was accurate in most 
cases before death, the cause of death was fre- 
quently unknown. Almost all autopsies demon- 
strated new diagnoses, and knowledge of these 
new findings would have changed medical ICU 
therapy in many cases. In the critical care set- 
ting, autopsies continue to provide information 
that could be important for education and qual- 
ity patient care. 

Outcome of Intensive Care Patients in a 
Group of British Intensive Care Units — 

Goldhill DR. Sumner A. Crit Care Med IW8: 
26(8): 1 3.37. 

OBJECTIVE: To identify priorities for inten- 
sive care unit (ICU) intervention and research. 
DESIGN: Analysis of a large intensive care da- 
tabase. SEITING: Twenty-four ICUs in the 
North Thames region of the United Kingdom. 
PATIENTS: All patients admitted to an ICU 
between January I. 1W2. and Apnl 31. IW6. 
on whom data had been entered nito the data- 
base. Patients who were admitted after cardiac 
surgery, who hail burns, or were < 1 6 yrs of age 
were excluded from the study, as were data 
from patients with a previous ICU admission 

w ithin 6 mos or where ICU or hospital outcome 
was unknown. Data were excluded from units 
that had entered <300 patients into the data- 
MENTS & MAIN RESULTS: A total of 23.331 
admissions with complete records were avail- 
able. After exclusions, 12,762 admissions from 
\5 ICUs were selected for analysis. Haspital 
inortality was 32.5% with a mortality ratio of 
1.14 (95% confidence interval 1. 10 to 1.17). 
Nonsurvivors were older than survivors and had 
longer ICU stays. Patients admitted from wards 
had a higher mortality than patients from the 
operating room/recovery or the emergency de- 
partment. Observed percentage mortality in- 
creased linearly with mortality predicted by 
Acute Physiology and Chronic Health Evalua- 
tion II, although the number of patients who 
died remained broadly constant across the range 
of predicted mortality. Twenty-seven percent 
of all deaths occurred after discharge from the 
ICU. Patients admitted after cardiopulitionary 
resuscitation constituted 30% of all deaths. Thir- 
ty-four percent of patients were in the ICU (or 
>2 days, and they accounted for nearly 8 1 % of 
bed days. CONCLUSIONS: Early identifica- 
tion of patients at risk, both before admi.ssion 
and after discharge from the ICU, may allow 
treatment to decrease mortality. Research and 
resources may be best directed at patients who 
die, despite a relatively low predicted mortality. 
Although these patients are a sinall percentage 
of the low-risk admissions, they constitute a 
large number of ICU deaths. Many patients die 
after discharge from ICU and this inortality may 
be decreased by minimizing inappropriate early 
discharge to the ward, by the provision of high- 
dependency and step-down units, and by con- 
tinuing advice and follow-up by the ICU team 
after the patient has been discharged. Interven- 
tion before ICU admission and support of pa- 
tients after discharge from the ICU should be 
part of the effort to decrease mortality for ICU 
patients. Inadequate provision of resources for 
critically ill patients may result in excess inten- 
sive care mortality that is not detected with ICU 
outcome prediction methods. 

A Multicenter Evaluation of a New Contin- 
uous Cardiac Output Pulmonary Artery 
Catheter System — Mihm IG. Getlinger A. 
Hanson CW 3rd. Gilbert HC. Stover EP, Vender 
JS. cl al. Crit Care Med 1998:26(81:1.346. 

OBJECTIVE: To validate a new system of con- 
tinuous cardiac output monitoring. DESIGN: 
Multicenter, prospective, nonrandomized cliiii 
cal study. SETflNG: Four university hospii.iK 
PATIENTS: Forty-seven adult intensive caie 
unit patients. INTERVENTIONS: Pulmonary 
artery catheterization. MEASUREMENTS & 
MAIN RESULTS: Continuous and bolus car 
diac output measurements were obtaineil over 
72 hrs. The 327 continuous cardiac output inea 
suretnenis compared favorably with bolus car 

diac output measurements (bias = 0.12 L/miii. 
precision = ±0.84). The continuous cardiac 
measurement was not adversely affected by tem- 
peratures of <37 degrees C or >38 degrees C, 
high (>7.5 L/min) or low (<4.5 L/min) cardiac 
output values, or duration (72 hrs) of the study. 
CONCLUSIONS: This continuous cardiac out- 
put system provides a reliable estimate of car- 
diac output for clinical use if applied in condi- 
tions similar to this study. The combination of 
a continuous measure of cardiac output with 
other continuous physiologic monitoring (arte- 
rial and mixed venous oxygen saturation, oxy- 
gen consumption, etc.) may provide important 
information that no single parameter could 

No Difference Exi.sts in the Alteration of Cir- 
cadian Rhythm between Patients with and 
without Intensive Care llnit Psychosis — Nut- 
tall GA, Kumar M. Murray MJ. Crit Care Med 

OBJECTIVE: To determine if a difference ex- 
ists in the circadian rhythm entrainment between 
patients with and without intensive care unit 
(ICU) psychosis. DESIGN: Retrospective chart 
reviews from 149 consecutive patients admitted 
to our ICU during the period of January 1993 to 
August 1993. Twelve patients with a hi.story of 
mental illness or alcohol or substance abuse 
were excluded from the study. SETTING: A 
20-bed surgical ICU at a large teaching hospi- 
tal. PATIENTS: Patients who reinained in the 
ICU for a minimum of 2 days after undergoing 
thoracic or vascular operations. INTERVEN- 
RESULTS: Hourly temperature and urine out- 
put were ascertained from the patient records. 
The time of temperature and urine output nadir 
was used as a marker of circadian rhythm. Of 
the 137 patients included in the study, 17 
(12.4%) developed ICU psychosis as defined 
by standard criteria. The time of temperature 
nadir was randomly distributed around the clock 
for each group. Cosinar rhythinomelry analysis 
of temperature data showed a lack of circadian 
rhythm entrainment in most patients up to the 
third postoperative day. No statistically signif- 
icant difference exists in the deviation of such 
impairment between the groups. CONCLU- 
SION: Either patients who develop ICU psy- 
chosis have an increased sensitivity to an alter- 
ation of theircircadian rhythm, or ICU psychosis 
develops inde|Viidcnt of rhythm ah- 

hnporlancc of (he .Sampling Site for Mea- 
surenunl of Mixed Venous Oxygen Satura- 
tion in Shock— Edwards JD. Mayall RM. Crit 
Care Med I998;26(8):I356. 

OBJI'CI'IVI'S: To determine if oxyhemoglo- 
bin saliualioii ui blood samples taken Ironi the 
superior \cii.i c.i\:i or right atrium cin he sub 


RiispiRAioRY Care; • Novembi-r '98 Vol 4.^ No 1 1 


stiluled lor oxyhemoglobin .s;itur;ilion in blood 
taken from the proximal pulmonary artery 
(SV02) in patients in shock. DESIGN: Pro- 
spective clinical investigation. SETTING: 
Mixed surgical/medical intensive care unit in a 
university hospital. PATIENTS: Thirty consec- 
utive patients in severe circulatory shock who 
required insertion of a pulmonary artery flota- 
tion catheter (PAFC) immediately on intensive 
care unit admission. All patients fulfilled the 
criteria described below which were established 
in advance. MEASUREMENTS & MAIN RE- 
SULTS: Oxyhemoglobin saturation in the su- 
perior vena cava, right atrium, and pulmonary 
artery (SV02) was measured by cooximetry in 
con.secutive blood samples from each site dur- 
ing initial insertion of the PAFC. The mean 
standard deviation of values from these sites 
was similar: 74± 2.5%, 70.±13%, and 
71.,^± I2.7'7r, respectively. However, when su- 
perior vena cava and right atrial oxyhemoglo- 
bin saturations and Sv02 were compared, the 
ranges and 95% confidence limits were found 
to be clinically unacceptable. The ranges were 
- 1 y..^ to 2.^. I % and - 1 9.7 to 1 6.7%, respectively, 
and the 95% confidence limits were -18.4 to 
24.2% and - 1 8.6 to + 1 7.3%, respectively. CON- 
CLUSIONS: These wide range differences and 
confidence limits would lead to large errors if 
superior vena cava or right atrial oxyhemoglo- 
bin saturations were substituted for true mixed 
venous blood in oxygen transport or pulmonary 
venous admixture calculations, or if clinical de- 
cision making was based on individual results. 
In patients in shock in whom clinical decisions 
may be based on the value of mixed venous 
oxyhemoglobin, oxyhemoglobin saturation is 
only reliably measured in samples taken from 
the pulmonary artery. 

Cardiorespiratory Eflects of Manually Com- 
pressing the Rib Cage during Tidal P^xpira- 
tion In Mechanically Ventilated Patients Re- 
covering from Acute Severe Asthma — Van 

der Touw T, Mudaliar Y. Nayyar V. Crit Care 
Med I998:26(8):I.^6I. 

OBJECTIVES: To determine the cardiorespi- 
ratory effects of manual expiratory rib cage com- 
pression in mechanically ventilated patients re- 
covering from acute severe asthma; and to 
extrapolate these findings to emergency asthina 
management where ventilation cannot be 
achieved by positive-pressure ventilation. DE- 
SIGN: A prospective, clinical study. SETTING: 
Intensive care unit. PATIENTS: Four intubated, 
mechanically ventilated (volume-controlled), 
adult patients recovering from acute .severe 
asthma. INTERVENTIONS: Patients were stud- 
ied before, during, and after a 2- to 3-min pe- 
riod of manual compressions applied bilaterally 
over the lower rib cage (ribs 8 to 10) during 
consecutive tidal expirations. MEASURE- 
MENTS & MAIN RESULTS; Air How (pneu- 
motachograph), airway pressure, radial or bra- 

chial arterial pressure, and the hand pressure 
applied to the patient's rib cage were monitored 
and recorded on magnetic tape. Playback of the 
recorded data enabled measurement of changes 
in lung volume (air flow integration). Changes 
during rib cage compression consisted chietly 
of small decreases in lung volume and peak 
inspiratory airway pressure that were only ob- 
served in the least obstructed patient and were 
fully reversed after the cessation of compres- 
sions. Air tlow-time and air flow-volume plots 
demonstrated expiratory air How limitation dur- 
ing essentially the entire tidal expiration in each 
patient, except the least obstructed patient. 
CONCLUSION: The results suggest that man- 
ual compression of the rib cage during consec- 
utive tidal expirations would be ineffective in 
reducing pulmonary hyperinflation during the 
emergency management of asthma when air 
flow obstruction is so severe that ventilation 
cannot be achieved by positive-pressure venti- 

Simplified Acute Physiology Score II for Mea- 
suring Severity of Illness in Intermediate 
Care Units — Auriant I, Vinatier I, Thaler F, 
Tourneur M, Loirat P. Crit Care Med 1998; 
26(8): 1368. 

OBJECTIVES: To assess the efficacy of the 
Simplified Acute Physiology Score (SAPS II) 
in intermediate care units. A number of patients 
hospitalized in the intensive care unit (ICU) 
could be hospitalized in alternative structures, 
intermediate care units, which are equipped to 
handle their monitoring needs and able to pro- 
vide adequate treatment at a lower cost. Char- 
acterization of the patients relies on the assess- 
ment of their severity of illness by severity 
scores. The efficiency of severity scores has 
been established in ICU patients, but not in the 
setting of intermediate care units. DESIGN: Pro- 
spective study. SETTING; Intermediate care 
unitof amultidisciplinary hospital. PATIENTS: 
Four hundred thirty-three patients admitted to 
the intermediate care unit. INTERVENTIONS: 
SULTS: Of 561 consecutive patients admitted 
to the intermediate care unit during a 12-mo 
period, 433 patients could be included in the 
analysis. Patients were admitted from the emer- 
gency ward (60.9%). Of the study patients, 
60.9% were admitted from the emergency ward 
for mostly (96%) medical reasons. Average 
length of stay was 3.1 ± 2.3 (SD) days. Death 
rate in the intermediate care unit was 2.7% (n = 
II). Average SAPS II was 22.3 ± 12.0 (range 
6 to 73). Hospital death rate was 8.1%, whereas 
the expected mortality rate derived from SAPS 
II was 8.7%. To as.sess the performance of the 
system, a formal goodness-of-fit test was per- 
formed to evaluate calibration. Calibration was 
accurate using the C coefficient of Hosmer- 
Lemeshow statistics (C = 2.4; p> 0.5). The 
discriminant power of SAPS 11. measured by 

the area under the receiver operating character- 
istic curve was excellent (0.85 ± 0.04). CON- 
CLUSIONS: The SAPS II assessment of sever- 
ity of illness in patients admitted to an 
intermediate care unit is reliable. These results 
will need to be confirmed, using different pa- 
tient samplings from intermediate care units. 

Exogenous Surfactant and Positive End-Ex- 
piratory Pressure in the Treatment of Endo- 
toxin-Induced Lung Injury — Lutz CJ. Piconc 
A. Gatto LA, Paskanik A, Landas S. Nieman 
GF. Cm Care Med 1 998:26(8): 1379. 

OBJECTIVE: To evaluate the efficacy of treat- 
ing endotoxin-induced lung injury with single 
dose exogenous surfactant and positive end-ex- 
piratory pressure (PEEP). DESIGN: Prospec- 
tive trial. SETTING: Laboratory at a university 
medical center. SUBJECTS: Nineteen certified 
healthy pigs, weighing 15 to 20 kg. INTER- 
VENTIONS: Pigs were anesthetized and surgi- 
cally prepared for hemodynamic and lung func- 
tion measurements. Animals were randomized 
into four groups: a) Control pigs (n = 4) re- 
ceived an intravenous infusion of saline with- 
out Escherichia colilipopolysaccharide (LPS); 
b) the LPS group (n = 5) received an intrave- 
nous infusion of saline containing LPS (100 
microg/kg); c) the PEEP plus saline group (n = 
5) received an intravenous infusion of saline 
containing LPS. Two hours after LPS infusion, 
saline was instilled into the lung as a control for 
surfactant instillation, and the animals were 
placed on 7.5 cm H20 of PEEP; d) the PEEP 
plus surfactant group (n = 5) received an in- 
travenous infusion of saline containing LPS. 
Two hours following LPS infusion, surfactant 
(50 mg/kg) was instilled into the lung and the 
animals were placed on 7.5 cm H20 of PEEP. 
PEEP was applied first and surfactant or saline 
was instilled into the lung while maintaining 
positive pressure ventilation. All groups were 
studied for 6 hrs after the start of LPS injection. 
At necropsy, bronchoalveolar lavage was per- 
formed and the right middle lung lobe was fixed 
for histologic analysis. MEASUREMENTS & 
MAIN RESULTS: Compared with LPS with- 
out treatment. PEEP plus surfactant significantly 
increased Pa02 (PEEP plus surfactant = 
156.6 ± 18.6 [SEMI lorr [20.8 ± 2.5 kPal; 
LPS = 79.2 ±21.9 torr [10.5 ± 2.9 kPa|; 
p<.05), and decreased venous admixture (PEEP 
plus .surfactant = 12.5 ± 2.0%; LPS = 46.9 ± 
14.2%; p< .05) 5 hrs after LPS infusion. These 
changes were not significant 6 hrs after LPS 
infusion. PEEP plus surfactant did not alter ven- 
tilatory efficiency index ( VEI = 3800/[peak air- 
way pressure - PEEP| x respiratory rate x 
Pac02), or static compliance as compared with 
LPS without treatment at any lime point. Cy- 
tologic analysis of bronchoalveolar lavage fluid 
showed that surfactant treatment significantly 
increased the percentage of alveolar neutrophils 
as compared with LPS w ithout treatment (PEEP 

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plus surfactant = 39.1 ± 5.5%: LPS = 17.4 ± 
6.6%: p< .05). Histologic analysis showed that 
LPS caused edema accumulation around the air- 
ways and pulmonary vessels, and a significant 
increase in the number of sequestered leuko- 
cytes (LPS group = 3.4 ± 0.2 cells/6400 mi- 
cro2: control group = 1.3 ± 0.1 cells/6400 mi- 
cro:; p < .05). PEEP plus .saline and PEEP plus 
surfactant significantly increased the total num- 
ber of sequestered leukocytes in the pulmonary 
parenchyma (PEEP plus surfactant = 8.2 ± 0.7 
cell.s/6400 micro2; PEEP plus saline = 3.9 ± 
0.2 cells/64()0 micro2; p <.05) compared with 
the control and LPS groups. CONCLUSIONS: 
We conclude thai PEEP plus surfactant treat- 
ment of endotoxin-induced lung injury tran- 
siently improves oxygenation, but is unable to 
maintain this salutary effect indefinitely. Thus, 
repeal bolus dosing of surfactant or bolus treat- 
ment followed by continuous aerosol delivery 
may be necessary for a continuous beneficial 

Coniparisun of Sodium Bicarbonate, Carbi- 
carb, and THAM during Cardiopulmonary 
Resuscitation in Dogs — Bai-Joseph G, Wein- 
berger T, Castcl T. Bar-Joseph N. Laor A, Bursz- 
tein S, Ben Haim S. Crit Care Med 1998:26(8): 

OBJECTIVES: During cardiopulmonary resus- 
citation (CPR), elimination of C02 was shown 
to be limited by low tissue perfusion, especially 
when very low perfusion pressures were gen- 
erated. It has therefore been suggested that so- 
dium bicarbonate {NaHC03). by producing 
C02, might aggravate the hypercarbic compo- 
nent of the existing acidosis and thereby worsen 
CPR outcome. The objectives of this study were 
to evaluate the effects of C02 producing and 
non-C02 producing buffers in a canine model 
of prolonged ventricular fibrillation followed 
by effective CPR. DESIGN: Prospective, ran- 
domized, controlled, blinded trial. SETTING: 
Experimental animal research laboratory in a 
university research center. SUBJECTS: Thirty- 
eight adult dogs, weighing 20 to 35 kg. INTER- 
VENTIONS: Animals were prepared for study 
with thiopental followed by halothane, diaze- 
pam, and pancuronium. Ventricular fibrillation 
was electrically induced, and after 1 mins, CPR 
was initiated, including ventilation with an FI02 
of 1.0. manual chest compressions, administra- 
tion of epinephrine (0.1 mg/kg every 5 mins), 
and defibrillation. A dose of buffer, equivalent 
to 1 mmol/kg of NaHC03, was administered 
every 10 mins from start of CPR. Animals were 
randomized to receive either NaHC03, Carbi- 
carb. THAM, or 0.9% sodium chloride (NaCl). 
CPR was continued for up to 40 mins or until 
return of spontaneous circulation. MEASURE- 
MENTS & MAIN RESULTS: Buffer-treated 
animals had a higher resuscitability rate com- 
pared with NaCl controls. Spontaneous circu- 
lation returned earlier and at a significantly 

higher rate after NaHC03 (in .seven of nine 
dogs), and after Carbicarb (six often dogs) com- 
pared with NaCl controls (two of ten dogs). 
Spontaneous circulation was achieved twice as 
fast after NaHC03 compared with NaCl (14.6 
vs. 28 mins. respectively). Hydrogen ion (H+) 
concentration and base excess, obtained 2 mins 
after the first buffer dose, were the best predic- 
tors of resuscitability. Arterial and mixed ve- 
nous Pco2 did not increase after NaHC03 or 
Carbicarb compared with NaCl. CONCLU- 
SIONS: Buffer therapy promotes successful re- 
suscitation after prolonged cardiac arrest, re- 
gardless of coronary perfusion pressure. 
NaHC03. and to a lesser degree, Carbicarb, are 
beneficial in promoting early return of sponta- 
neous circulation. When epinephrine is used to 
promote tissue perfusion, there is no evidence 
for hypercarbic venous acidosis associated with 
the use of these C02 generating buffers. 

Single-Breath CO, Analysis as a Predictor of 
Lung Volume in a Healthy Animal Model 
during Controlled Ventilation — Slenz Rl. 
Grenier B, Thompson JE, Arnold JH. Crit Care 
Med 1998:26(8): 1409. 

OBJECTIVE: To examine the utility of single- 
breath C02 analysis as a measure of lung vol- 
ume. DESIGN: A prospective, animal cohort 
study comparing 21 parameters derived from 
single-breath C02 analysis with lung volume 
measurements determined by nitrogen washout 
in animals during controlled ventilation. SET- 
TING: An animal laboratory in a university- 
affiliated medical center. SUBJECTS: Seven 
healthy lambs. INTERVENTIONS: The single- 
breath C02 analysis station consists of a main- 
stream capnometer, a variable orifice pneumo- 
tachometer, a signal processor and computer 
software with capability for both on- and off- 
line data analysis. Twenty-one derived compo- 
nents of the C02 expirogram were evaluated as 
predictors of lung volume. Lung volume was 
manipulated by 3 cm H20 incremental increases 
in positive end-expiratory pressure from to 2 1 
cm H20. and ranged between 147 and 942 niL. 
ty-five measurements of lung volume were 
available for comparison with derived variables 
froin the C02 expirogam. Stepwise linear re- 
gression identified four variables that were most 
predictive of lung volume: a) dynamic lung com- 
pliance: b) the slope of phase 3: c) the slope of 2 divided by the mixed expired C02 ten- 
sion; and d) airway deadspace. The multivari- 
ate equation was highly statistically significant 
and explained 94% of the variance (adjusted r2 
= .94. p < .0001 ). The bias and precision of the 
calculated lung volume was .00 and 51. respec- 
tively. The mean percent difference for the lung 
volume estimate derived from the single-breath 
C02 analysis station was 0.79%. CONCLU- 
SIONS: Our data indicate that analysis of the 
C02 expirogram can yield accurate informa- 

tion about lung volume. Specifically, four vari- 
ables derived from a plot of expired C02 con- 
centration vs. expired volume predict changes 
in lung volume in healthy lambs with an ad- 
justed coefficient of determination of .94. Pro- 
spective application of this technology in the 
setting of lung injury and rapidly changing phys- 
iology is essential in determining the clinical 
usefulness of the technique. 

Chronic Obstructive Pulmonary Disease — 

Madison JM, Irwin RS. Lancet 1998:.352(9126): 

Acute exacerbations of underlying COPD are a 
common cause of respiratory deterioration. De- 
velopments have been made in preventive mea- 
sures, but admission to hospital for acute exac- 
erbations can be expected to remain common. 
Several expert consensus guidelines have been 
published to define the appropriate management 
of COPD patients. These consensus guidelines 
generally agree, but all acknowledge a lack of 
large well-controlled clinical studies, especially 
studies focusing on the management of acute 
exacerbations. Consequently, many potential 
controversies exist about the details of manag- 
ing patients with acute exacerbations. Although 
studies of many fundamental aspects of man- 
agement are still needed, the results of con- 
trolled clinical trials are sufficient to emphasise 
the importance of a careful clinical assessment, 
supplemental oxygen, inhaled bronchodilators 
to partially improve airway obstruction, corti- 
costeroids to decrease the likelihood of treat- 
ment failures and to speed recovery, antibiotics, 
especially in severe patients, and non-invasive 
positive-pressure ventilation for treatment of 
acute ventilatory failure in selected patients. 

Acid-Base— Gluck SL. Lancet 1998:352 

Acid-base disorders are common clinical prob- 
lems resulting from a wide variety of patho- 
physiological conditions, including newly 
recognised acquired and genetic causes. The 
history and physical examination and measure- 
ment of blood and urinary indices allow iden- 
tification of the underlying cause of these dis- 
orders in most cases. Treatment directed at 
correction of electrolyte abnormalities and the 
underlying cause for the disorder is essential 
for preventing the acute and long-term meta- 
bolic consequences of acid-base derangements. 

Coping Strategies used by Nurses to Deal 
with the Care of Organ Donors and Their 
Families — Pelletier-Hibbert M. Heart Lung 

OBJECTIVE: To identify the different types 
and numbers of coping .strategies used by nurses 
who care for organ donors and their families 
during the anticipation, confrontation, and post- 

Respiratory Care • November '98 Vol 43 No 1 1 



conlVontation sUis;c> of the org;iii donalion pro- 
cess. DESIGN: Qualilative study. SETTING: 
The home or work facility constituted the .set- 
ting for the interviews. The nurses were em- 
ployed in a neurologic intensive care unit 
(NICU) ul 2 hospitals involved in organ re- 
trieval in eastern Canada. PARTICIPANTS: 
Seventeen nurses who had provided care to or- 
gan and tissue donors in neurologic intensive 
care units. RESULTS: The coping strategies 
that were used changed in number and type as 
the 3 stages of the organ donation process un- 
folded. Exercising control over their emotions, 
distancing themselves, and taking time-out were 
the most frequently used during these respec- 
tive stages. CONCLUSIONS: To assist nurses 
in providing care to the donors and their fam- 
ilies, nurses may benefit from having access to 
a clinical nurse specialist; receiving more edu- 
cation in the areas of grief, crisis interventions, 
stress, and coping theories; and having oppor- 
tunities to participate in debriefing sessions or 
to attend a workshop to exchange feelings and 
lo learn more effective ways of providing care. 

The Current Practice Patterns of Mechani- 
cal \'entilation for Respiratory Failure in Pe- 
diatric Patients — Hard Y. Niranjan V. Evans 
BJ. Heart Lung |WS;27(4):2.W. 

OBJECTIVE: To quantify the current practice 
patterns of mechanical ventilation for respira- 

tory laikirc in pediatric patients. DESIGN: Mail 
survey using 2 hypothetical case studies sent to 
pediatric critical care physicians, MEASURE- 
MENTS & MAIN RESULTS: The required ar- 
terial blood gas (ABG) on conventional me- 
chanical ventilation (CMV) is pH = 7.2? to 
7.29. P02 = 50 to 59 torr. 02 saturation = 
CS.? to 0.89. Most of our survey participants 
will treat a patient failing conventional mechan- 
ical ventilation in their pediatric intensive care 
units (PICUs) with inverse ratio ventilation 
(IRVl (9.'i%) and with high-frequency oscilla- 
tory ventilation (HFOV) (92%). CONCLU- 
SION: Most of the surveyed pediatric critical 
care physicians practice permissive hypercap- 
nia in the treatment of their patients who re- 
ceive ventilatory assistance. More than 90% of 
surveyed pediatric critical care physicians are 
presently using inverse ratio ventilation and 
high-frequency oscillatory ventilation. These 
data suggest that these innovative modes of ther- 
apy are already accepted as part of the standard 
therapeutic spectrum by the surveyed group of 

Factors Related to the Kmotional Responses 
uf Intubated Patients to Being Unable to 

Speak— Menzel LK. Heart Lung I99S;27(4): 


OBJECTIVES: The purpose of the study was to 
examine the relationships among the intensity 

of intubated patients' negative emotional rc- to being unable to speak and selected 
personal and situational variables. DESIGN: 
Prospective correlational. SETTING: Four in- 
tensive care units in a midweslern, university- 
afniialed medical center. PATIENTS: A con- 
venience sample of 48 patients intubated for 24 
or more hours, alert and oriented to person, 
place, and situation. OUTCOME MEASURES: 
Emotional responses (anger and worry/fear) to 
being unable to speak. RESULTS: Multiple re- 
gression showed that self-esteem, severity of 
illness, difficulty with communication, and the 
number of days intubated at data collection were 
significantly associated with patients' emotional 
responses. CONCLUSIONS: Results from this 
study extend prior research and support the need 
for nurses to facilitate communication and to 
support self-esteem in patients receiving venti- 
latory assistance, particularly in the early days 
of intubation. Implications for future research 
are discussed. 

Predictors of Self-Assessed Work Ability 
among Subjects with Recent-Onset Asth- 
ma — Balder B. Lindholm NB. Lowhagen O. 
Palmqvist M. Plaschke P. Tunsater A. Toren K. 
Rcspir Med I998;92(5):729. 

The objective of the study was to find predic- 
tors for work disability among adults with re- 
cent-onset asthma. The study was performed in 

ee]3 moving. 

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a group of 332 subjects with recent-onset 
asthma. The predictors were ascertained hy 
structured interviews, puhiionary function mea- 
surements, methacholine challenge tests and 
skin prick tests. Asthma severity was classified 
into mild, moderate or severe, based on the nim- 
imum medication required to maintain asthma 
control. Work ability was based on self-assess- 
nicnl by inquiring about the subjects' present 
work ability, expressed in percent. The self- 
reported work ability decreased significantly 
with increasing number of days off work, indi- 
cating that .self-reported work ability reflects 
the actual work ability. The majority iSbVr ) of 
the subjects reported 100% working ability, 
Ainong women, but not among men, working 
ability was negatively correlated (rs = -0.33) 
with age. Among subjects with PC20 < 1 6 mg 
ml-1 work ability increased with increasing 
PC20. There was no relation between FEV 1 , 
FVC and working ability. Asthma severity and 
current respiratory symptoms at the work place 
showed a significant negative relation with work 
ability. In a logistic regression model, when 
controlling for age. gender, smoking and weekly 
working hours, decreased work ability was as- 
sociated w ith asthma severity, respiratory symp- 
toms at the workplace and PC20 < or = 4 mg 
ml-1. In conclusion, the work ability was as- 
sessed as normal in most asthmatic subjects. 
Significant predictors for decreased work abil- 
ity were asthma severity, workplace-associated 
respiratory symptoms and bronchial hyperre- 
sponsiveness. The results indicate that work abil- 
ity among asthinatics could be improved by re- 
ducing the workplace-associated symptoms, 
either by reducing the exposure to triggers or 
by improving the asthma therapy. 














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Pediatric Risl< of Mortality: An Assessment 
of Its Performance in a Sample of 26 Italian 
Intensive Care Units — Bertolini G. Ripamonii 
D. Caltaneo A. Apolone G. Crit Care Med 1 99S; 

OBJECTIVE: To assess the validily ot llie Pe- 
diatrie Risjv of Mortality (PRISM) scoring sys- 
tem in accurately predicting the probability of 
mortality in an Italian intensive care unit (ICU) 
sample. DESIGN: Prospective, observational, 
multieenter study. SETTING: Twenty-six Ital- 
ian ICUs classified into two groups: a) ICUs 
specifically dedicated to treating pediatric pa- 
tients; and b) adult ICUs treating children on a 
regular basis. PATIENTS: Consecutive patients 
(n = l.-'i33) < l.'i yrs of age admitted during 1 
MENTS & MAIN RESULTS: To assess the 
performance of the PRISM scoring system, the 
discrimination and calibration measures were 
adopted both in the whole population and in 1 2 
preselected subgroups. A good diseriminalion 
capability of the scoring system was observed 
for both the whole population and subgroups 
(areas under the receiver operating characteris- 

tic curves were never <0.82). On the other hand, 
we documented an unsatisfactory calibration ca- 
pability in the whole population and in most 
subgroups (p values of the Hosmer-Lemeshow 
goodness-of-fit test were <.001 in all but two 
subgroups). CONCLUSIONS: The analyses 
suggest that the unsatisfactory calibration of 
PRISM can be attributed to various reasons. 
Among those reasons, a poor performance of 
the system, us well as its .sensitivity to factors 
not connected to clinical ICU performance, seem 
particularly iinportant. A special caution is 
needed in adopting a severity of illness scoring 
system to assess quality of care, particularly in 
contexts different from the one in which the 
instrument was originally developed. 

Tunneling Short-Term Central Venous Cath- 
eters To Prevent Catheter-Related Infection: 
A Mcta-Analysis of Randomized, Controlled 

Trials— Randolph AG. Cook DJ, Gon/alcs CA. 
Brun-Buisson C. Crit Care Med 1998:26(8): 

OBJECTIVE: To evaluate the efficacy of tun- 
neling short-term central venous catheters to 
prevent catheter-related infections. DATA 
proceedings, citation review of relevant primary 
and review articles, personal files, and contact 
with expert informants. STUDY SELECTION: 
From a pool of 225 randomized, controlled tri- 
als of venous and arterial catheter management, 
we identified 12 relevant trials and included 
seven of these trials in the analysis. DATA EX- 
TRACTION: In duplicate, independently, we 
abstracted data on the population, intervention, 
outcomes, and methodologic quality. DATA 
SYNTHESIS: Tunneling decreased bacterial 
colonization of the catheter by 39% (relative 
risk of 0.61: 95% confidence interval |CI1 of 
0.39 to 0.95 ) and decreased catheter-related sep- 
sis with bacteriologic confirmation by 44% (rel- 
ative risk of 0.56: 95% CI of 0.31 to I) in 
comparison with standard placement. The ma- 
jority of the benefit in the decreased rate of 
catheter-sepsis came from one trial at the inter- 

RESPiRATf)RY Care • November 

Vol 43 No 1 1 



nal jugular site (relative risk of 0.30. 95% CI of 
0.10 to 0.89) and the reduction in risk was not 
signit"icanl when the data from five .subclavian 
catheter trials were pooled (relative risk of 0.7 1 . 
95% CI of 0.36 to 1.43). Tunneling was not 
associated with increased risk of mechanical 
complications from placement or technical dif- 
ficulties during placement. However, this out- 
come was not rigorously evaluated. CONCLU- 
SIONS: Tunneling decreases central venous 
catheter-related infections. However, current ev- 
idence does not support routine tunneling until 
its efficacy is evaluated at different placement 
sites and relative to other inlerventions. 

Determination of Cardiac Output during Me- 
chanical Ventilation by Electrical Bioiniped- 
ance or Thermodllution in Patients with 
Acute Lung Injury: Effects of Positive End- 
Expiratory Pressure — Genoni M. Pelosi P. Ro- 
mand JA. Pedoto A. Moccetti T. Malacrida R. 
Crit Care Med 1998;26(S):1441. 

OBJECTIVE: To evaluate the usefulness of 
transthoracic electrical hioimpedance in sedated 
and paralyzed patients with acute lung injury 
during mechanical ventilation with and without 
early application of positive end-expiratory pres- 
sure (PEEP). DESIGN: Prospective, repeated- 
measures study. SETTING: University-affili- 
ated intensive care center. PATIENTS: Ten 
patients with acute lung injury. INTERVEN- 
TIONS: Simultaneous, three-paired cardiac out- 
put (CO) measurements by transthoracic elec- 
trical bioimpedance (TEE) and themiodilution 
(TD) were made at and 1 5 cm H20 of PEEP. 
average of the TD-CO measurements was 
7.22 ± 2.12 (SD) L/min during cm H20 of 
positive end-expiratory pressure (ZEEP). and 
6.91 ± 1.72 L/min during PEEP (NS). The av- 
erage of the TEB-CO measurements was 
4.48 ± 1.37 L/min during ZEEP. and 6.03 ± 
2.03 L/inin during PEEP (p < .05). For each 
level of PEEP, bias and precision between meth- 
ods were calculated. Bias calculations between 
TD-CO and TEB-CO ranged from - 1 .54 ± 7.02 
L/min at ZEEP to -2.52 ± 4.28 L/ min at PEEP, 
and -2.47 ± 6.09 L/min for mixed data at ZEEP 
and PEEP. There was no significant correlation 
between the percent change with PEEP in 
TEB-CO and TD-CO (r2 = .05. NS ). CONCLU- 
SIONS: In patients with acute lung injury: a) 
the agreement between TEB-CO and TD-CO 
measuremenis is poor; b) agreement is not clin- 
ically improved by application of PEEP; and c) 
TEH cannot monitor trends in CO. 

I.anguajji' of Dyspnea in Assessment of Pa- 
tients »illi Acute Asthma Treated with Neh- 
ulized Alhulerol- Moy ML. l.anlm Ml., liar 
ver A. Schwarizslein RM. Am J Respir (ril 
Care Med I998;158(3):749. 

To investigate whether the language of dyspnea 
provides relevant clinical information in addi- 
tion to that provided by ratings of overall dys- 
pnea intensity when assessing subjective re- 
sponse to therapy, we conducted a prospective 
.study in a cohort of 25 patients with acute asthma 
presenting to the emergency department of a 
tertiary care hospital. Patients received nebu- 
lized albuterol treatments every 20 min with a 
maximum of three doses. At presentation and 
after each treatment, patients completed spirom- 
etry, rated overall dyspnea intensity on a mod- 
ified Borg scale, and selected phrases that 
described qualities of breathlessness from a 15- 
item questionnaire. Paired Student's t tests re- 
vealed significant improvements in FEV, (from 
1.39 ± 0.66 L to 1.80 ± 0.76 L, p < 0. 001) 
and reductions in dyspnea intensity (from 
5.12 ± 2.08 to 2.82 ± 1.59. p < 0.001) after 
the first albuterol treatment. Dyspnea intensity 
continued to decrease significantly in response 
to the second treatment, modified Borg rating 
2.26 ± 1.52, although there was no positive 
bronchodilator response. The results from Coch- 
ran Q tests revealed that the frequency of the 
experience of "chest tightness" decreased sig- 
nificantly across the phases of treatment. How- 
ever, the sensations of "work" or "breathing 
effort" persisted at the same time that the FEV, 
revealed ongoing airways obstruction. We con- 
clude that attention to the language of dyspnea 
would alert health care providers to residual air 
fiow obstruction despite decreases in overall 
dyspnea intensity. 

Comparison of Serial Monitoring of Peak Ex- 
piratory Flow and FEV, in the Diagnosis of 
Occupational Asthma — Leroyer C, Perfetti L, 
Trudeau C, L'Archcveque J. Chan-Yeung M. 
Malo JL. Am J Respir Crit Care Med 1998; 

Peak expiratory flow (PEF) monitoring is often 
used to establish the relationship between oc- 
cupational exposure and asthma. FEV, has been 
found to be a better physiologic index than PEF 
in the measurement of airfiow obstruction. The 
aim of this study was to compare the accuracy 
of .serial monitoring of PEF and FEV, in the 
diagnosis of occupational asthma. Twenty con- 
secutive subjects referred for possible occupa- 
tional asthma were asked to perform serial mon- 
itoring of PEF and FEV, using a portable 
ventilometer. Two sets of graphs were plotted 
for both PEF and FEV,: graphs with the best of 
all values and graphs with the best of two re- 
producible values. Three observers interpreted 
both PF.F and FEV, recordings by the vi.sual 
method in a blind, randomized manner as either 
compatible with occupational asthma or not. 
Eleven of the subjects had a positive inhalation 
challenge test (high-niolecular-weight agents, 
n = 6; low -molecular-weight agents, n = 5). In 
the case of analysis of the graphs plotted with 
the best of all values, the .sensitivity of the PEF 

recording interpreted by the three observers was 
82. 73. and 73%. and of the FEV, recording as 
55. 55. and 45%; specificity of PEF recording 
was 89. 100, and 100%. and of FEV, was 56, 
89. and 100%. When an agreement between 
two of the three readers was required to define 
occupational asthma, sensitivity and specificity 
were 73 and 100% for PEF and 55 and 89% for 
FEV|. Lower sensitivities were found when the 
same analyses were performed with the graphs 
plotted with the best of two reproducible val- 
ues. It was concluded that unsupervised FEV, 
is not more accurate than unsupervised PEF 
monitoring in the diagnosis of occupational 
asthma. Plotting graphs using the best value 
gives better diagnostic accuracy than plotting 
them with the best of two reproducible values. 

Risk of Emergency Care, Hospitalization, and 
ICU Stays for Acute Asthma among Recip- 
ients of Salmeterol — Lanes SF. Lanza LL. 
Wentworth CE 3rd. Am J Respir Crit Care Med 


We used automated health insurance claims 
records of a New England insurer to assess the 
relation between salmeterol and severe nonfatal 
asthma. We identified 61.712 members who re- 
ceived a beta-agonist from January I. 1993 to 
August 31. 1995. including 2.708 recipients of 
salmeterol. Compared with recipients of other 
beta-agonists, future salmeterol recipients had 
higher rates of asthma hospitalization and dis- 
pensings of asthma medications during the year 
before they received salmeterol. We selected as 
a comparison group 3.825 recipients of sus- 
tained-release theophylline. We defined a base- 
line period as the year before the start of the 
follow-up period, and we characterized patients 
according to age, sex, calendar period, presence 
of baseline hospitalizations for asthma, pres- 
ence of chronic obstructive pulmonary disease 
(COPD). and baseline dispensings of asthma 
medications. After adjusting for ba.seline fac- 
tors, incidence rates of severe asthma in the 
salmeterol group were not elevated for emer- 
gency care (rate ratio estimate [RRI = 0.69. 
95% confidence intervals [CIl = 0.42. 1.11), 
hospitalization (RR = 1.09. 95% CI = 0.60, 
1.98). or intensive care unit (ICU) stays (RR = 
0.81. 95% CI = 0.25. 2.62). We conclude that 
salmeterol was prescribed preferentially to high- 
risk patients and, after adjusting for baseline 
risk, salmeterol recipients did not have a greater 
risk than theophylline recipients of .severe non- 
lalal asthma. 

Potential Masking KITecIs of .Salmeterol on 
Airway Inflammation in Asthma — Mcivor 
RA, Pizzichini E, Turner MO. Hussack P, Har- 
grcave FE. Sears MR. .Am ,1 Respir Crit Care 
Med 199S;158(3):924. 

We hypothesized that regular use of long-act- 
ing beta-agonists could delay recognition of 


Ri;spiKAi()in CarI' • N()VI-:mbi-:r '98 Vol 4."^ No 

Jonuikfti 29-30 

*Diseose Morioqemerit: 


aPo^-Oroiluote Course lot 

'Resf^irototij TKerof^ists 


Qmerieoftfltte gtoti bttfef fet^>iwt^ Cote 


Hie UftiMeisifai of Texas 

ffeobk Seienee Center at Soft Clnto«it» 

DefNtftment of 'Res|»iiab>tif Cote 

at tke 44t(lMt SartCliftotlib' OUrfHHt 

• AaBJ^VA • 


iday, jfanuafy 29, ^999 


,iday, 5anL,a.-y 30, 1999 

7:00 -8:00 a.m. 

Attendee CKeck-in 

8:00 -9:00 a.m. 

Inpatient Management o{ COPD 

8:00 -9:30 a.m. 

Disease Management 

9:00 - 10:00 a.m. 

Overview of a Comprehensive Pulmonary 

9:30 -10:00 a.m. 

Overview oi Astnma 

Rehahilitation Program 

10:00 -10:16 a.m. 


10:00- 10:15 a.m. 


10:15- 11:15 a.m. 

Assessment anJ Classification of Astlnna Severitv 

10:15 -11:15 a.m. 

Assessment of the COPD Patient for Disease 


Inpatient Treatment oi Astnma and CuiTent 

Management: This Is Comprehensive Pulmonary 



12:15- 1:30 p.m. 


Disease Education: What Does the Patient Need 

11:15- 12:15 p.m. 

Developnient of a Care Plan for the COPD 

1:30- 1:45 p.m. 


to Know? 

12:15 -1:30 p.m. 

Lunch on vour own 

1:45 -2:00 p.m. 

Pharmacology: Recovery versus Maintenance Dnigs 

1:30 -2:00 p.m. 

Home Care for the COPD Patient 

2:00 - 3:00 p.m. 

Home Environment and Asthma Triggers 

2:00 - 2:30 p.m. 

Follow-up Care 

3:00 -3:15 p.m. 


2:30 - 2:45 p.m. 


3:15 -3:30 p.m. 

Exercise and Stress Reduction 

2:45 -3:30 p.m. 

Putting Together a Pulmonary Rehahilitation 

3:30 -3:45 p.m. 

Symptom laentirication ana Episode Management 
Developing tke Care Plan: "Bringing All tlie 


3:45 -4:00 p.m. 

3:30 -4:15 p.m. 

Reimhursement Issues with Pulmonary 

Components Together" 


4:00 -4:15 p.m. 

Documentation and Outcomes Measurement 

4:15 -4:45 p.m. 

Question and Answer Period 

4:15 -4:45 p.m. 

Reimbursement and Marketing tke Program 

4:45 p.m. 

Summary and Wrap-up 

4:45 p.m. 

Summary and Wrap-up 

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('"mask"! iiKTcasing airway intlaminalidn. We 
studied sleroid-sparing and "masking" effects 
of salineterol versus placebo in 13 asthmatic 
individuals requiring >= 1.500 microgram in- 
haled corticosteroid daily. Corticosteroid doses 
were reduced weekly until criteria were met for 
an exacerbation or the corticosteroid was fully 
withdrawn. Subjects were restabilized on their 
original dose of inhaled corticosteroid for 4 wk 
before crossover to the alternative treatment. 
Subjects maintained symptom and peak expi- 
ratory tlow ( PEF ) diaries, and underw ent weekly 
spiromelrie. methacholine challenge, sputum 
eosinophil, and serum eosinophil cationic pro- 
tein (ECP) measurements. Mean corticosteroid 
dose was reduced by 87% during salmeterol 
treatment, versus 69% with placebo (p = 0.04). 
Sputum eosinophils increased before exacerba- 
tion despite stable symptoms. FEV,. and PEF. 
In the week before clinical exacerbation, spu- 
tum eosinophil counts were higher in the sal- 
meterol-treatment arm (19.9 ± 29.8% (mean ± 
SDj. versus placebo 93 ± 17.6%; p = 0.006). 
Five subjects showed > 10% sputum eosino- 
philia before exacerbation during salmeterol 
treatment, as compared with two receiving pla- 
cebo. In this model, salmeterol controlled symp- 
toms and lung function until inflammation be- 
came significantly more advanced. We conclude 
that the bronchodilating and symptom-relieving 
effects of salmeterol can mask increasing in- 
flammation and delay awareness of worsening 

Respiratory Function among Preterm Infants 
W hose Mothers Smoked during Pregnancy — 

Hoo A1-. llcnschen M. De/aleux C. Costeloe 
K. Stocks J. Am J Respir Crit Care Med 1998: 

We exanuncd whether the adverse effects of 
prenatal exposure to tobacco on lung develop- 
ment are limited to the last weeks of gestation 
by comparing respiratory function in preterm 
Mifanls whose mothers had and had not smoked 
during pregnancy. Maximal forced expiratory 
flow (Vmax FRO and time to peak tidal expi- 
ratory flow as a proportion of total expiratory 
lime (TPTEF:TE) were measured prior to dis- 
charge from hospital in 108 preterm infants 
(mean |SD| gestational age, ^?,.5 1 1.8] wk), 40 
of whose mothers had smoked during pregnancy, 
liilani urniary colinine was less than 4 ng/niL in 
those born to nonsniokers. but it was as high as 
4.'i8 ng/mL in exposed infants (p < O.OOOI). 
TPTEF: TE was significantly lower in infants 
exposed to tobacco in utcro (mean |SD|. ()..Vi9 
|().109|| when compared with who were 
not (0.426 jO.l.Vij) (p <= 0.02). Vmax FRC 
was also reduced in exposed infants (mean |SD|. 
8.S.2 141.7) mL/s versus lO.I.X [49.7] mL/s) 
(p = 0.07). After allowing for sex. ethnic group, 
body si/e, postnatal age, and socioeconomic sta- 
ins. Tl'Ti;! 'I'l; remained significantly dimin- 
ished III III!. Mils exposed prenalally lo tobacco 

(p < 0.05). Thus, impaired respiratory function 
is evident in infants born on average 7 wk prior 
to the expected delivery date, suggesting that 
the adverse effects of prenatal exposure to to- 
bacco are not limited lo the last weeks of preg- 
nancy. See ihe reldleileilitoriiil: Maternal smok- 
ing and infant lung function. Further evidence 
for an in utero effect. Moii^an WJ. Am J Respir 
Crit Care Med IW.S: l5S(j):6S9-69(). 

Maternal Cigarette .Smoliing Is Associated 
with Increased Inner Airway Wall Thickness 
in Children Who Die from Sudden Infant 
Death Syndrome — Elliot J. Vullermin P. Rob 
inson P. Am J Respir Crit Care Med 1998. 

The harmful effects of passive cigarette smoke 
exposure to infants include an increased fre- 
quency of asthma exacerbations, lower respira- 
tory viral infections, and the sudden infant death 
syndrome (SIDS). Because of a difficulty in 
obtaining airway tissue from infants, little in- 
formation is available on the effects of passive 
cigarette smoke exposure on the structure of the 
infant airway wall. We examined airway di- 
mensions in 19 children who died from SIDS 
whose mothers smoked more than 20 cigarettes 
a day prenatally and postnatally. and compared 
these data with those from 1 9 infants who died 
from SIDS and had nonsmoking mothers. Total 
inner and outer wall areas were calculated for 
each airway and expressed in terms of the base- 
ment membrane perimeter (Pbm). Inner airway 
wall thickness was greater in the larger airways 
of those infants whose mothers had smoked more 
than 20 cigarettes a day. These findings suggest 
that infants exposed to a high level of passive 
cigarette smoke develop significant structural 
changes in their airways. Increased airway wall 
thickness may contribute to exaggerated airway 
narrowing and may help explain the previously 
observed abnormalities in neonatal lung func- 
tion that have been described in infants of smok- 
ing mothers. 

Effects of Changes in Fresh Fruit Consump- 
tion on Ventilatory Function in Healthy Brit- 
ish Adults— Carey IM. Slrachan DP. Cook DCi. 
Am J Respir Crit Care Med 1998;158(.M:728. 

Cross-sectional studies have shown frcquciU 
fresh fruit consumption lo be associated with 
higher lung function in both children and adults. 
This relationship is investigated longitudinally 
in a national .sample of 2.171 British adults age 
18 to 7.^ initially exaniincd in I9S4. wlio were 
reexamined 7 yr later, .iiul Ii.kI no icpoilcd his- 
tory of chronic respiratory disease Ihroughoiil. 
Outcome was assessed by change in forced ex- 
piratory volume in one second (FEV, ) bclwccn 
Ihc Iwo cxaminalions. slandaidi/cd for age. 
hcighl, and sc\ and ivlaleil lo fresh Iriiil con- 
simiplioii cslimalcd h\ food rict|iicncv qucs- 
lioiinaiivs al bolli csamiii.ilions Alter adjiisl- 

ment for region, social class, and smoking, 
changes in fresh fruit consumption levels were 
positively associated with changes in FEV, 
(p = 0.002). highlighted by a more marked fall 
in FEV, ( 107 mL; 95% confidence interval. 36 
to 178 niL) in subjects who reduced their fresh 
fruit consumption the greatest compared with 
those with no change. In contrast, average lev- 
els of fruit intake were not associated with 
change in FEVl (p = 0.695). The implication 
is that the cross-sectional effects of fresh fruit 
consumption on ventilatory function appear to 
be reversible and not progressive, such that con- 
sistently low levels of fresh fruit intake do not 
appear to increase lung function decline. 

Control of Ventilation during Lung Volume 
Changes and Permissive Hypercapnia in 

Dogs— Carl ML. Schelegle ES. HoUslien SB. 
Green JF. Am J Respir Crit Care Med 1998: 

We investigated the effect changes in end-ex- 
piratory lung volume (EEVL) had on Ihe re- 
sponse to progressive hypercapnia (CO,- 
response curve) in eight open-chest, 
anesthetized dogs, in order lo clarify Ihe role 
that vagal lung mechanoreceptors have in al- 
tered respiratory drive during permissive hy- 
percapnia. The dogs were ventilated using a 
positive-pressure ventilator driven by phrenic 
neural activity. Systemic arterial CO, tension 
(PaCO,) was elevated by increasing the frac- 
tion of CO, delivered to the ventilator. EEVL 
was altered from approximated functional re- 
sidual capacity ("FRC") lo 1.5 and 0.5 "FRC" 
by changing positive end-expiralory pressure. 
Although the tidal volume (VT)-PaCO, and in- 
spiratory time (Tl)-PaCO, relationships were 
not affected, decreasing EEVL from 1.5 "FRC" 
to "FRC" and then to 0.5 "FRC" caused a sig- 
nificant (p < 0.01) upward shift in Ihe CO,- 
lesponse curves for minute ventilation (V I) 
and frequency (f ). and a significant (p < 0.01) 
downward shift in the CO,- response curve for 
expiratory time (TE). We conclude that these 
shifts were explained by a decrease in the in- 
hibitory activity of slowly adapting pulnionaiy 
stretch receptors (PSRs) as EEVL was lowered. 
In addition, increases in EEVL from 0.5 "FRC" 
lo 1.5 "FRC" caused a significant (p < 0.05) 
increase in the apneic threshold, which we at- 
inbulc lo an inhibitory effect on central drive 
caused by increased PSR activity. 

Aerosolized Surfactant Improves Pulmonary 
Function in F.ndotoxin-lnduced Lung Inju- 
ry — l.ul/C. Carney D. I'inckC. Picoiic A.GatIo 
LA. Paskanik A. el al. Am .1 Respir Cm Care 
Med I998:15S(.?):84I). 

Surfactant dysfunction is a primary pathophys- 
iologic component in patients with adult respi- 
ratory distress syndrome lARDS). In lliis sliidy 
we Icsled llic criic:icv ol ,iciosoli/cd siiir.icl.iiil 


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(SI ) rcplucernent m a sc\erc lung iiijuiy model 
ol' cndotoxin-induced ARDS. Twenty-one cer- 
llfied healthy pigs were anesthetized, surgically 
prepared for measurement of hemodynamic and 
lung function, then randomized into one of four 
groups: { I ) control (n = 5). surgical instrumen- 
tation only; (2) lipopolysaccharide (LPS) (n = 
(i). infused with Escherichia coli LPS ( 1(10 mi- 
crogram/kgl without positive end- expiratory 
pressure (PEEP) and ventilated with a nonhu- 
midified gas mixture o{ 509c N,0 and ^iKc O,; 
(3) LPS + PEEP (n = 4). infused with LPS. 
placed on PEEP (V.."! cm H^O), and ventilated 
with a humidified gas mixture; and (4) LPS -I- 
PEEP + Sf (n = 6). infused with LPS. placed 
on PEEP, and ventilated with aerosolized Sf 
( Infasurf. ONY. Inc. ). All animals were studied 
for 6 h. Arterial PO, significantly decreased in 
both the LPS and LPS + PEEP groups (LPS + 
PEEP = 74 ± 19 mm Hg; LPS = 74 ± 19 mm 
Hg. p < 0.05) while venous admixture (Q S/Q 
T) increased in these groups (LPS + PEEP = 
4.^.3 ± 3.9<7r; LPS = 47.7 ± 1 19^. p < 0.05) as 
compared with the control group. PEEP + Sf 
reduced the fall in PO, (142 ± 20 inm Hg) and 
rise in Q S/Q T (15.1 ± 3.6%) caused by LPS. 
Delayed induction of PEEP (2 h following LPS) 
did not significantly improve any parameter over 
the LPS group without PEEP in this ARDS 
model. LPS without PEEP (3.4 ± 0.2 cells/ 
6.400 iTiicrometer2) caused a marked increase 
in the total number of sequestered leukocytes in 
(he pulmonary parenchyma as compared with 
(he control group (1.3 ± 0.1 cells/6.400 inicro- 
meter2). LPS -I- PEEP -I- Sf (2.3 ± 0.2 cells/ 
6,400 inicrometer2) significantly decreased 
while LPS + PEEP significantly increased 
(4.0 ± 0.2 cells/6.400 niicrometer2) the total 
nuniber of sequestered leukocytes as compared 
with the LPS without PEEP group. In sum- 
mary, aerosolized surfactant replacement de- 
creased leukocyte sequestration and improved 
oxygenation in our porcine (node! of cndolox- 
in-(nduccd lung injury. 

KlfectlNeness and Cost of .Selective Decon- 
lumination of the Diucstive Tract in Criti- 
cally III Intubated Patients: \ Randomized. 
Double-Blind. Placebo-Controlled. Mulli- 
center Trial — Sanchez Garcia M, Cambronero 
fialache JA, Lopez Diaz J, Cerda Cerda E, Ru- 
bio Biased J, GcKncz Aguinaga MA, et al. Am J 
Respir Cril Care Med 1 998; 1 58(3 1:908. 

We evaluated the effect of selective decontam- 
ination of the digestive tract (SDD) on the in- 
cidence of ventilator-associated pneumonia 
(VAP) and its associated morbidity and cost in 
a mixed population of intubated patients. Two 
hundred seventy-one consecutive patients ad- 
mitted to the intensive care units (ICUs) of live 
leaching hospitals and who had an expected 
need for intubation exceeding 48 h were en- 
rolled and received topical antibiotics or pla- 
cebo. I'ninfecled patients additionally received 

ceftriaxone or placebo for 3 d. VAP occurred in 
1 1 .4% of SDD-treated and 293% of control- 
group patients (p < 0.001; 95% confidence in- 
terval |CI]: 7.8 to 27.9). The incidence of non- 
respiratory infections in the two groups was 
19.1% and 30.7%. respectively (p = 0.04; 95% 
CI: 0.7 to 22.7). Among survivors, the median 
length of ICU stay was 1 1 d (interquartile range: 
7 to 21.5 d) for the SDD-treated group and 16. 
5 d (10 to ,30 d) for the control group (p = 
0.006). Mean per survivor was $1 1.926 for 
treated and $16,296 for control-group patients. 
Mortality was 38.9% and 47.1%. respectively 
(p = 0.57). In decontaminated patients, the prev- 
alence of grain-negative bacilli fell within 7 d 
from 47.4% to 13.0% (p < 0.001). whereas 
colonization with resistant gram-positive strains 
was higher (p < 0. 05) than in the placebo 
group. In a mixed population of intubated pa- 
tients. SDD was associated with a significant 
reduction of morbidity at a reduced cost. Our 
findings support the use of SDD in this high- 
risk group. 

As.sessment of Inspiratory FIovv Limitation 
Invasively and Noninvasively during Sleep — 

Clark SA. Wilson CR. Satoh M. Pegelow D, 
Demp.sey JA. Am J Respir Crit Care Med 1998; 

To define the standard of airway flow limita- 
tion, pharyngeal pressure and flow rate were 
measured during wakefulness and sleep in seven 
habitual snorers with widely varying degrees of 
sleep-induced increases in upper airway resis- 
tance. Inspiratory pressure:tlow relationships 
were used to group breaths into four categories 
of flow limitation, including linear (Level I), 
mildly alinear (Level 2), constant flow rale with 
no pressure dependence (Level 3), and decreas- 
ing flow rate throughout significant portions of 
inspiration, i.e.. negative pressure dependence 
(Level 4). These pressure:now rate gold stan- 
dards of flow limitation were used to evaluate a 
How limitation index derived from the time pro- 
file (or "shape") of three noninvasive estimates 
of flow rate: ( 1 ) pneumotach flow rate. (2) dif- 
ferentiated sum respiratory inductance plethys- 
mography (RIP), and (3) nasal pressure. A non- 
flow limited template for each of these 
noninvasive measurements was taken from 
awake breaths and the difference in area deter- 
mined between the template breath and each of 
the noninvasive signals measured during non- 
rapid eye movement (NREM) sleep. The non- 
invasive flow limitation indices were found to 
be effective in differentiating severe types of 
inspiratory flow limitation, i.e.. Level I versus 
Level 3 or Level 4 (.sensitivity/specificity > 
80%). On the other hand, these indirect indices 
were not able to consistently detect mild levels 
of flow limitation (Level 1 versus Level 2; sen- 
siiivity/specificity = 62 to 72%); nor were these 
noninvasive estimates of (low rate "shape" sen- 
sitive (o breaths \mi1i .i hiyh bul fixed resistance 

throughout inspiration. The area index derived 
from measurements of pressure at the nares (Pn) 
was the most sensitive, nonperturbing. nonin- 
vasive measure of flow rate and flow limita- 
tion, and we recommend its use for recognizing 
most of the common types of moderate to se- 
vere levels of airway How limitation in sleeping 

Expiratory Muscle Function in Amyotrophic 
Lateral Sclerosis — Polkey MI. Lyall RA. Green 
M. Nigel Leigh P. Moxham J. Am J Respir Crit 
Care Med 1998;I58(3):7,34. 

Few data exist concerning expiratory muscle 
function in amyotrophic lateral sclerosis { ALS). 
We studied 26 patients with ALS (16 with re- 
spiratory symptoms and 10 without) and mea- 
sured the maximal static expiratory mouth pres- 
sure (MEP), the gastric pressure during a 
maximal cough (Cough Pga), and the gastric 
pressure after magnetic stimulation of the lower 
thoracic nerve roots (Tw Pga). These measure- 
ments were related to the ability to generate 
transient supramaximal flow during a cough 
(cough spikes), to arterialized capillary blood 
gases, and to inspiratory muscle strength. Vocal 
cord motion was examined endoscopically in 
1 1 of the 16 symptomatic patients. Expiratory 
mu.scle weakness was related to inability to gen- 
erate cough spikes with a threshold effect such 
that spikes were absent for Cough Pga < 50 cm 
H,0 (p = 0.009) or Tw Pga < 7 cm H,0 (p = 
0.006) and was usually associated with inspira- 
tory muscle weakness. However, in multivari- 
ate analysis, PaCO, was only significantly as- 
sociated with the maximal sniff esophageal 
pressure (p = 0.02). Symptomatic patients had 
significantly lower inspiratory muscle strength, 
whereas, of the expiratory muscle tests, only 
Tw Pga was significantly lower (p = 0.0009) in 
symptomatic patients. Abnormal vocal cord mo- 
tion was observed in two of the 1 1 patients 
examined. We conclude that abdominal muscle 
weakness in ALS. when substantial, results in 
an inability to generate transient supramaximal 
flow during a cough. However, the primary de- 
terminant of both ventilatory failure and respi- 
ratory symptoms seems to be inspiratory mus- 
cle weakness. 

The Effect of .Adding Ipratropium Bromide 
to Salhutamol in the Treatment of Acute 
Asthma: A Pooled Analy.sis of Three Trials — 

Lanes SF, Garrett JE. Wentworth CE 3rd, 
Fitzgerald JM, Karpel JP, Chest 1998:114(2): 

OBJECTIVE: To assess the effect on FEV, and 
clinical outconies ol adding ipralidpiiini bio 
midc lo salbiilamol in (he licalmeni ol acule 
asthma. METHODS: We conducted a pooled 
analysis of three randomized double-blinded 
clinical trials conducted in the United States. 
Canada, and Ncu Zealand. The studies enrolled 


Rfspikviory Cari: • No\ I:MBLR "yiS Vol 43 No 1 1 


1.064 palicnls aged 18 to 55 years who prc- 
senlcd at the emergency department with aciito 
asthma. Patients were randomized to Ireatmcnl 
with a combination of nebulized 2.5 mg salbu- 
lamol plus 0.5 mg ipratropium bromide, or 2.5 
nig salbutamol alone. Medications were admin- 
istered at baseline and. in the US study, at 45 
min. FEV| was measured at baseline, 45 min, 
and yO min. Patients were followed up for 48 h 
after hospital discharge for occurrence of asthma 
exacerbation and hospitalization. RESULTS: 
Treatment groups were comparable at baseline. 
Of the 1,064 patients randomized, 1,015 pa- 
tients (95%) remained in the study for measure- 
ment at 45 inin, and 961 patients (90%) com- 
pleted the final measurement at 90 min. 
Comparison of overall improvement in FEV, at 
45 min indicated a belter response for patients 
receiving combination therapy (mean differ- 
ence=4.1 mL. 95% confidence interval [CI|20. 
1071. The distribution of change in FEV, was 
skewed by a small number of patients with ex- 
treme values (38 of 1,064=3.6%) that may have 
been due to unreliable lung function testing. 
Removing these outliers produced a larger and 
more precise estimate of effect (mean differ- 
ence = 55 mL. 95% CI=2.107). Because the dis- 
tribution was skewed, we performed nonpara- 
melric analyses that showed evidence of a 
beneficial effect of combination therapy. The 
dilTerence between median values at 45 min is 
40 mL (Wilcoxon p value=0.03). In addition, 
4.9%> (95% CI1%, 11%) more patients in the 
combination group achieved at least 20% of 
their potential improvement, as measured by 
the difference between their baseline FEV, and 
their predicted FEV,. Patients receiving com- 
bination therapy had lower risk for each of three 
clinical outcomes: the need for additional treat- 
ment (relative risk |RR] = 0.92, 95% Cl=0.84. 
1.0), risk of a.sthma exacerbation (RR=0.84. 
95% CI=0.67, 1.04), and risk of hospitalization 
(RR=0.80, 95% CI=0.61, 1.06). CONCLU- 
SION: Adding ipratropium bromide to salbuta- 
mol in the treatment of acute asthma produces 
a small improvement in lung function, and re- 
duces the risk of the need for additional treat- 
ment, subsequent a.sthma exacerbations, and 
hospitalizations. These apparent benefits of add- 
ing ipratropium bromide were independent of 
the amount of beta-agonist that had been used 
earlier in the attack, and possibly related to a 
recent upper respiratory tract infection. Confir- 
matory studies are needed, especially for clin- 
ical outcomes. 

Hemodynamic. Cardiac, and Electrolyte Ef- 
fects of how-Dose Aerosolized Terbutaline 
Sulfate in Asthmatic Patients — Braden GL. 
Germain MJ. Mulhern JG. Hater JG Jr. Bria 
WF. Chest 1998:1 14(2);380. 

STUDY OBJECTIVE: Aerosolized beta2-ago- 
nisls have been associated with increased mor- 
bidity in asthmatics. These drugs cause tran- 

sient increases in heart rate and decreases in 
scrum potassium levels after these drugs are 
first utilized. This study is designed to elucidate 
whether beta-adrenergic tolerance to the hemo- 
dynamic, cardiac, and electrolyte effects of in- 
haled terbutaline occurs during 1 4 days of main- 
tenance therapy. DESIGN: Eight patients with 
stable asthma weaned off beta2-agonist therapy 
were studied in a randomized, double-blinded, 
placebo-controlled study utilizing aerosolized 
terbutaline, 400 microg q6h. Hemodynamic 
measurements and M-mode echocardiography 
were performed before and 15 and 30 min after 
the initial dose of terbutaline or placebo and 
after a dose of aerosolized terbutaline after 14 
days of aerosolized terbutaline maintenance 
therapy. Holier monitors were worn on the first 
day of placebo or terbutaline therapy and on 
day 14 of terbutaline therapy. Plasma potas- 
sium, bicarbonate, and glucose levels. pH, re- 
nin activity, and serum insulin and aldosterone 
levels were measured before and after 24 and 
48 h after terbutaline or placebo therapy and 
after 14 days of aerosolized terbutaline inain- 
tenance therapy. RESULTS: Terbutaline in- 
creased cardiac index and decreased systemic 
vascular resistance greater after 14 days of ther- 
apy coiTipared with the first dose (5.2 ±0.5 vs 
4.4±0.6 L/min/m2; p<0.05: and 760±62 vs 
1.016±118 dyne x s x cm(-5), p<0.01). After 
14 days of terbutaline therapy, the mean max- 
imum heart rate and number of episodes of heart 
rate > 100 beats/min were higher compared 
with the other study day (p<0.05). Plasma po- 
tassium level decreased from 4.29±0.09 to 
3.65 ±0. 1 6 mmol/L after 24 h of terbutaline and 
to 3.90±0.1 1 mmol/L after 48 h. Plasma po- 
tassium level returned to baseline after 14 d of 
terbutaline therapy. Plasma glucose and serum 
insulin levels rose significantly 24 h and 48 h 
after terbutaline and returned to baseline after 
14 d of terbutaline therapy. Serum aldosterone 
level decreased significantly as serum potas- 
sium level decreased in the first 48 h of ter- 
butaline therapy but returned to baseline levels 
after 14 d of terbutaline. CONCLUSIONS: Car- 
diovascular beta2-receptors in patients with sta- 
ble asthma do not develop tolerance to the ef- 
fects of low-dose aerosolized terbutaline after 
1 4 days of maintenance therapy. In contrast, the 
homeostatic mechanisms regulafing serum po- 
tassium develop tolerance to low-dose terbutal- 
ine maintenance therapy. Lack of cardiovascu- 
lar tolerance to maintenance of aerosolized 
beta2-agonists may be important in increased 
morbidity if excessive amounts of these drugs 
are administered during asthma exacerbations. 

Identification of Smokers Susceptible to De- 
velopment of Chronic Airflovi Limitation: A 
13-Y'ear Follow-Up — Slanescu D. Sanna A. 
Veriter C, Robert A. Chest 1998:1 14(2):416. 

BACKGROUND: Cigarette smoking is the car- 
dinal cause of COPD, but only a relafively small 

percentage of smokers have development of 
clinically overt disease. OBJECTIVES: To iden- 
tify high-risk subjects and to assess the prog- 
nostic significance of "small airways" tests. 
SETTING: University teaching hospital. SUB- 
JECTS: Fifty-six smokers and ex-smokers of 
mean age 62.5 years (SD, 2.7) with a smoking 
history of 40.6 (18.9) pack-years were studied 
at the end of a 1 3-year follow-up period. MEA- 
SUREMENTS: Questionnaire and lung func- 
tion tests, including static and dynamic lung 
volumes, airway resistance, maximal expiratory 
flow rates, and small airways tests, such as ni- 
trogen slope of the alveolar plateau (N2 slope) 
and closing volume. RESULTS: Eighty-two per- 
cent of subjects with a normal FEV, /vital ca- 
pacity (VC) ratio at the start of the study (half 
of them w ith abnormal results of small airways 
tests) still had a normal FEV|/VC ratio 13 years 
later. In the remainder, all but one had final 
FEVl/VC values >60%. About 80% of sub- 
jects with a decrea-sed FEV|/VC at the start 
(subjects with airflow obstruction) reached at 
the end of study lower than predicted FEV,/VC 
values. Only about 1 0% of these subjects showed 
an accelerated loss of FEV,, reaching end 
FEV|/VC values of <45%. Initial N2 slope pre- 
dicted about 80% of end FEV, values. CON- 
CLUSION: Middle-aged smokers are at no ev- 
ident risk of functional deterioration if their 
FEV|/VC ratio is normal. This is so even if 
results of small airways tests are abnormal. A 
decreased FEV,/VC rafio has no serious impli- 
cations in itself Only an associated high N2 
slope adds the necessary information to predict 
a low FEV,. Present data suggest that a sub- 
group of smokers in their 50s, characterized by 
a low FEV|/VC rafio and a high N2 slope, are 
probably the susceptible smokers at high risk 
for development of COPD. 

The Validity of Radiographic Estimation of 
Total Lung Capacity in Patients with Respi- 
ratory — Pappas GP. Brodkin CA, 
Sheppard L, Balmes J, Horike M, Barnhart S. 
Chest 1998;114(2):513. 

STUDY OBJECTIVE: To evaluate the validity 
of a state-of-the-art computerized planimetry 
technique for estimation of total lung capacity 
(TLC) from chest radiographs, when applied to 
patients with clinical lung disease receiving rou- 
tine chest radiographs. DESIGN: Retrospective 
clinical survey. SETTING: An occupational 
medicine diagnostic clinic. PATIENTS: A con- 
venience sample of 40 subjects with asbestos- 
related lung disease, 5 patients with nonasbes- 
tos-related restrictive defects, 15 subjects with 
occupational asthma, and 10 subjects with irri- 
tant tracheobronchitis. RESULTS: Estimation 
of TLC using state-of-the-art computerized al- 
gorithms demonstrated limited agreement with 
conventional measures of TLC when applied to 
patients with occupational lung disease receiv- 
ing routine chest radiographs. The most pro- 

Respiratory Care • November "98 Vol 43 No 1 1 



noiinccil liincrcnces occurred in patients with 
asbeslos-relaleil lung disease and reslrielive de- 
fects, where the radiographic method of mea- 
surenienl significantly overestimated helium di- 
lution TLC by 986 niL (r=0.73. p<O.OOI ) and 
1.135 niL(r=0.82. p<0.05). respectively. Good 
inspiratory effort was associated with signifi- 
cantly increased radiographic TLC relative to 
helium dilution TLC; however, radiographic 
features did not fully account for the observed 
differences between radiographic and helium 
dilution techniques. CONCLUSIONS: Our find- 
ings suggest that this planimetric technique 
should not be used as a substitute for conven- 
tional measures of TLC in clinic populations 
receiving routine radiographs. The large diag- 
nostic group specific mean differences observed 
between radiographic and conventional mea- 
sures of TLC also suggest that this method is of 
limited utility in clinical evaluation of occupa- 
tional lung disease. 

Identification and Modiflcation of Environ- 
mental Noise in an ICU Setting — Kahn DM. 
Cook TE. Carlisle CC, Nelson DL, Kramer NR, 
Millman RP. Chest I99X;I I4(2):S35. 

STUDY OBJECTIVES: Noise levels in the hos- 
pital .setting are exceedingly high, especially in 
the ICU environment. We .set out to determine 
what caused the noises producing sound 
peaks > or = 80 A-weighted decibels (dBAl in 
our ICU settings, and attempted to reduce the 
number of sound peaks > or = 80 dB A through 
a behavior modification program. DESIGN; The 
study was divided into two separate phases; 
noise identification and a trial of behavior mod- 
ification. During the identification phase 
we simultaneously recorded sound peaks and 
the loudest noise heard subjectively by one ob- 
server in the medical ICU (MICU) and the re- 
spiratory ICU (RICU). During the behavior 
modification phase of the study we implemented 
a behavior modification program, geared toward 
noise reduction, in all of the MICU staff Sound 
levels were monitored before and at the end of 
the behavior modillcation trial. SETTING: The 
MICU and RICU of a 720-bed teaching hospi- 
tal in Providence. Rl. PARTICIPANTS: All ICU 
staff during the .study period. INTERVEN- 
TIONS: Once the noises that were determined 
to be amenable to behavior modification were 
identified, a behavior modification program was 
conducted during a 3-week period in our MICU. 
Baseline and post-behavior modification noise 
recordings were compared in 6-h intervals after 
sites were matched by number of patients in a 
room and Acute Physi<ilogy and Chronic Health 
Evaluation II (APACHE 11) scores. MEASURE- 
MENTS AND RESULTS: We identified sev- 
eral causes of sound peaks > or - 80 dBA 
amenable to behavior modification; television 
and talking accounted for 49'/, . We ;ilso signil- 
icantly reduced the 24-h mean peak noise level 
(p O.OOOI), as well as the mean peak iioisc 

level (p = 0.OOOI) and the number of sound 
peaks > or = 80 dBA (p = 0.000l ) in all 6-h 
blocks except for the 12 AM to 6 AM period, 
CONCLUSIONS: We conclude that many of 
the noises causing sound peaks > or =80 dBA 
are amenable to behavior modification and that 
it is possible to reduce the noise levels in an 
ICU setting significantly through a program of 
behavior modification. 

The Use of Continuous I.V. Sedation Is As- 
sociated uitli Prolongation of Mechanical 
Ventilation— KollcfMH. Levy NT, AhrensTS, 
Schaiff R. Prentice D, Sherman G. Chest 1998: 

STUDY OBJECTIVE: To determine whether 
the use of continuous i.v. .sedation is associated 
with prolongation of the duration of mechanical 
ventilation. DESIGN: Prospective observational 
cohort .study. SETTING: The medical ICU of 
Barnes-Jewish Hospital, a university-affiliated 
urban teaching hospital. PATIENTS; Two hun- 
dred forty-two consecutive ICU patients requir- 
ing mechanical ventilation. INTERVENTIONS: 
Patient surveillance and data collection. MEA- 
outcome measure was the duration of mechan- 
ical ventilation. Secondary outcome measures 
included ICU and hospital lengths of .stay, hos- 
pital mortality, and acquired organ system de- 
rangements. A total of 93 (38.4%) mechani- 
cally ventilated patients received continuous i.v. 
sedation while 149 (61. 67^) patients received 
either bolus administration of i.v. sedation 
(n = 64) or no i.v. sedation (n = 85) following 
intubation. The duration of mechanical ventila- 
tion was significantly longer for patients re- 
ceiving continuous i.v. sedation compared with 
patients not receiving continuous i.v. sedation 
(I8.'>±I90 h vs 55.6±75.6 h; p<0,00l). Simi- 
larly, the lengths of intensive care (I3..'i±33.7 
days vs 4.8±4.l days; p<0.001) and hospital- 
ization (2I.0±25.1 days vs I2.8±I4.1 days; 
p<0.00l) were .statistically longer among pa- 
tients receiving continuous i.v. .sedation. Mul- 
tiple linear regression analysis, adjusting forage, 
gender, .severity of illness, mortality, indication 
for mechanical ventilation, of chemical pa- 
ralysis, presence of a tracheostomy, and the num- 
ber of acquired organ system derangements, 
found the adjusted duration of mechanical ven- 
tilation to be significantly longer for patients 
receiving continuous i.v. .sedation compared 
with patients who did not receive continuous 
i.v. sedation (148 h |9.*i'/f confidence interval: 
1 2 1 . 1 7.'i hi vs 7X.7 h |9.S% confidence interval; 
68.9, 88.6 hj; p<().()OII. CONCLUSION: Wc 
conclude from these preliminary observational 
data that the use of continuous i \ sedation 
may be associated with the prolong;ilioii ol nic 
chanical ventilation. This study suggests that 
strategics targeted at reducing the use of con- 
liiuious i.v. sedation could shorten the duration 
of mechanical venlilallon lor some p;Uiciits. Pro- 

spective randomized clinical trials, using well- 
designed sedation guidelines and protocols, are 
required to determine whether patient-specific 
outcomes (eg. duration of mechanical ventila- 
tion, patient comfort) can be improved com- 
pared with conventional sedation practices. 

Does Positive End-Expiratory Pressure Ven- 
tilation Improve Left Ventricular Function? 
A Comparative Study by Transesophageal 
Echocardiography in Cardiac and Noncar- 
diac Patients — Fellahi JL. Valtier B. Beauchet 
A. Bourdarias JP. Jardin F. Chest I998;l 14(2): 

STUDY OBJECTIVES: Positive end-expira- 
tory pressure (PEEP) has been proposed to im- 
prove cardiac output in patients with left ven- 
tricular (LV) dysfunction. This study was 
designed to compare quantitative global and re- 
gional LV performance in response to PEEP in 
patients with normal and poor LV function. DE- 
SIGN: A prospective clinical trial. SETTING; 
Adult medical ICU in a university hospital. PA- 
TIENTS; Twelve critically ill patients requiring 
respiratory support and divided into two groups 
according to baseline transesophageal echocar- 
diographic (TEE) measurements: normal LV di- 
mensions and fractional area of contraction 
(FAC=6l±.'i%) (n = 7) and dilated cardiomy- 
opathy with reduced FAC (21 ±1%) (n=5). 
tients were studied when two successive levels 
of PEEP (best PEEP as the highest value of 
respiratory compliance and high PEEP as best 
PEEP-l-10 cm HoO) were applied. Global sys- 
tolic LV performance and quantitative regional 
wall motion analysis performed by the center- 
line method were assessed on the TEE trans- 
gastric short-axis view. End-systolic wall stress 
(ESWSl was used as a reliable indication of LV 
afterload. PEEP reduced LV dimensions asym- 
metrically in both groups of patients and sep- 
tolateral diameter significantly decreased with- 
out affecting global LV systolic performance. 
Additionally, high PEEP produced a significant 
impairment in .septal kinetics as evidenced by 
the centerline method. High PEEP also de- 
creased ESWS for all patients (-279r in normal 
group and -231 in cardiac group, p<0.0.'i) with- 
out significant improvement in global systolic 
LV performance (FAC; -1-2% in normal group 
and +0% in cardiac group; not significant). 
CONCLUSIONS; PEEP cannot be recom- 
mended routinely to improve LV performance 
in patients with severe dilated cardiomyopathy. 

Effects of Repetitive Use and Cleaning Tech- 
niques of Disposahie ,|et Nebulizers on .\ero- 
sol Generation — Standaert TA. Morlln GL. 
W illiams-Warren J, Joy P, Pepe MS. Weber A. 
Ramsey BW, Chest I99S; Il4(2l:.-i77, 

.Slum OHJIX'IIVi;: I'alicms with cyslic fi- 
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administration of antibiotics. DNase, and bron- 
chodiiators several times per day. Most patients 
elect to reuse their disposable nebulizers. The 
purpose of this study was to determine if sig- 
nificant changes in particle size distribution or 
output (mL/min) occurred with reuse. DESIGN: 
In vitro studies were performed using four dis- 
posable models and one durable jet nebulizer 
for up to 100 runs; measurements of particle 
size and output were obtained at 10 run inter- 
vals, using saline solution alone, tobramycin, 
genlamicin, or a mixture of albuterol and cro- 
molyn. Particle size determinations were made 
with a laser diffraction analyzer. RESULTS: 
There was no significant difference between the 
baseline performance of the four disposable 
models and the durable Pari LC, when measur- 
ing particle size distribution of the aerosol; the 
Pari LC had an output rate two to three times 
higher than the four disposable models. For each 
of the four solutes tested, there was no clini- 
cally significant change in performance for up 
to 100 cycles, when the nebulizers were prop- 
erly cleaned between uses. Unwashed units con- 
taining tobramycin started to fail by 40 runs. 
CONCLUSIONS: When property maintained, 
there was no trend of deterioration of perfor- 
mance with repeated use of disposable nebuliz- 
ers. Microbial contamination was not addressed 
in this study and must be considered prior to 
recommendations for the reuse of disposable 

Selection of Peak Flowmeters in Ambulatory 
Asthma Patients: A Review of the Literature 

(review) — Kennedy DT. Chang Z. Small RE. 
Chest I99S;1I4(2):.S87. 

The National Asthma Education and Preven- 
tion Program recently published updated guide- 
lines that stress the importance of peak flow 
monitoring for patients with moderate-to-severe 
persistent asthma. In this specific patient pop- 
ulation, a peak flowmeter provides a simple, 
quantitative, objective measurement of large air- 
way function. The purpose of this article is to 
describe indications for peak flow monitoring 
in asthmatic patients, review technical require- 
ments for peak flowmeters as described by the 
National Heart, Lung, and Blood Institute, and 
evaluate the literature on commercially avail- 
able peak flow devices to aid the health profes- 
sional in selecting an appropriate meter for the 
patient with moderate-to-severe persistent 

The Timing of Tracheotomy: A Systematic 

Review— Maziak DE. Meade MO. Todd TR. 
Chest 1998;1I4(2):60.<;. 

STUDY OBJECTIVE; To examine the impact 
of the timing of tracheotomy on the duration of 
mechanical ventilation, the secondary changes 
to the trachea, and the clinical course of criti- 
cally ill patients in the ICU. DESIGN: A sys- 

tematic review of the literature. METHODS; 
Two independent reviewers conducted a MED- 
LINE .search for relevant literature in the form 
of randomized or observational controlled clin- 
ical studies. Studies were selected for review 
by criteria determined a priori; and the meth- 
odologic quality of .selected studies was evalu- 
ated by duplicate independent review, also us- 
ing criteria determined a priori. RESULTS: Five 
studies were identified, of which three were 
quasiiandomized and none were blinded. Agree- 
ment between reviewers of methodologic qual- 
ity was high (kappa=0.87). CONCLUSIONS: 
There is insufficient evidence to support that 
the timing of tracheotomy alters the duration of 
mechanical ventilation or extent of airway in- 
jury in critically ill patients. See the related 
editorial: Timing Tracheotomy: Calendar 
Watching or Individualization of Care? 
HeffnerJE. Chesi IWS : 1140:361-365. 

Bilateral Pneumothorax following Air Bag 
Deployment — Morgenstern K. Talucci R. 
Kaufman MS. Samuels LE. Chest 1998:1 14(2); 

Air bags have been shown to decrease mortality 
from automobile accidents. Herein is a unique 
case of bilateral pneumothorax following de- 
ployment and rupture of an air bag with no 
other associated chest trauma. One may posit 
that rupliire of the air bag allowed high-pres- 

Respiratory Care • November 

Vol 43 No 1 1 


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sure gases Ui he expelled into the patient's lungs 
resulting in explosive harotraunia. 

Enuresis and Obstructive Sleep Apnea in 

Adults— Kramer NR. Bonitati AE, Millman RP. 
Chest 1W8; II 4(2 1:634. 

Adult enuresis is an unusual symptom of oh- 
structive sleep apnea (OSA). Although it is de- 
seribed as a classic symptom of childhood OSA, 
enuresis is encountered infrequently in adult 
sleep medicine. Five adults with enuresis asso- 
ciated with sleep apnea presented to our Sleep 
Disorders Center. In all five cases, the onset of 
enuresis was associated with the progression of 
sleep apnea symptoms. In each case, the enure- 
sis resolved with treatment with nasal continu- 
ous positive airway pressure. Current medical 
literature on the postulated mechanisms of noc- 
turia and enuresis in sleep apnea is reviewed. 
Based on the experience of the authors and re- 
view of the medical literature, one may conclude 
that severe OSA may lead to new-onset enuresis 
in adults and that effective treatment of OSA is 
associated with resolution of enuresis. 

Influence of Pulse Oximeter Settings on the 
Frequency of Alarms and Detection of Hy- 
poxemia: Theoretical Effects of Artifact Re- 
jection, Alarm Delay, Averaging, Median Fil- 
tering or a Lower Setting of the Alarm 
Limit — Rheineck-Leyssius AT, Kalkman CJ. 
J Clin Monit Comput l998;14(-3 1:131. 

OBJECTIVE: The potential benefit of a reduced 
frequency of false pulse oximeter low oxyhe- 
moglobin saturation (SpO,l alarms is that the 
attention of personnel is only directed to pa- 
tients who experience hypoxemia. The present 
study was undertaken to better understand the 
effects of different settings of the pulse oxime- 
ter on false (artifact) and true (hypoxemia) 
alarms. METHODS: Using the original SpO, 
data of 200 postoperative patients, we calcu- 
lated off-line the effects of five methods (arti- 
fact rejection, alarm delay (2-44 s, 2 s incre- 
ments), averaging (10-90 s). median filtering 
( 10-90 s) and decreasing the alarm limit from 
9()'/f to 85%) on the number of (true- and false) 
alarms. RESULTS: 830 episodes of hypoxemia 
(SpO, < or = 90%) and 73 episodes of severe 
hypoxemia (SpO, < or = 85%) occurred. With 
a SpOi alarm limit of 90%, the alarm was trig- 
gered 1535 times (830 true. 705 false). Artifact 
rejection reduced alarms by almost 50%. An 
alarm delay of 6 s or an averaging or median 
nitering epoch of 10 s resulted in an alarm re- 
duction of almost 50%. No differences were 
found in the reduction of alarms between aver- 
aging and median filtering. Changing the alami 
limit to 85% reduced the number of alarms by 
82%. A similar reduction of alarms was ob- 
tained with either an alarm delay of 18 s or an 
averaging or median filtering epoch of 42 s. 
Ho\ve\er. an alarm limit of 85% reduced the 

number of false alarms less than the other three 
algorithms (p < 0.01). CONCLUSIONS: The 
data from the present study suggest that in or- 
der to effectively suppress false alarms caused 
by pulse oximeter artifacts, it may be preferable 
to use a longer filtering epoch of approximately 
40 s, rather than to decrease the lower alarm 

Propagation of Nitric Oxide Pools during 
Controlled Mechanical Ventilation — Skim- 
ming JW, Stephan PJ. Blanch PB. Banner MJ. 
J Clin Monit Comput 1998;14(3):I57. 

OBJECTIVE: Infusing nitric oxide at a con- 
stant rate into a breathing circuit with intermit- 
tent mainstream flow causes formation of nitric 
oxide pools between successive breaths. We hy- 
pothesized that incomplete mixing of these pools 
can confound estimates of delivered nitric ox- 
ide concentrations. METHODS: Nitric oxide 
flowed at a constant rate into the upstream end 
of a standard adult breathing circuit connected 
to a lung model. One-milliliter gas samples were 
obtained from various sites within the breathing 
system and during various phases of the breath- 
ing cycle. These samples were aspirated peri- 
odically by a microprocessor controlled appa- 
ratus and analyzed using an electrochemical 
sensor. RESULTS: The pools of nitric oxide 
distorted into hollow parabolic cone shapes and 
remained unmixed during their propagation into 
the lungs. In our preparation, time-averaged ni- 
tric oxide concentrations were minimal 60 cm 
downstream of the infusion site (18 ppm) and 
maximal 15 cm upstream of the Y-piece (36 
ppm). The concentrations were mid-range 
within the lung (23 ppm), yet were substan- 
tially less than predicted by assuming homoge- 
neity of the (31 ppm). Generally, nitric 
oxide concentrations within the lung were dif- 
ferent from all other sites tested. CONCLU- 
SION: Incomplete mixing of nitric oxide con- 
founds estimates of delivered nitric oxide 
concentrations. When nitric oxide is infused at 
a constant rate into a breathing circuit, we doubt 
that any sampling site outside the patient's lungs 
can reliably predict delivered nitric oxide con- 
centrations. Strategies to ensure complete mix- 
ing and representative sampling of nitric oxide 
should be considered carefully when designing 
nitric oxide delivery systems. 

The Rise and Dwell Time for Peak Expira- 
tory Flow in Patients with and without Air- 
flow Limitation — Miller MR. Pedersen OF. 
Quanjer PH. Am J Respir Crit Care Med 1998; 
158(1 ):23. 

The response of peak expiratory flow (PEF) 
meters may be affected by the magnitude of 
PEF. the time taken to get to PEF, and the 
duration that the peak is sustained. We under- 
took a retrospective study to define the 10 to 
90% rise time (RTl and dwell time for flow 

above 90% (DT90) and 95% (DT95) of PEF. 
Blows were analyzed thai had been recorded 
using a pneumotachograph from 912 patients 
older than 17 yr of age (556 men) who rou- 
tinely attended a lung function laboratory. For 
each subject, that blow with the largest PEF 
was used to derive the PEF, FEV,, FVC. RT, 
DT90, and DT95. The values for RT, DT90, 
and DT95 were negatively .skewed with the me- 
dian values for men of 58, 29, and 19 ms, re- 
spectively, being significantly shorter than those 
for the women of 67, 49, and 3 1 ms. From the 
912 subjects, there were 277 (153 men) who 
had all their spirometric indices within the nor- 
mal range, and 305 (220 men) had both PEF 
and FEV, more than I. 645 SD below pre- 
dicted, indicating airflow limitation. For sub- 
jects with airflow limitation the median RT was 
significantly smaller than in the normal sub- 
jects (men: 46 versus 72 ms, women: 50 versus 
72 ms), and the same was found for DT90 (men: 
22 versus 40 ms, women: 27 versus 56 ms) and 
DT95 (men: 15 versus 26 ms, women: 18 ver- 
sus 34 ms). We conclude that the dwell times 
for PEF are shorter in men. and the rise and 
dwell times are shorter in patients with airflow 
limitation. Profiles used to test PEF meters should 
encompass the range of rise and dwell times found 
in subjects most likely to be using PEF meters, 
that IS. those with airflow limitation. 

Inhaled Corticosteroids and the Prevention 
of Readmission to Hospital for Asthma — 

Blais L. Ernst P. Boivin JF. Suissa S. Am J 
Respir Crit Care Med I998;158( 1 ):126. 

Despite the proven efficacy of inhaled cortico- 
steroids in reducing airway inflammation and 
their increasing use for the treatment of asthma 
since the mid 1980s, hospitalization for asthma 
has been increasing in frequency in several coun- 
tries. Only few studies, reporting contradictory 
results, have investigated the role of inhaled 
corticosteroids in the prevention of hospitaliza- 
tions for asthma. Using a cohort of 2,059 hos- 
pitalized asthmatic patients between 5 and 54 
yr of age, we estimated the effectiveness of 
inhaled corticosteroids in preventing a readmis- 
sion to hospital for asthma as a function of the 
duration of therapy. The cohort was selected 
from the databases of Saskatchewan Health from 
1977 to 1993. The rate ratio (RR) of a readmis- 
sion for asthma varied with duration of regular 
therapy with inhaled corticosteroids. During the 
first 15 d of regular therapy, users of inhaled 
corticosteroids were as likely as nonusers of 
these medications to be readmitted for asthma 
with a RR of 1.2 (95% CI: 0.8-1.8). Subjects 
treated regularly with inhaled corticosteroids for 
at least 16 d and as long as 6 mo were 40% less 
likely to be readmitted for asthma (RR = 0.6; 
95% CI: 0.4-0.9). while after 6 mo of regular 
treatment the protective effect disappeared 
(RR = 1 .3; 95% CI: 0.7-2.4). We conclude that 
regular therapy with inhaled corticosteroids can 

Respiratory Care • November 

Vol 43 No 1 1 


EnviroNOx EN-500 Monitor 

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suh.M;inli;illy reJuce Ihe risk of a readmissioii 
for asthma after only 13 d of use. Confounding 
by severity appears as the most likely explana- 
tion for the disappearance of the beneficial ef- 
fect after 6 nio of regular therapy. 

Environmental Tobacco Smoke and Adull 
Asthma: The Impact of Changing Expo.sure 
Status on Health Outcomes — Eisner MD. Ye- 
lin EH. Henke J. Shihoski SC. Blanc PD. Am J 
RcspirCrit Care Med 1998;1?8(1 ):170. 

The effect of environmental tobacco smoke 
(ETS) exposure on adults with asthma has not 
been well characterized. In a prospective cohort 
study of 45 1 nonsmoking adults with asthma, 
we evaluated the impact of ETS exposure on 
asthma severity, health status, and health care 
utilization over 18 mo. There were 129 subjects 
(29%: 95?'r CI. 25-33%) who reported regular 
ETS exposure, falling into three categories: ex- 
posure at baseline but none at follow-up (n = 
43. 10%). no ba.seline exposure and new expo- 
sure at follow-up (n = 56. 12%). and exposure 
at both baseline and follow-up (n = 30. 7%). In 
cross-sectional analyses, subjects with baseline 
ETS exposure had greater severity-of-asthma 
scores (score difference, 1 .7: 95% CI. 0. 2-3. 1 ). 
worse asthma-specific quality of life scores 
(score difference. 3.5: 95% CI. 0.03-7.0). and 
worse scores on the Medical Outcomes Study 
SF-36 physical component summary (score dif- 
ference. 3. 0; 95% CI. 0-6.0) than unexposed 
subjects. They also had greater odds of emer- 
gency department visits (odds ratio [OR] = 2.1; 
95% CI. 1.2-3.5). urgent physician visits 
(OR = 1.9: 95% CI. 1.1-3.3). and hospitaliza- 
tions (OR = 1.9; 95% CI. 1.02-3.6). In longi- 
tudinal follow-up. subjects reporting ETS ces- 
sation showed improvement in severity-of- 
asthma scores (score reduction. -3.2; 95% CI. 
-4.4 to -2. 0) and physical component summary 
scores (score increase. 5.3; 95% CI, 2.6-8.1). 
Environmental tobacco smoke cessation de- 
creased the odds of emergency department vis- 
its (OR = 0.4; 95% CI. 0.2-0.97) and hospi- 
talizations (OR = 0.2; 95% CI, 0.04-0.97) after 
adjustment for covariates. Environmental to- 
bacco smoke initiation was associated with 
greater asthma severity only in subjects with 
high-level (>= 3 h/wk) exposure (score in- 
crease. 1.4; 95% CI. 0.03-2.7). In conclusion, 
self-reported ETS exposure is associated with 
greater asthma severity, worse health status, and 
increased health care utilization in adults with 

Survival and P'EV, Decline in Individuals 
with Severe Deficiency of Alphal-Antitryp- 
sin. The Alpha- 1 -Antitrypsin Deficiency Reg- 
istry Study Group. Am J Respir Crit Care Med 

Subjects >= IS yr of age with serum alphal- 
antitrypsin (alphal-AT) levels <= 1 1 microM 


or a ZZ genotype were followed for 3.5 to 7 yr 
with spirometry measurements every 6 to 12 
mo as part of a National Heart, Lung, and Blood 
Institute Registry of Patients with Severe Defi- 
ciency of Alpha- 1 -Antitrypsin. Among all 1,129 
enrollees, 5-yr mortality was 19% (95% CI: 16 
to 21%). In multivariate of 1. 048 sub- 
jects who had been contacted >= 6 mo after 
enrolling, age and baseline FEV|% predicted 
were significant predictors of mortality. Results 
also showed that those subjects receiving aug- 
mentation therapy had decreased mortality (risk 
ratio [RR) = 0.64. 95% CI: 0. 43 to 0.94. p = 
0.02) as coinpared with those not receiving ther- 
apy. Among 927 subjects with two or more 
FEV| measurements >= 1 yr apart, the mean 
FEV| decline was 54 niL/yr, with more rapid 
decline in males, those aged 30 to 44 yr, current 
smokers, those with FEV, 35 to 79% predicted, 
and those who ever had a bronchodilator re- 
sponse. Among all subjects. FEV, decline was 
not different between augmentation-therapy 
groups (p = 0.40). However, among subjects 
with a mean FEV, 35 to 49% predicted. FEV, 
decline was significantly slower for subjects re- 
ceiving than for those not receiving augmenta- 
tion therapy (mean difference = 27 mL/yr. 95% 
CI: 3 to 51 niL/yr: p = 0.03). Because this was 
not a randomized trial, we cannot exclude the 
possibility that these differences may have been 
due to other factors for which we could not 

Lung Volume Reduction Surgery Has Vari- 
able Effects on Blood Gases in Patients v»ith 
Emphysema — Albert RK. Benditt JO. Hilde- 
brandt J. Wood DE. Hlastala MP. Am J Respir 
Crit Care Med 1998;158( 1 ):71. 

Most studies of bilateral lung volume reduction 
surgery (LVRS) report increases in arterial ox- 
ygenation (PaO,). Some suggest this results 
from an increased alveolar ventilation, but oth- 
ers imply that ventilation-perfusion heterogene- 
ity is reduced. We measured arterial blood gases 
(ABGs) on air before and 3 mo following LVRS 
in 46 patients (61% of eligible patients), esti- 
mate the difference between alveolar and arte- 
rial O, (AaPO,). and conelated the changes 
observed with preoperative ABGs, and with pre- 
and postoperative pulmonary function. The 
mean ± SD change in PaO, and AaP02 was 
-1-3 ± 10 mm Hg (p = 0.058) and -H ± 1 1 mm 
Hg (p = NS), respectively, and the range of 
change was large (-17 to -1-29 mm Hg and -24 
to -1-23 mm Hg. respectively). The mean change 
in PaCO, was -3 ± 5 mm Hg (p < 0.05) and 
ranged from -11 to 4-5 mm Hg. Changes in 
PaO, and AaPO, were poorly correlated with 
changes in PaCO, or with pre- or postoperative 
pulmonary function. Although some patients 
had a marked improvement in ABGs following 
LVRS. almost as many deteriorated. On aver- 
age, only minimal effects were seen. Although 
mean alveolar \cntilation improved somewhat. 





Provena United Samaritans Medical Center 
is currently seeking full-time and part-time 
Registered Respiratory Therapists or 
Certified Respiratory Therapy Technicians 
for second and third shifts. The qualified 
candidates will have graduated from an 
approved School of Respiratory Therapy 
and have appropriate certification or 
registration. At least one year of experience 
In respiratory therapy Is preferred but not 
required. The selected candidates will have 
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We offer an excellent compensation and ben- 
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Qualified candidates should submit their re- 
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United Samaritans 
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Human Resources 
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An Equal Opportunity Employer m/f/d/v 

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the effect of LVRS on PaO, primarily resulted 
from alterations in ventilation-perfusion heter- 

Capitation, Managed Care, and Chronic Ob- 
structive Pulmonary Disease — Grasso ME. 
Weller WE, Shaffer TJ, Diette GB, Anderson 
GF. Am J Respir Crit Care Med 1998;158( 1 ): 

Expenditure and utilization patterns of aged 
Medicare beneficiaries with chronic obstructive 
respiratory disease (COPD) (n = 42,472) were 
compared with all Medicare beneficiaries (n = 
1 ,22 1 ,6 1 5 ) using a 5% nationally representative 
sample of aged Medicare beneficiaries partici- 
pating in the fee-for-service program in 1992. 
Per capita expenditures for an aged Medicare 
beneficiary with COPD were 2.4 times the per 
capita expenditures for all Medicare beneficia- 
ries. The most expensive 10% of Medicare ben- 
eficiaries with COPD accounted for nearly half 
of total expenditures for this population. Higher 
comorbidity, as measured by the Deyo-adapted 
Charlson index, was associated with higher ex- 
penditures. For Medicare Part B claims, inter- 
nal medicine accounted for the largest portion 
of physician expenditures (14%). Per capita ex- 
penditures for pulmonologists were 7.5 times 
higher for beneficiaries with COPD compared 
with all Medicare beneficiaries. Results from 
this study suggest that there is a subgroup of 

Respiratory Care • November "98 Vol 43 No 1 1 


Clinical Practice Guidelines 

CPG 1 
CPG 2 
CPG 3 
CPG 4 
CPG 5 

CPG 7 

CPG 8 
CPG 9 





CP620 ■ 
CPG21 ■ 
CPG22 ■ 
CPG23 - 

CPG24 - 

- Spirometry, 1996 Update • $1 

■ Oxygen Therapy in Acute Care Hospital • $1 

■ Nasotracheal Suctioning • $1 

■ Patient- Ventilator System Checks • $1 

■ Directed Cough ■ $1 

In-Vitro pH and Blood Gas Analysis and 
Hemoximetry • $1 

■ Use of Positive Airway Pressure Adjuncts to 
Bronchial Hygiene Therapy • $1 
Sampling for Arterial Blood Gas Analysis ■ $1 
Endotracheal Suctioning of Mechanically 
Ventilated Adults and Children with Artificial 
Airways • $1 

■ Incentive Spirometry ■ $1 

■ Postural Drainage Therapy ■ $1 

■ Bronchial Provocation ■ $1 

■ Selection of Aerosol Delivery Device • $1 

■ Pulse Oximetry ■ $1 

Single-Breath Carbon Monoxide Diffusing 

Capacity • $1 

Oxygen Therapy in the Home or Extended Care 

Facility • $1 

Exercise Testing for Evaluation of Hypoxemia 

and/or Desaturation • $1 

Humidification during Mechanical Ventilation ■ $1 

Transport of the Mechanically Ventilated 

Patient ■ $1 

• Resuscitation in Acute Care Hospitals • $1 

• Bland Aerosol Administration • $1 
Fiberoptic Bronchoscopy Assisting • $1 
Intermittent Positive Pressure Breathing 
(IPPB) • $1 

■ Application of CPAP to Neonates Via Nasal 
Prongs or Nasopharyngeal Tube • $1 

CPG25 — Delivery of Aerosols to the Upper Airway • $1 
CPG2G — Neonatal Time-Triggered, Pressure-Limited, 

Time-Cycled Mechanical Ventilation ■ $1 
CPG27 — Static Lung Volumes • $1 
CPG28 — Surfactant Replacement Therapy ■ $1 
CPG29 — Ventilator Circuit Changes • $1 
CPG30 — Metabolic Measurement using Indirect 

Calorimetry during Mechanical Ventilation ■ $1 
CPG31 — Transcutaneous Blood Gas Monitoring for 

Neonatal & Pediatric Patients • $1 
CPG32 — Body Plethysmography • $1 
CPG33 — Capillary Blood Gas Sampling for Neonatal & 

Pediatric Patients • $1 
CPG34 — Defibrillation during Resuscitation • $1 
CPG35 — Infant/Toddler Pulmonary Function Tests • $1 
CPG36 — Management of Airway Emergencies • $1 
CPG37 — Assessing Response to Bronchodilator Therapy at 

Point of Care • $1 
CPG38 — Discharge Planning for the Respiratory Care 

Patient • $1 
CPG39 — Long-Term Invasive Mechanical Ventilation in the 

Home • $1 
CPG40 — Capnography/Capnometry during Mechanical 

Ventilation • $1 
CPG41 — Selection of an Aerosol Delivery Device for 

Neonata and Pediatric Patients ■ $1 
CPG42 — Polysomnography • $1 
CPG43 — Selection of an Oxygen Delivery Device for 

Neonatal and Pediatric Patients • $1 
CPG44 — Selection of a Device for Delivery of Aerosol to 

the Lung Parenchyma ■ $1 
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of Patient and Caregiver Educator • $1 
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CPG99 - Complete Set in Binder • $35 

($60 AARC nonmembers) 
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11030 Abies Ln., Dallas, TX 75229-4593 

Call (972) 243-2272 or fax to (972) 484-2720 
with MasterCard, Visa, or Purchase Order Number 

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individuals wich COPD who are likely to be 
very expensive during the year. Additional an- 
alytic studies are needed to more specifically 
identify characteristics associated with these in- 
dividuals. As more Medicare beneficiaries en- 
roll in managed care and as physicians are in- 
creasingly being paid on a capitated basis this 
information will be useful to physicians as they 
monitor the care provided to patients and assess 
the financial risks they accept under capitation. 

Acute Respiratory Distress Syndrome 
Caused by Pulmonary and Extrapulmonary 
Disease. Different Syndromes? Gattinoni L, 
Pelosi P, Suter PM, Pedoto A, Vercesi P. Lis- 
soni A. Am J Respir Crit Care Med 1998; 

To assess the possible differences in respiratory 
mechanics between the acute respiratory dis- 
tress syndrome (ARDS) originating from pul- 
monary disease (ARDSp) and that originating 
from extrapulmonary disease (ARDSexp) we 
measured the total respiratory system (, 
chest wall (Est.w) and lung (Est.L) elastance, 
the intra-abdominal pressure (lAP), and the end- 
expiratory lung volume (EELV) at 0, 5, 10, and 
15 cm H,0 positive end-expiratory pressure 
(PEEP) in 12 patients with ARDSp and nine 
with ARDSexp. At zero end-expiratory pres- 

sure (ZEEP), and EELV v\ere similar in 
both groups of patients. The Est.L, however, 
was markedly higher in the ARDSp group than 
in the ARDSexp group (20.2 ± 5.4 versus 
1 3.8 i 5.0 em H,0/L, p < 0.05), whereas Est.w 
was abnormally increased in the ARDSexp 
group (12.1 ±3.8 versus 5.2 ± 1 .9 cm H,0/L, 
p < 0.05). The lAP was higher in ARDSexp 
than in ARDSp (22.2 ± 6.0 versus 8.5 ± 2.9 
cm H;0, p < 0.01), and it significantly corre- 
lated with Hst,w (p < 0. 01). Increasing PEEP 
to 15 cm HiO caused an increase of Est,rs in 
ARDSp (from 25.4 i 6.2 to 31.2 ± 11.3 cm 
H2O/L, p < 0.01) and a decrease in ARDSexp 
(from 25.9 ± 5.4 to 21.4 ± 55.5 cm H,0/L. 
p < 0.01). The estimated recruitment at 15 cm 
HjO PEEP was -0.031 ± 0.092 versus 0.293 ± 
0.241 L in ARDSp and ARDSexp. respectively 
(p < 0.01 ). The different respiratory mechanics 
and response to PEEP observed are consistent 
with a prevalence of consolidation in ARDSp 
as opposed to prevalent edema and alveolar col- 
lapse in ARDSexp. 

Noninvasive Monitoring of Cardiac Output 
in Critically III Patients Using Transesopha- 
geal Doppler— Valtier B, Cholley BP, Belot 
JP. de la Coussaye JE, Mateo J. Payen DM. 
Am J Respir Crit Care Med 1998;158(1):77. 

Measurement of cardiac output using thermodi- 
lution technique in mechanically ventilated pa- 
tients is associated with significant morbidity. 
The goal of the present study was to assess the 
validity of cardiac output measurement using 
transesophageal Doppler in critically ill patients. 
Forty-six patients from three different intensive 
care units underwent 136 paired cardiac output 
measurements using thermodilution (COTH) 
and transesophageal Doppler (COTED). In ad- 
dition, simultaneous suprasternal Doppler and 
indirect calorimetry (Pick principle) were used 
to measure cardiac output in 26 patients from 
one center. A good correlation was found be- 
tween COTH and COTED (r = 0.95), with a 
small systematic underestimation (bias = 0.24 
L/min) using transesophageal Doppler. The lim- 
its of agreement between COTH and COTED 
were +2 L/min and -1.5 L/min. Variations in 
cardiac output between two consecutive mea- 
sures using either transesophageal Doppler or 
thermodilution techniques were similar in di- 
rection and magnitude (bias = L/min; limits 
of agreement = ±1.7 L/min). Suprasternal 
Doppler and indirect calorimetry yielded simi- 
lar correlations and agreements in the sub.set of 
patients in whoin they were used. These results 
confirm that transesophageal Doppler can pro- 
vide a noninvasive, clinically useful estimate of 
cardiac output and detect hemodynamic changes 
in mechanically ventilated, critically ill patients. 

Buyer's Guide Online 

The 1998 
Buyer's Guide of 
Care Equipment 
& Supplies is also 
available on the 
Internet. Visit the 
AARC web site at and select Buyer's 
Guide from the main menu. 

Respiratory Care • November '98 Vol 43 No 1 1 



Mortality for Pediatric Acute Respiratory Distress Syndrome 
(ARDS) in 1998: Has It Changed? 

Appearing in this and next month's issues of Respira- 
tory Care is a collection of articles written by authors 
with broad clinical and research experience involving re- 
spiratory failure in children. These authors have extensive 
knowledge concerning primary treatments and adjuncts to 
treatment modalities that are available to clinicians caring 
for pediatric patients with acute respiratory distress syn- 
drome (ARDS). The purpose of these articles is to give the 
reader a broader understanding of the modalities available 
and their potential indications and outcomes. 

Winston Churchill once wrote. "Americans will always 
do the right thing once they have tried everything else." 
This sentiment may be applicable in the context of ARDS, 
considering the number and variety of therapies that have 
been applied to children. The history behind this prolifer- 
ation of modalities dates back to the late 1980s. At that 
time, little information was available about the outcome of 
pediatric ARDS. Single institution series demonstrated 
mortality rates greater than 60%.'- In 1992, the Pediatric 
Critical Care Study Group (PCCSG) undertook a retro- 
spective study of approximately 50 pediatric centers to 
analyze mortality rates and identify predictors of outcome. 
The results of this study demonstrated a mortality rate of 
about 50%.' Secondary analyses of these data demonstrated 
a decreased mortality in patients treated with extracorpo- 
real membrane oxygenation (ECMO).-* 

Shortly after this study was completed, a number of new 
modalities became available using novel and conventional 
technologies.'' The new modalities included high-frequency 
oscillatory ventilation (HFOV)," inhaled nitric oxide 
(INO),''''* surfactant replacement therapy,'' and partial liq- 
uid ventilation (PLV). Each modality was supported by 
laboratory research that demonstrated its potential bene- 
fits. With the exception of PLV, small clinical studies 
using these modalities demonstrated some benefit in pe- 
diatric patients. The availability of these modalities to the 
clinician created a dilemma. In anecdotal experience, each 
treatment option appeared to be beneficial, but data did not 
exist to support the superiority of one therapy or a combina- 
tion of therapies. Since these decisions involved the emotion- 
ally charged field of the life and death of a child, caution had 
to be exercised because the road from experimental therapies 
to the standard of care can be short in these situations. 

Given the lack of outcome data from randomized clin- 
ical trials, the application of these new therapies has re- 
mained at the discretion of the clinician. Almost all ther- 
apies were utilized as 'rescue' therapies. The timing of 

their use and specific indications varied greatly between 
providers within institutions and between institutions. Dur- 
ing this time, 2 multicenter trials involving pediatric ARDS 
patients were started, and implications of the above ther- 
apies can be seen in their results. The first was a 10-center 
trial to examine the use of ECMO in over 300 pediatric 
ARDS patients. Less than 5 years after the PCCSG study, 
this study showed that mortality in pediatric ARDS patients 
had dropped to less than 20% in ECMO-eligible patients.'" 
This drop in mortality appeared to be associated with the use 
of a protective lung strategy in conventional mechanical ven- 
tilation and with the more frequent use of HFOV. 

Just before the completion of the first study, another 
multicenter trial was started in the same patient popula- 
tion. This was an industry-sponsored trial, which included 
over 50 centers throughout the United States and Canada, 
directed by Dr Bradley Fuhrman, on the use of PLV." The 
results of this trial again illustrate the difficulties facing 
clinicians in 1998. In this trial, mortality was further re- 
duced as compared to the PCCSG trial of the early nine- 
ties; mortality was low in both the control and PLV groups. 
Again, the use of HFOV was increased. No clear advan- 
tage could be found for the patients receiving PLV as 
compared to the conventional arm of therapy. The initial 
interpretation of these results would lead one to conclude 
that PLV was not beneficial. However, upon further in- 
vestigation, the results are not that clear. In the design of 
the study, patients in the PLV group were limited to PLV 
as their only 'rescue.' Patients in the conventional group 
could receive INO, HFOV, and ECMO, or any combina- 
tion of these rescue therapies. Therefore, PLV not only 
had to have a greater impact on mortality, it had to do so 
without the advantage of additional therapeutic adjuncts. 

Another factor complicating the PLV study was that 
most clinicians in the study were experienced in the use of 
conventional mechanical ventilation, HFOV, and ECMO, 
but had limited experience with PLV. Since PLV did have 
a reduced mortality rate as compared to previous studies 
from the late eighties and early nineties, without associ- 
ated complications, it should be considered another poten- 
tial therapy for further study. 

In next month's issue, Dr Fuhrman cites the difficulties of 
prospective randomized trials in ARDS. Potential problems 
cited by Dr Fuhrman, as well as points stated in this editorial, 
should be considered in planning future trials of patients with 
ARDS. Another crucial reading is the most recent report from 
the American-European Consensus Conference. '- 


Rf.spiratory Care • November '98 Vol 43 No 1 1 

Has ARDS Mortality Changed? 

The care of pediatric patients with ARDS in 1998 has 
evolved due to the increase in treatment modalities avail- 
able to clinicians and a redirection of conventional thera- 
pies. In a recent presentation at the Pediatric Critical Care 
Colloquium, approximately 100 pediatric intensivists were 
surveyed" concerning the case presentation of a pediatric 
patient with ARDS: 839^ of those responding agreed that 
tidal volume should be limited to 10 mL/kg or less; 53% 
believed that peak inspiratory pressure should be limited 
to 35 cm H^O, while 36% of the physicians limited it to 40 
cm HiO. These responses demonstrate that the majority of 
pediatric intensivists at this meeting were utilizing a low 
volume or low stretch approach to conventional mechan- 
ical ventilation in their patients. In this survey, 84% re- 
sponded that they would use HFOV if they had to exceed 
the above parameters to treat persistent hypoxemia. It is 
our opinion that these responses, along with the informa- 
tion presented in these articles, begin to explain why mor- 
tality appears to be decreasing in pediatric patients with 
ARDS. Clinicians in 1998 are reducing iatrogenic injury to 
the lung with a more protective conventional approach and 
with the early use of other modalities when conventional 
therapies appear to be failing. We are encouraged by these 
data and the information presented in this and next month's 
issues. Substantial progress has been made. We hope these 
issues of Respiratory Care provide direction and incen- 
tive to advance toward even better outcomes. Many clin- 
ical studies (some "merely" standardizing care and analyz- 
ing experiences) are still needed to better define each 
therapy and the combinations of therapies. But we agree 
with Dr Fuhrman's comments in next month's issue that 
with decreasing mortality rates, perhaps our focus should 
be other measurable end-points, not mortality. 

The future for clinicians and therapists caring for pedi- 
atric patients with ARDS is promising. The need to con- 
stantly re-evaluate our patients and the treatment modali- 
ties best for them continues to be an ongoing challenge. 
However, we believe this is an effort that is greatly rewarded 
by a decrease in mortality for this patient population. 

Mark J Heulitt MD 

Associate Medical Director of Respiratory Care Services 

Arkansas Children's Hospital 

Department of Pediatrics 

Division of Critical Care Medicine 

University of Arkansas for Medical Sciences 

Little Rock. Arkansas 

James Fackler MD 

Clinical Director. Pediatric Critical Care 

Medical Director, Respiratory Therapy 

The Johns Hopkins Hospital 

Department of Pediatrics 

Johns Hopkins University School of Medicine 

Baltimore, Maryland 


We would like to acknowledge the editorial assislanee of Tracy Thurman 
and Shirley Holt RRT. and the .secretarial assistance of Susan Benton. 
This special collection of articles for Respiratory Care could not have 
been completed without their help and patience. 


1. Timmons OD, Dean JM. Vernon DD. Mortality rates and prognostic 
variables in children with adult respiratory distress syndrome. J Pe- 
diatr I99l;l 19(6):896-899. 

2. Tamburro RF. Bugnitz MC. Stidham GL. Alveolar-arterial oxygen 
gradient as a predictor of outcome in patients with nonneonatal pe- 
diatric respiratory failure. J Pediatr 1991;l 19(6):935-938. 

3. Timmons OD, Havens PL, Fackler JC. Predicting death in pediatric 
patients with acute respiratory failure. Pediatric Critical Care Study 
Group. Extracororeal Life Support Organization. Chest 1995;108(3): 

4. Green TP. Timmons OD, Fackler JC. Moler FW, Thompson AE, 
Sweeney MF. The impact of extracorporeal membrane oxygenation 
on survival in pediatric patients with acute respiratory failure. Crit 
Care Med l996;24(2):323-329. 

5. Heulitt MJ, Anders M, Benham D. Acute respiratory distress syn- 
drome in pediatric patients: redirecting therapy to reduce iatrogenic 
lung injury. Respir Care 1995:40(1 ):74-83. 

6. Arnold JH. Hanson JH, Toro-Figuero LO. Gutierrez J, Berens RJ. 
Anglin DL. Prospective randomized comparison of high-frequency 
oscillatory ventilation and conventional mechanical ventilation in 
pediatric respiratory failure. Crit Care Med 1994:22(10):1330-1539. 

7. Demirakca S. Dotsch J. Knothe C. Magsaam J. Reiter HL. Bauer J, 
Koehl PG. Inhaled nitric oxide in neonatal and pediatric acute re- 
spiratory distress syndrome: dose response, prolonged inhalation, 
and weaning. Crit Care Med 1996:24(1 1): 1913-1919. 

8. Goldman AP. Tasker RC. Hosiasson S, Henrichsen T, Macrae DJ. 
Eariy response to inhaled nitric oxide and its relationship to outcome 
in children with severe hypoxemic respiratory failure. Chest 1997: 

9. Wilson DF, Bauman LA, Zarinsky A, et al. Instillation of calf's lung 
surfactant extract (Infasurf) is beneficial in pediatric acute hypox- 
emic respiratory failure. Crit Care Med (in press). 

10. Fackler J, Bohn D, Green T, Heulitt M, Hirschl R. Klein M, Steinhart 
C, Nichols D, Ware J. ECMO for ARDS: Stopping a RCT (abstract). 
Respir Crit Care Med 1997:I.'i.'i(4):A.'i()4. 

11. Fuhrman BP. Partial liquid ventilation and the challenges of random- 
ized, controlled trials in ARDS. Respir Care I998:43(12):(in press). 

12. Artigas A. Bernard GR, Carlet J, Dreyfuss D, Gattinoni L, Hudson 
L, et al. The American-European Con.sensus Conference on ARDS. 
part 2: Ventilatory, pharmacologic, supportive therapy, study design 
strategies, and issues related to recovery and remodeling. Acute re- 
spiratory distress syndrome. Am J Respir Crit Care Med 1998:157(4 
Pt 0:1332-1347. 

13. Schexnayder SM, Heulitt MJ, Management of pediatric patients with 
ARDS: a survey of pediatric intensivists. Respir Care 1998:43(1 1): 

Correspondence & Reprints: Mark J Heulitt MD, Critical Care Medicine. 
Arkansas Children's Hospital, 800 Marshall St. Little Rock AR 72202. 

Respiratory Care • November '98 Vol 43 No 11 


Reviews, Overviews, and Updates 

Analgesia and Sedation for Ventilated Children and Infants 

K J S Anand MBBS DPhil 


Central Processing of Painful Experiences 

Clinical Consequences of Untreated Pain and Stress 

Therapeutic Options for Analgesia and Sedation 

Nonsteroidal Anti-Inflammatory Agents 

Opioid Analgesics 




Other Opioid Drugs 

Opioid Tolerance and Other Side Effects 
Local and Regional Analgesia 

Topical Preparations 

Spinal and Epidural Analgesia 
Other Classes of Analgesic Drugs 


Tricyclic Antidepressants 

Novel Analgesic Approaches and Techniques 

[RespirCare I998;43(l 1):942-951] Key words: Mechanical ventilation, seda- 
tion and analgesia, pain control, opioid analgesics, local analgesia, regional 
analgesia, pediatrics, neonates. 


Ventilated children in the intensive care unit (ICU) are 
constantly exposed to acute, continuous, or chronic pain as 
a result of their disease processes or as a result of life- 
supporting therapies. The perceptual content of being crit- 
ically ill is, for the most part, characterized by these pain- 
ful experiences, despite the present availability of several 

K J S Anand MBBS DPhiJ, Chief. Division ol Crilicul Cure Medicine. 
Arkansas Children's Hospital, and Department of Pediatrics, University 
of Arlsansas for Medical Sciences, l.iltle Rock, Arkansas. 

Supported hy grants from the National Insiiiuie lor Child Health and 
Human Development (HD 01 12.1-02). 

Correspondence: Dr K J S Anand, Division of Critical Care Medicine, 
Department of Pediatrics. Arkansas Children's Hospital, S-43 1 . 800 Mar- 
shall Street. Little Rock. AR 72202. 

techniques for providing adequate analgesia and sedation. 
This review provides a clinical rationale for the impor- 
tance of analgesia and sedation, lists the drugs and tech- 
niques available for use in the pediatric ICU (PICU), and 
describes a role for local anesthetics and adjuvant analge- 
sic agents. Clinical applications that are experimental and 
do not have a proven record of safety and efficacy in 
children are not included. Professionals engaged in the 
routine care of pediatric patients have a moral responsi- 
bility to provide adequate analgesia and sedation, mini- 
mize patient discomfort, and improve their patients' tol- 
erance for ICU interventions, including ventilation. 

It is natural to expect that awareness in a ventilated 
critically ill patient will be filled with the experiences of 
pain, fear, anxiety, and feelings of helplessness. The pain 
experienced in the ICU originates from multiple sources, 
such as the underlying critical illness, incidental surgical 
procedures, and procedures such as endotracheal tube suc- 


Respiratory Care • November '98 Vol 43 No 1 1 

Analgesia and Sedation during Mechanical Ventilation 

tioning, dressing changes, awkward positioning, and pain 
caused by intravenous (l.V.) injections. Lack of attention 
to or treatment of these sources of pain or stress will 
adversely affect the clinical outcome for infants and chil- 
dren following surgery or critical illness.' - Much progress 
is needed in the treatment of pain and discomfort in crit- 
ically ill children,' who often receive intramuscular (I.M.) 
injections and "as needed" (pm) administration for anal- 
gesia.^'^ Most children will prefer to suffer prolonged pe- 
riods of severe postoperative pain rather than receive an- 
other painful "shot,"'"-^ perhaps because of an association 
of I.M. injections with the memory of immunizations dur- 
ing infancy.** 

The inadequacies of analgesia and sedation are not lim- 
ited just to the pediatric or neonatal ICUs. Desbliens et al'^ 
found that 5Q9c of 9000 adults who survived critical illness 
recalled painful and stressful experiences, which were de- 
scribed as severe to extremely severe by 15% of the pa- 
tients. Most critically ill patients have recalled anxiety, 
agitation, and multiple unpleasant experiences during their 
critical illness.'''' '" In order to provide our patients with 
humane care, effective approaches for analgesia and seda- 
tion for all critically ill patients will need to be developed 
and maintained through constant vigilance by all patient 
care professionals. This is not only an important therapeu- 
tic goal, but also an ethical imperative for those responsi- 
ble for the management of ICU patients. Some understand- 
ing of pain and pain processing is a necessary prerequisite 
to the development of a rational and scientific approach to 
analgesia in our patients. 

Central Processing of Painful Experiences 

Painful experiences include a sensory-discriminative 
component, which maps the painful stimulus in terms of 
intensity, location, and duration; an affective-motivational 
component, which is associated with complex behavioral 
attributes, emotional responses, anxiety, depression, and a 
'need state" to limit the duration and intensity of the pain 
that is experienced; and a cognitive-interpretational com- 
ponent, which relates the painful experience to its envi- 
ronmental context and its psychosocial or medical signif- 
icance and compares it to similar previous experiences. 
Although the processing for each of these components 
may occur in different areas of the brain, a considerable 
degree of overlap occurs within the same subject and be- 
tween subjects to illustrate the elegant plasticity of the 
pain system. ' ' 

Recent imaging techniques and previous ablation stud- 
ies have suggested that processing of the sensory-discrim- 
inative aspects of pain occurs in the primary somatosen- 
sory (SI) cortex and the ventrobasal thalamic complex. 
Similarly, the affective-motivational component of pain 
was associated with the nucleus submedius. secondary so- 

matosensory (S2) and premotor cortical sites, the limbic 
system, and anterior parts of the cingulate gyrus. Wider 
distribution for the cognitive-interpretational aspects of 
pain was noted, with dense processing in the prefrontal, 
parietal, and insular cortex, posterior parts of the cingulate 
gyrus, and the limbic system. Some overlap occurs be- 
tween these components of the pain experience from most 
experimental paradigms, leading to arbitrary differentia- 
tion between their associated structures. 

The nature of the painful experience depends on phe- 
nomena such as temporal summation (or 'windup"), spatial 
summation, central sensitization, long-temi potentiation, 
long-term inhibition, and concurrent neuronal activity in 
non-nociceptive areas and foci in the brain. Temporal sum- 
mation is a neurophysiologic phenomenon defined as the 
progressive increase in the response of a central neuron 
with the repetition of a fixed stimulus applied to C-fibers 
at low frequencies. This response characteristic, which was 
first described in dorsal horn cells by Mendell and Wall'- 
and labeled as 'windup," has been discovered in thalamic 
neurons" and other areas. Spatial summation results from 
the brain" s ability to integrate several different excitatory 
stimuli located close to each other to reach a threshold 
response within central neurons. Central sensitization 
shares similar cellular mechanisms with windup, although 
it may be produced by repetitive as well as nonrepetitive 
stimuli (eg, inflammation, post-injury). Neurophysiologic 
characteristics of central sensitization include an increased 
neuronal excitability, changes in the receptive field of the 
neuron, reduction in action potential threshold, and re- 
sponsiveness to previously subthreshold stimuli. '■'''' Clin- 
ical correlates of central sensitization include the spread of 
abnormal or increased .sensitivity to noninflamed/uninjured 
areas of skin (secondary hyperalgesia) and the generation 
of pain by low-threshold stimuli, such as touch (allo- 

Long-term potentiation refers to the specialized charac- 
teristics of subpopulations of central nervous system neu- 
rons that manifest very prolonged effects of activity-de- 
pendent plasticity. Here, brief inputs lead to a potentiated 
response to subsequent inputs for very prolonged periods 
of time, and repetitive stimulation is not required. Long- 
term inhibition is a similar phenomenon, wherein the neu- 
ron manifests hyperpolarization and decreased excitability 
lasting for prolonged periods. Hyperalgesia occurs when 
the pain threshold is reduced in the area surrounding the 
site of tissue injury, and allodynia occurs when previously 
non-noxious stimuli are perceived as noxious in this area. 
The experience of pain from a variety of sources results in 
the expression or self-report of pain, a multitude of be- 
havioral responses to pain, neurophysiologic alterations, 
neuroendocrine responses, and cellular neurobiologic 



Analgesia and Sedation during Mechanical Ventilation 

Table I, Physiologic and Clinical Responses to Stress 







Protein catabolism 


Sodium retention 


Free water retention 

Increased blood pressure 

Increased heart rate 

Increased cardiac output 


Increased O, consumption 

Diaphragmatic splinting 

Gastric acid secretion 

Decreased gut motility 


Other physiologic responses 
Transcellular K*, Mg^*, 

and Ca* * shifts 
Increased fibrinolysis 
Altered immune function 
Increased cytokine 


Fever, increased oxygen consumption 
Hyperosmolar stale, diuresis 
Metabolic acidosis 
impaired healing and growth 
Ketone production, acidosis 

Congestive heart failure 
Increased "third space" 

Increased afterload. bleeding 
Myocardial ischemia 

Increased work of breathing 


Decreased ventilation, atelectasis 

Stress ulcers, gastrointestinal 

Paralytic ileus, biliary sludge 

Mucosal ischemia, bacterial 


Electrolyte disorders 

Thrombotic complications 
Die. hemorrhage 
Infectious complications 
Reperfusion injury 

Shock, hepatorenal syndrome 
Capillary leak syndrome 

SIADH = Syndrome nf i 
inlravascular coagulalKin. 

Clinical Consequences of Untreated Pain and Stress 

Critically ill patients mount a variety of physiologic- 
responses that complicate their ventilator and metabolic 
management and adversely affect their recovery from acute 
respiratory distress syndrome (ARDS) and other critical 
illnesses (Table I ). Following chest tube insertion or tho- 
raco-abdominal surgery, patients develop diaphragmatic 
splinting, with a decreased vital capacity possibly leading 
to atelectasis, postoperative pneumonia, and increased me- 
chanical ventilation. Prolonged exposure to pain impairs 
immune function, increases clotting time and librinolysis, 
and may accentuate the pathologic changes occuiTing with 
ARDS. Impaired oxygen uptake in acute lung injury is 
compoundcil by increased oxygen consumption associated 

with pain and agitation, excessive movement, muscle con- 
traction, increased temperature, and hypermetabolism." 
Stress-induced release of endogenous catecholamines will 
increase sympathetic tone, reduce oxygen delivery to vital 
tissues, and lead to potential end-organ dysfunction.'^ '" 
Prolongation of these stress responses plays an iinportant 
role in perpetuating the trauma-septic state and eventual 
multiorgan system failure and death. '^ 

Therapeutic Options for Analgesia and Sedation 

Several therapeutic approaches and clinical interven- 
tions are available for providing adequate analgesia and 
sedation. These include nonpharmacologic interventions, 
nonopioid and opioid analgesics, regional and local anes- 
thetic techniques, and delivery systems, such as patient- 
controlled analgesia. Commonly used analgesic agents are 
listed in Table 2, drugs and techniques used for regional or 

Table 2. Classification of Analgesic Agents 

Class, agent 

Pure opioid agonists 







Partial opioid agonists 



Nonsteroidal anti-innammatory agents 


Acetyl.salicylic acid 


Ketorolac troniethamme 

Anesthetic agents 


Nitrous oxide 


Miscellaneous agents 

a, -adrenergic agonists (eg. clonidinc) 

Stimulants (eg. dextroamphetamine, mcthylphenidalc) 

Tricyclic antidepressants (eg. amilryptaline. imipraniine) 

Anticonvulsants (eg. phenytoin. carbamazepine) 

Corticosteroids (eg. decadron) 

Enkephalinase inhibitors 

NMDA antagonists 

NMDA = /V-mclhyl n-aspari 


Rfspiratory Care • November '98 Vol 4.^ No 1 1 

Analgesia and Sedation during Mechanical Ventilation 

Table 3, Local/Regional Analgesic Agents and Techniques 

Technique, agent 

Amide local anesthetics 






Topical applications 

EMLA cream (lidocaine/prilocaine) 

TAC (tetracaine/adrenaline/cocaine) 

LET (lidocaine/epinephrine/tetracaine) 

Lidocaine gel (30%) 

Iontophoresis (lidocaine/epinephrinel 

Ethylene chloride spray 
Peripheral techniques 

Local infiltration 

Ring block 

Nerve blocks 

Plexus blocks 

Ganglion blocks 
Ester local anesthetics 




Neuraxial techniques 

Epidural anesthesia 

Spinal anesthesia 

Patient-controlled epidural analgesia 

Sympathetic chain blocks 
Other drugs 







Ketorolac tromethamine 

topical analgesia are listed in Table 3. and sedative agents 
are classified in Table 4. A recent national survey of an- 
algesic and sedative practices from 157 pediatric intensiv- 
ists noted the use of opioids and benzodiazepines in 
> 75% of patients. These agents were often used for pro- 
longed periods of time with or without the use of neuro- 
muscular blocking agents."* A practical approach to anal- 
gesia in critically ill pediatric patients is described below, 
and recent pharmacologic advances are surveyed at the 
end of this article. 

Nonsteroidal Anti-Inflammatory Agents (NSAIDs) 

In critically ill patients, NSAIDs are primarily used for 
treating mild or moderate pain or for reducing the doses of 

Table 4. Sedative Drugs 

Class, agent 












Tricyclic antidepressants 







Chloral hydrate 






Other drugs 

opioids or other analgesic agents. The mechanism of ac- 
tion for most NSAIDs results from their inhibition of pros- 
taglandin synthesis by the cyclooxygenase pathway. By 
decreasing prostanoid synthesis, these agents inhibit the 
firing of peripheral nociceptors at the site of tissue injury 
or inflammation and diminish nociceptive transmission in 
spinal and supraspinal centers."'-" NSAIDs are particu- 
larly useful for minimizing the development of hyperal- 
gesia and allodynia. in addition to their antipyretic ef- 
fects.-' NSAIDs should be administered pre-emptively and 
continued on a fixed dosing schedule (not a prn basis) for 
maximum efficacy in postoperative or other patients. Their 
clinical use may be limited by potential side effects-- and 
the need for enteral administration (Table 5). 

Ketorolac tromethamine and ibuprofen lysine (not avail- 
able in the U.S.) are the only NSAIDs that can be given 
I.V. and have been used effectively in the clinical settings 
of postoperative pain, vaso-occlusive crises, inflammation, 
and musculoskeletal pain.-' -^ Major advantages include 
the lack of respiratory depression or significant cardiovas- 
cular effects and the potentiation of opioid analgesia when 
both groups of drugs are used concomitantly. 

NSAIDs have several potential side effects, including 
prolongation of bleeding time, decreased renal function, 
gastritis, and dyspepsia. These drugs should be used with 
caution in patients with altered hemostasis or extensive 
surgical dissection.-- A clinical trial of NSAID therapy in 
children undergoing tonsillectomy reported increased post- 
operative blood loss,-^ although this was refuted in other 

Respiratory Care • November '98 Vol 43 No 1 1 


Analgesia and Sedation during Mechanical Ventilation 

Table 5. Non-Steroidal Aiiti-Intlammatorv Drugs* 


Dose. Frequency 




l()-l? mg/kg q 4 h 


:t)-25 mg/kg q 4 h 



10-15 mg/kg q 6-8 h 



5-7 mg/kg q 8-12 h 



0.5 mg/kg q 6 h (ma.ximum: 30 n 

ig) I.V. 

0.2-0.3 mg/kg q 6 h 

jsctl in pediatric patients are listed. 


•Only drugs c 

:onimonl>' i 

I.V. = intravenous. 

Studies.-^ Prolonged administration (> 5-7 d) of NSAIDs 
or concurrent use with other nephrotoxic drugs should be 
avoided in patients with preexisting renal dysfunction. -^■-- 
The use of NSAIDs in patients with severe pain is limited 
by the therapeutic ceiling effects of the drugs; thus, esca- 
lating doses in severe pain produce excessive side effects 
with no additional analgesic benefit. 

Recent evidence shows that NSAIDs can potentiate the 
analgesic effects of opioid analgesics by blockade of pros- 
taglandin production in the cyclooxygenase pathway, thus 
leading to a greater availability of arachidonic acid for 
metabolism by the 12-lipoxygenase pathway. Metabolites 
of the 12-lipoxygenase pathway stimulate the inwardly 
rectifying K^ current that is also stimulated via opiate 
receptors.-'*-^ Thus, mechanisms for the two oldest anal- 
gesics, aspirin and opium, converge on the same K^ chan- 
nel to hyperpolarize the neuronal cell membrane, produc- 
ing effects that are clinically identified as analgesia! 

Opioid Analgesics 

Pure opioid agonists form the mainstay of therapy for 
.severe pain in the ICU. Increasing doses of these agents 
will produce increasing degrees of analgesia by the stim- 
ulation of peripheral, spinal, and supraspinal opioid recep- 
tors. These receptors also mediate the sedation, respiratory 
depression, and other observed side effects from opioid 

In critically ill patients, factors that may potentiate the 
side effects of opioids include altered hepatic and renal 
function, changes in the volume of distribution, altered 
protein binding, and other pharmacokinetic variables. Deep 
sedation and amnesia are not achieved with opioids alone 
and require combined therapy with sedatives and anxio- 
lytics (Table 6). 


Morphine is the most widely used opioid in the PICU 
because ol its elTecliveness. availability, and low cost. 

Intravenous morphine rapidly produces analgesia, with 
maximal effects achieved within 20 min and lasting 1-3 
hours in children and adults. Intemiittent or prn adminis- 
tration of morphine may lead to alternating periods of 
intense analgesia and excruciating pain in the critically ill 
patient. Effective analgesia requires the maintenance of 
constant serum and cerebrospinal fluid (CSF) morphine 
concentrations, which are achieved by continuous mor- 
phine infusions at 10-30 /ng/kg/hour. without any associ- 
ated respiratory depression. -"■-' A loading dose at the be- 
ginning of the infusion achieves rapid analgesia, and 
intermittent boluses may be given for breakthrough pain or 
invasive procedures. Similar effects can be achieved with 
morphine patient-controlled analgesia in children (4-12 
years old) following surgery, bone marrow transplanta- 
tion, or sickle cell vaso-occlusive crises.-^ '" 

Hepatic metabolism produces morphine-6-glucuronide 
and moiphine-3-glucuronide. which are secreted in the 
bile, with intestinal reabsotption and renal excretion. Mor- 
phine-6-glucuronide has 20 times the analgesic potency 
and a longer half-life than morphine, leading to prolonged 
.sedation in patients with renal failure or ileus."-''- The 
clearance of morphine is increased in patients with exten- 
sive bums or sickle cell disease, thus requiring higher 
doses titrated to clinical effect.-^-' 


Fentanyl, a synthetic opioid, is used frequently in the 
PICU because of its ability to provide rapid analgesia, 
maintain hemodynamic stability, block endocrine stress 
responses, and prevent pain-induced increases in pulmo- 
nary vascular resistance. Fentanyl is 80-100 times more 
potent, crosses the blood brain barrier more rapidly, and 
causes less histamine release than morphine (Table 6). 
Fentanyl is highly lipophilic and therefore accumulates in 
fatty tissues, prolonging its sedative and respiratory de- 
pressant effects after extended use. As with other analgesic 
agents, tolerance to fentanyl necessitates the frequent es- 
calation of doses during prolonged administration. 

Fentanyl infusions can be initiated at 1 — I /ng/kg/liour 
following an initial bolus of 1-3 /xg/kg. Analgesia for 
short procedures is best provided by administering 0.5-1 
/xg/kg I.V. every 1-2 min until the desired clinical effect 
is obtained. Chest wall rigidity may follow rapid I.V. ad- 
ministration of doses > 5 /xg/kg and can be managed by 
administering a neuromuscular relaxant or naloxone (or 

Transdermal and liansmucosal preparations of fentanyl 
are potential adjuncts for standard pain management when 
I.V. access is limited. Transdermal patches (absorption 
rates of 25, 50, 75, and 100 iig/h) maintain constant serum 
levels after 12-24 hours of placement, thus eliminating 
■peaks and troughs' for the managenienl ol cancer and 


Re.spiratory Care • November "98 Vol 43 No 1 1 

Analgesia and Sedation during Mechanical Ventilation 

Table 6. Opioid Analgesics* 


Starting Dose 


Intermittent I.V. 

Continuous I.V. 


Intermittent I.V. 

Continuous I.V. 






0.05-0.1 mg/kg/dose 

0.025-2.6 mg/kg/h 

1-2 /ng/kg/dose 

Initial bolus: 1-2 ;xg/kg/dose. then 1 pig/kg/h; titrate upward; 

usual: 1-3 ;ag/kg/h 
0.5-1 mg/kg/dose q 4-6 h prn; maximum: 60 mg/dose 
0. 1 mg/kg/dose q 4 h X 2-3 doses, then q 6. 12, or 24 h 
0.1 mg/kg/ q 4 h X 2-3 doses, then q 6, 12, or 24 h; 

maximum: 10 mg/dose 

5-10 min 

1-3 h 

0-2 min 

30-60 min 

30-60 min 

4-6 h 

10-20 min 

4-6 h 

30-60 min 

6-8 h; increases to 22^8 h 

with repeated doses 

chronic pain. Transmucosal absorption with a 'fentanyl 
lolHpop" provides doses of 10-20 ju,g/kg, -"■''■' for preoper- 
ative sedation or analgesia for invasive and noninvasive 
procedures. The potential problems associated with trans- 
dermal fentanyl in the PICU are related to a slow increase 
in the plasma concentration to therapeutic levels, alter- 
ations in the rate of absorption related to skin perfusion, 
and a gradual 'tail-off after the patch is removed due to 
continued transfer from a reservoir of fentanyl located in 
the adipose tissue underlying the patch. 


Methadone is a synthetic opioid with a long half-life 
(15-30 h) following I.V.. oral, or rectal administration 
(507f-707f enteral bioavailability). Clinical effects occur 
at 15-30 min following an I.V. dose, peak effect at 1-2 
hours, and the duration of action is 6-24 hours. Metha- 
done produces less sedation and gastrointestinal side ef- 
fects than other opioids, and it provides a smooth transi- 
tion from I.V. to oral opioids and the ability to wean 
opioid-tolerant patients. Equianalgesic doses of methadone 
are based on the patient's current opioid dosage and ad- 
justed for methadone's bioavailability and half-life. Out- 
patient weaning can be accomplished with minimal with- 
drawal symptoms by scheduled tapering of oral 

Other Opioid Drugs 

The use of other opioids (eg, codeine, meperidine, oxy- 
codone, sufentanil, and alfentanil) in the PICU is limited 
because of their route of administration, side effects, du- 
ration of action, and cost. Meperidine was widely u.sed for 
postoperative analgesia but has no advantages over mor- 
phine and is no longer recommended for critically ill pa- 
tients.''''" It is metabolized to normeperidine, which may 
accumulate in patients with impaired renal function, lead- 

ing to central nervous system excitation and seizures. Mixed 
agonist-antagonist opioids (nalbuphine, buprenorphine. bu- 
torphanol) have the theoretical advantage of causing less 
respiratory depression than pure opioids. Their use in se- 
vere pain is limited by their ceiling effects and their po- 
tential to reverse pure opioid agonist effects and precipi- 
tate withdrawal.-"'"''** 

Opioid Tolerance and Other Side Effects 

Medical professionals have traditionally limited the use 
of opioid drugs in children and adults because of their 
concerns with acute side effects, such as respiratory de- 
pression, and long-term effects, such as tolerance and ad- 
diction. Although clinical studies have not shown an in- 
creased sensitivity to respiratory depression in neonates or 
young infants,'"' they were thought to possess a higher 
proportion of /x^-receptors (associated with respiratory de- 
pression) compared with the density of /a,- and K-recep- 
tors associated with analgesia.-"-' 

Additional acute side effects include nausea, vomiting, 
sedation, dysphoria, and seizures. Stimulation of the che- 
moreceptor trigger zone in the brainstem causes nausea 
and vomiting.^" All opioid agonists have anticholinergic 
effects, which may cause bradycardia (following rapid I.V. 
injection), urinary retention, decreased intestinal motility, 
and an increased tone in the biliary tract and sphincter. 
Histamine release by morphine and its congeners may lead 
to significant clinical problems with pruritus, vasodilation, 
and hypotension. These side effects can be reversed with 
naloxone or treated with laxatives, antihistamines, urinary 
catheters, and antiemetics (eg. promethazine, ondansetron, 
or transdermal scopolamine). The naloxone doses required 
to reverse opioid side effects are much lower (0.01-0.05 
mg/kg) than the doses required for treatment of opioid 
overdose (0.1 mg/kg). Pruritus may be treated with small 
doses of a mixed agonist-antagonist (nalbuphine 10 /xg/kg 
I.V. every 6 h) without affecting the degree of analgesia. 

Respiratory Care • November 

Vol 43 No 1 1 


Analgesia and Sedation during Mechanical Ventilation 

Adjuvant therapy with stimulant drugs (methylphenidate. 
dextroamphetamine) will potentiate the degree of opioid 
analgesia and will antagonize the opioid sedation and re- 
spiratory depression, thereby allowing patients to use their 
cognitive skills for coping with severe pain.-" 

Opioid dependence may be defined as a physiologic 
state characterized by the development of withdrawal symp- 
toms following abrupt discontinuation in patients treated 
with opioids for > 5 days. Addiction that occurs with 
illicit drug abuse is characterized by a psychologic state of 
compulsive drug abuse, drug-seeking behavior, and fre- 
quent relapses following withdrawal of the drug. Addic- 
tion does not occur in pediatric patients receiving opioids 
in a medical setting. If rapid discontinuation of I.V. opioid 
therapy becomes necessary, then the signs and symptoms 
of opioid withdrawal can be minimized by oral adminis- 
tration and outpatient tapering of opioids and by clonidine 

Tolerance refers to increasing dosage requirements to 
achieve the same level of analgesia following the repeated 
administration of opioids. Tolerance is usually treated by 
increasing the dose or changing to another opioid, and it 
may be prevented by concomitant therapy with ketamine 
or dextromethorphan (N-methyl d-aspartate receptor an- 
tagonists).-*- The need for escalating opioid doses may not 
always represent tolerance but may be due to advancement 
of the underlying disease or an improper choice of clinical 
end points (eg. sedation). Very high opioids doses may be 
required in patients with terminal cancer and extensive 
bums (due to hypermetabolism).-'^-" 

Local and Regional Analgesia 

Regional analgesic techniques provide a high therapeu- 
tic ratio, prevent hyperalgesia and stress responses by de- 
creased nociceptive input into the spinal cord, and may 
cause vasodilation and improved tissue perfusion. Local 
anesthetic agents can be combined with opioids, clonidine. 
and NSAIDs to decrease their systemic absorption and the 
incidence of side effects. Techniques for regional anesthe- 
sia include: local infiltration of wounds, ring blocks, re- 
gional and peripheral nerve blocks, plexus blocks, gan- 
glion blocks, spinal anesthesia, and epidural analgesia 
(single dose, intermittent, or continuous infusion). Cre- 
ative approaches, such as a femoral sheath catheter (triple 
block) or an interscalene brachial plexus catheter in pa- 
tients with lower or upper limb fractures, respectively, can 
maintain regional anesthesia with major dosage reductions 
in opioids or other systemic analgesics.-*^ Adverse effects 
can result from inadvertent intravascular injection of local 
anesthetic agents and include seizures, dysrhythmias, and 
myocardial depression.'" The use of regional and topical 
anesthesia is increasing in the PICU: however, a complete 

discussion of these techniques is beyond the scope of this 

Topical Preparations 

Local anesthetic agents have been combined with cuta- 
neous vasoconstrictors or other drugs to produce several 
topical preparations for application on intact skin or for 
subcutaneous and submucosal infiltration. Preparations, 
such as EMLA cream (Astra Pharmaceuticals. Sodertalje. 
Sweden), lidocaine 30% gel. amethocaine patch.-"" or li- 
docaine iontophoresis,-*^ can be applied to the skin, whereas 
lidocaine (0.5%, \%. 2%). TAC (tetracaine 0.5%, adren- 
aline 1:2000, cocaine 11.8%), and LET (4% lidocaine, 
1:2000 epinephrine, and 0.5% tetracaine) can be applied 
by subcutaneous or submucosal infiltration. Formulation 
of LET and TAC in a gel also allows cutaneous applica- 
tion for effective analgesia,-*** but the lidocaine gel may or 
may not be effective.-*'^-"' 

Topical analgesia is indicated for procedures such as 
LV. insertion, lumbar punctures, suturing, thoracentesis, 
paracentesis, chest tube in.sertion, joint aspiration, and skin, 
bone marrow, and kidney biopsies. Bicarbonate may be 
mixed with the local anesthetic solution (1:1, vol/vol) to 
diminish the burning sensations from the infiltration of 
local anesthetics. Serum drug levels after subcutaneous 
lidocaine infiltration or blood methemoglobin levels fol- 
lowing application of EMLA cream are well below those 
associated with systemic toxicity-"'-''' 

The preparation of TAC requires high concentrations of 
cocaine, which provide most of its anesthetic and vaso- 
constrictive effects.'- Its nonproprietary formulation and 
status as a controlled substance may cause immense dif- 
ficulties for routine clinical use. Recently, a randomized 
clinical trial comparing LET and TAC found comparable 
efficacy and safety for both preparations.' ' thus providing 
an effective alternative for replacing TAC. The use of 
opioids as topical analgesic agents was investigated by 
intra-articular injections for arthroscopy, although addi- 
tional applications have also been developed.'-* Rapid (8-10 
min) analgesia on intact skin was also achieved by lido- 
caine iontophoresis, a novel method for cutaneous drug 

Spinal and Epidural Analgesia 

The use of various classes of drugs (opioids, clonidine. 
local anesthetics, NSAIDs) applied to the spinal neuraxis 
has led to exciting developments in regional anesthesia for 
pediatric patients and to a clearer understanding of spinal 
cord physiology. These techniques may be used for diag- 
nostic and therapeutic purposes, to treat intraoperative and 
postoperative pain." '^ neuropathic pain, sympathetically- 


Re.spiratory Cari; • November "98 Vol 43 No 1 1 

Analgesia and Sedation during Mechanical Ventilation 

maintained pain, severe cancer pain,'** vaso-occiusive sickle 
ceil crises, and ischemic conditions.'^'' 

Local anesthetic drugs produce a nonselective biocicade 
of sodium channels in axonal membranes, thereby inhib- 
iting depolarization and preventing conduction of nerve 
impulses in somatosensory, sympathetic, and somatic mo- 
tor nerves,"^' Other mechanisms of action include biocicing 
neurotransmitter release from primary afferents, stimulat- 
ing inhibitory neurons in the dorsal horn, or interrupting 
impulse transmission directly.- '■^•'' Epidural opioids selec- 
tively modulate nociceptive input through opioid receptors 
located in the dorsal horn and in supraspinal centers and, 
therefore, have less effect on motor or sympathetic func- 
tion. Respiratory depression after neuraxial opioids occurs 
mostly in patients who have received concomitant therapy 
with I.V. opioids; therefore, the two routes of administra- 
tion should not be combined. 

Several clinical factors and the expertise and experience 
available locally help to determine the choice of regional 
anesthetic techniques used. Advantages of epidural anal- 
gesia include a slow onset of block, ease of placement via 
the sacral hiatus, a decreased risk of high spinal blockade, 
and the possibility of providing prolonged blockade. The 
large doses of local anesthetics required to produce sen- 
sory analgesia above TIO is a major disadvantage for this 
approach. Segmental block at any spinal level can be ob- 
tained with smaller doses if the local anesthetic is deliv- 
ered at the level of that spinal segment. Advantages of 
spinal anesthesia include a 10-fold lower dose (allows re- 
dosing), a definitive end point for needle placement (CSF 
aspiration), quicker onset of action, and profound motor 
blockade (if muscle relaxation is required during surgery). 
Disadvantages include a shorter duration of action, tech- 
nical difficulties, postoperative motor blockade (delaying 
ambulation), and the risk of total spinal anesthesia (asso- 
ciated with respiratory arrest, seizures, and circulatory col- 
lapse). Common side effects include pruritus, nausea and 
vomiting, urinary retention, and respiratory depression 
(which may be delayed for 24 hour following epidural 
morphine).'"''" Hypotension occurs rarely following pedi- 
atric regional anesthesia, but is commonly reported in adult 
patients. These techniques are contraindicated in patients 
with local infections and ongoing coagulopathies. 

in the PICU: ketamine, tricyclic antidepressants, and 


Ketamine is a dissociative anesthetic, which may be 
administered orally or intravenously. When administered 
intravenously, ketamine has rapid onset and short duration 
of action and minimal side effects in hemodynamically 
unstable patients. Ketamine will increase heart rate, blood 
pressure, and airway secretions. These effects are medi- 
ated by endogenous catecholamine release and generally 
mask the direct myocardial depressant effects of ketamine; 
the latter effects may be manifested in catecholamine-de- 
pleted patients (eg, following prolonged critical illness). 
Ketamine should be avoided in patients with elevated in- 
tracranial pressure or ocular injuries. Pretreatment with 
glycopyrrolate or atropine or the application of cricoid 
pressure (or both) will prevent aspiration of the increased 
secretions during deep sedation with ketamine. 

Tricyclic Antidepressants 

Tricyclic antidepressants are effective in reducing pain 
and analgesic requirements in patients with increasing opi- 
oid requirements. Tricyclics act centrally on the monamin- 
ergic pain inhibitory pathway, reducing pain, improving 
mood, and preventing insomnia at doses lower than those 
required for antidepressant effects (5-23 mg qhs). Appro- 
priate doses of these agents can produce anxiolysis and 
analgesia, and may eliminate the need for polytherapy."" 


Clonidine is an a^-adrenergic agonist and acts centrally 
at the locus coeruleus, the dorsal horn neurons of the spi- 
nal cord, and other presynaptic noradrenergic sites, effec- 
tively producing sedation and analgesia."" Clonidine produces 
effective analgesia in surgical and bum patients,'"' and re- 
duces postoperative vomiting,'^- the stress responses to sur- 
gical trauma,"" ''^ and symptoms of opioid withdrawal.^' 

Novel Analgesic Approaches and Techniques 

Other Classes of Analgesic Drugs 

The systemic or local analgesics reviewed above are 
usually combined with other classes of drugs for patients 
with chronic or intractable, severe pain. The analgesic ef- 
ficacy of corticosteroids, anticonvulsants, muscle relax- 
ants, psychostimulants, antidepressants, and antispasmod- 
ics has been demonstrated in specific clinical situations. ■'^ 
A review of all these measures is not within the scope of 
this article. The following drugs are used most commonly 

The analgesic therapies described above are used cur- 
rently in most ICUs. Development of novel drug delivery 
methods has eliminated the necessity for I.M. injections to 
provide analgesia or sedation. These methods include de- 
livery by transdermal, transmucosal (nasal, rectal, or oral 
mucosa),-*' or intratracheal routes,"-* and the use of ionto- 
phoresis (facilitates absorption of polarized drugs through 
intact skin by a small continuous current). -'^■'''^ The devel- 
opment of newer drugs with fewer side effects or increased 
potency (eg, tramadol, remifentanil)''''''^ and novel treat- 

Respiratory Care • November '98 Vol 43 No 1 1 


Analgesia and Sedation during Mechanical Ventilation 

ment modalities (eg. spinal cord stimulation)'''* have in- 
creased the availability of analgesia in different clinical 
situations. Further understanding of the pain system and 
the factors that modulate pain and stress in critically ill 
patients holds great promise for the future. 


Multiple classes of drugs and techniques are currently 
used to relieve pain in the intensive care setting. To ade- 
quately utilize these techniques, an extensive knowledge 
of the capabilities, limitations, and side effects of the var- 
ious pharmacologic agents and techniques is necessary. 
Caregivers must believe in the authenticity of a patient's 
pain, particularly if that patient is an infant or child. As 
noted from the physiologic rationale listed in Table 2. it is 
clearly evident that the benefits of adequate analgesia far 
outweigh the potential side effects. Adequate and early 
pharmacologic interventions for pain relief minimize pa- 
tient discomfort, maintain metabolic homeostasis, and im- 
prove a patient's tolerance of ICU therapies and nursing 
interventions. The appropriate drug selection and method 
of delivery are determined by the intensity of pain expe- 
rienced and expected treatment goals and by the patient's 
clinical condition. We believe that adequate analgesia can 
be and should be provided to all intensive care patients, 
regardless of their age and clinical condition, using the 
drugs, techniques, and novel approaches reviewed above. 


I sincerely acknowledge the help of C Robert Chambliss MD. Thomas 
Mancuso MD. and Edress Darcey PharmD for their contributions to ihe 
preparation of this manuscript. 


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Respiratory Care • November '98 Vol 43 No 1 1 


Lung-Protective Strategy in Pediatric Patients with Acute Respiratory 

Distress Syndrome 

Mark J Heulitt MD and Desmond Bohn MB BCh FRCPC 


Special Considerations in Pediatric Patients 

Outcome Studies in Pediatric Acute Respiratory Failure 

Pathophysiology of Acute Respiratory Distress Syndrome 

Evolution of Positive Pressure Ventilation 

Ventilator-Induced Lung Injury 

Conventional Mechanical Ventilation 

Alternative Conventional Mechanical Ventilation Strategies 

Increased Inspiratory Time Ventilation 

Prone-Position Ventilation 

[RespirCare 1998;43( 11 ):95 2-960] Key words: Pediatric ARDS, mechauiccd 
ventilation, lung-protective strategy, ventilator-induced liuig injury, barotrauma. 
acute respiratory failure 


The use of positive pressure ventilation (PPV) as an 
effective treatment of acute respiratory failure (ARF) was 
first demonstrated 40 years ago during the poliomyelitis 
epidemic in Europe and Scandinavia. During this epidemic, 
patients received artificial airways and were manually ven- 
tilated for prolonged periods with gases delivered by a 
simple anesthetic circuit.' This in turn ushered in an era of 
intensive care medicine and the development of the first 
positive pressure mechanical ventilators by Engstrom in 
Scandinavia and Emerson in North America. Clinical de- 
mand for ventilatory support led to the development of 
these positive pressure mechanical ventilators but not im- 
mediately to the discovery of the iatrogenic lung injury 
associated with it. 

Mark J Heulitl MD. Associate Direclor of RcspiraUiry Care Services. 
Arkansas Children's Hospital, ami Department of Pediatrics. Division ol 
Critical Care Medicine. University of Arkansas for Medical Sciences, 
l.itllc Rock, Arkansas. Desmond Bohn MB BCh FRCPC. Associate Chiel, 
Departmeni of Critical Care Medicine. The Hospital lor Sick Childien. 
Toronto. Canada. 

Correspondence & Reprints: Mark J Heiilill Ml). Cnlical Care Medicine. 
Arkansas Children's Hospital. XOO Marshall St. Little Rock AR 72202. 

Since the introduction of the first ventilators, we have 
seen major technologic advances in ventilator design: how- 
ever, until recently, there has been no improvement in the 
survival of the respiratory failure patients they were de- 
signed to support. Application errors in the use of venti- 
lators may be attributed to the mistaken concept that pos- 
itive pressure mechanical ventilators should mimic normal 
physiology. Because of this, ventilator settings were cho- 
sen to achieve normocarbia with tidal volumes (Vj) and 
respiratory rates appropriate for the normal lung. 

In the past 5 years, there has been a rethinking of this 
approach in pediatric patients due to a growing body of 
evidence in the scientific literature suggesting that there 
may be a clinically significant lung injury secondary to 
mechanical ventilation. This lung injury appears to be di- 
rectly related to inadequate levels of positive end-expira- 
tory pressure (PEEP) and supraphysiologic Vj. Thus, clin- 
ical practice has been modified to open the lung without 
causing overdistention.- 

In this review, we present the scientific literatinv as it 
relates to acute respiratory distress syndrome (ARDS) and 
ventilatory support. Even though the focus of this article is 
pediatric ARDS, available data are still limited, so data 
from adult animal studies and clinical trials will be tili- 
li/.ed. This discussion will be limited to conventional me- 
chanical ventilation since other articles in this issue will 
deal with iionconvcnlional and adjinicl therapies. 



Lung-Protective Strategy in Pediatric Patients with ARDS 

Tahle 1. Summary of Studies of Pediatric Patients with Acute Respiratorv Distress Syndrome 


Study Duration, years Study Design* 

Inclusion Criteria 

Number of Patients 

Mortality (9c) 









R, P 










*R - rctrospeclive. P = prospective 
tPIP = peiik inspiratory pressure 
iPEEP = positive end-expiraiory pressure 
§ECMO = exlriicorporeal membrane oxyge 

F,o, 0.9, PIPt > 25 cm H,0 
F,o, 0.5. PEEPI > 6 cm H,0 
F|o, 0.6. PaO, < 60 mm Hg 
Lung injury score > 2.5 
F,o, > 0.5. PEEP > 6 cm H,0 
F,n, > 0.5. PEEP > 6 cm H,0 






CMO§ Eligible. 17: 
ECMO Inelicible. 43 

Special Considerations in Pediatric Patients 

Peiiiatric patients may be predisposed to an increased 
risk of iatrogenic injury from meciianical ventilation be- 
cause they differ anatomically and developmentally from 
adults. Postnatal age is inversely related to alveolar epi- 
thelium permeability.'' Microvascular protein permeability 
in 4- to 6-week-old rabbit lungs was compared to that of 
the lungs of 3 groups of adult rabbits after ventilation with 
peak inspiratory pressures (PIPs) of 15. 30, or 45 cin HiO 
for 1 hour."* The pulmonary capillary filtration coefficient 
of the young rabbit lungs was higher by 91% at a PIP of 
15 cm H,0 and by 440% at a PIP of 45 cm H,0. The 
authors postulated that the amplified injuries seen in the 
younger lungs could be attributed to their measured higher 
chest wall compliance. The inverse relationship of chest 
wall compliance and risk of microvascular damage with 
mechanical ventilation is supported by the lack of edema 
seen with chest wall restriction when compared with pro- 
gressively increasing edema in the unimpaired chest wall 
and in excised lungs. "^ The higher chest wall compliance of 
infants'' and small children provides less protection against 
the occurrence of iatrogenic lung injury, especially if pres- 
sure cycled ventilation leads to large V.p. Furthermore, 
concentrations of lung elastin (which correlate with elastic 
recoil of the lung) and of lung collagen (which is associ- 
ated with structural integrity of the lung) are slow to reach 
adult levels in the rat, which is considered to be a good 
model of postnatal lung growth in humans.^ 

Outcome Studies in Pediatric ARF 

One obstacle to the evolution of new therapies used in 
the management of ARF is that we lack good outcome 
markers. ARDS has many different etiologies, and the 
outcome will be greatly influenced by the underlying cause. 
For instance, the mortality in ARDS associated with sepsis 

is higher than that associated with trauma or in patients 
with single-system lung disease without other organ dys- 
function. In a published series concerning adult patients 
with ARDS. hypoxia was the primary mode of death in 
only 16% of patients, the rest being due to sepsis and 
multiorgan failure.** Therefore, the ability to demonstrate 
improved oxygenation alone using a nonconventional ap- 
proach would be unlikely to have a significant impact on 
outcome unless it could be shown that it either decreases 
the amount of lung injury or shortens the duration of ven- 
tilator support. There is now experiinental evidence that 
shows that lung overdistention results in the release of 
cytokines that may be responsible for multiorgan injury 
and dysfunction.'^ This provides a further rationale for the 
use of ventilator strategies that protect the lungs. 

A number of studies of pediatric patients with ARDS 
have been reported. These are summarized in Table 1. 
Most of these are small series that show published mor- 
tality rates of 407f-70% for children with ARDS. The 
most recent was a multicenter prospective series that col- 
lected data over a 2-year period and evaluated survivors 
among > 320 patients with ARF (cardiac disease exclud- 
ed). Patients were required to have a combination of frac- 
tion of inspired oxygen (F|o,) — 0.5 and a PEEP > 6 cm 
H2O for > 12 hours. Overall mortality was split into 2 
groups, those eligible for extracorporeal membrane oxy- 
genation (ECMO) and those not eligible. Mortality was 
higher in those not eligible for ECMO due to the inclusion 
of patients with oncologic disease.'^ Overall, mortality 
was markedly lower than was reported in earlier studies. 
There were two reasons for this reduction: the use of a 
protective lung strategy with reduced PIPs and the use of 
high-frequency ventilation. 

This improved survival was recently reported in 2 stud- 
ies of adult patients with ARDS. In the first study, it was 
shown that with the titration of PEEP to above the lower 
inflection point and with minimization of cyclic parenchy- 

Respiratory Care • November "98 Vol 43 No 1 1 


Lung-Protective Strategy in Pediatric Patients with ARDS 

mal stretch, better lung compliance, oxygenation, and a 
higher weaning rate were produced."' In a second study by 
the same investigators, this approach produced an improve- 
ment in 28-day survival.'^ However, Stewart et al"* did 
not confirm this improved outcome in adult patients 
w ith ARDS in another multicenter. randomized trial that 
used pressure limitation without PEEP above the inflec- 
tion point. 

Pathophysiology of ARDS 

ARDS is characterized by severe ventilation-perfusion 
mismatch, with pulmonary hypertension causing severe 
hypoxemia and decreased cardiac performance.''' At the 
American-European Consensus Conference on ARDS. 
adult respiratory distress syndrome was renamed acute re- 
spiratory distress syndrome because pediatric patients de- 
velop this disease.-" The syndrome was also subclassified 
according to the severity of the oxygenation defect. When 
the other features of the syndrome were present. ARDS 
was present when the ratio of arterial o.xygen tension (P.,o,) 
to F,o, was < 200 mm Hg. and acute lung injury (ALI) 
was present when the Pao,^io, ratio was < 300 mm Hg. 

In the nondiseased state, total cardiac output passes 
through the pulmonary capillaries, which are either juxta- 
posed to the alveoli (intra-alveolar) or contained within the 
interstitial space (extra-alveolar), with minimal leakage of 
fluid. In the normal state, junctions between the capillary 
endothelial cells are permeable to fluid flux and imperme- 
able to both fluids and solutes. The small amount of fluid 
that leaks into the interstitial space is reabsorbed by the 
lymphatics. The epithelial lining is impermeable to both 
fluid and solutes. This normal state can be disturbed by 
inhalational injury to the endothelial lining (eg. aspiration 
and smoke inhalation), by systemic disease that damages 
the endothelial lining (eg, sepsis, trauma, and fat embo- 
lism), or by primary surfactant deficiency, which results in 
a number of pathologic changes within the lung. Any of 
these processes can initiate ARDS. 

ARDS can be subdivided into four clinical phases.-' In 
the initial phase, the radiograph is normal, with the patient 
presenting with dyspnea, tachypnea, and normal P.,q . 
Within 12 to 24 hours, the second phase begins, with 
cellular pathologic and physiologic evidence of lung in- 
jury and with radiographic flndings of patchy alveolar in- 
liltratcs. Signiflcant advances have been made in under- 
standing cellular pathobiology as it relates to ARDS. 
However, the exact mechanisms of acute alveolar injury 
are unknown. Tissue injury may be related to the produc- 
tion of endogenously released products from macrophages 
and neutrophils.-- -' The initial inciting events causing the 
release of these products are diverse, but the responses are 
similar. l-'or examjilc. in sepsis, endotoxins activate mac- 

rophages that release cytokines, such as interleukin 1 and 
tumor necrosis factor.--* Once elaborated, tumor necrosis 
factor preferentially binds to organs, such as the kidney, 
liver, and lung, where local macrophages are activated and 
release more bioactive compounds.-'^ Through the release 
of oxygen radicals, proteolytic enzymes, and products of 
arachidonic acid metabolism (leukotrienes and thrombox- 
anes), activated neutrophils may initiate or amplify injury. 
These bioactive compounds, acting singly or jointly, can 
cause direct vascular injury and induce adherence and ac- 
tivation of neutrophils, coagulation proteins, and com- 
plement by vascular endothelial cells. These neutrophils 
migrate to the lung, where they attach to the endothe- 
lium and open tight junctions, resulting in leakage of 
fluid and protein initially into the interstitial space and 
subsequently into the alveoli. 

Many of these reactions cause further release of bioac- 
tive compounds and tissue injury. Tissue injury can be due 
to the leakage of proteinaceous material containing fibrin, 
resulting in the inhibition of surfactant activity and the 
formation of hyaline membranes around the alveolar lin- 
ing. Also, epithelial injury can result in damage to surfac- 
tant-producing Type 2 cells. The leakage of fluids into the 
interstitial space along with the loss of surfactant causes 
the lung to some of its elasticity. The earliest symp- 
tom of the loss of elasticity is tachypnea as functional 
residual capacity (FRC) falls and the lung becomes stiffer. 
In addition, there is frequently plugging of pulmonary ini- 
crocirculation with platelet thrombi, and this, together with 
the of thromboxane, produces a rise in pulmonary 
vascular resistance and the development of pulmonary hy- 

If ARDS progresses, then a third phase develops. This 
phase is characterized by ARE. radiographic findings of 
diffuse alveolar infl Urates, air bronchograms. and decreased 
lung volume requiring increasing mechanical ventilatory 
support and F|q . It is during this phase that the continued 
release of bioactive substances from the pulmonary mac- 
rophages may be due to the exposure of the lungs to in- 
jurious effects of mechanical ventilation and elevated lev- 
els of inspired oxygen. If resolution does not occur, a 
fourth phase develops, which is characterized by progres- 
sive respiratory failure, pulmonary fibrosis, and recurrent 

Evolution of Positive Pressure Ventilation 

Since the early days of mechanical ventilation, it has 
been recognized that positive pressure respiration does not 
mimic normal breathing. If it did, patients with normal 
lungs could be ventilated on an F,o, of 0.21 at the same Vy 
and respiratory rates seen in spontaneous breathing. In 
196.^ Bendixen et al-'' showed that durini: ueneral anes- 


Ri;,si'iRAT()in' Carh • Novi:mbf.r "98 Vol 4."^ No 1 

Lung-Protective Strategy in Pediatric Patients with ARDS 

thesia. mechanical ventilation in patients with normal lungs 
was associated with a fall in P^q, and a rise in partial 
pressure of carbon dioxide in arterial blood (PacoJ- He 
ascribed this change to the development of atelectasis due 
to loss of the normal intermittent 'sighing' present in the 
unanesthetized, spontaneously breathing human. He pro- 
posed the use of an intermittent large Vj breath or 'sigh' 
to overcome this problem, which then became a design 
feature of ventilators of that period. It was not until a 
decade later that Froese and Bryan-'' showed that major 
atelectasis with the induction of anesthesia and muscle 
relaxation was due to a loss of lung volume from a ceph- 
alad movement of the diaphragm. To compensate for this 
physiologic aberration, we have resorted to increasing in- 
spired oxygen concentration and delivered Vj well in ex- 
cess of those used in spontaneous respiration. 

However, in diseased lungs, what seemed like a medical 
imperative (to normalize blood gases in patients with dif- 
fusely atelectatic, low compliant lung disease by using 
ever larger V-p) rarely resulted in survival. It was not until 
the 1970s that it was shown that oxygenation could be 
improved by maintaining a positive expiratory pressure. 
Ashbaugh et al-** showed that PEEP was effective in ven- 
tilated adult patients with ARDS, and Gregory et al-" went 
on to show that a similar strategy, continuous positive 
airway pressure, could be used successfully in spontane- 
ously breathing newborn infants with infant RDS (IRDS). 
During the succeeding 20 years, the use of positive pres- 
sure mechanical ventilators with PEEP has proved suc- 
cessful in improving oxygenation in both ARDS and IRDS. 

Ventilator-Induced Lung Injury 

While pulmonary overinflation is a potential source of 
iatrogenesis in the intensive-care unit, maintenance of an 
appropriate lung volume is equally important in the appli- 
cation of mechanical ventilatory support in ARDS. Indeed, 
Dreyfuss and Saumon""* characterized this challenge with 
the analogy of the Homeric voyage between Scylla (the 
rock on the Italian side of the Strait of Messina) and Charyb- 
dis (a whirlpool in the strait), or, in other words, being 
between a rock and a hard place. Suter et al" found that 
static compliance is suboptimal if PEEP is set either too 
low or too high. 

In pediatric patients, the selection of optimal PEEP is 
problematic. Sivan et al-^- -'-'' observed in pediatric patients 
with ARDS that the level of clinician-determined PEEP 
failed to normalize FRC in most patients. PEEP levels that 
did normalize FRC were up to 2009^ higher than those 
clinically chosen. 

The evidence for PEEP as a protective tool is ample. 
Webb and Tierney''-* found that pulmonary edema result- 
ing from ventilation with a PIP of 45 cm H2O could be 

mostly prevented with the addition of a PEEP of 10 cm 
HiO. PIP was held constant in this study, and therefore, 
the degree of cyclic inflation was reduced when PEEP was 
added. With end-inspiratory pressure and volume constant 
during a comparison of mechanical ventilation strategies 
in a canine acid-aspiration model, a large Vj-low PEEP 
approach resulted in significantly more pulmonary edema 
than did a low Vj-high PEEP strategy. The pattern of 
lung injury seen in the 2 groups was distinctly different. 
Edema was primarily located in the dependent regions of 
the lung in the low Vj-high PEEP group, whereas a more 
uniform edema was present in the large V-^-low PEEP 
group. Although a similar type of lung injury was ob- 
served in rats ventilated with high volumes and PEEP, the 
degree of pulmonary insult was markedly decreased com- 
pared with that in rats ventilated with high volumes with- 
out PEEP.'"^ 

Applying the proper amount of PEEP is essential to 
ensure protection. In a study by Muscedere et al,^* iso- 
lated, nonperfused lungs excised immediately after surfac- 
tant washout were either ventilated at (1) zero PEEP 
(ZEEP), (2) with 4 cm H.O PEEP (below the inflection 
point of the inflation pressure-volume curve), (3) at a PEEP 
above the inflection point on the inflation limb of the 
pressure-volume curve, or (4) not ventilated, with a set 
PEEP of 4 cm HiO. Their work demonstrated that the 
level of PEEP could influence both the degree and site of 
lung injury. Lung injury scores were significantly worse 
with a PEEP set below the inflection point on the inflation 
limb of the pressure-volume curve, with the worst lung 
injury score occurring at ZEEP. The location of injury 
with the ZEEP group was significantly higher in the re- 
spiratory bronchioles, while the percentage of alveolar ducts 
with hyaline membranes was significantly higher in the 
group ventilated with a set PEEP of 4 cm H2O. The lung- 
injury score for the group ventilated with PEEP set above 
the inflection point of the inflation limb of the pressure- 
volume curve was not significantly different from the score 
for the group that was not ventilated. The author specu- 
lated that it was the opening and closing of small airways 
that caused shear stress and lung injury during mechanical 
ventilation. PEEP may act to splint the airways, thus re- 
ducing shear stress. 

The protective function of PEEP may be related to re- 
duction in shear stress, ^"^ recruitment of FRC," mainte- 
nance of surfactant function,'" -"' and a hemodynamic ef- 
fect.-" In an effort to determine the effect of cardiac output. 
Dreyfuss and Saumon-*' demonstrated that increased pul- 
monary edema suppressed by PEEP returned when an in- 
fusion of an inotropic agent, dopamine, was started. 

In the 197Gs, pathologists frequently referred to the con- 
stellation of findings associated with ventilator-induced 
lung injury as 'respirator lung." Clinicians argued that the 
ventilator allowed time for the full expression of the un- 

Respiratory Care • November '98 Vol 43 No 1 1 


Lung-Protective Strategy in Pediatric Patients with ARDS 

deriving disease and that these lesions had nothing to do 
with the ventilator. The only damage that was considered 
unequivocally due to the ventilator was the group of air- 
leak syndromes known collectively as barotrauma. Any- 
thing else was attributed to oxygen toxicity. 

It is important to recognize that barotrauma is a poor 
measure of lung injury since it represents the end stage 
rather than the beginning of lung injury. The first clear 
study of this problem was done by Webb and Tiemey. ''■* 
Rats with normal lungs were mechanically ventilated with 
room air for 1 hour. Those ventilated at pressures of 45 cm 
H2O developed severe hypoxemia and decreased compli- 
ance and died with postmortem evidence of extensive al- 
veolar and perivascular edema. Those ventilated at 30 cm 
H2O had a reasonable gas exchange, no change in com- 
pliance, and all survived. Thus, a dose response was be- 
ginning to emerge for the induction of lung injury. Drey- 
fuss et aH- added a time dimension: In normal animals 
after 5 min of PPV at 45 cm H2O. there was perivascular 
edema with no visible epithelial lesions; after 20 min at the 
same pressure, there was widespread alveolar flooding with 
swelling and disruption of the epithelium. The applicabil- 
ity of these studies has been questioned because they were 
done in rodents with highly compliant chest walls or in 
open-chest animals. However, this may more accurately 
reflect neonatal and pediatric patients, who generally have 
higher chest wall compliance. 

The increase in protein permeability of the pulmonary 
vasculature resulting from high PIP or lung volume ap- 
pears to be a threshold phenomenon-''' that is reversible 
when periods of high-volume ventilation are short. ■*■* Du- 
ration of exposure is an important consideration. In a rep- 
lication of a lung-injury model established by Kolobow et 
aH'' and Borelli et al,-"' normal adult sheep were ventilated 
with a PIP of 50 cm H^O. resulting in initial V^ of 50-70 
mL/kg. Following 18 hours of this type of ventilation. 2 
groups of subjects were randomized to conventional ven- 
tilation (with Vj of 10-15 mL/kg) or to extracorporeal 
CO2 removal. Three of 1 1 survived in the conventional 
group, while 9 of 1 1 in the extracorporeal CO2 removal 
group survived. Subsequently, after 27 hours of mechan- 
ical ventilation with a PIP of 50 cm HjO, 2 additional 
groups were randomized to either conventional ventilation 
or extracorporeal CO2 removal: None of the animals 

The important variable is not airway pressure but 
transpulmonary pressure (the difference in pressure be- 
tween the alveolus and the pleural space and resultant 
overdistention). Increasing evidence deinonstrates that ex- 
cessive volume results in overdistention and is implicated 
in iatrogenic lung injury. An increase in pulmonary vas- 
cular permeability has been observed in 2 studies of spon- 
taneously breathing humans with increased lung vol- 
umes. ■'^■"' Dreyfuss et af^ compared the development of 

lung pathology in normal rats ventilated with a high V^ 
(40 mL/kg) and low PIP (negative pressure via an iron 
lung) strategy and that of rats ventilated with high PIP (45 
cm HiO) and low V-p (achieved by thoracoabdominal strap- 
ping) with controls ventilated with a Vj of about 13 mL/kg 
and a PIP of 13 cm H2O. Subjects in the high PIP-low V^- 
group had lungs that were normal and comparable to those 
of controls at necropsy, The lungs of the high Vj-low PIP 
group exhibited marked protein permeability and micro- 
vascular structural abnormalities. 

These findings were supported by subsequent studies. 
Hernandez et al'' ventilated young rabbits with full-body 
casts placed around the chest and abdomen, and they ven- 
tilated isolated excised lungs in young rabbits. The capil- 
lary filtration coefficient, a reflection of microvascular per- 
meability, increased by 850% after ventilating the isolated 
excised lungs with a PIP of just 15 cm H2O. In the closed- 
chest group, ventilation with a PIP of 45 cm H2O resulted 
in an increase of 4309J- in the capillary filtration coeffi- 
cient. No change in the capillary filtration coefficient oc- 
curred at any PIP used during the study in subjects with 
body casts applied to limit inflation volume of the lungs. 

Deleterious effects of volutrauma are greater if pre-ex- 
isting pulmonary disease is present. ^'^ Hernandez et al^ 
studied isolated, excised lungs of young rabbits, compar- 
ing the effects of mechanical ventilation alone (PIP of 25 
cm H2O) with the effects of both mechanical ventilation 
and oleic acid injury. The lungs that received mechanical 
ventilation and those that received oleic acid were not 
significantly different from each other. However, the lungs 
exposed to mechanical ventilation and oleic acid injury 
had a significantly greater increase in the wet-to-dry-lung- 
weight ratio than the other 2 groups. 

Conventional Mechanical Ventilation 

Following is an outline of a strategy for conventional 
mechanical ventilatory support for pediatric patients with 
ARDS. The strategy is based on the preclinical and clinical 
data presented previously and the premise of protecting 
the lung from overdistention with supraphysiologic Vj 
and distending pressures while still maintaining FRC. Thus, 
the objectives are to prevent lung overdistention by the use 
of PEEP and low Vy and to reduce the F^, to the lowest 
level compatible with adequate oxygenation. A balance 
has to be struck between what would be desirable in all 
situations (low PIP, low Vj and low F,,,,) and what would 
be tolerable in situations of severe lung disease in order 
not to aggravate any lung injury. This approach clearly 
.separates ventilation (CO; elitnination) — dictated by PIP. 
Vy, and ventilator rate — from oxygenation, which is de- 
termined by PEEP and F|o,. This strategy is our recom- 
mendation and has yet to be evaluated in large pediatric 
clinical trials. We have limited our discussion to ventilator 


Respiratory Care • November '98 Vol 43 No 1 1 

Lung-Protective Strategy in Pediatric Patients with ARDS 

Table 2. Basis of Protocol for Conventional Mechanical Ventilatory 
Support for Pediatric Patients with Acute Respiratory 
Distress Syndrome 

Desirable Objective 


Ventilation PIP* < 30 cm H,0. normal 

pH or compensated 
respiratory acidosis (pH 
> 7.20) 

Oxygenation F,,,, < 0.5, S,,o, 90% 

PIP < 35 cm H,0. 

pH 7.10 

•PIP = peak iiispir 

modes in which we have experience with pediatric pa- 
tients. Thus pressure-control ventilation (PCV) and pres- 
sure-regulated volume control (PRVC) are the only modes 
discussed. We recognize that there are other modes capa- 
ble of offering a decelerating flow pattern with pressure or 
volume guarantee, such as volume-assured pressure sup- 
port ventilation, but to our knowledge their use in pediatric 
patients is limited. The basis for this protocol is shown in 
Table 2. 

The strategy to achieve the above parameters would be 
to use pressure-limited (utilizing PCV) or volume-limited 
(utilizing PRVC) modes to a maximum PIP (plateau) of 35 
cm HiO and Vj of 10 mL/kg; to ignore hypercarbia and 
target the pH rather than the P.^co,- w'th the objective of a 
compensated respiratory acidosis (pH >7.20) but a toler- 
ance for a pH down to 7.10; and to increase the PEEP to 
a level that enables reduction of the F|o, to £ 0.5, which 
is compatible with a saturation of 90%. 

The above strategy can be implemented by utilizing a 
pressure-limited strategy with PCV or a volume-limited 
strategy utilizing PRVC. Both modes have decelerating 
flow patterns, but one is pressure limited (PCV) and the 
other volume limited (PRVC). The goals are the same: to 
open the lung with adequate FRC and to limit overdisten- 
tion with high PIP and V-j-. Once the lung is open with 
adequate FRC, ventilation usually will improve. 

It should be noted that limiting PIP might not address 
the very important issue of transpulmonary pressure. As 
discussed earlier, excessive transpulmonary pressure may 
lead to overdistention of the lung units and lung damage. 
It should also be noted that inadequate transpulmonary 
pressure could be seen in patients with increased pleural 
pressure (Pes)- and it could cause lung collapse. Ideally, 
performing pressure-volume curves could eliminate the 
above problem, but these may be difficult to obtain in 
pediatric patients. 

In those situations when despite the strategies described 
above, the goal is not met, then alternative strategies can 
be applied. 

Alternative Conventional Mechanical 
Ventilation Strategies 

Increased Inspiratory Time (T,) Ventilation 

Mechanical ventilation that attempts to follow physio- 
logic principles demands that T, be considerably shorter 
than expiratory time (T,.), usually in a ratio of inspiration- 
to-expiration (I-E) 1:2 or 1:3. An alternative method of 
improving oxygenation in hypoxic pulmonary failure has 
been prolongation of inspiration to the extent of reversal of 
the I-E (inverse ratio ventilation, IRV) in an attempt to 
overcome the regional inhomogeneity of differing lung 
units. Utilizing computerized tomography, Gattinoni et al'" 
studied ARDS patients in whom > 50% of the lung was 
either poorly aerated or nonaerated. This study provides 
evidence that the lungs in ARDS are inhomogeneous. 

The first mechanical ventilators that were introduced 
into clinical medicine were pressure limited and time cy- 
cled. With the development of volume ventilators, they 
were largely replaced, except in neonates and infants, in 
whom mechanical ventilation is still managed using the 
pressure-control mode. The two types of ventilation differ 
very significantly in terms of the pattern of gas flow into 
the lungs, the change in lung volumes, and the pressure 
waveform generated within the airway. In volume-control 
ventilation, with the opening of the inspiratory valve, gas 
flow into the lung rises rapidly to its peak, maintains a 
plateau during inspiration, and then falls abruptly to zero 
with the opening of the expiratory valve. Airway pressure 
shows a small immediate rise due to resistance of the 
endotracheal tube and rises ramp-like as the resistive forces 
in airways are overcome. During the expiratory phase, gas 
flows out of the lung in a decaying exponential curve. In 
PCV and PRVC (Servo Ventilator 300, Siemens Medical 
Systems Inc, Danvers, Massachusetts), ventilation gas flow 
into the lung increases quickly with the opening of the 
inspiratory valve as airway pressure rapidly rises to its 
preset value. During the remainder of the inspiratory cy- 
cle, gas flow declines exponentially in order to maintain 
airway pressure at its present level (decelerating gas flow). 
Airway pressure is maintained at a plateau level for the 
duration of the inspiratory cycle before rapidly falling to 
the end-expiratory levels as the inspiratory valve closes. In 
the conventional approach in both modes, expiration is 
typically longer than inspiration (ratio of 1:2 or 1:3). 

Airway pressures used to inflate the lung will be differ- 
ent when 2 different modes of ventilation are compared in 
the same model of lung disease. With PCV. the peak air- 
way pressure is set by the operator, and the V-p delivered 
will depend on the compliance and resistive characteristics 
of the patient's lung. The opposite is true in PRVC. In 
volume control ventilation, the V-,. delivered by the ventilator 

Respiratory Care • November '98 Vol 43 No 1 1 


Lung-Protective Strategy in Pediatric Patients with ARDS 

is fixed, and the airway pressure generated is dependent on 
those same compliance and resistive properties. 

During the inspiratory phase of mechanical ventilation, 
positive pressure is used to overcome resistance in the 
endotracheal tube and airways. This inspiratory phase also 
inflates the terminal lung units and maintains them in the 
open position during this phase of the respiratory cycle to 
allow for diffusion of oxygen. In the setting of ARF. high 
airway pressure and alveolar pressures are required to ex- 
pand the alveoli and maintain inflation during inspiration. 
In addition, to prevent lung collapse with the onset of 
expiration, airway pressure is prevented from declining to 
zero by the application of PEEP. Therefore, positive pres- 
sure within the lung is governed by a combination of PIP, 
PEEP. T| and T^. and gas flow rate. This can be expressed 
as the mean airway pressure (MAP) and represents the 
pressure measured at the airway averaged over time. 

There is obviously a direct relationship between MAP 
and mean alveolar pressure, but the relationship between 
airway pressure and lung volume is not a straight line due 
to the hysteresis properties of the lung. With the conven- 
tional settings of volume-control PPV, we most frequently 
alter MAP by changing PIP or by increasing PEEP. An 
alternative approach is to increase MAP by using the third 
variable in the formula, T,. MAP is increased by prolong- 
ing T| so that the conventional I:E is increased from 1 :2 to 
1:1 or actually reversed to 2:1 or longer. The physiologic 
consequences of this approach are that the alveoli are held 
open longer during the respiratory cycle. Keeping the al- 
veoli open longer in the setting of lung edema and atelec- 
tasis will directly influence oxygenation. However, longer 
T|S may also have serious side effects when injudiciously 
applied: The high MAP and short Tp: may trap gas in the 
terminal lung units, with alveolar pressure remaining pos- 
itive at end expiration. This phenomenon, known as auto- 
PEEP, can lead to pulmonary barotrauma and lung rup- 
ture. Increases in MAP will also result in increased 
intrathoracic pressure, which can be transmitted to vascu- 
lar structures and reduce cardiac output. In reality, lung 
volumes rather than MAP should be measured, consider- 
ing that lung volumes more accurately determine the bal- 
ance between the best oxygenation and the least overdis- 

Inverse-ratio ventilation (IRV) can be delivered in ei- 
ther the pressure-control (or PRVC) or volume-control 
mode. In ventilators with the PCV/PRVC option, switch- 
ing to this mode produces a square wave pressure profile, 
the length of which can be extended so that Tp is reduced. 
MAP will rise directly proportional to the duration of in- 
spiration. The expectation is that this sustained increase in 
MAP may recruit collapsed lung units more effectively 
than transient increases associated with conventional set- 
tings. Sustained alveolar inflation also appears to decrease 
dead space and therefore to improve the cITiciency of al- 

veolar ventilation, allowing for lower Vj settings. Expe- 
rience with this mode of ventilation suggests that recruit- 
ment of lung volume is time dependent and most likely to 
occur in the early exudative phase of ALL The inherent 
hazard of this technique, particularly in the pressure-con- 
trol mode, is that inadvertent auto-PEEP may not be rec- 

When the 2 options of pressure- or volume-control IRV 
are compared, the former has the theoretical advantage in 
that the decelerating gas flow pattern allows for better 
mixing, and the sustained square wave is more likely to 
recruit collapsed alveoli. On the other hand, others would 
argue that the high initial gas flow at the beginning of 
inspiration might result in greater shear stress damage to 
already damaged lung tissue. 

Most experience with IRV in the setting of ALl has 
been limited to pressure-control mode with IRV. Published 
series are generally short-term studies (< 1 hour) or an- 
ecdotal reports that compare oxygenation and ventilator 
settings when switched from volume- to pressure-control 
IRV in patients with ALI.^'-'^- The majority showed that 
PIP can be reduced without a reduction or even with an 
improvement in alveolar ventilation and that there were 
(mostly) modest increases in P.,o, related to the increase 
MAP when the level of extrinsic PEEP was reduced. It is 
debatable whether raising MAP by applying square wave 
pressure with prolonged inspiration and significant amounts 
of intrinsic PEEP is less damaging to an injured lung than 
raising the level of extrinsic PEEP. Certainly, none of 
these studies showed any change in mortality with the 
switch to pressure-control IRV. It should be emphasized 
again that in these studies, ventilation protocol was pres- 
sure controlled and not pressure limited: in other words, 
the accepted convention was a Vj of 10-15 mL/kg with 
the target of a normal P^co,- 

In conclusion, considering the potential complications 
associated with IRV, its use should be limited to those 
times when conventional mechanical ventilation fails to 
provide adequate oxygenation without potentially toxic lev- 
els of oxygen, high V^, or dangerously high peak airway 
or alveolar pressures. 

Prone-Position Ventilation 

It is now recognized that the standard supine position 
for the nursing of critically ill ARF patients may be less 
than ideal. Froese and Bryan-^ showed 20 years ago that 
during PPV. there was cephalad movement of the dorsal 
part of the diaphragm and loss of lung volume in people 
with normal lungs who were ventilated in the supine po- 
sition. With PPV in the supine position, there is preferen- 
tial perfusion of dependent lung regions. Computed to- 
mography images of patients with ARDS have shown that 
this is the most prominent area for hemoiihage and edema 


Re.spiratoky Care • November '98 Vol 43 No 1 1 

Lung-Protective Strategy in Pediatric Patients with ARDS 

formation. Several studies have described improvement in 
oxygenation and decrease in intrapulmonary shunt when 
hypoxic patients with ARF are turned to the prone posi- 
tion, although this finding is not universal. '^'"^■' This im- 
provement in oxygenation has also been demonstrated in 
neonatal patients with surfactant deficiency. '^■^^'^ 

The proposed mechanisms for this improvement are in- 
creased FRC. change in regional diaphragm motion, re- 
distribution of blood flow to less injured lung units, and 
improved secretion clearance. Studies of experimental lung 
injury have shown that preferential perfusion does not shift 
to the ventral part of the lung, and edema is more uni- 
formly distributed along the gravitational axis, when pa- 
tients are turned to the prone position.'^'' There was also no 
change in FRC or regional diaphragm movement. The 
explanation for decreased shunting seen with the prone 
position seems to be that the gravitational distribution of 
Pgs is much more uniform in the prone position. In the 
supine position, gravitational forces result in P^.^ becoming 
positive in the dependent lung regions, and dorsal lung 
units are below closing volume. This finding suggests that 
transpulmonary pressure may not exceed airway pressure 
in this region, resulting in lung collapse. Gravitational P^,^ 
differences in the thorax are much less in the prone posi- 
tion, resulting in less of the lung below closing volume and 
decreased shunt. 

Clinical and physiologic studies seem to suggest that 
there may be a benefit from changing patients from the 
supine to the prone position when ventilating them with 
hypoxemia due to ARDS.'^'^ ''' Whether this will benefit all 
patients has yet to be demonstrated, and there are certain 
caveats to this technique. Ventilating patients in the prone 
position makes nursing and the observation of the patient 
more difficult. There is also the increased risk of neck 
injury when turning paralyzed patients. 


In the pediatric population with ARDS. survival appears 
to be improving. This improvement can be tied to the 
increased use of a protective lung strategy and high-fre- 
quency ventilation. Since both strategies utilize a low- 
volume and decreased pulmonary stretch approach, similar 
results are not surprising. Future recommendations in the 
care of pediatric patients with ARDS must include the use 
of a protective lung strategy. 


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Respiratory Care • November "98 Vol 4.^ No 1 

High-Frequency Ventilation in Pediatric ARDS 

John H Arnold MD 

Animal Data 
Clinical Data 

Use in Neonates 

Use in Older Children 

Use in Adults 

[Respir Care 1998;43(1 1):96 1-965] Key words: High-frequency ventilation, 
acute respiratoiy failure, neonates, pediatrics, animal studies, human studies 


Acute respiratory failure remains a major cause of mor- 
bidity and mortality in both pediatric and adult popula- 
tions. The reported annual incidence in the United States 
may be as high as 150.000 cases, with published mortality 
rates generally ranging between 507c and 70%.' Although 
there is some indication that there have been improve- 
ments in outcome,- the underlying pathophysiology re- 
sponsible for the clinical syndrome is not precisely tar- 
geted by continuing modifications of conventional therapy. 
Although progress has recently been made, particularly 
regarding the role of the cytokines and adhesion molecules 
as essential components of the inflammatory cascade in 
acute lung injury.-'' the use of nonconventional modes of 
supporting gas exchange is becoming increasingly popular 
in many centers.-* One of the most promising alternative 
modes, high-frequency ventilation (HFV), has been exam- 
ined in a number of animal models of lung injury and in 
several human populations. 


The effects of rapid ventilatory rates on gas exchange 
were first described in 1915 by Henderson and Chilling- 

Dr John H Arnold. MullidiscipHnary Intensive Care Unil. Children's 
Hospital. Boston. Massachusetts, and Harvard Medical School, Boston. 

Correspondence & Reprints: John H Arnold MD. Multidisciplinary In- 
tensive Care Unil. Farley 5. Children's Hospital. 300 Longwood Avenue. 
Boston MA 021 \5. 

worth, and in 1952 Jack Emerson was the first to patent a 
high-frequency device for clinical use.' The theoretical 
advantages of HFV include a smaller phasic volume and 
pressure change, gas exchange at significantly lower air- 
way pressures, and less depression of endogenous surfac- 
tant production. The mechanisms of gas exchange involved 
during HFV have been reviewed in detail elsewhere.'^ In 
summary, the mechanisms of gas exchange that are most 
important during HFV are bulk axial flow, interregional 
gas mixing, and molecular diffusion. Previous work on an 
animal model convincingly showed that the phenornenon 
of interregional gas mixing (Pendelluft) is greatly enhanced, 
especially during high-frequency oscillatory ventilation 

Animal Data 

There is emerging recognition that mechanical ventila- 
tion-induced lung injury is related to cyclic volume change. 
In a classic study, Webb and Tierney^ showed that venti- 
lating normal rats with peak inspiratory pressures of 45 cm 
HiO produced significant perivascular edema and an in- 
crease in lung weight. In addition, these investigators 
showed that an end-expiratory pressure of 10 cm H^O was 
protective, suggesting that the absolute level of inspiratory 
pressure is not as important as the volume change expe- 
rienced by the lung during the duty cycle. It has also been 
shown in normal animals that binding of the chest and 
abdomen, with restriction of chest wall movement, pre- 
vented lung injury during ventilation with peak inspiratory 
pressures of 45 crn HiO.** This study provided important 
evidence that microvascular permeability is related not to 

Respiratory Care • November 

Vol 43 No 1 1 


High-Frequency Ventilation in Pediatric ARDS 

pressure but lo volume change. Dreyfuss et aP provided 
similar data from experiments in rats, demonstrating that 
volume change is a much more significant contributor to 
lung injury than is absolute pressure level and that positive 
end-expiratory pressure (PEEP) may well be protective in 
an animal model of mechanical ventilator-induced lung 

Mathieu-Costello and West'" have shown that large cy- 
clic volume changes during conventional ventilation are 
associated with a significant increase in the disruption of 
the alveolar capillary, and they have elegantly documented 
breaks in the capillary endothelium that are produced by 
large tidal volumes. Their research convincingly demon- 
strates that pulmonary edema is an important component 
of mechanical ventilator-induced lung injury. Fluid and 
protein in the alveolar space are well-known inhibitors of 
surfactant function and thereby act synergistically to de- 
crease lung compliance and further aggravate the cycle of 
repetitive cyclic overdistention and further lung injury. 

A series of experiments in a saline-lavaged rabbit model 
demonstrated that lung volume maintenance with minimi- 
zation of alveolar pressure and volume change using a 
piston oscillator device is associated with the least degree 
of mechanical ventilator-induced lung injury."''' McCul- 
loch et aP- demonstrated in animal studies that HFOV 
using an optimal lung volume strategy designed to reverse 
atelectasis resulted in significant improvements in oxygen- 
ation and minimized histopathologic evidence of lung in- 
jury when compared with results in a conventional venti- 
lation treatment with HFOV and a low lung volume strategy. 
More recently. Sugiura et aF'^showed in the saline-lavaged 
rabbit that HFOV results in significantly less activation of 
pulmonary neutrophils than conventional ventilation, as 
evidenced by both chemiluminescence and chemotaxis. 
These findings have been confirmed by a separate group 
of investigators using luminol-dependent chemilumines- 
cence."' Furthermore, it has also been convincingly dem- 
onstrated that HFOV prevents the release of thromboxane 
B2 and platelet-activating factor, which are important chem- 
ical mediators of inflammatory lung injury.'^ 

There is compelling animal evidence that HFOV may 
be most effective when used early in the course of respi- 
ratory failure in both premature baboons"^'"' and adult 
surfactant-depleted rabbits.'- Furthermore, despite the con- 
ceptual appeal of providing gas exchange at reduced air- 
way pressures, there is abundant evidence that an optimal 
lung volume during HFOV is best achieved utilizing an 
aggressive volume recruitment strategy using relatively 
high mean airway pressures."-" It should also be noted 
that despite the use of high proximal airway pressures 
there is an important difference between measurements 
made at the proximal airway, the trachea, and the alveolus. 
There is a clinically important gradient in both peak and 
mean airway pressures from ventilator to alveolus'' that 

results in limited volume change in the alveolus, which 
may well be the most important variable in producing 
mechanical ventilator-induced lung injury. -- 

Clinical Data 

Use in Neonates 

The initial clinical experience with HFOV in premature 
infants with hyaline membrane disease raised significant 
concerns about adverse effects on cerebral hemodynamics 
and the ductus arteriosus as well as for an increased inci- 
dence of air leak.-' However, a well-conducted meta-anal- 
ysis of nine studies comparing high-frequency ventilation 
and conventional ventilation failed to demonstrate a sig- 
nificant increase in the incidence of intraventricular hem- 
orrhage.-^ Furthermore, the methods used in the HIFI 
study,-' have been criticized.-'^ and the conclusions reached 
by this multicenter collaborative effort regarding the util- 
ity of HFOV in this population should be viewed with 
some skepticism. 

Clark et al,-^ in a single-center study using a uniform 
ventilator strategy, demonstrated that premature infants 
treated with HFOV have a significantly reduced incidence 
of chronic lung disease (CLD). A recent study in prema- 
ture infants with severe hyaline membrane disease has 
shown a significant improvement in oxygenation and a 
reduced incidence of air leak syndromes in the infants 
managed with HFOV.-^ In a large, multicenter, prospec- 
tive examination of early intervention with HFOV using a 
lung recruitment strategy following surfactant administra- 
tion, Gerstmann et al-*^ demonstrated improved short- and 
long-term outcomes and a significant reduction in total 
hospital costs attributable to early institution of HFOV. Of 
interest, a large, multicenter, randomized study of high- 
frequency jet ventilation (HFJV) in preterm infants showed 
the best pulmonary and neurologic outcomes in the HFJV 
patients managed with an optimal rather than a low lung 
volume approach.-'^ 

These data suggest that for preterm infants, the volume 
recruitment approach is beneficial independent of the high- 
frequency device utilized. In most neonatal centers, cur- 
rent ventilatory options include some form of HFV and a 
recognition that aggressive volume recruitment using either 
incremental increases in mean airway pressure or intermit- 
tent sustained inflation maneuvers is essential to success. 

Use in Older Children 

There is limited published information available regard- 
ing the use of HFOV in pediatric patients. We previously 
described our rescue experience in a small group of pedi- 
atric patients with weights ranging from 3 to 42 kg.'" We 
utili/ed an aggressive approach to rapidly attain and main- 


Ri;spiRAroRY Care • November "98 Vol 43 No 1 1 

High-Frequency Ventilation in Pediatric ARDS 

tain optimal lung volume. This typically requires an in- 
crease of mean airway pressure of 5-8 cm H^O when 
converting from conventional ventilation to HFOV. Of 
interest, despite significant increases in mean airway pres- 
sure, hemodynamic coinpromise, as indicated by decreased 
cardiac index or oxygen delivery, does not appear to be an 
important problem when using this 'ideal lung volume' 
strategy. We recently completed a prospective, multicenter. 
randomized clinical study comparing HFOV and conven- 
tional mechanical ventilation in pediatric patients with ei- 
ther diffuse alveolar disease or air leak syndrome.-^' The 
data from the study demonstrate that HFOV offers rapid 
and sustained improvements in oxygenation without ad- 
verse effects on ventilation. 

The increase in mean airway pressure utilized during 
use of HFOV does not result in an increase in the inci- 
dence of barotrauma, and the oxygenation index declines 
significantly during the first 72 hours of HFOV. Despite 
the use of higher mean airway pressures, the optimal lung 
volume strategy used in this study was associated with a 
lower incidence of barotrauma, as indicated by the require- 
ment for supplemental oxygen at 30 days and by improved 
outcome compared with the outcome with conventional 
mechanical ventilation. When ventilator subgroups were 
compared, those patients who were managed with HFOV 
had outcomes ranked only significantly better than those 
for patients who were managed with conventional venti- 
lation, and the patients who crossed over from conven- 
tional ventilation to HFV had outcomes that were ranked 
significantly better than those for patients who crossed 
over from HFV to conventional ventilation. 

Given the success of high-frequency oscillation in im- 
proving outcome, time-sensitive predictors of survival in 
patients managed with high-frequency oscillation would 
be quite helpful in developing a stepped ventilatory ap- 
proach to the patient with acute lung injury. Specifically, 
are there precise predictors of HFOV-failure that would 
identify the population of patients who may benefit from 
alternative modes of respiratory support, such as extracor- 
poreal membrane oxygenation^- or liquid ventilation?'-'' In 
our prospective, randomized clinical trial," the oxygen- 
ation index in survivors was significantly lower then that 
in nonsurvivors during the first 72 hours of therapy; fur- 
thermore, there was a significant association between time 
and a decreasing oxygenation index in survivors and be- 
tween time and a rising oxygenation index in nonsurvi- 
vors. An oxygenation index of > 42 at 24 hours predicted 
mortality with an odds ratio of 20.8, a .sensitivity of 62%, 
and a specificity of 937f. There is also evidence that early 
institution of HFOV in the pediatric population is associ- 
ated with a lower incidence of barotrauma in the patients 
who survive. In our prospective, randomized study, pa- 
tients who were treated with HFOV within 72 hours of 
intubation had a significantly lower incidence of CLD; 

specifically, the odds ratio for CLD in survivors was 25.2 
in patients who received > 72 hours of conventional ven- 
tilation prior to institution of HFOV. 

Use in Adults 

The adult experience with high-frequency techniques is 
difficult to interpret. The only prospective, randomized 
study thus far published examined the use of a HFJV in 
309 adults with respiratory failure. '■* This study included 
both immunocoinpetent and immunocompromised patients 
and did not have a standardized severity of illness measure 
for inclusion into the study. The patients managed with 
HFJV achieved similar oxygenation and ventilation at lower 
airway pressures. However, duration of intensive care unit 
stay and mortality were not significantly different between 
the two groups and the authors concluded that HFJV was 
equivalent, but not superior to, conventional volume-cy- 
cled ventilation. A subsequent, uncontrolled report of HFJV 
at higher frequencies showed improved gas exchange at 
lower airway pressures following initiation of HFV. -'^ How- 
ever, effects on outcome cannot be evaluated in the ab- 
sence of concurrent controls, and the authors also reported 
a 15% incidence of mucus dessication, raising significant 
concerns about the adequacy of humidification in the de- 
vice studied. A recent, uncontrolled study of HFOV in 17 
adults with severe acute respiratory distress syndrome 
(ARDS) (mean arterial oxygen tension/fraction of inspired 
oxygen [Pao,V[F|oJ ratio at entry 66 mm Hg) showed a 
significant increase in Pao/Fio, ratio over the first 48 hours 
after initiation of HFOV.""^ The nonsurvivors in this cohort 
were treated with conventional ventilation for a longer 
period and had a higher pre-HFOV oxygenation index 
than the survivors. Several centers are currently collabo- 
rating in a prospective, randomized study of HFOV versus 
conventional mechanical ventilation in adults with ARDS. 


In summary, recognition that lung injury (and lung me- 
chanical properties) in patients with ARDS is inhomoge- 
neously distributed and that repetitive cyclic overdisten- 
tion of the compliant (predominantly nondependent) areas 
of lung produces lung injury can lead to significant im- 
provements in supportive care in this patient population. 
To make sense of the complex interactions between repet- 
itive cyclic stretch of the acutely injured lung, transpul- 
monary pressure amplitude, and the tremendous shear 
stresses generated during alveolar re-expansion, it is useful 
to keep in mind 3 important variables: the relationship 
between end-expiratory pressure and the critical opening 
pressure of lung units (the so-called 'lower inflection 
point"); the magnitude of cyclic stretch forces applied dur- 
ing tidal conventional ventilation; and the relationship be- 

Respiratory Care • November '98 Vol 43 No 11 


High-Frequency Ventilation in Pediatric ARDS 

tween end-inspiratory lung volume and the upper "deflec- 
tion point" of the pressure-volume curve. 

Recently, a prospecti\e randomized study of adults with 
ARDS demonstrated that minimizing cyclic parenchymal 
stretch with titration of PEEP according to the lower in- 
flection point produces better oxygenation, lung compli- 
ance, and a higher weaning rate." These investigators have 
also recently demonstrated that this approach produces 
significant improvements in survival. ^'^ 

In practical terms, in most settings it will be simpler to 
avoid the lower and upper inflection points and to mini- 
mize cyclic stretch injury by using HFV. Our data suggest 
that early institution of HFOV in pediatric patients with 
acute lung injury is associated with a lower incidence of 
subsequent CLD. Furthermore, ranked outcomes analysis 
of these data demonstrates improved outcomes in patients 
who are managed with HFOV either primarily or follow- 
ing a failure of conventional mechanical ventilation. The 
ideal ventilatory approach in patients with hypoxemic re- 
spiratory failure may be early institution of an "open-lung" 
strategy using high-frequency oscillation with rapid iden- 
tification of patients who are not likely to survive in order 
to allow institution of other modes of gas exchange prior 
to the onset of irreversible lung injury. 


1 . Bernard GR, Artiga.s A, Brigham KL. Carlet J. Falke K. Hud.son L. 
et al. The American-European Con.sensus Conference on ARDS. 
Definitions, mechanisms, relevant outcomes, and clinical trial coor- 
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2. Milberg JA. Davis DR. Steinberg KP, Hudson LD. Improved sur- 
vival of patients with acute respiratory distress syndrome (ARDS): 
1983-199.\ JAMA 199.');273(4):.'?06-309. 

3. Stricter RM. Kunkel SL. Acute lung injury: the role of cytokines in 
the elicitation of neutrophils (review). J Investig Med 1994:42(4): 
640-65 1 . 

4. Ring JC, Slidham GL. Novel therapies for acute respiratory failure 
(review). Pediatr Clin North Am 1994;4I(6):1325-1363. 

.5. Wetzel RC. Gioia PR. High frequency ventilation (review). Pediatr 
Clin North Am 1987:34(1 ):15-38. 

6. Lchr JL, Butler JP, Westerman PA, Zatz SL, Drazcn JM. Photo- 
graphic measurement of pleural surface motion during lung oscilla- 
tion. J AppI Physiol 1985;.')9(2):623-633. 

7. Webb HH, Tierney DP. Experimental pulmonary edema due to in- 
termittent positive pressure ventilation with high inflation pressures: 
protection by positive end-expiratory pressure. Am Rev Respir Dis 
1974:1 1 0(5):.').'i6-565. 

8. Hernandez LA. Peevy KJ. Moise AA, Parker JC. Chest wall restric- 
tion limits high airway pressure-induced lung injury in young rab- 
bits. J Appl Physiol 1989:66(.'i):2364-2368. 

9. Dreyfuss D. Solcr P, Basset G. Saumon G. High inllation pressure 
pulmonary edema: respective effects of high airway pressure, high 
tidal volume, and positive end-expiratory pressure. Ain Rev Respir 
Dis 1988;I37(5):1 159-1 164. 

10. Mathicu-Costello OA, West JB. Are pulmonary capillaries suscep- 
tible to mechanical stress? (review) Chest 1994:105(3 Suppl):102S- 

Hamilton PP. Onayemi A, Smyth JA, Gillan JE, Cutz E, Proese AB, 
Bryan AC. Comparison of conventional and high-frequency venti- 
lation: oxygenation and lung pathology. J Appl Physiol 1983:55(1 Pi 

McCuUoch PR. Forkert PG. Proese AB. Lung volume maintenance 
prevents lung injury during high frequency oscillatory ventilation in 
surfactant-deficient rabbits. Am Rev Respir Dis 1 988: 1 37(5): 1 185- 

Byford LJ, Finkler JH, Proese AB. Lung volume recruitment during 
high-frequency oscillation in atelectasis-prone rabbits. J Appl Physiol 

Bond DM. Proese AB. Volume recruitment maneuvers are less del- 
eterious than persistent low lung volumes in the atelectasis-prone 
rabbit lung during high-frequency oscillation. Crit Care Med 1993; 

Sugiura M. McCuIloch PR, Wren S, Dawson RH, Proese AB. Ven- 
tilator pattern influences neutrophil influx and activation in atelec- 
tasis-prone rabbit lung. J Appl Physiol 1994;77(3):1355-1365. 
Matsuoka T. Kawano T. Miyasaka K. Role of high-frequency ven- 
tilation in surfactant-depleted lung injury as measured by granulo- 
cytes. J Appl Physiol 1994:76(2):539-544. 

Imai Y. Kawano T. Miyasaka K. Takata M, Imai T, Okuyama K. 
Inflammatory chemical mediators during conventional ventilation 
and during high frequency oscillatory ventilation. Am J Respir Crit 
Care Med 1994:150(6 Pt 11:1550-1554. 

deLemos RA. Coalson JJ. Meredith KS. Gerstmann DR. Null DM Jr. 
A comparison of ventilation strategies for the use of high-frequency 
oscillatory ventilation in the treatment of hyaline membrane 
Acta Anaesthesiol Scand Suppl 1989:90:102-107. 
Meredith KS, deLemos RA, Coalson JJ, King RJ, Gerstmann DR. 
Kumar R. et al. Role of lung injury in the pathogenesis of hyaline 
membrane disease in premature baboons. J Appl Physiol 1989:66(5): 

Froese AB. Role of lung volume in lung injury: HPO in the atelec- 
tasis-prone lung (review). Acta Anaesthesiol Scand Suppl 1989;90: 

Gerstmann DR. Pouke JM. Winter DC, Taylor AP. deLemos RA. 
Proximal, tracheal, and alveolar pressures during high-frequency os- 
cillatory ventilation in a normal rabbit model. Pediatr Res 1990: 

Sykes MK. Does mechanical ventilation damage the lung? (review) 
Acta Anaesthesiol Scand Suppl 1991:95:35-38. 
The HIFI Study Group. High-frequency oscillatory ventilation com- 
pared with conventional mechanical ventilation in the treatment of 
respiratory failure in preterm infants. N Engl J Med 1989:320(2): 

Clark RH. Dykes PD, Bachman TE, Ashurst JT. Intraventricular 
hemorrhage and high-frequency ventilation: a meta-analysis of pro- 
spective clinical trials. Pediatrics 1996:98(6 Pt 1): 1058-1061. 
Bryan AC. Proese AB. Reflections on the HIFI trial. Pediatrics 1991; 

Clark RH, Gerstmann DR, Null DM. Jr, deLemos RA. Prospective 
randomized comparison of high-frequency oscillatory and conven- 
tional ventilation in respiratory distress syndrome. Pediatrics 1992; 

HiPO Study Group. Randomized study of high-frequency oscillatory 
ventilation in infants with sex ere respiratory distress syndrome. J Pe- 
diatr 1993;122(4):6()9-619. 

Gerstmann DR, Minton SD. Stoddard RA, Meredith KS, Monaco F, 
Bertrand JM, et al. The Provo multicenter earl> high-frequency oscil- 
latory ventilation trial: improved pulmonary and clinical outcome in 
respiratory distress syndrome. Pediatrics 1996:98(6 Pt 1 ):1044-I057. 
Keszler M, Modanlou HD. Brudno DS. Clark PI, Cohen RS, Ryan 
RM. et al. Multicenter controlled clinical trial of high-frequency jet 


Respiratory Care • November '98 Vol 43 No 1 1 

High-Frequency Ventilation in Pediatric ARDS 

ventilation in preterm infants with uncomplicated respiratory distress 
syndrome. Pediatrics 1997:100(4):593-599. 

Arnold JH. Truog RD, Thompson JE, Fackler JC. High-frequency 
oscillatory ventilation in pediatric respiratory failure. Crit Care Med 

Arnold JH, Hanson JH, Toro-Figuero LO, Gutierrez J, Berens RJ, 
Anglin DC. Prospective, randomized comparison of high-frequency 
oscillatory ventilation and conventional mechanical ventilation in 
pediatric respiratory failure. Crit Care Med I994;22(I0):1530-1539. 
Moler FW, Palmisano J, Custer JR. Extracorporeal life support for 
pediatric respiratory failure: predictors of survival from 220 patients. 
Crit Care Med 1993;2I(I0):I60-I-16I I. 

33. Fuhrman BP. Pertluorocarbon liquids and respiratory support (edi- 
torial). Crit Care Med I993;21{7):95l. 

34. Carlon GC, Rowland WS. Ray C, Miodownik S, Griffin JP. Groeger 
JS. High-frequency jet ventilation: a prospective randomized evalu- 
ation. Chest 1983;84(5):55l-559. 




35. Gluck E. Heard S, Patel C. Mohr J, Calkins J. Fink MP. Landou L. 
Use of ultrahigh frequency ventilation in patients with ARDS: a 
preliminary report. Chest 1993;103(5):14I3-1420. 

36. Fort P, Farmer C, Westerman J, Johannigman J. Beninati W, 
Dolan S, Derdak S. High-frequency oscillatory ventilation for 
adult respiratory distress syndrome: a pilot study. Crit Care Med 

37. Amato MBP, Barbas CSV, Medeiros DM. Schettino G de P. 
Lorenzi-Filho G. Kairalla RA, et al. Beneficial effects of the 
"open lung approach" with low distending pressures in acute 
respiratory distress syndrome: a prospective randomized study on 
mechanical ventilation. Am J Respir Crit Care Med 1995:152(6 Pt 

38. Amato MBP, Barbas CSV, Medeiros DM, Magaldi RB, Schettino 
GP, Lorenzi-Filho G, et al. Effect of a protective-ventilator strategy 
on mortality in the acute respiratory distress syndrome. N Engl 
J Med l998;338(6):347-354. 



MARCH 1999 

Respiratory Care • November '98 Vol 43 No 1 1 


Extracorporeal Life Support in Pediatric Respiratory Failure: 
Past, Present, and Future 

Heidi J Dalton MD and Mark J Heulitt MD 


Patient Population 

Basic Principle 

Selection Criteria for Extracorporeal Life Support Patients 

Types of Extracorporeal Membrane Oxygenation 



Alternative Techniques 
Management of Pediatric Patients on Extracorporeal Support 

Anticoagulation and Bleeding 

Pulmonary Therapy 



Complications with Extracorporeal Membrane Oxygenation 



Mechanical Complications 
Neurologic Outcomes Following Extracorporeal Membrane Oxygenation 
Changes in Support of Respiratory Failure Patients 

Permissive Hypercapnia 

Prone Positioning 

High-Frequency Ventilation 

Inhaled Nitric Oxide 

[Respir Care 1998:43(1 1):966-977] Key words: Extracorporeal membrane ox- 
ygenation, extracorporeal life support, pediatric acute respiratoiy distress syn- 
drome, outcomes, mechanical ventilation, supportive therapy, complications. 

Introduction ferred to as extracorporeal membrane oxygenation 

(ECMO), this technique has supported > 13.000 neonates 

Extracorporeal life support (ECLS) is a modified form with severe respiratory failure over the last 10 years, with 

of cardiopulmonary bypass, which provides support for an overall survival of > 809^.--* Because of the success of 

both the heart and lung function of the patient.' Also re- ECMO in neonates, other patient populations have 

Heidi J Dallon MD, Director, Pediatric and Adult ECLS. Deparlniem of 

Pediatric Critical Care Medicine, Georgetown University Medical Cen- Correspondence & Reprints: Heidi J Dalton MD. Associate Professor, 

ter, Washington, DC, and Mark J Heulitt MD, Associate Director of Pediatrics, Director, Pediatric and Adult ECLS, Pediatric Critical 

Respiratory Care Services, Arkansas Children's Hospital, and Depart- Care Medicine, Suite 5414 CCC Building. Georgetown University 

ment ol' Pediatrics, Division of Critical Care Medicine, University of Medical Center, .1800 Reservoir Road, Washington. DC 20007. 

Arkansas for Medical Sciences, Little Rock, Arkansas. 

966 Respiratory Care • November '98 Vol 43 No 11 

ECMO IN Pediatric ARDS 

Extracorporeal Lite Support hy Patient Group 
and Diagnosis 

Table 2. Pediatric Extracorporeal Lite Support for 
Respiratory Failure 








Air leak syndrome 


Cardiac surgery 





Bacterial pneumonia 

Viral pneumonia 



Other respiratory diagnoses 

Pre- or post-transplant 

Mitral valve replacement 

Other cardiac diagnoses 
























CDH - congenilal diaphragmatic hernia. MAS = meconium aspiration syndrome. PPHN = 
persistent pulmonary hypertension, RDS = respiratory distress syndrome. ARDS - acute 
respiratory distress syndrome, (From Reference 4. with permission.) 

been supported with ECLS (Table 1).^-" This report will 
focus on the use of ECMO in pediatric patients with re- 
spiratory failure. General principles of ECMO, patient se- 
lection criteria, access techniques, major complications, 
and outcomes of pediatric ECMO will all be discussed. In 
addition, the role of new techniques for supporting patients 
with respiratory failure and the impact that these proce- 
dures have had on pediatric ECMO will be presented. 

Patient Population 

The increase in application of ECMO to pediatric 
patients outside the neonatal period began in 1990. To 
date, > 1,500 children have received ECMO for res- 
piratory failure, with an overall survival of 53%. Under- 
lying diagnoses prior to ECMO include viral and 
bacterial pneumonia, aspiration, acute respiratory distress 
syndrome (ARDS), and a variety of other conditions, such 
as rare infections, sickle cell chest syndrome, and asthma 
(Table 2).-* 

Bacterial pneumonia 
Viral pneumonia 
Pulmonary hemorrhage 

Pneumocystis cariiiii piicumoiii 

No. of Patients 

% Survival 

















. with pel 

Basic Principle 

ECMO replaces the need for two basic cardiopulmonary 
functions. It provides carbon dioxide (COj) removal and 
oxygenation of venous blood, thereby supplanting the need 
for active lung function. It also allows drainage of venous 
blood from the right heart and the return of oxygenated 
blood into the arterial circulation at high pressure, which 
allows bypass of the native cardiac circulation. 

Selection Criteria for Extracorporeal 
Life Support Patients 

It is difficult to determine which patients are failing less 
invasive therapies and have reversible injury that may im- 
prove with lung rest provided by ECMO. Various mortal- 
ity prediction criteria have been put forth as indicators of 
when ECMO rescue is best applied. However, many of 
these criteria are derived from historic data for respiratory 
failure patients at single institutions or extrapolated from 
neonatal respiratory failure data.'--'** Attempts to provide 
universally accepted objective criteria for the institution of 
ECMO have proved difficult. The 'criterion for placement 
on ECMO support' is one of the items recorded in the 
registry of the Extracorporeal Life Support Organization 
(ELSO), which maintains an international database of 
ECMO patients.-* 

The predominant criterion listed for placing a pediatric 
patient on ECMO remains 'failure to respond." This se- 
lection criterion may be interpreted as the clinician deter- 
mining that cunent support was insufficient to provide 
adequate oxygenation or ventilation and that death was 
imminent without ECMO rescue. Over 50% of pediatric 
ECMO patients reported to the ELSO registry have "fail- 
ure to respond' as the major criterion for initiation of 

The alveolar-to-arterial oxygen tension difference 
(Pt.A-aio,) has proved useful in the neonatal population but 

Respiratory Care • November "98 Vol 43 No 1 1 


ECMO IN Pediatric ARDS 

less accurate in pedialric patients.'''-" The P,A-;i)0, ^^ '-"'i'" 
ciliated as follows: 

F|(, (barometric pressure — t7)-P.,(-.Q -P.,q , 

where F,o, is the fraction of inspired oxygen, P^.co, '^ the 
arterial carbon dioxide tension, and P,^,^ is the arterial 
oxygen tension. 

In neonates a P|a-.i)0, of > 610 mm Hg for 8 hours or 
> 605 mm Hg for 4 hours at a peak inspiratory pressure 
(PIP) of > 38 cm H.O has a predicted mortality of > 80%. 
In a single-center study, researchers found that a P,a-u)0, 
of > 450 mm Hg for 16 hours in 32 pediatric patients 
predicted death with 86% sensitivity and 100% specifici- 
ty.-"-' Factors that may alter the significance of the Pi^. 
a)0, as a selection criterion for ECMO include the fact that 
it incorporates no other measure of mechanical support 
other than F|q^. In addition. P|A-a)o, can be altered by 
manipulation of Paco, levels. The P,A-a)o, has been re- 
ported in < 1% of pediatric patients in the ELSO registry 
as the primary criterion for initiation of ECMO.^ 

The oxygenation index (01) has also proved useful in 
pediatric patients. The 01 is calculated as follows: 

01 = mean airway pressure x F|o, x lOO/P^io,. 

In retrospective studies of infants with respiratory fail- 
ure, an OI > 40 cm H^O/mm Hg corresponded to a 90% 
mortality rate, and an 01 between 25-40 cm H^O/mm Hg 
rellected a mortality risk of > 50%.-- An OI of 40 cm 
HnO/mm Hg or continued OIs in the 25-40 cm HiO/mm 
Hg range, rising over time, are often used as ECMO se- 
lection criteria. 

Although reports of the OI in pediatric patients are few. 
those that include the 01 as a severity of illness score 
reflect that an OI > 40 cm H-,0/mm Hg is often found in 
patients who expire or who are placed on ECMO rescue. 
In a single center study. Timmons et al-' found 91% mor- 
tality in patients with an OI > 55 cm H^O/mm Hg. In a 
later multi-center study of > 300 pediatric respiratory fail- 
ure patients from 42 centers. Timmons and associates--* 
found that an 01 > 29 cm H20/mm Hg had a positive 
predictive value of death of 71%-94%. In a subgroup 
analysis of these same patients, an OI > 25 cm HoO/mm 
Hg (when coupled with the Pediatric Risk of Mortality 
.score) was also highly correlated with death. -■^-'' In an 
analysis of 28 pediatric patients placed on ECMO for re- 
spiratory failure, Morton et al-^ noted that the n)ean OI 
was 45 cm H^O/mm Hg. 

Difficulties with use of the 01 for ECMO selection cri- 
teria have included the fact that many centers do not rou- 
tinely measure or report mean airway pressure (a ivc|uired 

factor for calculation of the score). There is also some 
concern that since mean airway pressure in high-frequency 
ventilation (HFV) is often higher than that used with con- 
ventional mechanical ventilation, this may elevate the 01 
but not accurately predict the risk of death. Sarnaik et al-** 
noted, however, that the combination of an initial OI of > 
20 cm HoO/mm Hg and a failure to decrease the OI by > 
20% within 6 hours of initiation of HFV predicted death 
with 88% sensitivity and 837f specificity. 

Thus, the 01 remains a useful score for assessing the 
severity of respiratory failure and the overall risk of mor- 
tality. The ELSO registry lists 01 as a primary indication 
for ECMO in only 1 % of pediatric patients, however. Other 
criteria for initiation of ECMO listed in the ELSO registry 
include barotrauma (1%), acute deterioration (1%), car- 
diac arrest (< 0.05%), transpulmonary shunt > 30% (< 
0.05%). and others (1%). 

Exclusion criteria for ECMO include major bleeding 
(since heparinization is required), immunosuppression, 
known neurologic damage, irreversible underlying di.sease, 
and mechanical ventilation for > 7- 1 days prior to ECMO. 
Patients with prior mechanical ventilation for > 7-10 days 
have significantly poorer survival with ECMO rescue than 
do patients in whom ECMO is applied earlier in the course 
of mechanical ventilation.-*-'" These data suggest that, past 
a point in time, the relative lung rest provided by ECMO 
is insufficient to halt the ongoing respiratory pathology 
that leads to death and that recovery is not possible. Un- 
fortunately, no exact means exist to determine which pa- 
tients will recover or identify those that are certain to 
expire. The above guidelines reflect past experience and 
current recommendations. Further data collection and anal- 
ysis may help develop treatment algorithms for institution 
of therapies such as ECMO and lead to more specific 
predictors of death. 

Types of Extracorporeal Membrane Oxygenation 

1. Venoarterial 

Venoarterial (VA) ECMO (Fig. 1 ) gives support to lung 
and heart function, serving as the predominant form of 
ECMO support. In pediatric patients, > 65% have re- 
ceived VA ECMO. Venoarterial EMCO has been described 
in detail." In brief, cannulas are placed to drain venous 
blood from the right atrium (usually via the internal jug- 
ular to superior vena cava/right atrial junction or femoral 
vein to right atrium). This venous blood then goes to a 
pump (usually a roller-head device), which advances the 
blood to the membrane oxygenator. 

As blood passes through the oxygenator, oxygen is added 
and CO, is removed.'-" The oxygenated blood is then 
rewarmed to body temperature and returned to the arterial 
circulation. Aileiial reliuii is tliiecteil into llie arch of the 


Ri si'ikAtoKV Cari- • N()vi:mhi:r "98 Voi. 4.3 No 1 1 

ECMO IN Pediatric ARDS 


Fig. 1. Modified venoarterial extracorporeal membrane oxygen- 
ation (ECMO) circuit with femoral access. Note venous drainage 
from inferior vena cava (IVC)-right atrium junction and arterial re- 
turn into iliac artery via femoral artery. Cannulas may also be placed 
via one side of body unless severe venous stasis or impaired distal 
perfusion occurs. Distal cannulation of the femoral artery is some- 
times needed to maintain blood flow to the leg beyond the cannula 
insertion site. For increased carbon dioxide removal, 2 oxygen- 
ators may be used in parallel to increase surface area. 

aorta via cannulation of tiie right carotid or femoral artery. 
With more blood being drained into the ECMO circuit, 
less will flow through the damaged native heart/lung cir- 
culation. By increasing ECMO flow, more oxygenated 
blood will be returned to the patient's arterial circulation. 
Limiting the amount of blood flow through the native 
pulmonary circuit will diminish arterial oxygen desatura- 
tion from intrapulmonary shunting of blood through dis- 
eased lungs. This will decrease the amount of ventilator 
support required to maintain gas exchange. Ventilator set- 
tings and concentrations of inspired oxygen can be mini- 
mized to avoid ongoing barotrauma/volutrauma and oxy- 
gen toxicity as the damaged lung attempts to heal itself. 
The amount of venous blood available for bypass to the 
ECMO circuit is dependent on the patient's venous pres- 
sure and the length and location of the venous drainage 
cannula. The caliber of both the cannula and the venous 
drainage tubing used in the ECMO circuit also vary the 
amount of blood available. Although a large cannula placed 
into the right atrium may be sufficient to bypass almost all 
of the venous blood returning to the right heart, ECMO is 
not usually performed in a 'complete' fashion, whereby 
the heart is bypassed totally. Coronary artery perfusion is 

primarily dependent on left ventricular ejection, not flow 
returning from the ECMO circuit, and this is one reason 
why some venous blood is allowed to proceed through the 
normal heart/lung circulatory pattern. There is also evi- 
dence that complete ECMO may result in damage to the 
pulmonary circulation by severe alkalinization of the lung 
parenchyma or ischemia of pulmonary capillary beds."""* 

For these reasons. ECMO is usually performed in a 
partial manner. In this type of ECMO. venous drainage is 
limited to only enough to provide adequate oxygenation 
and perfusion to the patient, allowing some blood flow to 
go through the native heart/lung circuit. About 60%- 80% 
of the cardiac output is required usually to maintain oxy- 
genation and hemodynamics. As the lungs heal and native 
gas exchange becomes more efficient, the need for ECMO 
support decreases. When the patient can provide adequate 
oxygenation, ventilation, and perfusion to meet systemic 
needs at reduced ventilator settings and minimal ECMO 
flow. ECMO is discontinued. One of the major disadvan- 
tages of VA ECMO is that the artery frequently requires 
ligation following ECMO because of damage from pro- 
longed cannulation. Other complications include air. clots, 
and debris returning from the ECMO circuit and emboli- 
zed into the arterial circulation, possibly resulting in ce- 
rebral emboli if the carotid artery is used for arterial ac- 
cess.''-'' -^•'^ The long-term effects of increased risk of stroke 
from ligation or repair of carotid vessels cannulated during 
ECMO will not be known for many years. Some centers 
repair arterial vessels during decannulation with reported 
good results and continued patency on follow-up exami- 
nations. '''"■" 

2. Venovenous 

Venovenous (VV) ECMO (Fig. 2) allows supplementa- 
tion of pulmonary gas exchange but relies on adequate 
function of the heart to supply perfusion to the body."*- "" 
Venovenous ECMO has been used as the primary route of 
ECMO support in —20% of pediatric respiratory failure 

In this type of ECMO support, the venous blood is 
drained from the right atrium or inferior vena cava. It is 
then sent to the ECMO circuit and membrane oxygenator, 
where it undergoes removal of CO^ and addition of oxy- 
gen just as in VA ECMO. The saturated blood is then 
rewarmed and returned to the patient's venous circulation. 
About 50% of the cardiac output usually can be obtained 
for processing to the oxygenator, since some of the oxy- 
genated blood is recirculated back into the ECMO circuit 
before it goes out to the systemic circulation. This recir- 
culation effect can be limited (but not eliminated) by care- 
ful placement of the venous cannulas. The cannulas should 
be placed so that they are not so close together that the 
drainage cannula withdraws a larae amount of the relurn- 

Respiratory Care • November 

Vol 43 No 1 1 


ECMO IN Pediatric ARDS 

Fig. 2. Venovenous extracorporeal membrance oxygenation 
(ECMO) circuit. Note venous drainage from superior vena cava 
(SVC)-right atrium junction and return Into the inferior vena cava 
(IVC) via femoral vein. For Increased carbon dioxide removal, 2 
oxygenators may be used in parallel to Increase surface area. 

ing oxygenated blood before it reaches the systemic cir- 
culation. Cannulas for drainage are placed either in the 
internal jugular vein to the right atrium or the inferior vena 
cava. Oxygenated blood returning to the patient is directed 
into either the inferior vena cava or the right atrium. In- 
fusion of oxygenated blood directly into the right atrium 
has the advantage of avoiding most recirculation problems 
but has the disadvantage of then requiring the drainage 
cannula to the placed in another site (the inferior vena 
cava). Venous drainage from the vena cava is limited com- 
pared with that of the right atrium, so that the amount of 
cardiac output that can be sent to the ECMO circuit is 

The membrane oxygenator is extremely efficient at re- 
moval of CO, even at low ECMO flows; in fact, gas 
exchange via the lungs for this puipose is not required. 
Since the proportion of cardiac output that is drained into 
the ECMO circuit with VV cannulation is less, the arterial 
saturation in VV ECMO is less than that with VA EMCO. 
To maintain adequate oxygen delivery, some oxygen up- 
take via the lungs must be maintained. This usually re- 
quires that higher levels of inspired oxygen be maintained 
through the ventilator than in VA ECMO. Positive end- 
expiratory pressure (PEEP) is also used to retain lung ex- 
pansion and optimize oxygenation. 

In most patients, arterial saturations of > 80^-85% are 
adequate to maintain tissue needs and are easily obtainable 
with VV ECMO. Patients who develop cardiac dysfunc- 
tion or who do no! receive enough systemic oxygen de- 

livery with VV ECMO may require conversion to VA 
ECMO for more support. About 30% of patients cannu- 
lated for VV ECMO have been converted to VA support. 
The advantage of VV support is that it limits the risk of 
embolization to the central nervous system of air. clots, or 
debris returning from the ECMO circuit (since these em- 
boli will presumably he trapped in the pulmonary circu- 
lation). Venovenous support also avoids potential damage 
or ligation of the carotid or femoral artery. There is also a 
possibility that the highly saturated venous blood reaching 
the pulmonary artery will lower pulmonary arterial pressures 
and improve healing in the pulmonary circuit. 

Alternative Techniques 

A double-lumen single cannula exists for use in VV 
ECMO; however, it is available in only a 14-Fr size (Bio- 
medicus Inc. Eden Prairie MN). and its use is limited to 
patients weighing < 10 kg."*-*^"^ A larger European double- 
lumen catheter, available in 16-20 Fr (Jostra Corporation. 
Hirrlingen. Germany) may be obtainable in the United 
States in the near future. The advantages of such a cannula 
are that only one surgical site is required for placement of 
the catheter and cannulation time may be reduced. 

Experience with percutaneous access and placement of 
ECMO cannulas has increased over the last few years. -'^ 
This technique may shorten cannulation time and may 
prevent some of the bleeding complications that can ac- 
company surgical placement of ECMO cannulas through 
an open cutdown. For larger pediatric and adult patients, 
percutaneous insertion kits are available in sizes from I .^-2 1 
Fr (Biomedicus Inc.). 

An alternative cannulation technique has been used suc- 
cessfully at Georgetown University Medical Center in 
larger patients. This technique combines venous access, 
usually from the femoral vein to the right atrium, with 
arterial return into the low descending aorta via the fem- 
oral artery. In this mode, oxygenated blood is returned into 
the lower body arterial circulation. It then must go through 
the native heart/lung circuit prior to distribution to the 
upper body and head. Since the arterial return mixes with 
native venous blood, saturation is decreased by the amount 
of intrapulmonary shunt. Upper body arterial saturations 
are similar to those obtained with VV ECMO. The arterial 
saturation is best monitored on the ear. nose, or upper 
extremity to ensure that adet|uate cerebral oxygenation 

This technique avoids the risk ol' cerebral emboli trom 
traditional VA ECMO and reduces recirculation problems 
noted in VV ECMO. When this technique was used in 4 
adult and larger pediatric patients in the author's institu- 
tion, arterial saturations in the head were 8()%-8.S%, and 
ailec|uate oxygen delivery was obtained. In 2 additional 
patients, sepsis occurred iluring ECMO am! necessitated 


Ri:si'iRAr()k'i' Cari: • NoviiNUii-R "98 Vol 4.'^ No 1 1 

ECMO IN Pediatric ARDS 

conversion to traditional VA ECMO. An additional arte- 
rial cannula was placed in the carotid artery, or the low- 
lying femoral artery cannula was replaced with a longer 
catheter that reached the arch of the aorta. 

Management of Pediatric Patients on 
Extracorporeal Support 

While more specific patient management discussions 
can be found in a variety of reviews, the basic premise of 
ECMO is to limit iatrogenic damage from mechanical ven- 
tilation. Another primary objective is to avoid complica- 
tions that could require early separation from the ECMO 
circuit before adequate lung healing has occurred. ■*'■*" 

Anticoagulation and Bleeding 

Heparinization is required to prevent clotting of the 
ECMO circuit. Most centers use the activated clotting time 
(ACT) to guide the rate of continuous heparin infusion.^'' 
Normal ACTs are 90-1 10 s. Levels of ACT between ISO- 
ZOO s are commonly maintained during pediatric ECMO. 
In larger patients in whom ECMO flow is greater or in 
patients in whom bleeding develops, the ACT can be de- 
creased to 160-180 s. If bleeding continues, heparin can 
be discontinued for short periods (we have done this for > 
12 h in a large patient) with careful monitoring of the 
ECMO circuit to identify clotting.^" To limit the risk of 
bleeding, the platelet count is maintained at > 100,000/ 
mL. Fibrinogen levels should also be monitored, and fresh 
frozen plasma or cryoprecipitate should be administered if 
levels are low. The ability to measure and replace anti- 
thrombin III has also been helpful in limiting bleeding 
complications. Continued bleeding may require surgical 
exploration, which can be accomplished, even during he- 
parinization, with careful hemostasis. 

Pulmonary Therapy 

Ventilator pressures are reduced once the patient is suc- 
cessfully placed on the ECMO circuit and adequate oxy- 
genation and ventilation are being supplied through by- 
pass. Peak inspiratory pressures are lowered to < 30-35 
cm HiO (or less), inspiratory rates are maintained between 
6-10 breaths/min, and inspired oxygen concentrations are 
weaned to < 50% as long as adequate oxygen delivery via 
the ECMO circuit is maintained. Positive end-expiratory 
pressures are maintained at levels between 6-15 cm H^O 
to prevent complete atelectasis of the lung.-'^' Since pedi- 
atric patients often have severe parenchymal disease, com- 
pliance is poor. If lung collapse occurs, reinflation of lung 
tissue can prove difficult. Further, lung collapse makes 
pulmonary toilet difficult, and atelectatic areas may be- 
come breeding grounds for infection and abscesses. Nor- 

mally, the improvement in lung expansion and compliance 
that herald recovery of the lung can be assessed simply by 
the clearing of the chest radiograph over time.'*- 

Some patients with severe barotrauma and air leak may 
require extreme limitation of inspiratory and expiratory 
pressures to seal bronchopulmonary fistulas. Continued air 
leak at low pressures may necessitate removal from the 
ventilator for 24-48 hours, by which time fistulas 
will have healed. "^^ Unlike the situation in neonates with 
this scenario, reinflation in older patients is more difficult, 
and mortality is higher. When conventional mechanical 
ventilation has proven ineffective in reinflation, we have 
used bronchoscopy to remove inspissated secretions. Sur- 
factant (to improve compliance) and HFV have also been 
used with results ranging from good to poor. 


Although many patients initially require intravenous 
(l.V.) hyperalimentation to maintain caloric intake, enteral 
feeding retains integrity of gut mucosa and may limit trans- 
location of enteric bacteria into the bloodstream.'^-' If tol- 
erated by the patient, enteral feeding can provide total 
nutrition, and even low levels of feeding supplemented 
with hyperalimentation may be beneficial to the gastroin- 
testinal tract. Previous concerns that l.V. lipid administra- 
tion may cause damage to the membrane oxygenator have 
proven unfounded, and lipids may be used as needed. We 
have noted that lipid infusion into the ECMO circuit has 
occasionally resulted in damage to infusion stopcocks, and 
we now give lipids directly to the patient if access is 
available. Adequate nutrition to augment healing is man- 
datory. Although the exact caloric requirement during 
ECMO is not known. 80-100 kcal/kg per day has been 
shown to provide positive nitrogen balance by day 3 of 
ECMO in one study.'^'^ 


Many patients are volume overloaded due to resuscita- 
tion efforts prior to ECMO.''^ In addition, the nonpulsatile 
flow from the ECMO circuit may alter renal blood flow, 
increasing renin, aldosterone, or antidiuretic hormone. 
Atrial natriretic hormone may also be elevated due to de- 
creased atrial filling pressures in VA ECMO. These fac- 
tors may encourage fluid retention and limit urine out- 
put.'^ Diuretics, infusion of low-dose dopamine (3-5 /xg/ 
kg/min), or hemofiltration can all be used to maintain 
adequate fluid balance. Continuous infusion of furosemide 
has proved useful in many of our patients. 


Although neuromuscular blockade is discontinued once 
the patient is on ECMO, most children will require seda- 

Respiratory Care • November '98 Vol 43 No 1 1 


ECMO IN Pediatric ARDS 

tion and analgesia. Tolerance to infused medications often 
develops over time, and the doses required to give ade- 
quate pain and anxiety relief may become large. A com- 
bination of a benzodiazepine and a narcotic is usually 
sufficient for most patients. 

Complications with Extracorporeal 
Membrane Oxygenation 


Since the patient supported with ECLS requires sys- 
temic heparinization to prevent clotting of the ECLS cir- 
cuit, bleeding is a potentially life-threatening complication 
of this therapy. According to the ELSO registry,'^ 27% of 
pediatric ECLS patients had surgical-site bleeding, 6% had 
significant gastrointestinal hemorrhage, and 5% had intra- 
cranial hemorrhage. Bleeding complications may be man- 
aged by reducing the heparin dosage and limiting eleva- 
tion in coagulation parameters, by replacement of platelets, 
fresh frozen plasma, and other blood products.'''*-'''' Sur- 
gical intervention to control bleeding is also used success- 
fully in patients on ECLS. It is rarely necessary to remove 
a patient from ECLS of excessive bleeding. Bleed- 
ing occurring late in the course of ECLS, particularly from 
thoracic or pulmonary sites, is often associated with on- 
going lung destruction and a poor outcome. 


Culture-proven infections have occurred in 20'%) of pe- 
diatric ECLS cases in the ELSO registry.* In a recent 
report of experience at Arkansas Children's Hospital, nos- 
ocomial infections were found in 23% of pediatric patients 
supported with ECLS. Patients in whom nosocomial in- 
fections developed were supported for longer periods than 
those without infection (mean, 230 vs 140 h: p < 0.01).''' 
Bloodborne infections occurred most often while patients 
were cannulated. Urinary tract and wound infections oc- 
curred more commonly after decannulation. Fungal organ- 
isms were isolated in 50% of nosocomial infections. Pa- 
tients with fungal infections had a higher infection-related 
mortality rate. The mechanism by which nosocomial in- 
fections develop during ECLS is not well elucidated. Im- 
mune dysfunction caused by lymphopenia, neutropenia, 
alterations in T cell populations, and activation of com- 
plement occurs in neonatal patients supported with 
HCLS. "-■''' These factors, along with the disruption of the 
barrier protection supplied by the skin, prolonged expo- 
sure to broad-spectrum antimicrobial agents, and difficulty 
in eradicating organisms from the ECLS circuit once in- 
fection occurs, place patients at risk for nosocomial infec- 

Mechanical Complications 

Mechanical complications of ECLS include cannula mal- 
position, clots in the circuit, tubing rupture, air in the 
circuit, pump malfunction, and heat exchange malfunc- 
tion. Since the duration of pediatric ECMO is frequently > 
1 week, failure of the membrane oxygenator is an expected 
event. The placement of tubing bridges or "diamonds' prior 
to and after the oxygenator in the circuit allows the oxy- 
genator to be replaced without removing the patient from 
ECMO support. 

Neurologic Outcomes Following Extracorporeal 
Membrane Oxygenation 

Long-term developmental outcomes for ECLS patients 
are only available for neonatal and pediatric patients with 
respiratory illness.''-"''^ In neonatal patients, severe devel- 
opmental delay is found in only 2%-8% of patients.'''' 
Significant developmental delay (defined as a score > 2 
standard deviations from the mean) was found in 5%-2l% 
of patients. Patients with congenital diaphragmatic hernia 
represent the group with the worst developmental out- 
comes. Similar to results noted in premature infants, an 
association exists between residual pulmonary damage in 
neonatal ECLS patients and risk of developmental delay. 
Whether this association represents pre-ECLS damage from 
barotrauma and hypoxia is not known. For pediatric pa- 
tients, developmental outcome is good following ECLS 
support. Of more than 35 pediatric patients with respira- 
tory failure supported with ECLS at Arkansas Children's 
Hospital, only 15% had significant developmental sequelae, 
as determined by comparison with their pre-ECLS assess- 
ment.'''' Georgetown University Medical Center has also 
noted good neurologic outcomes with pediatric patients, 
unless complications such as infarct or bleeding occur dur- 
ing ECLS. 

Experiences of 13 preschool-age pediatric patients from 
Georgetown University Medical Center, Oschner Clinic 
(Baton Rouge, LA), and Children's Hospital of Pittsburgh 
who received ECMO were reviewed. In this group, 30% 
demonstrated some abnormal neurologic development, al- 
though only 2 had severe morbidity."** For 13 school-age 
children, their parents reported that only 15% were per- 
forming below average in school. The depth and duration 
of hypoxia prior to ECMO may influence the obser\ed 
morbidity in children but to what extent is unknown since 
there are no randomized, controlled trials of ECMO versus 
conventional therapy in older children. 

Changes in Support of Respiratory Failure Patients 

Pediatric |ialicnts who receive ECMO have failed con- 
ventional mechanical ventilation and other less invasive 


RnspiRATORY Carf. • NovnMiu-R "98 Vol 43 No 1 1 

ECMO IN Pediatric ARDS 

alternative therapies. Up until the last few years, conven- 
tional mechanical ventilation was the only method of sup- 
porting patients with severe respiratory failure prior to 
ECMO. The toxic effects of high levels of inspired oxygen 
are well known, presumably with ongoing lung damage 
occurring at inspired oxygen concentrations > 60%. Re- 
.search and experience have also shown that use of PIP of 
> 35-40 cm H,0 and large tidal volume (Wj) (10-15 
mL/kg) contribute to ongoing barotrauma or volutrauma in 
the damaged lung. PIP and Vj at higher levels may impair 
recovery and induce further harm.'"'' ''- 

In a 1991 multicenter study of over 400 pediatric pa- 
tients with severe respiratory failure, Timmons et al-"* 
showed that mortality was 527f in pediatric patients who 
met entry criteria with an F|o, requirement of > 50% and 
a PEEP > 6 cm HiO for 12 hours. In a subgroup analysis 
of patients in the original dataset, those patients who re- 
ceived ECMO had significantly higher survival rates than 
those treated with conventional ventilation or HFV.-^ De- 
spite this finding, use of ECMO in pediatric patients is 
declining, while use of alternative therapies is increasing. 
Although there are few published reports outlining the 
impact of alternative therapies on mortality, preliminary 
data indicate that survival is increasing in pediatric pa- 
tients with severe respiratory failure. A brief review of 
alternative therapies is given below. 

Permissive Hypercapnia 

Recently, use of limited peak alveolar pressures (to < 
35-40 cm H.O) and smaller V^ (5-7 mL/kg) has been 
reported to limit iatrogenic lung damage induced by me- 
chanical ventilation in severe lung disease. Since ventila- 
tion is often impaired at lower pressures and V^ in dis- 
eased lungs. CO; tensions may Allowing CO; tensions 
to rise to a 60 mm Hg has been shown to improve sur- 
vival in some patients with high predicted mortality 
rates. ^■''■'■' This concept, known as permissive hypercapnia. 
has become a standard of care in severe lung injury in the 
last few years. This method of treatment assumes that 
adequate renal compensation will occur for the respiratory 
acidosis that accompanies elevated CO; levels. Most pa- 
tients will re-establish normal acid-base balance through 
renal retention of buffer within 24 hours of permissive 
hypercapnia. If acidosis is severe (pH < 7.20). I.V. buffer 
in the form of sodium bicarbonate or tris(hydroxymethyl) 
aminomethane can be administered. This technique is not 
advised for patients in whom elevated CO, tension or 
transient acidosis is likely to be harmful, as in patients 
with head injuries or cardiac dysrhythmia. 

Prone Positioning 

Another change in traditional management of severe 
respiratory failure patients is the use of prone positioning. 

This technique involves placing the patient prone rather 
than in the traditional supine position, and it has resulted 
in improvements in oxygenation and compliance. '"^■^'' This 
in turn may allow reduction of inspired oxygen concen- 
trations and ventilator settings. A recent study by Lamm et 
aF^ indicated that expansion of dorsal (back) lung tissue 
occurs during prone positioning. Expansion of dorsal lung 
tissue improves ventilation/perfusion matching, lowers in- 
trapulmonary shunt, and improves oxygenation. Care must 
be taken to avoid dislodgment of endotracheal tubes or 
other access catheters during turning. While pressure on 
fragile areas, such as the eyes, must be avoided, the tech- 
nique has been used successfully in patients ranging from 
premature neonates to large adults. Prone positioning is 
contraindicated in patients whose conditions would be ag- 
gravated by manipulation of the spine or any other move- 
ment (eg, as with head or spinal cord injury patients). 
While both permissive hypercapnia and prone positioning 
are advocated to lessen lung injury and improve oxygen- 
ation, there have been no randomized controlled trials com- 
paring survival among patients who were treated with ei- 
ther of these two techniques with survival among patients 
who were not treated with them. Nonetheless, the ability to 
lower peak airway pressures or oxygen concentrations may 
be of benefit. 

High-Frequency Ventilation 

Advances in technical support also allow alternatives to 
conventional mechanical ventilation for patients with se- 
vere respiratory failure. HFV has been shown to reduce the 
need for ECMO in neonatal populations. Experience with 
this technique has increased dramatically in pediatric pa- 
tients over the last few years. ^'^■''' In 1994. Arnold et aP" 
reported that HFV resulted in significantly improved out- 
comes and a lower need for oxygen at 30 days in a ran- 
domized, controlled trial of HFV versus conventional me- 
chanical ventilation in pediatric patients with severe lung 
injury. In 1996, Sarnaik et al-** analyzed 31 pediatric pa- 
tients with a Pao/Fio, ■''itio of < 150 mm Hg requiring a 
PEEP of > 8 cm H;6 or a P^co,) > 60 mm Hg with an 
arterial pH of < 7.25 who were failing conventional ven- 
tilation. Within 6 hours of HFV, survivors showed an im- 
provement of arterial pH. P.,o,. and P;,oyF|o. 'ind ^ de- 
crease in Paco, compared with nonsurvivors. As mentioned 
earlier, patients with an initial 01 of > 20 cm H^O/mm Hg 
and a decline of < 20% in the 01 by 6 hours of initiation 
of HFV had high mortality. 

Inhaled Nitric Oxide 

Inhaled nitric oxide (INO) has also improved oxygen- 
ation in selected patients with severe lung disease, and it 
has allowed reduction in inspired oxygen concentrations 

Respiratory Care • November 

Vol 43 No 1 1 


ECMO IN Pediatric ARDS 

and ventilator settings. Although the use of INO in neo- 
natal respiratory failure has clearly been associated with a 
decrease in the need for ECMO rescue, the benefit of INO 
in older pediatric patients is less striking.*"'*- These dif- 
ferences may reflect the fact that neonatal respiratory fail- 
ure often has a large component of pulmonary hyperten- 
sion contributing to hypoxia and that INO may reduce 
pulmonary hypertension, thus radically improving oxy- 
genation. In older patients, however, lung disease occurs 
from a variety of underlying etiologies, and greater paren- 
chymal injury exists than in the neonatal patient. Hypoxia 
is then due to inadequate alveolar gas exchange more than 
to pulmonary hypertension. 

Improved oxygenation by vasodilation of the pulmo- 
nary system obtained with INO is often not as dramatic as 
in the neonate. Abman et aP' noted that INO improved 
oxygenation, decreased mean pulmonary artery pressures, 
and decreased intrapulmonary shunt in 17 children with 
severe hypoxemia. Survival was 10% overall: Survival in 
patients with ARDS was 50% compared with 100% in 
patients with respiratory failure related to respiratory syn- 
cytial virus or influenza pneumonia. No patients received 
ECMO in this study. Goldman noted that the percent im- 
provement in 01 from baseline on exposure to INO for 60 
min was associated with survival.**'* Patients with an im- 
provement in 01 of < 15% on exposure to INO had 100% 
mortality (despite availability of ECMO), compared with 
61% mortality in patients with a > 30% decline in 01 with 
INO. At Georgetown University Medical Center, we also 
found that improved oxygenation and decline in 01 in 5 of 
10 ECMO candidates on exposure to INO was associated 
with 80% survival without need for ECMO rescue.'*'* In 5 
patients, who had no improvement in oxygenation to re- 
duce the 01 to < 40 cm H^O/mm Hg, mortality was 100%, 
even with ECMO rescue. Whether response to INO is a 
marker for reversible lung disease or an indicator of pre- 
dicted survival with techniques such as ECMO requires 
further study. 

While these techniques and devices may improve oxy- 
genation and allow reduction in ventilator settings, whether 
they have truly improved survival is still debatable. Stein- 
hart et al*** reported that in a recently completed random- 
ized trial of pediatric ECMO based on risk of death com- 
puted from a 1 99 1 data collection project in pediatric ARDS 
patients, use of ECMO was extremely limited (< 1%). 
Overall, survival without ECMO rescue was improved from 
57% in 1991 to 85% in 1997 in patients without contra- 
indications to ECMO. Patients were allowed to receive 
conventional mechanical ventilation. HFV, INO or other 
therapies prior to ECMO. Since the number of patients 
receiving other therapies was small, the impact of partic- 
ular treatments on mortality could not be statistically 
proven. In a recently analyzed group of 42 pediatric pa- 
tients from 4 pediatric intensive care luiits in the Mid- 

Atlantic region, overall survival in patients without con- 
traindications to ECMO was 85% versus 55% in patients 
with exclusion criteria."'' 

Development and implementation of a national interac- 
tive database via the Internet is underway and may help 
determine if a particular therapy (eg, HFV, INO) is asso- 
ciated with improvement in survival. It may also provide 
nationwide trends in treatment and survival in pediatric 
respiratory failure. From these data, algorithms for care to 
optimize outcome can be developed. 


Use of ECLS for pediatric patients with respiratory fail- 
ure has shown a slight decline in the last year or so, falling 
from 200 cases reported in 1993 to 175 in I996.'*'***« The 
number of pediatric patients treated with ECLS in any one 
center has always been smaller than that of neonatal pa- 
tients, with the majority of centers reporting < 5 cases per 
year of pediatric respiratory failure ECLS support. Only 1 
center reported use of ECMO in > 20 pediatric patients 
with respiratory failure in 1996. Evaluation of survival 
data based on the number of patients receiving ECLS per 
center shows that improved survival is obtained in centers 
with between 5 and 20 patients per year, although the 
number of centers available for analysis was small. Over- 
all, survival in pediatric ECLS is still 50%-60%. The 
decline in number of pediatric ECLS patients per center 
may be related to improved survival with pre-ECLS ther- 
apies, such as HFV or INO. as has been shown in neo- 
nates. The smaller number of cases per center may also 
reflect regional competition for patients due to the in- 
creased number of ECLS centers that now provide pedi- 
atric support, thus diluting the number of patient referrals 
to a particular site. 

Although fewer in number, pediatric patients supported 
with ECLS are often more complicated and need support 
of much longer duration than do neonatal patients sup- 
ported with ECLS. It is possible to maintain adequate 
training of ECLS personnel even with few patients be- 
cause the total number of patient days for pediatric ECLS 
is significantly longer than that for neonates. The average 
duration of ECMO in neonates is < 7 days, while in 
pediatric patients, it lasts an average of 1 1 days and may 
extend to a month or longer with survival obtained. Sup- 
port of other ECMO patient groups in the institution (such 
as neonates and cardiac or adult patients) may also broaden 
the experience of the ECMO team. The ability to support 
various patient populations not only decreases the over- 
head cost associated with running a small pediatric or 
adult prograrn but also helps to maintain ECLS proficiency. 

Centers that support larger numbers of pediatric patients 
(> 10 per year) may be large referral sites for regional 
ECMO candidates or they may apply ECLS earlier in the 


Respiratory Care • November '98 Vol 43 No 1 1 

ECMO IN Pediatric ARDS 

1994 1995 


I < 5 cases l I 5-10 case 
|(n=41-51) 1 ^(n=7-13) 

; 11-20 cases I 
j(n=1-3) I 

I >20 cases 

Fig. 3. Pediatric respiratory extracorporeal membrane oxygenation 
(ECMO) survival by cases per center (n = number of centers). 
(From Reference 4, with permission.) 

course of alternati\e therapies. Those centers with large 
ECLS numbers also may not have access to pre-ECLS 
therapies, such as high-frequency oscillatory ventilation or 
INO. While Fig. 3 may appear to show improved survival 
in centers that support more pediatric ECLS patients, it 
should be remembered that only 1 center reported sup- 
ported 1 1 -20 patients and only 1 center supported > 20 
ECLS patients. 


A decline in the number of pediatric patients with re- 
spiratory failure who receive ECMO is due to the seeming 
improvement in survival rates of these patients who are 
receiving alternative therapies. The alternative therapies 
are not as invasive, labor-intensive, or associated with com- 
plications as severe as with ECMO. In addition, the ex- 
pense of maintaining ECLS equipment and personnel to 
provide minute-to-minute ECLS circuit coverage is high. 
Many hospitals may find that the overhead expenses re- 
lated to ECLS for the number of patients supported per 
year is too great. Whether there will ever be regionaliza- 
tion of ECLS centers to concentrate the greatest number of 
patients at a single ECLS site is unknown but probably 
unlikely. Although this would eliminate many of the fi- 
nancial issues that ECLS creates in terms of personnel and 
equipment, it would also mean that hospitals would have 
to refer patients out of their own institutions. This would 
create a financial risk of its own. Subsequently, referring 
centers might lose some of the "full service" reputation that 
is important for marketing and managed care contracts if 
they close their small ECLS program to support a larger 
ECLS programs at another institution. 

Whatever the future holds, at this time, ECLS is still a 
life-saving therapy for selected patients. As understanding 
of the prevention, pathophysiology, and treatment of car- 
diorespiratory disease advances, more concrete data will 
be obtained on survival of patients with severe respiratory 

failure. With the benefit or hazards of alternative therapies 
more clearly defined, the need for such invasive therapies 
as ECLS may become obsolete. Until that time, efforts to 
identify which patients may benefit from ECLS support, at 
what time period in illness ECLS should be applied, 
and how to make ECLS safer and more efficient should 


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Respiratory Care • November '98 Vol 43 No 1 1 


Inhaled Nitric Oxide: Medical Miracle or Passing Fad? 

Heidi J Daiton MD 



Clinical Applications of Inhaled Nitric Oxide 

Method of Action 

Potential Toxicities of Inhaled Nitric Oxide 

Inhaled Nitric Oxide in Neonates 

Inhaled Nitric Oxide in Pediatrics Patients 

Inhaled Nitric Oxide in Older Patients 

Inhaled Nitric Oxide in Congenital Heart Disease 

Inhaled Nitric Oxide in Primary Pulmonary Hypertension 

Inhaled Nitric Oxide in Lung Transplantation 

Inhaled Nitric Oxide in Heart Transplantation 

[Respir Care 1998:43( 1 1):978-987J Key words: Nitric oxide, mechanical ven- 
tilation, pediatric acute respiratory distress syndrome, complications, pulmo- 
nary hypertension. 


Like many medical breakthroughs, the discovery of ni- 
tric oxide (NO) occurred almost as an accident. In 1980, 
Furchgott and Zawadzki.' two basic scientists involved in 
studying the regulation of vascular tone, were continuing 
their work on control of smooth muscle tone. They noted 
that strips of blood vessels that had the endothelium inad- 
vertently damaged did not relax when exposed to known 
vasodilating substances, such as adenosine diphosphate 
(ADP) or acetylcholine (Ach): however, vessels with in- 
tact endothelium relaxed when exposed to these same sub- 
stances. When vessel strips with intact endothelium were 
placed adjacent to vessel strips with damaged endothe- 
lium, stimulation of the undamaged tissue produced relax- 
ation in the adjacent vessel strips. From these findings, it 
was concluded that the endothelium produced a substance 
that controlled vasodilation in smooth muscle. This sub- 

Heidi J Dallon MO. AssckmIc I'ldlcsscir. Pcdialilcs. Dirccliir, Pcdialric 
and Adult ECMO, Pcdialrii.- C'rillcal C'aru ML-ditinc, Gciirgclown Uni- 
versity Medical Center, Waslunglon IX" 

Correspondence & Reprints: Heidi J Daiton MD. Pediatric Critical 
Care Medicine, Suite .'i4l4 CCC Buildinj!, Georgetown tJniversily 
Medical Center. .^800 Reservoir Rd, Washington DC 20007. 

Stance was initially called endothelium-derived relaxant 
factor (EDRF).- Further work identified that EDRF had 
the same properties as NO, an industrial pollutant found in 
cigarette smoke, bus exhaust, and other frequently studied 
substances.' -• In 1988, Furchgott concluded that EDRF 
was NO."^ This study was rapidly corroborated by other 
researchers, such as Ignarro and associates"^ and Moncada 
et al.** Since that time, more than 15,000 articles have been 
published regarding the mechanisms of NO production 
and metabolism and its biologic actions on different re- 
gions of the body. ''■"' 


The general scheme of NO production and action is 
outlined in Fig. I. Nitric oxide is produced from L-argi- 
nine and oxygen. Stimulation from a variety of substances 
(eg, ADP, Ach) increases the production of NO synthase 
(NOS), the enzyme that catalyzes the conversion of L- 
arginine to citrulline. As part of this conversion, NO is 
produced in the endothelial cell. It then diffuses to adja- 
cent smooth muscle, where NO increases the production of 
soluble guanylate cyclase." This enzyme converts GTP 
(guanosine 5'-triphosphate) to cGMP (cyclic guanosine 
.^'..'^'-monophosphate), which is thought to be the final 
producl that causes rcla\alioii of vascular siiioolh muscle 


RiHSPiRAioKV Cari- • NOVI-.MBRR '98 VoL 4.3 No I I 

Inhaled Nitric Oxide in Pediatric ARDS 

shear stress 


endothelial cell 

Fig. 1. The NO (nitric oxide)-cGMP (cyclic guanosine 3',5'-mono- 
phosphate) signal transduction system. LPS = lipopolysaccha- 
ride; GTP = guanosine 5'-triphosphate. (From Ichinose F, Hurford 
WE, Zapol WM. Evaluation of inhaled NO in experimental models 
of lung injury. In: Zapol WM, Bloch KD, eds. Nitric Oxide and the 
Lung. [L'Enfant C, ed. Lung Biology in Health and Disease.] New 
York: Marcel Dekker Inc; 1997:251; with permission.) 

cells. The relaxation is believed to take place by alterations 
in calcium or potassium channels. Nitric oxide is avidly 
bound to hemoglobin in the bloodstream and is inactive in 
this form. It is eventually broken down into nitrates and 
nitrites and excreted in the urine. Its other multiple actions 
are outlined in a review by Moncada et al.'- At least 3 
types of NOS exist: a constitutive or endogenous form, 
which is responsible for maintaining basal vascular tone in 
the body; a neuronal NOS, which is specific to the brain; 
and an inducible NOS, which is produced only under trig- 
gering conditions, such as sepsis." 

Clinical Applications of Inhaled Nitric Oxide 

Once the actions of NO that produce vascular relaxation 
were identified, administration of it to patients followed. 
Since NO exists in a gaseous form, Frostell and colleagues''' 
applied it to pulinonary smooth muscle by giving it as an 
inhaled gas. They found that inhaled NO (INO) in amounts 
as small as 10-80 parts per million (ppm) reversed the 
increase in pulmonary artery pressure (PAP) and pulmo- 
nary vascular resistance that was induced by vasoconstric- 
tion with thromboxane analogues or the heparin-protamine 
reaction. They also noted that INO produced no change in 
systemic arterial pressure or systemic vascular resistance, 
making INO the first seemingly selective pulmonary va- 

sodilator.''^ Other pulmonary vasodilators, such as nitro- 
prusside and nitroglycerin, also cause systemic decreases 
in both pressure and resistance. This feature often limits 
their usefulness in the clinical setting because of the con- 
comitant decreases in systemic blood pressure and cardiac 
output. INO only seems to affect vascular smooth muscle 
in the vicinity of the aerated alveoli it reaches. It increases 
pulmonary blood flow to areas of the lung where gas ex- 
change can occur. This results in a more normal matching 
of ventilation and perfusion and decreased intrapulmonary 
shunting. The combination of decreasing PAP, pulmonary 
vascular resistance, and intrapulmonary shunt results in an 
increase in oxygenation without known deleterious sys- 
temic effects."' The reduction of PAP and resistance may 
also result in improved performance of the right ventricle 
and an increase in cardiac output.'^ 

Zapol et al' '' and Kinsella et al'** applied INO to patients 
with severe acute respiratory distress syndrome (ARDS) 
and observed a decrease in PAP and pulmonary vascular 
resistance, which resulted in improved arterial oxygen sat- 
uration. Since these initial studies, INO has been applied 
to many clinical situations, from neonatal pulmonary hy- 
pertension to children and adults with ARDS or with heart 
failure.'""-^ Many of these studies have demonstrated the 
beneficial effects of INO on lowering pulmonary vascular 
resistance, reducing intrapulmonary shunt, and improving 
oxygenation. Whether INO truly reduces mortality in pa- 
tients with severe lung injury is not yet known. 

Method of Action 

The scheme of action of INO is outlined in Fig. 2. INO 
is blended with the air and oxygen from the ventilator and 
then introduced to the lung. The NO diffuses into the 
vascular smooth muscle close to the aerated alveoli, in- 
ducing the conversion of GTP to cGMP. This results in 
relaxation of vascular smooth muscle. The NO then dif- 
fuses into the endothelial lining of the blood vessel, where 
some of it is metabolized to nitrate and nitrite. The re- 
maining NO dissolves in the bloodstream, where it is im- 
mediately and avidly bound to hemoglobin. This NO-he- 
moglobin complex is then returned to the left heart and the 
systemic circulation. This complex is inactive and pro- 
duces no vasodilatory effects systemically. The NO-hemo- 
globin is broken down by methemoglobin reductase and 

Potential Toxicities of Inhaled Nitric Oxide 

Animal studies showed that extremely high concentra- 
tions of INO (5000 ppm in dogs) caused lung damage, 
including pulmonary edema and alveolar destruction. It 
produced a histologic picture quite similar to that seen 
with ARDS.-*'^-'' At the clinically relevant doses used cur- 

Respiratory Care • November '98 Vol 43 No 1 1 


Inhaled Nitric Oxide in Pediatric ARDS 



Fig. 2. Rationale for NO (nitric oxide) inliaiation: Inliaied NO diffuses across the alveolar epithelium into the vascular endothelium and dilates 
adjacent pulmonary blood vessels. The NO that reaches the bloodstream is rapidly taken up and inactivated by circulating hemoglobin and 
does not reach the systemic circulation. (From Frattaci MD, Frostell CG, Chen TY, et al. Inhaled nitric oxide: a selective pulmonary 
vasodilator of heparin-protamine vasoconsthction in sheep. Anesthesiology 1991:75:990-999; with permission.) 

rently (5-80 ppm). lung damage has not been noted even 
after prolonged e.xpo.sure to low levels of INO. 

The by-product of INO and oxygen yields nitrogen di- 
oxide (NO;), which is a more highly toxic chemical that 
produces damage with amounts as small as 10 ppm. Some 
investigators have argued that prolonged exposure to even 
2 ppm of NO2 can be harmful to the lung. '" The ainount of 
NO; produced increases with either higher concentrations 
of NO or oxygen in the breathing mixture. Nitrogen diox- 
ide levels are also influenced by the contact tiine between 
NO and oxygen in the breathing circuit. For the widest 
clinical safety inargin, the lowest dose of INO and the 
lowest concentration of oxygen are used. Nitric oxide is 
usually blended into the ventilator circuit at the inspiratory 
limb, keeping the mixing time between oxygen and NO, 
as short as possible.''-'- Nitric oxide, oxygen concentra- 
tions, and NOi are monitored continuously. Even at con- 
centrations of near 100% oxygen and 10-40 ppin of INO 
for up to 35 days, we have not seen > 1 ppm of NO, in the 
breathing circuit. 

Nitric oxide exposure has also been associated with met- 
hemoglobinemia." Nitric oxide binds to the heme iron in 
both its oxidized and reduced forms. Binding of the oxi- 
dized form (Fe + 3) results in reduced oxygen delivery to 
the tissues. Significant methemoglobinemia has rarely been 
noted at clinically used levels of INO ( 10-40 ppm); how- 

ever, monitoring of methemoglobin levels in patients re- 
ceiving INO is prudent. An excellent review of the man- 
ufacture, toxicities, and proper placement of INO in the 
ventilator circuit can be found in Respimtoiy Care Clinics 
of North America.^-* The review also outlines the cuirently 
available devices for delivering and monitoring of INO.'-'' 

Inhaled Nitric Oxide in Neonates 

One of the patient groups in which INO has been shown 
to be beneficial is neonates with severe respiratory fail- 
ure."^' In a recent report by the Neonatal Inhaled Nitric 
Oxide Study Group, infants with respiratory failure were 
randomized to receive either INO or control gas (fraction 
of inspired oxygen [F|o,] = 1-0)." Entry criteria included 
an oxygenation index (OI) of > 25 cm H.O/mm Hg on 
two measurements at least 1 5 inin apart. Exclusion criteria 
consisted of < 34 weeks gestation, age > 14 days, or 
presence of congenital diaphragmatic hernia or known con- 
genital heart disease. Infants failing to respond to either 
treatment were eligible to receive extracorporeal life sup- 
port. Use of other therapies prior to INO. such as surfac- 
tant or high-frequency ventilation (HFV). was allowed. 
Patients were maintained on the type of ventilatory sup- 
port, either conventional or high-frequency, present at the 
time of randomization. 


Respiratory Care • November '98 Voi. 43 No 1 1 

Inhaled Nitric Oxide in Pediatric ARDS 

It was hypothesized that death occurring by 120 days 
and the need for extracorporeal membrane oxygenation 
(ECMO) in the INO group of infants would be decreased 
compared with that in controls. The secondary hypotheses 
were that within 30 min of administration, INO would 
improve oxygenation and decrease the 01 and the alveo- 
lar-arterial oxygen tension difference. The impact of INO 
on length of hospitalization, incidence of air leak, bron- 
chopulmonary dysplasia (BPD), and neurologic disability 
at 18-24 months was also assessed. 

The trial was performed in a blinded fashion, so that 
clinicians were unaware of which patients were receiving 
INO or control gas. INO was administered at a dose of 20 
ppm initially, and control gas was administered at 1 .0 F,o,. 
A complete response was defined as an improvement in 
arterial partial pressure of oxygen (P;,o,) of > 20 mm Hg 
from baseline. Infants having a complete response were 
maintained on study gas and weaned according to protocol 
algorithms. Infants failing to respond to the initial study 
gas received another trial of up to 80 ppm INO (or control 
gas) to elicit a response. The study gas could be continued 
for a maximum of 14 days. 

Of 1 14 infants treated with INO. 52 (46%) either died 
by 120 days or received ECMO, compared with 77 (64%) 
of the 121 control patients (p = 0.006). The difference in 
mortality was not significantly different between groups 
(INO group = 14%; control group = 16%). There was, 
however, a significant decrease in the need for ECMO in 
the infants treated with INO compared with those who 
received control gas (44/114, 39% vs 66/121, 55%; p = 
0.014). Survival with ECMO was equivalent whether pa- 
tients had received control gas or INO prior to ECMO 
(52% vs 47%, respectively). There were also significant 
increases in P^q, ^^^ decreases in the 01 in infants treated 
with INO. There were no significant differences in length 
of hospitalization, duration of mechanical ventilation, or 
incidence of air leak or BPD between groups. No toxic 
effects leading to discontinuation of study gas were ob- 
served, although 10% of infants in the INO group had 
elevations in methemoglobin levels that required reduction 
in the concentration of INO. 

In a similar analysis of 58 infants with persistent pul- 
monary hypertension (PPHN), 53% of infants experienced 
a doubling of systemic oxygenation with INO. Only 7% of 
the infants treated with control gas (90% F,o,) had similar 
results.""* Patients who received prior treatment with HFV 
were excluded, although the use of surfactant was allowed. 
The use of ECMO rescue was significantly reduced in 
patients receiving INO, compared with its use in control 
infants (12/30. 40% vs 20/28, 71%; p = 0.02). of INO 
was not associated with a decrease in systemic blood pres- 
sure. Mortality in both groups was similar (2 infants in 
each group died). One infant experienced an acute rise in 
methemoglobin (from 1% to 18%) in the first 24 hours of 

treatment. Discontinuation of INO led to a decreased met- 
hemoglobin level and an uneventful clinical course. In 
summary, this study showed that use of INO in patients 
with PPHN was associated with improved oxygenation 
and a reduced need for ECMO rescue. 

In another recently published study, patients with PPHN 
were randomized to INO or conventional ventilation. The 
patients had no prior use of surfactant and no concomitant 
use of HFV. The patients in this 25-center study were 
randomized in a placebo-controlled, dose-response fash- 
ion.'''* Entry criteria included use of F[o, = 1.0, a mean 
airway pressure of > 10 cm H^O, and echocardiographic 
evidence of PPHN. Patients were randomized to 0, 5, 20, 
or 80 ppm of INO and were maintained on a fixed dose 
until treatment was either successful, which was defined as 
improved oxygenation (P^q, > 60 mm Hg, F,o, < 0.6, and 
mean airway pressure < 10 cm HiO), or unsuccessful, 
which was defined as P^q, < 40 mm Hg for 30 min, 
patient met the center's ECMO criteria, patient had re- 
ceived 14 days of gas treatment, or hemodynamic insta- 
bility (mean systemic arterial pressure < 35 mm Hg) oc- 
curred. Elevation of NOi levels > 3 ppm for 30 min or 
methemoglobin levels > 7% were also considered treat- 
ment failures. 

Patients were weaned off study gas by an algorithm. 
Although it was hoped that 320 patients would be enrolled 
in the study, the number was stopped at 155 because of 
slowing enrollment. This was most likely due to study 
limitations on the use of surfactant and HFV, which have 
become heavily used in the last few years. As in other 
studies, INO produced significant increases in oxygen- 
ation (from 64 ± 39 to 109 ± 78 mm Hg) and a decrease 
in the OI (-5 from baseline) over the first 24 hours. 

The study calculated a Major Sequelae Index (MSI) 
comprising the incidence of death, neurologic injury, and 
BPD as well as the use of ECMO. The MSI rate was not 
significantly different between INO and control groups 
(50% and 59% respectively). The use of ECMO was 22% 
in the INO group versus 34% in control patients. With the 
exception of elevated NO, and methemoglobin levels in 
the group receiving 80 ppm INO. no adverse events were 
noted. Use of INO did not affect systemic blood pressure. 
There was not a statistically significant reduced MSI in 
INO patients in this study; however, even without con- 
comitant surfactant and HFV therapies, there was a 35% 
decline in ECMO use in the pooled INO group compared 
with the control group, a finding that is in keeping with 
other studies. Of equal importance was the finding that 
survival with ECMO was the same in both groups, despite 
the fact that time to ECMO was greater in INO patients 
than controls (42 ± 44 vs 22 ± 15 h). This study also 
found no adverse safety issues with the use of INO, except 
at the higher dose of 80 ppm. As in other studies, no 

Respiratory Care • November '98 Vol 43 No 1 1 

Inhaled Nitric Oxide in Pediatric ARDS 

increased benefit in oxygenation was observed at the 80 
ppm concentration of INO. 

Neonatal studies have demonstrated the efficacy of INO 
in improving oxygenation and reducing the need for ECMO 
rescue without adversely affecting survival. However, the 
fact that there is not a clear-cut improvement in mortality 
overall among control patients has led to continued ques- 
tions in the use of NO. This point was heavily evident at 
a recent meeting of the U.S. Food and Drug Administra- 
tion (FDA) Review Board (April 1998). This review board 
is responsible for Investigational New Drug study approval 
and will ultimately decide if clinical approval of INO as a 
medical therapy will be given. After many presentations 
and discussion, the panel decided that further work on the 
safety, efficacy and overall use of INO was required be- 
fore any final approval on its release into general use could 
be given. After much debate, the panel also accepted that 
the use of ECMO was a reasonable end point for neonatal 
study designs and that investigators did not have to go to 
the extreme of randomizing patients to the final end point 
of death. Since neonatal patients have good survival rates 
with ECMO (overall. 80% survive), to not allow patients 
in INO studies to receive ECMO as a rescue therapy would 
have made further studies unlikely to be performed. The 
panel also seemed to recognize that, despite the high sur- 
\ival rate with ECMO. its use is highly invasive. The 
discovery of other techniques that limit the use of ECMO 
without adversely affecting survival in patients who do not 
respond adequately to INO and require ECMO. is benefi- 
cial. It does not seem, at this point, however, that use of 
INO for neonatal respiratory failure will be approved for 
general use in the near future. More studies evaluating its 
use are needed. 

Inhaled Nitric Oxide in Pediatric Patients 

Data available on the use of INO in pediatric and adult 
patients also show that INO improves oxygenation. In one 
study that included both neonatal and pediatric patients. 
Demirakca et aH" found that INO improved the 01 by 56% 
from baseline and reduced the P,A.a)o, by 31% in 17 pa- 
tients with ARDS. None of the patients had to be rescued 
with ECMO. and 16 of 17 patients survived. The optimal 
dose of INO in this study was 10 ppm in pediatric patients 
and 20 ppm in neonates. In the author's institution, a study 
of 10 potential pediatric and adult ECMO candidates. INO 
reduced the need for ECMO by 50%,-*' Those patients 
responding to INO with improvement in oxygenation and 
a decline in the 01 to < 40 cm H.O/mm Hg had 100% 
survival compared with 100% mortality in the patients 
without such a response. Those patients who did not dem- 
onstrate more than a 15% decrease in the 01 from baseline 
or who retained an 01 of > 40 cm H20/mm Hg despite 
INO died, even with ECMO rescue. In addition, patients 

who did not respond to INO had a longer duration of 
mechanical ventilation prior to exposure to INO than did 
responders (7 vs 2 d). 

Similar to the findings in the above study. Goldman et 
aH- found that the magnitude of response to INO corre- 
lated with the outcome. In their review of 30 children 
(aged 1 mo to 13 years) with acute respiratory failure, they 
found 100% mortality in patients who failed to decrease 
their 01 by > 15% upon exposure to INO. Patients who 
required a mean airway pressure of > 30 cm H-,0 or 
patients with an underlying immune deficiency also died. 
These patients all had severe lung destruction on postmor- 
tem examination. A 39% mortality rate was observed even 
in patients who decreased their 01 by > 30% after expo- 
sure to INO. The high mortality in this patient group may 
be partly attributed to underlying disease (many patients 
had malignancies or were severely immunocompromised). 
In fact, of the 18 nonsurvivors. 12 would have been ex- 
cluded as ECMO candidates at our institution. Recent data 
have shown that patients with severe respiratory failure 
who are not candidates for ECMO have poor survival.-" 
Another feature of the study by Goldman et al is that INO 
was used relatively late in the course of mechanical ven- 
tilation. 8.4 ± 2.1 days. Whether application of INO ear- 
lier in the course of mechanical ventilation would have 
improved overall survival is unknown. However, duration 
of prior mechanical ventilation seems to be an important 
determinant of outcome in our patients, both in response to 
INO and in survival in ECMO rescue. 

The potential importance of the magnitude of response 
to INO and the previous duration of mechanical ventila- 
tion as 'screening tools" to predict which patients are likely 
to survive cannot be underestimated. For example, if pa- 
tients who have no response to INO (assuming that appro- 
priate lung recruitment techniques have been employed for 
optimal NO delivery) are all found to have irreversible 
lung injury and die, and if this lack of response can be 
correlated to time on the ventilator, underlying disease, or 
other factors, then a more scientific and effective means of 
identifying patients who will die from their disease will 
exist. This may prevent the inappropriate and futile use of 
ECMO or other invasive therapies. The cunent methods of 
deciding which patients are likely to benefit from ECMO 
are often subjectively based on the duration of prior me- 
chanical ventilation, underlying disease, and the ECMO 
center's experience with a particular type of patient. These 
criteria do not to always correlate with irreversible lung 
disease and are a matter of debate in the ECMO realm. The 
ability to use a screening tool, such as response to INO. 
which has been shown to correlate with irreversible lung 
disease and death, may allow both appropriate utilization 
of invasive, labor-intensive, and costly techniques, such as 
ECMO, while improving survival in ECMO-treated pa- 
tients. Whether the predictive ability of response to INO 


Respiratory Care • November '98 Vol 43 No 1 1 

Inhaled Nitric Oxide in Pediatric ARDS 

combined vvitli other factors remains highly associated with 
outcome will require more investigation and increased pa- 
tient data sets than those presented here. 

Inhaled Nitric Oxide in Older Patients 

Since the vast majority of older patients with respiratory 
failure have a greater degree of parenchymal lung injury 
and disease than pulmonary hypertension, it is perhaps not 
unexpected that the efficacy of INO is reduced in such 
patients. In addition, older patients with severe respiratory 
failure often develop secondary organ dysfunction that leads 
to death: however, they do not usually die from pure re- 
spiratory failure. In the largest blinded, multicenter adult 
study of ARDS patients (n = 177) randomized to receive 
INO or control gas. patients who received INO had im- 
proved oxygenation and a decrease in their OI.^*^ Patients 
who received INO also had a decline in their PAP. No 
change in mortality was ob.served between pooled INO 
groups and controls. This study used INO doses of 1 .25, 5, 
20. 40, and 80 ppm. The SO-ppm concentration was dropped 
after 60 patients were enrolled. International consensus 
suggested that use of 80 ppm of INO was no more effec- 
tive than lower doses. There was a slight trend toward 
improvement in the number of patients alive and off me- 
chanical ventilation by day 28 in the 5-ppm INO group 
compared with the controls (62% vs 44%; p < 0.05), 
although this was determined by post hoc analysis and 
may have been an incidental finding. 

This study did not demonstrate any adverse effects of 
INO. including any increase in renal dysfunction. The im- 
portance of this is highlighted by concern raised in a Eu- 
ropean adult INO study that patients receiving INO had 
elevated use of renal replacement therapy compared with 
use in the control group.* It is unknown whether patients 
in the European study received renal replacement therapy 
because of actual renal failure, or if such treatment was 
used as a means of reducing fluid overload, or for other 
reasons. Nonetheless, the concern underscores the need for 
continued study of INO to identify potential deleterious 
effects and to ensure that this forin of treatment is truly as 
safe as it appears. 

An interesting feature of the adult study was that both 
groups had an 01 of 17 at study entry. Although the OI has 
not been validated in adult patients as a marker of severity 
of injury and risk of death (the author's institution is cur- 
rently part of a large multicenter data-collection project to 
attempt to correlate the OI with risk of death in adults), a 
similar score in pediatric or infant patients would imply 
that patients do not have very severe lung injury. In fact. 

*U..S. Food ;md Drug Administration Review Board meeting. Washing- 
ton, DC. April |y9S; inipuhlished data. 

over the course of the first 7 days of treatment in the adult 
study, the OI in both control and INO groups of patients 
fell to a mean of 15. Since the cause of death in patients 
was not the focus of the published report, the nuinber of 
deaths related to respiratory causes versus other organ sys- 
tem failure is unknown. However, on the basis of OI cri- 
teria, few deaths should have occurred secondary to respi- 
ratory failure alone. 

Inhaled Nitric Oxide in Congenital Heart Disease 

Another large group of patients in whom INO is used 
with increasing frequency is infants and children with right 
heart failure or pulmonary hypertension following repair 
of congenital heart defects.-"^ -"* Inhaled NO has been 
shown to decrease pulmonary vascular resistance and PAP 
in patients with elevated PAPs. Journois and colleagues-""' 
studied 17 infants, who, following repair of congenital 
heart defects, demonstrated pulmonary arterial pressure 
exceeding 75% of the systemic arterial pressure. This el- 
evation was associated with a decrease in mixed venous 
oxygen saturation (SvO^) or arterial oxygen saturation (or 
both). All patients with pulmonary hypertensive events 
were initially treated with manual ventilation with 1007r 
oxygen and deepening of sedation (all were receiving con- 
tinuous infusions of pancuronium and fentanyl). Mainte- 
nance of P^eo, levels of ~ 30 mm Hg and administration 
of sodium bicarbonate were used to correct any metabolic 
acidosis. If these measures were unsuccessful in reducing 
PAP after 5 min. patients were given 20 ppm of INO. 
Inhalation of NO resulted in significant decreases in PAP 
(-32% ± 16%), mean PAP (-34% ± 21%) and diastolic 
PAP (-43% ± 20%). No differences were observed in 
systolic, mean, or diastolic arterial blood pressures. In- 
creases in arterial oxygen saturation (-l-9.7± 12%) and 
SvOt ( + 37% ± 28%) also occurred even though F|o, fell 
from 1.0 to 0.92 as a result of NO administration. Urinary 
output also increased with the administration of INO. in- 
dicating improvement in overall cardiac output. Patients 
were treated with INO for 44 ± 69 hours. Of 17 patients. 
15 (88%) were discharged from the intensive care unit. 

In perhaps one of the most elegant studies of INO in 
children, Wessel et al''" examined the impact of INO in 
children with pulmonary hypertension both before and af- 
ter cardiopulmonary bypass surgery. This study was based 
on the fact that cardiopulmonary bypass induces pulmo- 
nary endothelial cell damage. With endothelial cell dam- 
age, responsiveness to normal vasodilating substances, such 
as Ach, is lost. Acetylcholine induces production of NO, 
which in turn activates guanylate cyclase to produce cGMP 
and cause vasorelaxation. Loss of responsiveness to Ach 
can indicate the presence of endothelial cell damage. The 
hypothesis of the study was that the degree of pulmonary 
hypertension following cardiopulmonary bypass correlates 

Respiratory Care • November '98 Vol 43 No 1 1 


Inhaled Nitric Oxide in Pediatric ARDS 

with ihe degree of endothelial damage that has occuned. 
Since INO does not require normal endothelium to exert 
its vasodilating effects, it may reverse or reduce the ele- 
vation in pulmonary hypertension following bypass. 

Three protocols were used. In the first protocol, patients 
v\ith preoperative pulmonary hypertension were studied 
during cardiac catheterization and given an infusion of 
Ach. All of these patients had a decrease in PAP and 
vascular resistance and a decline in systemic blood pres- 
sure and vascular resistance. The cardiac index was un- 
changed. In protocol two, postoperative patients with ele- 
vated PAP or at increased risk for pulmonary hypertension, 
as determined by the presence of preoperative pulmonary 
hypertension, were given infusions of Ach. At doses of 
10 "^ to 10 '^ M, infusion of Ach produced no change in 
PAP or vascular resistance. No other hemodynamic or 
arterial blood gas variable changed significantly. At a dose 
of 10""^ M, Ach infusion resulted in a decline in systemic 
blood pressure, although PAP was unchanged. Several pa- 
tients also developed transient side effects (bronchospasm 
and tachycardia with hypotension lasting for 10-15 s) with 
10"^ M Ach. In protocol three, postoperative patients were 
treated at doses of 10 '' M Ach. Pulmonary arterial pres- 
sure and vascular resistance fell somewhat (p < 0.05) and 
was accompanied by a decrease in systemic blood pres- 
sure. The cardiac index and systemic vascular resistance 
were unchanged, and Ach infusion did not alter arterial 
blood gas variables. 

When preoperative and postoperative responses to Ach 
were compared, pulmonary vasodilation was markedly at- 
tenuated in postoperative patients. In preoperative patients, 
infusion of Ach reduced pulmonary vascular resistance by 
46 ± 5%, compared with an 1 1 ± 4% decline in postop- 
erative patients (p < 0.002). In contrast, inhalation of 80 
ppm NO for 15 min reduced PAP and resistance in all 
postoperative patients. A clinically small but statistically 
significant fall in right atrial pressure and systemic blood 
pressure also occurred. No changes in blood gas variables 
were observed with INO. Blood levels of cGMP (the final 
marker in the pathway of vascular relaxation) in postop- 
erative patients did not change on exposure to Ach infu- 
sion but rose by more than 3 limes baseline after 15 min of 
INO. This study suggests that following cardiopulmonary 
bypass, patients have endothelial cell dysfunction that in- 
hibits normal vasorelaxation responses. The findings also 
suggest a potentially important role for INO in both the 
diagnosis of reversible pulmonary hypertension and as ther- 
apy for patients with congenital heart delects. Further- 
more, NO could also be used for patients who demonstrate 
pulmonary hypertension following cardiopulmonary by- 
pass. Recently, use of INO in cardiac patients with pul- 
monary hypertension has become routine in many centers. 
Studies are ongoing lo ensuie efficacy wilhoul toxicity. 

Inhaled Nitric Oxide in Primary Pulmonary 

INO may also prove lifesaving in patients with primary 
pulmonary hypertension (PPH). This condition occurs in 
young adults when progressive pulmonary hypertension 
develops without an identifiable cause. With PPH, death 
often occurs within 3 years secondary to progressive right 
ventricular hypertrophy and cardiac dysfunction from fixed 
pulmonary hypertension.^' '^-' The use of vasodilators to 
reduce pulmonary pressure has been restricted because of 
a concomitant decrease in systemic arterial pressure. Hyp- 
oxia may also develop from nonselective vasodilation of 
pulmonary vessels. This leads to an increase in venous 
admixture and a deterioration of ventilation-perfusion 
matching. Compared with normal controls, patients with 
PPH have abnormal increases in levels of exhaled NO in 
response to exercise. '^-'^''" Whether these abnormal re- 
sponses in the endogenous NO system are the cause of or 
the result of endothelial injury in patients with PPH is 
unknown. INO has been used as a screening agent to pre- 
dict responsiveness of patients with PPH to commonly 
used long-term therapeutic agents, such as calcium chan- 
nel antagonists and prostacyclin.'"' A vasodilatory response 
in patients who inhale NO is predictive of a positive re- 
sponse to prostacyclin therapy. INO has also been shown 
to improve right ventricular performance (decreased PAP 
and end-diastolic pressure, as well as improved stroke vol- 
ume) in patients with PPH. 

Long-term of INO in patients with PPH has been 
hampered by the lack of an appropriate delivery system: 
however, work to overcome this obstacle is ongoing. An- 
other potential benefit of the use of INO in patients with 
PPH is its antiproliferative effects on vascular smooth mus- 
cle. In these patients, progressive myointimal smooth mus- 
cle growth leads to death. If use of NO can inhibit these 
changes, progression of the disease process may be slowed 
and survival prolonged.''-"*^ 

Inhaled Nitric Oxide in Lung Transplantation 

In a similar category of patients, kmg transplantation 
candidates often have elevated pulmonary resistance and 
are at great risk for the development of right heart failure 
during the process of transplantation."^ INO has been shown 
to reduce PAP. pulmonary vascular resistance, and in- 
trapulmonary shunt fraction following lung transplanta- 
tion.'* ''** It may also prove useful in the postoperative 
period since transient graft dysfunction occurs in as many 
as 2()'7f of these patients. This endothelial dysfunction re- 
sults in a decrease of endogenous NO production, which 
may contribute to elevated PAP. which is often seen clin- 
ically.'''"" Use of INO to reverse these postoperative 
chanues may limit (ho amouiil of mechanical ventilator 


Re.spiratory CarI' • Novr.MBF.R "98 Vol 43 No 1 

Inhaled Nitric Oxide in Pediatric ARDS 

support required. Prolonged need for nieehanical ventila- 
tory support of patients following lung transplantation is 
often assoeiated with poor outcome. The ability of NO to 
improve oxygenation and decrease intrapulmonary shunt- 
ing may allow faster separation of patients from the ven- 
tilator and reduce risk of nosocomial pneumonia and iat- 
rogenic lung injury. ^- 

Inhaled Nitric Oxide in Heart Transplantation 

Cardiac transplantation patients who develop right ven- 
tricular dysfunction may also benefit from the pulmonary 
vasodilatory properties of INO.-""^- However, care must 
be taken, because in some patients with concomitant left 
heart dysfunction, administration of INO has led to acute 
increases in left ventricular filling pressures and cardiac 
failure. This effect is most likely caused by the reduction 
in right ventricular afterload secondary to pulmonary va- 
sodilation that occurs with INO. The resultant increase in 
pulmonary blood flow may overwhelm the capacity of a 
weak left ventricle and result in pulmonary edema or acute 
left ventricular failure.^' 


Although this review has touched on the cardiac and 
pulmonary uses of NO. the importance of this substance in 
many other organ systems (eg. brain, coagulation, kidney) 
is also under increased scrutiny.^"* '^^ The use of INO in 
patients with cardiopulmonary dysfunction has shown en- 
couraging results in the improvement in oxygenation. It 
decreases the need for EMCO. a highly invasive proce- 
dure, in neonatal patients with respiratory failure. It seems 
safe and effective and is relatively easy to administer. 
What remains to be proven, however, is whether the use of 
INO actually decreases mortality. Optimism over its ben- 
eficial effects can only be turned into effective, everyday 
clinical practice when further research demonstrates that it 
improves morbidity and mortality without deleterious side 


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Respiratory Care • November 

Vol 43 No 1 1 


Special Articles 

Future ARDS Therapies 

James Fackler MD 


Focusing on the Right Outcomes 

Data Mining 

Need for New Approaches 

Genetic Therapies 



N-methyl D-aspartate Receptors 


[Respir Care 1998;43(1 1):988-994] Key Words: Pediatric ARDS, outcomes 

research, data mining, genetic therapy, steroids, retinoids. 

Humans are good ... at discerning subtle patterns that are 
really there- but equally so at imagining them when they 
are altogether absent. 

— Carl Sagan. Contact 


Therapies for acute respiratory distress syndrome 
(ARDS) have improved dramatically in the last few years, 
and although the reason for this improvement has not been 
firmly established, attention to lung-protective ventilator 
strategies has been crucial. Some future ARDS treatments 
are well delineated. Exogenous surfactant, nitric oxide, 
and perflurocarbon-augmented ventilation each have suf- 
ficient preliminary data to make continued clinical trials 
worth considering. Other therapies have been shown as 
worthless. Much remains to be learned about lung-protec- 
tive strategies. One therapy currently being studied is the 
use of high-frequency oscillatory ventilation in older chil- 
dren and adults. 

The development of new drugs could also be useful. 
However, if these new drugs behave as others have in the 
littered landscape of ARDS therapies, their use is ques- 

James Fackler MD. Clinical Director, Pediatric Critical Care, Medical 
Director, Respiratory Therapy, The Johns Hopkins Hospital, Baltimore. 

Correspondence: James Fackler MD. Blulock 9.^7. 600 North Wolfe St. 
Baltimore .MD 2I2K7. jfacklercawclchlink. 

tionable. In the past, new drugs, initially met with enthu- 
siasm, were followed by studies that were reinterpreted by 
each clinician in light of his or her own personal experi- 
ences and often resulted in variable use or nonuse of the 
new drug. 

One of the first physicians in American academic med- 
icine to call for outcomes analysis was Ernest Amory Cod- 
man (1869-1940). a surgeon from Massachusetts General 
Hospital. It was Codman and the surgeon Harvey W Cush- 
ing ( 1 869-1939) who first documented intraoperative care. 
Codman pushed further with his so-called "end result idea," 
which proposed that surgeons no longer be satisfied with 
survival to hospital discharge as their ultimate outcome. It 
was Codman who proposed that every hospital follow ev- 
ery patient long enough to determine whether the treat- 
ments were successful.' In the same era, the Canadian- 
American physician, William Osier (1849-1919), 
suggested that physicians "weigh evidence and not go be- 
yond it."' 

Yet, has that not been done since the earliest description 
of ARDS? Figure 1 shows a distribution, by year pub- 
lished, of the reports describing ARDS in children. Mor- 
tality differs substantially from study to study, with the 
lowest mortality being in a series with only 7 patients. 
These reports use variable definitions of the condition and 
provide insufficient data to allow adjustments for a series- 
to-series comparison. Most reports do not explicitly state 
that all cases are included in the analyses. Can conclusions 
be drawn from underspecified, incomplete experiences? 


Respiratory C.ark • November 

Vol 43 No 1 1 

Future ARDS Therapies 

1980 82 83 84 85 86 87 88 1990 92 

Year of Study 

Fig. 1. Published studies of patients witln pediatric ARDS from 
1980-1992. Shaded portion of columns = surviving patients, 
■ percent survived 

Randomized controlled trials (RCTs) in ARDS are 
deemed by some to be impossible. I prefer to consider 
them difficult — RCTs have been successfully perforined 
in adults (curiously often with negative results, as with 2 
studies of extracorporeal membrane oxygenation (ECMO) 
and 1 with corticosteroids).--* In children, the industry- 
sponsored RCT of perflubron-augmented mechanical ven- 
tilation'^ failed because the primary end point was incor- 
rectly chosen. The incon-ect end point was chosen mainly 
through disregard for the evolutionary phase through which 
ARDS was passing: mortality is falling. 

Focusing on the Right Outcomes 

As to the future of ARDS therapy, our thinking, in part, 
needs to follow Dr Codman's thinking. It is in the out- 
comes. It is in the perpetual analysis of all cases of ARDS. 
It is in understanding how some cases are similar and how 
their responses to similar therapies correlate. There are a 
few subpopulations of patients with ARDS who respond to 
therapy with some consistency. Children without a chronic 
disease when ARDS develops typically do quite well. Chil- 
dren with ARDS following a bone marrow transplant typ- 
ically do not survive. 

This leaves the vast majority of children with ARDS in 
the "not-typical" category. Because these children's syn- 
dromes are heterogeneous, it is impossible to study a suf- 
ficiently large population so that random assignment al- 
lows an even distribution of all factors. Furthermore, the 
ability to standardize care in a control arm has eluded most 
ARDS investigators. Finally, clinical care should be un- 
dergoing a constant evolution. Most often evolution in 
care is assumed to be good. However, it cannot be as- 
sumed that good results will be sustained. A quite disturb- 
ing recent report'' showed more patients died in "less so- 

phisticated centers" following carotid endartectomies. But. 
even in the 'highly sophisticated centers." mortality was 
low only during the period when carotid endartectomies 
were being studied. That is. the good evolution could not 
be sustained. Beware, therefore, that good results can nei- 
ther be generalized to all centers nor sustained even in 
sophisticated centers. 

At best, RCTs can be difficult to design, and if the 
results are not necessarily extensible or sustainable, how 
can the future be in the outcomes? What outcome? The 
key is in consistent data collection. Automation must play 
a central role. Large data sets with enormous amounts of 
data will be necessary and 'data mining" (sometimes re- 
ferred to as 'data torture") will lead the way. 

Figure 2 demonstrates visualization of an enormous data 
set within a domain far more commonplace and far better 
understood than ARDS. Data on baseball players, baseball 
stadiums, weather, and finances are readily available. Base- 
ball managers, presumably, analyze the statistics to de- 
velop rational game plans. However, these analyses soon 
become multidimensional, and for any individual to juggle 
all these parameters in his or her mind is impossible. Jug- 
gling all of a single patient's parameters (including miss- 
ing, incorrect, and old data) is 'even more' impossible. 
Data visualization techniques as shown in Figure 2 will be 
crucial. Each square is a different player with his career 
home runs plotted against his career at bats. If you want to 
see only those players who had been walked more than 40 
times, you would slide the 'walks' bar and all the players 
with less than 40 walks per season could be dropped from 
the graph. These patterns are limited only by the amount 
(and quality) of the data collected. Imagine that the data 
set represents, rather than baseball, a child with ARDS. 
Each square is a patient. The y-axis is the severity of 
illness score and the x-axis is days on mechanical venti- 
lation. The variables at the right could be medications, 
laboratory results, physical examination signs, or physio- 
logic parameters. What parameters might arise if only pa- 
tients who received albumin or steroids were highlighted? 
Patterns — the crucial grist for the design of future clinical 
trials — will be far easier to extract. 

The data necessary for discoveries in the setting of ARDS 
will require the continued evolution of automated data 
collection systems. Although commercial critical care bed- 
side charting systems have been available for more than a 
decade,'' an understanding of ARDS will require more data 
types than these systems typically collect (vital signs, lab- 
oratory data, some bedside device data). Historical data 
(although entered as text) is not captured by these systems 
in a forin that can be queried. Physical exam data, except 
for 'simple findings' like the Glasgow coma scale and pu- 
pillary size, are also not routinely collected by cuirent 
bedside charting systems. Radiologic findings will require 

Respiratory Care • November 

Vol 43 No 1 1 


Future ARDS Therapies 

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Fig. 2. An example of the depiction of a very large varied data set in graphic form, using data from baseball rather than from ARDS. This 
example is from Spotfire Pro, data exploration and visualization software that displays large amounts of data by using 3 analysis windows: 
Window 1 — scatter plots, histograms, or pie charts; Window 2 — range sliders, item sliders, check boxes, or radio buttons; Window 3 — user 
details on demand about specifically-selected data points, permitting the user to visually query the information for trends, anomalies, 
outliers and patterns. Given the constraints set by the user using the range slider, ie, runs between 58-130, and axis chosen as Career 
Home Runs vs Career at Bats, the result is 1 23/322 pertinent records (or 38.20% of the data set). Reproduced with permission, Luis Barros, 
Manager of Business Development, Spotfire Inc ( 

codification. Temporal relationships will require synchro- 
nization. Headway is being made in many of these areas. 

Data Mining 

Once the data-capture issues are solved, the ability to 
search for subtle patterns can begin. However, the admo- 
nition of Carl Sagan. which appears at the beginning of 
this article, must not be forgotten. 'Data mining' refers to 
a number of computer science techniques that address the 
issue of pattern discovery. Data mining, a technique best 
developed in business, is increasingly being applied within 
the financial domains of medicine and is beginning to see 
utilization in clinical medicine. Fundamentally, data min- 
ing uses large data sets upon which analysis techniques are 

applied. These analyses may be guided by known clinical 
principles. An example of a guided approach is the use of 
accepted Mendelian genetic principles to search for pat- 
terns of hereditary oncologic syndromes within a large 
data set of family histories. Preliminary efforts have shown 
data mining to accurately identify familial cancer patterns 
when using the literature and an expert opinion as the gold 
standard. Some patterns not recognized by the experts are 
also considered. '*■'' I believe caution should be expressed 
about such an approach lest we use data mining merely to 
reinforce our current beliefs. 

In contrast, a technique referred to as 'knowledge dis- 
covery in databases' (KDD) relies on an accurate and com- 
plete data set describing the clinical topic of interest. Com- 
puter learning techniques are applied to the clinical data 


Respiratory Care • November "98 Vol 43 No 1 1 

Future ARDS Therapies 

sets. These computer learning techniques may be guided 
with 'i<nown' medical and physiologic principles. Or the 
computer learning techniques may be completely unguided. 
with data sets being subjected to mathematical manipula- 
tions in a search for patterns. 

More traditional statistical queries or creation of neural 
networks may also be applied to these data sets. A pre- 
liminary effort with these techniques was reported from 
Duke University where a perinatal subset of their comput- 
er-based patient records used the records of 45,000 pa- 
tients over a 1 0-year period. ' " The database contained about 
9 million data elements. A .serious problem in the study 
was that about 9% of the data elements (of a closely scru- 
tinized subset of the data) were deemed unusable. How- 
ever, as KDD techniques become more ubiquitous, and 
user interfaces for data input and verification become more 
functional, the quality of data .sets will improve and these 
KDD techniques will bear fruit. 

Need for New Approaches 

beyond clinical ARDS research (beyond the snap answer 
of billions of dollars of research funding)? 

Arguably, clinical outcomes from ARDS are improving. 
MoiTis et al found that survival increased (over 2 years) in 
the controlled group of an adult population while perform- 
ing an ECMO randomized clinical trial.' Milberg et al 
documented an improvement in ARDS survival over a 
decade. This improvement was most dramatic in "young" 
adults (eg, < 45 yr old)." 

Improvement in ARDS survival is also seen in children. 
Preliminary data from 8 centers show a 62% survival in 
320 consecutive cases of ARDS in children. If "ECMO- 
ineligible' patients (eg, those children who have ARDS 
plus acute profound neurologic damage or immune sup- 
pression) are excluded, survival from ECMO-eligible chil- 
dren is now 81% ( 136 of 167).'- This latter group is most 
comparable to that reported by Timmons et al, in which 
the survival was only 57%.''' 

Genetic Therapies 

As to the issue of drugs, again, maybe we should be 
thinking more like oncologists. Decades ago, oncologists 
gave up using single drug therapy. Arguably, ARDS is not 
treated with a single therapy (including mechanical sup- 
port). Clinical trials have invariably studied a single inter- 
vention in .search of "the" cure. Against "standard therapy." 
this single therapy is tested. As with cancer therapy, in 
which drugs are combined to attack the cell cycle at mul- 
tiple points, why are we not testing multi-pronged ARDS 
therapies? If the early parenchymal lesion is treated simul- 
taneously with the vascular lesion, and then the late fibro- 
sis is approached with a third therapy, we would at least 
begin the codification of "rational" strategies and then be 
able to study iterations based on new basic science of the 
process or refinements in process-specific therapies. 

What makes multi-modality ARDS therapy a bit more 
complicated than cancer therapy is that the basic mecha- 
nisms of the syndrome"s etiology, maintenance, and res- 
olution are not as well understood. For decades, anti-mi- 
totic drugs have been rationally combined based on an 
effort to interrupt the cell cycle in multiple places. ARDS 
therapies must be designed with careful attention to the 
underlying pathophysiology. Multi-modality ARDS ther- 
apy must approach the lung on at least three levels: pa- 
renchymal, vascular, and neurological. 

Why should a systematic approach to ARDS prove more 
difficult than one used for cancer? The often-vocal nay- 
sayers suggest it is because ARDS is the common pathway 
of loo many processes. Are there not more types of cancer 
(each with its distinctive biology) than triggers for ARDS? 
Was it obvious in the early days of cancer chemotherapy 
which tumors respond to particular drug combinations? 
Why then has clinical cancer research advanced so far 

It should not come as a surprise that the genetic back- 
ground of an individual modifies the responses to any 
particular insult. Genetic "abnormalities" can render ad- 
vantage; heterozygotes for sickle cell hemoglobin resist 
malaria. Genetic abnormalities can render a disadvantage 
(eg. the spectrum of immune deficiencies). Except for the 
phenotypically obvious, a patient's genetic composition 
has received little attention in the critical care environ- 
ment. Examples must be sought outside of ARDS. 

A fascinating observation from the University of Glas- 
gow is that polymorphism of the apolipoprotein E gene 
(AFOE) influences both morbidity and mortality follow- 
ing head trauma. Although individuals who have it are 
phenotypically normal during the years when head trauma 
is most prevalent, the APOE genotype is the most impor- 
tant known genetic determinant of susceptibility to Alz- 
heimer's disease. Following head trauma, patients with the 
allele producing the e04 type of apolipoprotein E (APOE 
e04) have unfavorable outcomes 57% of the time, and 
patients without APOE e()4 have unfavorable outcomes 
27% of the time.'-* It has also been shown that patients 
with APOE e04 recover neurologic function less com- 
pletely following cardiopulmonary bypass than patients 
without APOE e04.'^ 

Somewhat more relevant to the setting of ARDS is an 
experiment of Streptococcus pneiiinonicie .sepsis in mice. 
Much attention has focu.sed on dysfunction of the endo- 
thelial cells in sepsis. As is the case in humans, mice 
deficient in both E- and P-selectin have increased suscep- 
tibility to infection. Mice deficient in either E- or P-selec- 
tin are phenotypically normal and are not more susceptible 
to spontaneous infections than normal mice. P-selectin- 
deficient mice were shown to have functional immune 

Respiratory Care • November "98 Vol 43 No 1 1 


Future ARDS Therapies 

system ahnorrnalities. No functional immune assay was 
abnormal in the E-selectin mice. When E-selectin deficient 
mice were inoculated with Streptococcus pneumoniae. 407c 
died in 24 hours (compared to 59f of normal mice), and 
92'7c were dead at 10 days (compared to 40% of normal 

That genetic backgrounds may alter clinical outcome is 
only moderately interesting (to the clinician) unless one is 
in a position to manipulate an acute process. Typically, 
genetic therapies have been applied as efforts to solve 
inborn metabolic errors (eg, cystic fibrosis) and acute pro- 
cesses are now being studied. 

An example of genetic manipulation of an acute process 
can be demonstrated in an animal model of wound healing. 
Yamasaki et al point to substantial evidence that nitric 
oxide is an important component in the wound healing 
process. In their inducible nitric oxide synthase (iNOS)- 
deficient mice, wound (a surgical abdominal incision) heal- 
ing was delayed 3]%. Wound healing could also be de- 
layed to the same extent if normal mice were given a 
partially selective INOS inhibitor. However, if the iNOS- 
deficient mice were given a single application of an ad- 
enoviral vector containing human iNOS cDNA, at the time 
the incision was made, wound healing returned to normal. 
iNOS was expressed in the wound from days 2 through 10 
and peaked during days 4 through 6.'^ 

Realizing there is an enormous gap between knockout 
mice and humans with ARDS, the possibility of episodic, 
local manipulation of a genetic response is now quite real. 
While much is known about the inflammatory process in 
ARDS, much more is necessary to understand the healing 
process and whether genetic manipulations will be bene- 


Steroids as treatment for ARDS have come, definitively 
gone,-" and come again.'** Yet "steroids" are a broad cate- 
gory of agents. Methylprednisolone was used in both the 
above studies (in the latter for a far longer treatment time). 
However, dexamethasone has a deleterious effect on lung 
growth: when given to newborn rats between postnatal 
days 4 to 13, dexamethasone inhibits saccule septation.'"' 

A substantially different steroid group, the 21-amino- 
steroids, nonglucocorticoid analogues of methylpred- 
nisolone, has recently received attention in the setting of 
sepsis and respiratory failure. Originally designed as a 
lipid peroxidation inhibitor and tested in the setting of 
cerebral i.schemia, the 21-aminosleroids (the so-called "la/- 
aroids" for their perceived ability to raise dead brains), 
have far more complicated effects than peroxidation inhi- 
bition. Fibroblast proliferation is inhibited by a la/.aroici 
(unrelated lo the peroxidation effect).-" Thus, early spec- 

ulation was that lazaroids might be beneficial in tissue 
remodeling following injury. 

Applying more directly to the problem of respiratory 
failure and a potential role of lazaroids are 2 animal stud- 
ies, similar in nature. In the first study, dogs were given a 
lazaroid (U-74389G) before administration of endotoxin. 
Although the hemodynamic effects of the endotoxin were 
identical in both the control and lazaroid-treated animals, 
systemic oxygenation and intrapulmonary shunting were 
preserved.-' In the second study, acute lung injury was 
induced with phorbol myristate acetate (PMA) in adult 
rabbits. Lazaroid (U74389F) pretreatment prevented sig- 
nificant deteriorations in blood gas abnormalities. Further- 
more, 75% of pulmonary neutrophils were distributed in 
the alveolar interstitial spaces or the extra-alveolar blood 
vessels compared to 80% of pulmonary neutrophils present 
in the alveolar spaces of the rabbits receiving only PMA. 
Interleukin 8 (IL-8) was significantly decreased in bron- 
choalveolar lavage (BAL) fluid. -- 

Recent confirmation and extension of the above find- 
ings were recently reported using the lazaroid tirilazad 
mesylate (U-74006F). Adult minipigs were made septic 
with an infusion of Pseudomonas aeruginosa. As in the 
PMA-rabbit model, the lazaroid had no effect on the he- 
modynamic abnormalities associated with sepsis. Plasma 
tumor necrosis factor a was not affected. Again, pretreat- 
ment with the lazaroid prevented any fall in systemic ox- 
ygenation. The lung wet-to-dry ratio in the lazaroid-pre- 
treated animals was greater than that in the control animals 
but less than in the sepsis group. As in the rabbit study, the 
neutrophil percentage of all cells in BAL fluid was sub- 
stantially reduced as compared to the sepsis animals. Lung 
and liver total peroxidation was diminished.-' 

In summary, lazaroids, as they were originally designed, 
have the potential to diminish oxidative damage, decrease 
fibroblast activity, prevent neutrophil extravasation into 
the alveolar airspaces, decrease IL-8 production and main- 
tain oxygenation during sepsis. Naturally, much work re- 
mains before consideration of clinical trials might com- 


That pulmonary development is retinoic acid-dependent 
has been known for decades. Vitamin A-deficient wean- 
ling rat trachea shows keratinized metaplasia. The abnor- 
malities reverse with introduction of vitamin A into the 
diet. Within the parenchyma of the lung, levels of cellular 
retinol and retinoic acid binding protein (CRABP) peak 
between days 10-15 after birth. In the rat, this is the same 
lime the lung is moving from sacules through septation 
and thinning to true alveolarization. However, disruption 
of both the cellular retinoic acid-binding protein genes 
does not affect limg development.-'* 



Future ARDS Therapies 

As mentioned above, dexamethasone has been shown to 
decrease alveolar surface area. Simultaneous administra- 
tion of retinoic acid, however, ameliorates the adverse 
etfects of dexamethasone. When retinoic acid was given 
alone to normal 3-day-old rats, their alveolar number in- 
creased by 50%, but because the alveoli were small, the 
total lung surface area was unchanged. If a neonatal lung 
is too small, one wonders whether retinoic acid might be 

A study relevant to a discussion of ARDS. from the 
same laboratory that performed the above retinoic acid and 
dexamethasone studies, involved retinoic acid reversal of 
experimental emphysema. Rats given intratracheal elas- 
tase developed the histopathology of emphysema after 25 
days. If given retinoic acid beginning on day 25 for 1 2 
days, the effects of the elastase were completely reversed. 
Although a mechanism is postulated — retinoic acid causes 
gene expression similar to that present during the saccule 
to septation period — there are no additional data.-'^ 

Retinoic acid has more effects than alveolar differenti- 
ation. IL-1 -induced IL-6 production is diminished in vitro 
within human lung fibroblasts.-'' Retinoic acid also inhib- 
its fibroblast growth in cultures.-'' 

A^-methyl-D-aspartate Receptors 

Another fa.scinating possibility for future ARDS thera- 
pies also comes from the neuro-resuscitation field. The 
family of A'-methyl-D-aspartate (NMDA) receptors is 
present throughout the brain and is a prominent compo- 
nent of the excitatory neurotransmitter system. There are 
compelling data to show that much of the central nervous 
system damage associated with trauma and ischemia is 
due to secondary damage associated with NMDA activa- 
tion. Addition of NMDA to the brain causes histopathol- 
ogy identical to anoxic encephalopathy. NMDA blockers 
will ameliorate this secondary neurotoxicity if given be- 
fore an insult.-''-'* and in one report of a similar compound, 
if given after an insult.-'^ 

Recently. NMDA receptors have been identified outside 
the brain and within the pulmonary parenchyma. In an 
isolated perfused rat lung, the addition of NMDA caused 
total pulmonary compliance to decrease, vascular resis- 
tance to increase, and the wet-to-dry ratio of the lung to 
increase. These anomalies were dose-dependent and were 
also blocked in a dose-dependent fashion by competitive 
NMDA receptor antagonists.-"'" 

The addition of vasoactive intestinal peptide also blocked 
the NMDA-induced lung injury. This and other evidence 
makes examination of vasoactive intestinal peptide in acute 
lung injury worth considering as well.'- 


The future progress of therapy for ARDS will be min- 
imal until a 'routine strategy" is articulated and imple- 
mented. This systematic approach must attack the ARDS 
processes at multiple points to maximize the overall effect. 
There must be a systematic approach to therapy, complete 
data collection, and presentation of the data in novel pat- 
tern-recognition software. Following implementation of a 
routine strategy, and reinforcing it with the data-acquisi- 
tion tools necessary for an accurate capture and analysis of 
the entire clinical picture, we can then understand where 
we are now. Without a clear picture of where care is today, 
even a well-articulated course for change only moves us to 
another position that cannot be identified. There is much 
work to be done. 


1. Millenson MM. Demanding medical excellence: doctors and ac- 
countability in the information age. Chicago: The University of Chi- 
cago Press. 1997:423. 

2. Zapol WM, Snider MT. Hill JD. Fallat RJ. Bartlett RH. Edmunds 
LH. et al. Extracorporeal membrane oxygenation in severe acute 
respiratory failure. A randomized prospective study. JAMA 1979; 

3. Morris AH. Wallace CJ. Menlove RL. Clemmer TP. Orme JF Jr. 
Weaver LK. et al. Randomized clinical trial of pressure-controlled 
inverse ratio ventilation and extracorporeal CO, removal for adult 
respiratory distress syndrome. Am J Respir Crit Care Med 1994; 
149(2 Pt l):295-305. 

4. Bernard GR. Luce JM. Sprung CL. Rinaldo JE. Tate RM. Sibbald 
WJ. et al. High-dose corticosteroids in patients with the adult respi- 
ratory distress syndrome. N Engl J Med 1987;317(25):1565-1570. 

5. Fuhmian BP. Partial liquid ventilation and the challenges of ran- 
domized, controlled trials in ARDS. Respir Care 1998;43( 12l:(in 

6. Wennberg DE. Lucas FL. Birkmcyer JD. Bredcnberg CE. Fisher ES. 
Variation in carotid endarlerectomy inortality in the Medicare pop- 
ulation: trial hospitals, volume, and patient characteristics. JAMA 

7. Gardner RM, Shabot MM. Computerized ICU data management: 
pitfalls and promises (review). Int J Clin Monit Comput 1990;7(2): 

8. Evans S. Lemon SJ. Deters C. Fusaro RM, Durham C. Snyder C. 
Lynch HT. Using data mining to characterize DNA mutations by 
patient clinical features. Proc AMIA Annu Fall Symp 1997:253-257. 

9. Evans S, Lemon SJ, Deters CA. Fusaro RM. Lynch HT. Automated 
detection of hereditary syndromes using data mining. Comput Biomed 
Res 1997;30(5):337-.348. 

10. Prather JC. Lobach DF. Goodwin LK. Hales JW. Hage ML. Ham- 
mond WE. Medical data mining: knowledge discovery in a clinical 
data warehouse. Proc AMIA Annu Fall Symp 1997:101-105. 

11. Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved sur- 
vival of patients with acute respiratory distress syndrome (ARDS): 
1983-1993. JAMA 1995:273(4):3()6-.309. 

12. Fackler J. Bohn D. Green T. Heulitt M. Hirshl R, Kleui M. et al. 
ECMO for ARDS; Stopping a RCT (abstract ), Am J Respir Cril Care 
Med 1997;155(4 Pt 2):A.504. 

13. Timmons OD. Havens PL. Fackler JC. Predicting death in pediatric 
patients with acute respiratory failure. Chest 1995:108:789-797. 

Respiratory Care • November 

Vol 43 No 1 1 


Future ARDS Therapies 

Teasdiik- GM. Nicoll JAR. Miirniy O. Hiddes M. Assiicialicin of 
apolipoprotein E polymorphism wilh oulcomc allcr head injury. Lan- 
ce! 1 997:350; 1 069- 1 071. 

Newman MF. Croughwell ND. Blumenthal JA. Lowry E. While 
WD. Spillane W, et al. Predictors of cognitive dechne after cardiac 
operation. Ann Thorac Surg 1995;.^9(.')):1326-1.^.^0. 
Munoz FM. Hawkins EP. Bullard DC, Beaudet AL, Kaplan SL. Host 
defense against systemic infection with Streptococcus pnewmmiae is 
impaired in E-, P-, and E-/P-selectin-deficient mice. J Clin Invest 

'^amasaki K, Edington HD, McClosky C. Teeng E, Lizonova A, 
Kovesdi I, et al. Reversal of impaired wound repair in iNOS-defi- 
cient mice by topical adenoviral-niediated iNOS gene transfer. J Clin 
Invest 1998;I0I(5):967-97I. 

Meduri GU. Headley AS, Golden E, Carson SJ, Umberger RA, 
Kelso T, Tolley EA. Effect of prolonged methylprednisolone therapy 
in unresolving acute respiratory distress syndrome: a randomized 
controlled trial. JAMA I998;280(2):I59-I65. 
Massaro GD. Massaro D. Postnatal treatment with retinoic acid in- 
creases the number of pulmonary alveoli in rats. Am J Physiol 1996; 
270(2 Pt l);L305-L3IO. 

Singh JP, Bonin PD. Inhibition of proliferation of fibroblasts by 
lazaroids (21-aminosteroids). Life Sci I99I:49(26);20.'i3-20.'SS. 
Johnson D, Hurst T, Prasad K, Wilson T, Saxena A, Murphy F, 
Mayers I. Lazaroid pretreatment preserves gas exchange in endotox- 
in-treated dogs. J Cril Care 1994;9(4);2l3-222. 
Miniati M. Cocci F, Monti S, Fiuppi E. Sarnelli R, Ferdeghini M, et 
al. Lazaroid U-74389F attenuates phorbol ester-induced lung injury 
in rabbits. Eur Respir J I996;9(4);7.';8-764. 

Nakayama M. Hasegawa N. Oka Y. Lutzke B. McCall JM, Raffin 
TA. Effects of the lazaroid, tirilazad mesylate, on scpsis- 

mduced acute lung injury m minipigs. Crit Care Med 1998:26(3); 

Chytil F. Retinoids in lung development (review). FASEB J 1996: 

Massaro GD, Massaro D. Retinoic acid treatment abrogates elastase- 
induced pulmonary emphysema in rats. Nat Med I997:3(6);675- 

Zitnik RJ. Kotloff RM, Latilpour J, Zheng T, Whiting NL, Schwalb 
J. Elias JL. Retinoic acid inhibition of IL- 1 -induced IL-6 production 
by human lung fibroblasts. J Immunol 1 994; 152(3); 14 1 9-1 427. 
Krnjevic K. Anoxia and NMDA receptors. In; Ben-Ari Y, editor. 
Excitatory amino acids and neuronal plasticity. New York; Plenum 
Press, l990;475-f79. 

Uematsu D, Greenberg JH, Araki N, Reivich M. Mechanism under- 
lying protective effect of MK-801 against NMDA- induced neuronal 
injury in vivo. J Cereb Blood Flow Metab 1991:1 1(5):779-785. 
Sheardown MJ. Nielsen EO, Han.sen AJ, Jacobsen P, Honore T. 
2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuro- 
protectant for cerebral ischemia. Science 1 990:247(4942 );57 1-574. 
Said SI, Berisha HI. Pakbaz H. N-methyl-D-aspartate receptors out- 
side the central nervous system; activation causes acute lung injury 
that is mediated by nitric oxide synthesis and prevented by vasoac- 
tive intestinal peptide. Neuroscience l995:65(4);943-946. 
Said SI, Berisha HI. Pakbaz H. Excitotoxicity in the lung; N-methyl- 
D-aspartate-induced, nitric oxide-dependent, pulmonary edema is at- 
tenuated by vasoactive intestinal peptide and by inhibitors of poly- 
(ADP-ribose) polymerase. Proc Natl Acad Sci USA 1996:93(10); 

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cells (editorial). J Clin Invest 1996;97( I()):2I6.V2I64. 






onLlne ^ 





'^ , 




Ri spiRATORY Cari; • N()vfmbi;r '98 Vol 4.^ No I I 


Management of Pediatric Patients with ARDS: 
A Survey of Pediatric Intensivists 

Stephen M Schexnayder MD and Mark J Heulitt MD 


Demographics of Participants 

Case 1 

Ventilatory Management 

Support Issues 

Response to Clinical Deterioration 
Case 2 

[RespirCare 1998;43(ll):995-998] Keywords: Pediatric ARDS, management, 
surveys, lung-protective ventilation, high frequency ventilation, extracorporeal 
membrane oxygenation 


The management of pediatric respiratory failure remains 
controversial due to the paucity of data available from 
prospective randomized, controlled trials for different ther- 
apeutic modalities. Expert opinion of treatment choices 
may be valuable. However, little is known about how pe- 
diatric intensivists collectively manage acute respiratory 
failure (ARF). We present data collected through the use 
of an audience feedback system at the 1997 Pediatric Crit- 
ical Care Colloquium (PCCC) held September 17-20, 1997 
in Hot Springs. Arkansas. This yearly symposium is one of 
the largest meetings of pediatric critical care practitioners 
in the U.S. 

Data were collected though a wireless electronic audi- 
ence response system (Options Technologies. Ogden, 
Utah). Two clinical cases were presented by the modera- 
tors of a plenary session at the PCCC. and audience re- 
sponses were tabulated using a notebook computer. Instant 
feedback of survey results was available after all respon- 
dents had registered their responses. 

Dr Schexnayder and Dr Heulitt are both affiliated with Arkansas Chil- 
dren's Hospital, and Department of Pediatrics. Division of Critical Care 
Medicine. University of Arkansas for Medical Sciences. Little Rock, 
Arkansas. Dr Heulitt serves as the Associate Director of Respiratory Care 
Services at Arkansas Children's Hospital. 

Correspondence: Stephen M Schexnayder MD, Arkansas Children's Hos- 
pital. 800 Marshall St, Little Rock AR 72202. 

Demographics of Participants 

Approximately 125 respondents participated in the sur- 
vey. Eighty percent were pediatric intensivists. Other re- 
spondents included anesthesiologists and other physicians, 
nurse practitioners, and respiratory therapists. Approxi- 
mately half (52%) practiced in a children's hospital, with 
another 15*?^ in university hospitals. The remainder prac- 
ticed in general hospitals. Most practiced in pediatric in- 
tensive care units (PICUs) with more than 10 beds, 20% in 
PICUs with 10-15 beds, and 44% in PICUs with >15 
beds. Only 14% practiced in PICUs with 5 or fewer beds. 
Most respondents had been out of training for < 10 years, 
as shown in Figure 1. 

The vast majority (92%) of practitioners reported using 
a iung-protective strategy' for their patients with respira- 
tory failure. Most (46%) believed that peak inspiratory 
pressure was the most important factor in preventing lung 
damage during mechanical ventilation, while 28% believed 
tidal volume was the most important factor, and 25%^ 
thought the inspired oxygen concentration was most im- 
portant. Most conference participants were unsure if a lung- 
protective strategy was actually improving survival. 

Case One 

A 3-year-old female presented to the emergency 
room with a 3-day history of fever and productive 
cough. Upon arrival at the local hospital emergency 
room, the patient was tachypneic and in inoderate 

Respiratory Care • November '98 Vol 43 No 11 


Pediatric ARDS Management Survey 

< 1 year 1-5 5-10 10-15 >15 years 

Fig. 1. Survey participants — time since completion of fellowship training (n = 104). 

respiratory distress. Physical examination revealed 
bilateral rales, no wheezes, and intercostal retrac- 
tions. While breathing room air, the patient's oxy- 
hemoglobin saturation by pulse oximetry was 87%. 
Chest radiograph revealed bilateral infiltrates. The 
patient was given oxygen via a nasal cannula at 4 
L/min and had a pulse oximeter saturation of 100%. 
After being placed on oxygen, her respiratory rate 
decreased and she appeared to have only mild work 
of breathing. Antibiotics (cefotaxime) were started. 
Laboratory evaluation revealed an elevated white 
blood cell count with a left shift. Approximately 4 
hours after admission, the patient developed signs 
of increased work of breathing. Physical exam 
showed bilateral crackles, intercostal retractions, and 
nasal flaring. Arterial blood gas values while the 
patient breathed 40% oxygen were pH 7.26, arterial 
carbon dioxide tension (Paco,) 48mm Hg. arterial 
oxygen tension (P„o,) 134 mm Hg, with a base 
excess of -3 mEq/L. 

Ventilatory Management 

While respondents (71 %) indicated that they would 
not institute mechanical ventilation in this patient, respon- 
dents were asked their preferences for management if me- 
chanical ventilation became necessary. Over half (53%) 
selected an initial Vj of 10 mL/kg, but another third se- 
lected < 10 mL/kg. Most respondents would tolerate a 
peak inspiratory pressure (PIP) of 35-40 cm H^O. with 
53% selecting 35 cm H^O as the upper tolerable limit, and 
another 36% accepting up to 40 cm H^O. Most respon- 
dents (66% ) selected a starting positive end-expiratory pres- 
sure (PEEP) of 5-10 cm H2O, with one third selecting 5 
cm HjO as the starting PEEP level. 

While most respondents started at modest PEEP levels, 
the group indicated a willingness to increase PEEP to high 
levels as long as cardiovascular stability was maintained. 
Thirty percent of the respondents would use a maximum 
PEEP of 10-15 cm H,0, while 43% would set 15-20 cm 
HjO as a maximum PEEP level. One quarter of the group 
would set no absolute limit for PEEP. 

Table 1 . Survey Respondents' Choices of Sedatives and Analgesics 


' Total Respondents 
(/I = 125) 

Intermittent midazolam 


Intermittent lorazepam 


Intermittent benzodiazepine in combination 


with a narcotic 

Continuous midazolam infusion with 


intermittent narcotic 

Continuous lorazepam infusion with 


mtermittenl narcotic 

Propofol infusion 


Continuous infusion of midazolam and 



Continuous infusion of lorazepam and fentanyl 


Support Issues 

Most respondents (64%) indicated they would not em- 
pirically change antibiotics at this point in the hypothetical 
case, and 72% would begin enteral nutrition by transpy- 
loric (70%) or continuous gastric feeding. Sedative and 
analgesic selection varied widely as indicated in Table 1 . 
The use of neuromuscular blocking agents was almost 
evenly split, with 45% indicating they would use neuro- 
muscular blockade, while 55% would not after the patient 
was placed on mechanical ventilatory support. Forty-five 
percent of the respondents indicated that they would use 
intermittent doses of vecuronium (20%) or pancuronium 
(25%). with 55% selecting continuous infusions of either 
vecuronium (41%) or pancuronium (14%). 

Reponse to Clinical Deterioration 

The audience was then given the following scenario: 

Over the next 12 hours, the patient had increased 
pulmonary opacification on the chest radiograph. 
Oxygenation worsened with a pulse oximeter satu- 
ration of 91% on fraction of inspired oxygen (F,,,,) 
O.^O. Vcntilator\ seltines at this lime were PEEP 17 


RnspiR.vroRV Carf; • Novembf'.r "98 Vol 43 No 1 1 

Pediatric ARDS Management Survey 

cm H,0, Vt- 8mL/kg, PIP 42 cm H,0 on pressure 
regulated volume control. Mean airway pressure was 
2! cm H,0. 

The vast majority of respondents (84<7f) said they would 
then switch to high-frequency oscillatory ventilation 
(HFOV), while 9% indicated an increase in PEEP would 
be the next step in management. The remaining 7% of 
respondents chose adding nitric oxide. Initial HFOV ven- 
tilator settings advocated included a mean airway pressure 
of 2 1 cm HjO (5%), 23 (7%), 25 (44%), or 27 (44%), then 
advanced up to a maximum of 30 (6%), 32 (2%), 34 (1 3%), 
36 (18%), or 40 (42%). Nine percent of respondents indi- 
cated they would increase the mean airway pressure to the 
maximum the ventilator would deliver. Most intensivists 
(58%) said they would decrease the HFOV frequency in 
the face of marginal oxygenation. 

The group was then presented with the scenario of wors- 
ening respiratory status despite the interventions. A mi- 
nority (33%) of the intensivists believed that the hypothet- 
ical patient was a candidate for extracorporeal membrane 
oxygenation (ECMO), although most (60%) said they 
would consider transport to an ECMO center. 

Case 2 

An intubated 3-month-old patient with a history of 
premature birth (28 wk gestation) was referred to 
your institution for further management. It is win- 
ter; the patient's enzyme-linked immunosorbent as- 
say (ELISA) test for respiratory syncytial virus 
(RSV) is negative. On physical examination, the 
patient initially had diffuse wheezes with a pro- 
longed expiratory phase. The patient was started on 
jS agonists with improvement in auditory wheezes. 
Over the next 24 hours, the patient's status im- 
proved and was being supported on conventional 
mechanical ventilation (CMV) with F,o, 0.35. En- 
teral feeding was started and the patient was receiv- 
ing antibiotics (cefotaxime). Over the next 2 days, 
the patient had no further evidence of wheezes but 
had an increased oxygen requirement. The patient 
continued on CMV, and PEEP was increased with- 
out improvement. 

Most respondents said they would continue j3 agonist ther- 
apy despite a decrease in oxygenation. Most (62%) would 
switch to HFOV, while 25% would use nitric oxide, and 
13% would use exogenous surfactant to improve oxygen- 
ation. Most respondents believed HFOV was not contra- 
indicated in patients with bronchospasm. 


Little is known about the practices of physicians treat- 
ing ARF. While this survey does not scientifically evaluate 

the actual practices of pediatric intensivists, the prevailing 
consensus opinion can be useful. When randomized con- 
trolled trials are lacking, a number of organizations use 
consensus expert opinion to develop clinical practice guide- 
lines. This survey offers some interesting insights into the 
management of patients with pediatric acute respiratory 
distress syndrome (ARDS). The majority of respondents 
utilized a low stretch (Vj <10 mL/kg) ventilator strategy 
with limited PIP. The justifications for this strategy are 
outlined elsewhere in this issue.' Such a strategy may 
theoretically reduce iatrogenic lung injury, and the results 
of this survey indicate most of the practitioners surveyed 
believe this strategy has merit at the bedside. While recent 
data suggest that mortality is decreasing in pediatric pa- 
tients with ARDS. this approach has not been proven in a 
randomized clinical trial.- Trials of lung-protective strat- 
egy or pressure-limited strategy in adults have shown con- 
flicting results.-''-* 

Another change in practice demonstrated in this survey 
is the early use of HFOV. The majority of respondents 
indicated that they would move quickly to HFOV when 
CMV was failing. Their definition of the 'failure" of CMV 
was based on a desire to limit iatrogenic lung injury with 
a strategy that liinits PIPs during CMV. This increased use 
of HFOV has been demonstrated in one of the most recent 
clinical trials involving pediatric patients with ARDS.- 
This increased use of HFOV is interesting because there is 
a paucity of data demonstrating its efficacy.^ The same 
issue exists for data supporting the use of ECMO pediatric 
patients with ARDS, but over half of the respondents would 
transfer their patient to an ECMO center if the patient's 
condition was worsening. 

General supportive practices varied among participants, 
but a pattern of early enteral nutrition with the liberal use 
of sedation and pain control was consistent among respon- 
dents. Despite the current climate of cost containment in 
the United States, most (61%) chose vecuronium over pan- 
curonium for neuromuscular blockade despite a significant 
cost savings when using pancuronium. 


In summary, a pressure-limited approach or lung-pro- 
tective strategy for the management of pediatric ARF has 
gained widespread acceptance despite a limited ainount of 
clinical data to support its use. The falling mortality rate 
for children with ARF may be a surrogate marker of this 
technique's efficacy, given its widespread use reported in 
this survey. 


1. Heulitt MJ; Bohn D. Lung-protective strategy in pediatric patients 
with acute respiratory distress syndrome. Respir Care I998;43(ll): 

Respiratory Care • November '98 Vol 43 No 1 1 


Pediatric ARDS Management Survey 

Facklcr J. Bohn D. Green T. Hculill M, Hirschl R. Klein M. el al. 
ECMO for ARDS: Slopping a RCT (abstract). Am J Respir Crit Care 
Med I997;155(4):A504. 

Stewart TE, Meade MO. Cook DJ. Granton JT, Hodder RV, Lapin- 
sky SE. et al. Evaluation of a ventilation strategy to prevent baro- 
trauma in patients at high risk for acute respiratory distress syn- 
drome. Pressure- and Volume-Limited Ventilation Strategy Group. 
New Engl J Med I998;338{6):355-36I. 

4. Amato MB. Barbas CS, Medeiros DM. Magaldi RB. Schettino GP. 
Lorenzi-Filho G, et al. Effects of protective-ventilator strategy on 
mortality in the acute respiratory distress syndrome. N Engl J Med 

5. Arnold JH. Truog RD, Thompson JE. Fackler JC. High-frequency 
oscillatory ventilation in pediatric respiratory failure. Crit Care Med 








Respiratory Care • November '98 Voi. 43 No 1 1 

CRCE through iheJournal-1998 
Answer Key 

For your information, the correct answers to tiie 50 questions for CRCE through 
the Joumai whicii appeared in the August 1998 issue of RESPIRATORY CARE, are 
given below. No scores will be available from the AARC until 1998 transcripts 
are released in early 1999. Deadline for submission of answer sheets for CRCE 
credit was October 30, 1998. 

1. c 







41. C 

2. A 







42. A 

3. B 







43. E 

4. D 







44. D 

5. D 







45. C 

6. C 







46. C 

7. C 







47. B 

8. A 







48. E 

9. E 







49. C 

0. C 







50. C 

Respiratory Care • November 1998 Vol 43 No 1 1 


American Thoracic Society 
Pulmonary Function Laboratory 
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And much more! 

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New Products 
& Services 

Pulse Oximeter. Nonin Medical Inc intro- 
duces its new pulse oximeter, the Xpod In- 
Line OEM Pulse Oximeter. Nonin describes 
this product as a unique device designed to 
simply plug into a multi-function monitor 
and that no board integration into the user's 
monitor is necessary. Company literature also 
says that low power draw (60mW @ 3-6 
volts DC), simplified design (3 wire inter- 
face), and environmental seal provide an eco- 
nomical alternative to incorporating pulse 
oximetry and that private labeling and cus- 
tom interface options are available. For more 
information from Nonin Medical Inc, circle 
number 167 on the reader service cai'd in this 
issue, or send your request electronically via 
"Advertisers Online" at http://www.aarc. 

Digital PSG for Sleep Studies. Grass InsUii- 
ment Division. Astro-Med Inc. introduces 
a newly designed portable digital polysomno- 

graph (PSG). The company calls the device 
the Albert Grass Heritage colleague PSG and 
describes it as a compact system that com- 
bines modular, high-performance amplifiers 
with a powerful software program called 
Gamma. Company literature says the heart 
of the system is comprised of the Grass 
amplifiers that give the user complete con- 
trol over all channels and settings. Grass also 
says the software package. Gamma, is Win- 
dows based and permits the user to record 
polysomnographic signals in real time, with 
rapid accurate scoring. For more informa- 
tion from Grass Instrument Division, Astro- 
Med Inc, circle number 168 on the reader 
service card in this issue, or send your request 
electronically via "Advertisers Online" at 

Critical Care Analyzer Literature Avail- 
able. AVL Scientific Corporation has made 
available product literature for the AVL 
OFTI"' Critical Care Analyzer. A company 
press release says that the new four-color 
booklet provides detailed information on 
product features and the benefits of the Opti 
analyzer's portability and ease-of-use. AVL 
says the device's features allow clinicians 
to perform rapid and reliable blood gas/elec- 
trolyte analyses at point-of-care sites. The 
company also says the literature contains 
descriptions of the Opti Critical Care Ana- 
lyzer's single-use cassettes feature which, 
according to AVL, conveniently store at 
room temperature and allow for seven dif- 
ferent measurement configurations in the 
analysis of a wide range of parameters, 
including pH, total hemoglobin, oxygen sat- 
uration, blood gas and electrolyte parame- 
ters, as well as a wide range of calculated 
parameters. For more information from AVL 
Scientific Corporation, circle number 169 
on the reader service card in this issue, 
or send your request electronically via 
"Advertisers Online" at http://www.aarc. 

Cardiac Assessment System. The Elec- 
tromedical Systems Division of Siemens 
Medical Systems Inc. introduces the Infin- 

ity Telemetry"" System. According to 
Siemens, this system is an integrated solu- 
tion for cardiac assessment that provides a 
complete view of a patient's ECG status from 
all points of care. A company press release 
says the device provides real-time 7-lead 
ECG monitoring with integrated SpO: mon- 
itoring and 7-lead ST segment analysis 
options. Siemens also says the system gives 
caregivers hospital-wide access to the infor- 
mation over a single Infinity Network"' that 
is based on open system architecture and 
adheres to international standards. For more 
information from Siemens Medical Systems 
Inc, circle number 170 on the reader service 
card in this issue, or send your request elec- 
tronically via "Advertisers Online" at 

Pediatric Mouthpiece. Vitalograph has 
introduced a pediatric version of their SafeT- 
way'" mouthpiece. The company says the 
device is designed to reduce both the pos- 
sibility of cross-infection and the need for 
cleaning PFT equipment between patients. 
Company literature says this is a low-cost, 
patented mouthpiece that incorporates a one- 
way flap valve which prevents the patients 
from breathing in, and therefore reduces the 
chances of breathing contaminated air. The 
company says that resistance to flow has been 
minimized by using the valve from the adult 
version in conjunction with the smaller 
mouth-piece tube. Vitalograph says the 
mouthpiece is compatible with most com- 
mon brands of peak flow meters and spirom- 
eters and that adapters are available for non- 
standard sizes. For more information from 
Vitalograph. circle number 171 on the reader 
service card in this issue, or send your request 



New Products & Services 

electronically via "Advertisers Online" at 




Portable Nebulizer. Omron Healthcare Inc. 
has introduced its new MicroAir' "go-any- 
where" nebulizer. Omron describes the bat- 
tery-operated nebulizer as lightweight, com- 

pact, quiet, and portable and says it uses ultra- 
sound medication delivery. The company 
says the device has 98% efficiency in deliv- 
ering required drug dosage and that it is an 
ideal option for children and infants who 
might otherwise be distressed by the noise 
and large sizes of .standard nebulizers. Omron 
says the nebulizer comes with an AC adapter, 
mouthpiece, mask, mesh caps, and carrying 
case along with an instructional video. For 
more information from Omron Healthcare 
Inc, circle number 172 on the reader service 
card in this issue, or send your request elec- 
tronically via "Advertisers Online" at 

Supplies for Blood Gas Instruments. Alko 
Diagnostic Corporation has recently intro- 
duced calibrators and accessory solutions 
for use on IL 1610 and 1620 instruments. 
Alko says the new product line includes 
6.840 Buffer, 7.384 Buffer, Flush Solution 
Kit, and Calibration Gases. Company lit- 

erature says the buffers provide calibration 
points for the pH electrode in the IL 1610 
and IL 1620 instruments; the flush solu- 
tion kit is used to flush the sample flow 
path; and that the calibration gases provide 
calibration points for the Pco; and the 
Po; electrodes. Alko literature also says the 
buffers and flush kits have a 2-year 
outdate. the calibration gases have a 3-year 
outdate, and that all of the calibrators are 
packaged to fit into the analyzer and are 
equivalent in volume to those products sold 
by the original manufacturer. Alko says 
all of their consumables serve as functional 
equivalents to those distributed by the 
original manufacturer and that correlation 
data are available upon request. For more 
information from Alko Diagnostic 
Corporation, circle number 173 on the 
reader service card in this issue, or send 
your request electronically via "Adver- 
tisers Online" at 
















'^ . 





Respiratory Care • November 1998 Vol 43 No 1 1 


For VOLUNTARY reportinjj 

by health professionals of ad\ erst- 

events and product problems 

I OMB No. 0910-0291 Eai 

FDA Use Only (Resp C 

1 1) 111 I s KHMIK 1 IN(. PKOI.KA 

A. Patient information 

1 Patient identifier 

In confidence 

Age at time 
of event: 

of birtti: 

3 Sex 

I I female 
I I male 


4 Weigtit 

B. Adverse event or product problem 

1, 1^ Adverse event and/or [ ^ Product problem (eg , defects/malfunclions) 

2 Outcomes attributed to adverse event | — , 

(check all ihal apply) I I disability 

r-| jjga,h D congenital anomaly 

— imo/day/yr) [^ required intervention to prevent 

I I life-ttireatening permanent impairment/damage 

I I hospitalization - initial or prolonged Lj other 

3 Date of 

4 Date of 
this report 

5. Describe event or problem 

6. Relevant tests/laboratory data, including dates 

7 Ottier relevant fiistory, including preexisting medical conditions (e g , allergies, 
race, pregnancy, smoking and alcohol use, hepatic/renal dysfunction, etc ) 

Mail to: mEDWaTCH or FAX to: 

5600 Fishers Lane 1 -800-FDA-01 78 

Rocl<ville, MD 20852-9787 

C. Suspect medication(s) 

1 Name (give labeled strength & mir/labeler, if known) 

2 Dose, frequency & route used 

3 Therapy dates (if unknown, give duration) 


4 Diagnosis for use (indication) 

6 Lot # (if known) 

7, Exp. date (if known) 

9 NDC * (for product problems only) 

5 Event abated after use 
stopped or dose reduced 

#inyesnho ngggpy"'' 

#2 Dyes Dno D^ggpy"'' 

8 Event reappeared after 

#1 Dyes Dho ngggpy"'' 

#2 Dyes n™ n&'" 

10 Concomitant medical products and therapy dates (exclude treatment of event) 

D. Suspect medical device 

1 Brand name 

2 Type of device 

3 lUlanufacturer name & address 

model # 

catalog # 

serial # 


other # 

4 Operator of device 

I I health professional 
I I lay user/patient 
□ other: 

5 Expiration date 

7 If implanted, give date 


9 Device available for evaluation? (Do not send to FDA) 
I I yes LJ no Q returned to manufacturer on 

1 Concomitant medical products and therapy dates (exclude treatment of event) 

E. Reporter (see confidentiality section on back) 

1 Name & address 

2 Health professional? 

D yes n ho 

3 Occupation 

5 If you do NOT want your identity disclosed to 
the manufacturer, place an " X " in this box. LJ 

4 Also reported to 

I I manufacturer 
I I user facility 
I I distnbutor 

FDA Form 3500 1/96) 

Submission of a report does not constitute an admission that medical personnel or the product caused or contributed to the e' :it. 


Report experiences with: 

• medications (drugs or biologies) 

• medical devices (including in-vitro diagnostics) 

• special nutritional products (dietary 
supplements, medical foods, infant formulas) 

• other products regulated by FDA 

Report SERIOUS adverse events. An event 
is serious when the patient outcome is: 

• deatfi 

• life-threatening (real risk of dying) 

• hospitalization (initial or prolonged) 

• disability (significant, persistent or permanent) 

• congenital anomaly 

• required intervention to prevent permanent 
impairment or damage 

Report even if: 

• you're not certain the product caused the 

• you don't have all the details 

Report product problems - quality, performance 
or safety concerns such as: 

• suspected contamination 

• questionable stability 

• defective components 

• poor packaging or labeling 

• therapeutic failures 

How to report: 

• just fill in the sections that apply to your report 

• use section C for all products except 
medical devices 

• attach additional blank pages if needed 

• use a separate form for each patient 

• report either to FDA or the manufacturer 
(or both) 

Important numbers: 

• 1-800-FDA-0178 to FAX report 

• 1-800-FDA-7737 to report by modem 

• 1-800-FDA-1088 to report by phone or for 

more information 
•1-800-822-7967 for a VAERS form 
for vaccines 

If your report involves a serious adverse event 
with a device and it occurred in a facility outside a doc- 
tor's office, that facility may be legally required to report to 
FDA and/or the manufacturer. Please notify the person in 
that facility who would handle such reporting. 

Confidentiality: The patient's identity is held in strict 
confidence by FDA and protected to the fullest extent of 
the law. The reporter's identity, including the identity of a 
self-reporter, may be shared with the manufacturer unless 
requested otherwise. However, FDA will not disclose the 
reporter's identity in response to a request from the 
public, pursuant to the Freedom of Information Act. 

The public reporting burden for this collection of information 
has been estimated to average 30 minutes per response, 
including the time for reviewing instructions, searching exist- 
ing data sources, gattiermg and maintaining the data needed, 
and completing and reviewing the collection of information. 
Send comments regardmg this burden estimate or any other 
aspect of this collection of information, including suggestions 
for reducing this burden to 

DHHS Reports Clears 

200 Independence Aveni 
Washington, DC 20201 

1 Projecl 10910-0291) 

Please do NOT 
return this forin 
to either of these 

Please Use Address Provided Below - Just Fold In Thirds, Tape and Mail 

Department of 

Health and Human Services 

Public Health Service 

Food and Drug Administration 

Rockville. MD 20857 

Official Business 

Penalty for Pnvate Use S300 











The FDA Medical Products Reporting Program 
Food and Drug Administration 
5600 Fishers Lane 
Rockville, MD 20852-9787 


1999 Respiratory Care Open Forum 

The American Association for Respiratory Care and its 
science journal, RESPIRATORY CARE, invite subinission of 
brief abstracts related to any aspect of cardiorespiratory care. 
The abstracts will be reviewed, and selected authors will be 
invited to present posters at the OPEN FORUM during the 
AARC International Respiratory Congress in Las Vegas. 
Nevada. December 13-16. 1999. Accepted abstracts will be 
published in the November 1999 issue of RESPIRATORY CARE, 
Membership in the AARC is not required for participation. 
All accepted abstracts are automatically considered for ARCF 
research grants. 


An abstract may report (1) an original study, (2) the eval- 
uation of a method, device or protocol, or (3) a case or 
case series. Topics may be aspects of adult acute care, con- 
tinuing care/rehabilitation, perinatology/pediatrics, cardio- 
pulmonary technology, or health care delivery. The abstract 
may have been presented previously at a local or regional — 
but not national — meeting and should not have been published 
previously in a national journal. The abstract is the only evi- 
dence by which the reviewers can decide whether the author 
should be invited to present a poster at the OPEN FORUM. 
Therefore, the abstract must provide all important data, find- 
ings, and conclusions. Give specific information. Do not write 
general statements, such as "Results will be presented" or 
"Significance will be discussed." 


Original study. Abstract must include 1 1 ) Background: 
statement of research problem, question, or hypothesis; (2) 
Method: description of research design and conduct in suf- 
ficient detail to permit judgment of validity; (3) Results: state- 
ment of research findings with quantitative data and statis- 
tical analysis; (4) Conclusions: intetpretation of the meaning 
of the results. 

Method, device, or protocol evaluation. Abstract must 
include ( 1 ) Background: identification of the method, device, 
or protocol and its intended function; (2) Method: descrip- 
tion of the evaluation in sufficient detail to permit judgment 
of its objectivity and validity; (3) Results: findings of the eval- 
uation; (4) Experience: summary of the author's practical expe- 
rience or a lack of experience; (5) Conclusions: interpreta- 
tion of the evaluation and experience. Cost comparisons should 
be included where possible and appropriate. 

Case report. Abstract must report a case that is uncom- 
mon or of exceptional educational value and must include ( 1 ) 
Introduction: relevant basic information important to under- 
standing the case. (2) Case Summary: patient data and response, 
details of interventions. (3) Discussion: content should reflect 
results of literature review. The author(s) should have been 
actively involved in the case and a case-managing physician 
must be a co-author or must approve the report. 


Accepted abstracts will be photographed and reduced by 
40%; therefore, the size of the original text should be at least 
10 points. Abstracts should be 400 words or less and may 
hare 1 clear, concise table or figure. A font like Helvetica 
or Geneva makes the clearest reproduction. The first line of 
the abstract should be the title in all capital letters. Title should 
explain content. Follow title with names of all authors (includ- 
ing credentials), institution(s). and location; underline pre- 
senter's name. Type or electronically print the abstract sin- 
gle spaced in a single paragraph in the space provided on 
the abstract blank. In,sert only one letter space between sen- 
tences. Text submission on diskette is encouraged but must 
be accompanied by a hard copy. Data may be submitted in 
table form, or a simple figure may be included provided it 
fits within the space allotted. No figure, illustration, or table 
is to be attached to the abstract fonn. Provide all author infor- 
mation requested. A clear photocopy of the abstract form may 
be used. Standard abbreviations may be employed without 
explanation; new or infrequently used abbreviations should 
be spelled out on first use. Any recurring phrase or expres- 
sion may be abbreviated, if it is first explained. Check the 
abstract for (1) errors in spelling, grammar, facts, and fig- 
ures: (2) clarity of language; and (3) conformance to these 
specifications. An abstract not prepared as requested may 
not be reviewed. Questions about abstract preparation may 
be telephoned to the editorial staff of RESPIRATORY CARE 
at (972) 406-4667. 

Early Deadline Allowing Revision. Authors may choose 
to submit abstracts early. Abstracts postmarked by April 2, 
1999 will be reviewed and the authors notified by letter only 
to be mailed by May 7, 1999. Rejected abstracts will be accom- 
panied by a written critique that should, in many cases, enable 
authors to revise their abstiacts and resubmit them by the Final 
Deadline (June 11, 1999). 

Final DeadHne. The mandatory Final Deadline is June 1 1, 
1999 (postmark). Authors will be notified of acceptance or rejec- 
tion bv letter onlx. These letters will be mailed by August 25, 

Mailing Instructions. Mail (do not fax!) 2 clear copies 

of the completed abstract form, diskette (if possible), and a 

stamped, self-addressed postcard (for notice of receipt) to: 

1999 Respiratory Care Open Forum 

11030 Abies Lane 

Dallas TX 75229-4593 

submit your Open forum abstract electronically 

, . 

1999 Respiratory Care Open Forum Abstract Form 

13.9 cm or 5.5" 

1. Title must be in all 
uppercase (capital) 
letters, authors' full 
names and text in upper 
and lower case. 

2. Follow title with all 
authors' names, includ- 
ing credentials (under- 
line presenter's name), 
institution, and 

3. Do not justify 

(ie, leave a 'ragged' 
right inarginl. 

4. Do not use type size 
less than 10 points. 

(Do not exceed 400 

5. All text and the table, 
or figure, must fit into 
the rectangle shown. 
(Use only 1 clear, con- 
cise table or figure.) 

6. Submit 2 clean copies. 
This form may be pho- 
tocopied if multiple 
abstracts are to be 

Mail original & 1 
photocopy (along with 
postage-paid postcard) to 

1999 Respiratory 
Care Open Forum 
11030 Abies Lane 
Dallas TX 75229-4593 

Earl\ Deadline is 
April 2. 1999 

Final Deadline is 

June 11. 1999 (postmark) 


Submission Is Now 

Available. Visit 

to find out more 

Name & Credentials 

Mailing Address 

Voice Phone & Fax 

Name & Credentials 

Mailing Address 

Voice Phone & Fax 


Manuscript Preparation Guide 

General Information 

Respiratory Care welcomes original manuscripts related to the 
science and technology of respiratory care and prepared accord- 
ing to these Instructions and the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals [Respir Care 1 997; 
42(6):623-634]. Manuscripts are blinded and reviewed by pro- 
fessionals who are experts in their fields. Authors are responsible 
for all aspects of the manuscript and receive galleys to proofread 
before publication. Each accepted manuscript is copyedited so that 
its message is clear and it conforms to the Journal's style. Published 
papers are copyrighted by Daedalus Inc and may not be published 
elsewhere without permission. 

Editorial consultation is available at any stage of planning or writ- 
ing. On request, specific guidance is provided for all publication cat- 
egories. To receive these Instructions and related materials, write 
to Respiratory Care, 600 Ninth Avenue, Suite 702, Seattle WA 
98104, call (206) 223-0558, or fax (2061 223-0563. 

Publication Categories & Structure 

Research Article: A report of an original investigation (a study). 
It includes a Title Page, Abstract, Introduction, Methods, Results, 
Discussion, Conclusions, Product Sources, Acknowledgments, Ref- 
erences, Tables, Appendices, Figures, and Figure Captions. 

Evaluation of Device/Method/Technique: A description and eval- 
uation of an old or new device, method, technique, or modification. 
It has a Title Page, Abstract, Introduction. Description of De- 
vice/Method/Technique, Evaluation Methods, Evaluation Results, 
Discussion, Conclusions, Product Sources, Acknowledgments, Ref- 
erences, Tables, Appendices, Figures, and Figure Captions. Com- 
parative cost data should be included wherever possible. 

Case Report: A report of a clinical case that is uncommon, or was 
managed in a new way, or is exceptionally instructive. All authors 
must be associated with the case. A case-managing physician must 
either be an author or furnish a letter approving the manuscript. Its 
components are Title Page, Abstract, Introduction, Case Summa- 
ry, Discussion, References, Tables, Figures, and Figure Captions. 

Review Article: A comprehensive, critical review of the literature 
and state-of-the-art summary of a pertinent topic that has been the 
subject of at least 40 published research articles. Title Page, Out- 
line, Introduction, Review of the Literature, Summary. Acknowl- 
edgments, References. Tables, Appendices, and Figures and Cap- 
tions may be included. 

Overview: A critical review of a pertinent topic that has fewer than 
40 published research articles. 

Update: A report of subsequent developments in a topic that has 
been critically reviewed in this Journal or elsewhere. 

Point-of-View Paper: A paper expressing personal but substanti- 
ated opinions on a pertinent topic. Title Page, Text, References, Tables, 
and Illustrations may be included. 

Special Article: A pertinent paper not fitting one of the foregoing 
categories may be acceptable as a Special Article. Consult with the 
Editor before writing or submitting such a paper. 

Editorial: A paper drawing attention to a pertinent concern; it may 
present an opposing opinion, clarify a position, or bring a problem 
into focus. 

Letter: A signed communication, marked "For publication," 
about prior publications in this Journal or about other pertinent top- 
ics. Tables and illustrations may be included. 

Blood Gas Corner: A brief, instructive case report involving blood 
gas values — with Questions, Answers, and Discussion. 

Drug Capsule: A mini-review paper about a drug or class of drugs 
that includes discussions of pharmacology, pharmacokinetics, 
and pharmacotherapy. 

Graphics Corner: A briefcase report incorporating waveforms for 
monitoring or diagnosis — with Questions, Answers, and Discussion. 

Kittredge's Comer: A brief description of the operation of respiratory 
care equipment — with information from manufacturers and edito- 
rial comments and suggestions. 

PET Corner: Like Blood Gas Corner, but involving pulmonary 
function tests. 

Cardiorespiratory Interactions. A case report demonstrating the 
interaction between the cardiovascular and respiratory systems. It 
should be a patient-care scenario: however, the case — the central 
theme — is the systems interaction. CRI is characterized by figures, 
equations, and a glossary. See the March 1996 Issue of RESPIRA- 
TORY Care for more detail. 

Test Your Radiologic Skill: Like Blood Gas Corner, but involv- 
ing pulmonary medicine radiography and including one or more radio- 
graphs; may involve imaging techniques other than conventional 
chest radiography. 

Review of Book, Eilm, Tape, or Software: A balanced, critical 
review of a recent release. 

Preparing the Manuscript 

Print on one side of white bond paper, 8.5 in. x 1 1 in. (216 x 279 mm) 
with margins of at least 1 in. (25 mm) on all sides of the page. Use 
double-spacing throughout the entire manuscript. Use a standard 
font (eg. Times, Helvetica, or Courier I at least 1 points in size, and 

Respiratory Care Manuscript Preparation Guide, Revised 2/98 

Manuscript Preparation Guide 

do not use italics except tor special emphasis. Number all pages in 
upper-right comers. Indent paragraphs 5 spaces. Do not justify. Do 
not put authors' names, institutional affiliations or allusions to 
institutional afTiliations in the text, or other identification any- 
where except on the title page. Repeat title only (no authors) on 
the abstract page. Begin each of the following on a new page: Title 
Page, Abstract. Text. Product Sources List, Acknowledgments, Ref- 
erences, each Table, and each Appendix. Use standard English in 
the first person and active voice. 

Center main section headings on the page and type them in cap- 
ital and small letters (eg. Introduction. Methods, Results, Discus- 
sion). Begin subheadings at the left margin and type them in cap- 
ital and small letters (eg. Patients, Equipment, Statistical Analysis). 

References, Cite only published works as references. Manuscripts 
accepted but not yet published may be cited as references: desig- 
nate the accepting journal, followed by (in press), and provide 3 copies 
of the in-press article for reviewer inspection. Cite references in the 
text with superscript numerals. Assign numbers in the order that ref- 
erences are first cited. On the reference page, list the cited works 
in numerical order. Follow the Journal's style for references. Abbre- 
viate journal names as in Index Medicus. List all authors. 

Article in a journal carrying pagination throughout volume: 

Rau JL. Harwood RJ. Comparison of nebulizer delivery methods 
through a neonatal endotracheal tube: a bench study. Respir Care 
1992:37(11): 1233- 1 240. 

Article in a publication that numbers each issue beginning with 
Page 1 : 

Bunch D. Establishing a national database for home care. AARC Times 

Corporate author journal article: 

American Association for Respiratory Care. Criteria for establish- 
ing units for chronic ventilator-dependent patients in hospitals. Respir 
Care 1988:33( 1 1 ): 1044- 1046. 

Article in journal supplement: (Journals differ in their methods of 
numbering and identifying supplements. Supply sufficient information 
to promote retrieval.) 

Reynolds HY. Idiopathic interstitial pulmonary fibrosis. Chest 1986; 


Abstract in journal: (Abstracts citations are to be avoided. Those more 

than .3 years old should not be cited.) 

Stevens DP. .Scavenging ribavirin from an oxygen hood to reduce envi- 
ronmental exposure (abstract). Respir Care iy90:3.'i( 1 1 1: 1087-1088. 

Editorial in journal: 

Enrighl P. Can we relax during spirometry? (editorial). Am Rev Respir 
Dis 1993;148(2):274. 

Editorial with no author given: 

Negative-pressure ventilation for chronic obstructi\c pulmonary dis- 
ease (editorial). Lancet 1992;.340(88.33):144()-I441. 

Letter in journal: 

Aelony Y. Ethnic norms for pulmonary function tests (letter). Chest 

Paper accepted but not yet published: 

Hess D. New therapies for asthma. Respir Care (year, in press). 

Personal author book: (For any book, specific pages should be cited 
whenever possible.) 

DeRemee RA. Clinical profiles of diffuse interstitial pulmonary dis- 
ease. New York: Futura; 1990. p. 76-85. 

Corporate author book: 

American Medical Association Department of Drugs. AMA drug eval- 
uations, 3rd ed. Littleton CO: Publishing Sciences Group; 1977. 

Chapter in book with editor(s): 

Pierce AK. Acute respiratory failure. In: Guenter CA, Welch MH, edi- 
tors. Pulmonary medicine. Philadelphia: JB Lippincott: 1977:26-42. 

Tables. Use consecutively numbered tables to display information. 
Start each table on a separate page. Number and title the table and 
give each column a brief heading. Place explanations in footnotes, 
including all nonstandard abbreviations and symbols. Key the foot- 
notes with conventional designations (*. t. +. §. II, |, **, t+) in con- 
sistent order, placing them superscript in the table body. Do not use 
horizontal or vertical rules or borders. Do not submit tables as pho- 
tographs, reduced in size, or on oversize paper. Use the same type- 
face as in the text. 

Illustrations. Graphs, line drawings, photographs, and radiographs 
are figures. Use only illustrations that clarify and augment the text. 
Number them consecutively as Fig. 1, Fig. 2, and so forth accord- 
ing to the order by which they are mentioned in the text. Be sure 
all figures are cited. If any figure was previously published, include 
copyright holder's written permission to reproduce. Figures for 
publication must be of professional quality. Data for the original 
graphs should be available to the Editor upon request. If color is essen- 
tial, consult the Editor for more information. In reports of animal 
experiments, use schematic drawings, not photographs. A letter of 
consent must accompany any photograph of a person. Do not place 
titles and detailed explanations on figures; put this information in 
figure captions. If possible, submit radiographs as prints and full- 
size copies of film. 

Drugs. Identify precisely all drugs and chemicals used, giving gener- 
ic names, doses, and routes of administration. If desired, brand names 
may be given in parentheses after generic names. Drugs should be 
listed on the product-sources page. 

Commercial Products. In parentheses in the text, identify any com- 
mercial product (including model number if applicable) the first time 
it is mentioned, giving the manufacturer's name. city, and state or 
country. If four or more products are mentioned, do not list any man- 
ufacturers in the text; instead, list them on a Product Sources page 
at the end of the text, before the References. Provide model num- 
bers when available and manufacturer's suggested price, if the study 
has cost implications. 

Ethics. When reporting experiments on human subjects, indicate 
that procedures were conducted in accordance with the ethical stan- 
dards of the World Medical Asxocialion Declaralion of Helsinki 
I Respir Care I997:42(6):635-636| or of the institution's committee 

Rl.SPIRAIOKY CaRI; Manuscript Prepaiation Guide. Rc\ iscd 2/98 

Manuscript Preparation Guide 

on human experimentation. State that informed consent was 
obtained. Do not use patient's names, initials, or hospital numbers 
in text or illustrations. When reporting experiments on animals, indi- 
cate that the institution's policy, a national guideline, or a law on 
the care and use of laboratory animals was followed. 

Statistics. Identify the statistical tests used in analyzing the data, 
and give the prospectively determined level of significance in the 
Methods section. Report actual p values in Results. Cite only text- 
book and published article references to support choices of tests. Iden- 
tify any general-use or commercial computer programs used, nam- 
ing manufacturers and their locations. These should be listed on the 
product-sources page. 

Units of Measurement. Express measurements of length, height, 
weight, and volume in metric units appropriately abbreviated: tem- 
peratures in degrees Celsius; and blood pressures in millimeters of 
mercury (mm Hg). Report hematologic and clinical-chemistry mea- 
surements in conventional metric and in SI (Systeme Internationale) 
units. Show gas pressures (including blood gas tensions) in torr. 
List SI equivalent values, when possible, in brackets following non- 
Si values— for example. "PEEP. 10 cm H:0 [0.981 kPa]." For con- 
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Kl■SIMU,^^()kY C'AKI- M;iTUiM.Tipl l'rcp;ir;iti(in C'niiilc. RexiscJ 2/98 

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of Events 


February' 10-12, 1999 — Clackamas. Oregon 
The OSRC presents its annual Pacific 
Northwest Respiratory Care Conference 
at the Monarch Hotel and Conference 
Center. Topics include respiratory 
mechanics, optimal humidification. 
smoking cessation, airway obstruction 
in children, ethical dilemmas, and 
COPD drug therapy. 
Contact: Irene Iwata-Morgan. RRT 
at (503) 494-6158 

April 7-9, \999— Gulf Shores. Alabama 
The Alabama Society for 
Respiratory Care will be hosting 
their state educational meeting at the 
Gulf State Park Resort Hotel and 
Convention Center. 
Contact: David Howard 
(205) 761-457.3 ore-mail 
William. Howard (s" 

Other Meetings 

December 2-4, 1998 — Brussels, Belgium 
The fourth postgraduate refresher 
course in Cardiovascular and 
Respiratory Physiology Applied to 
Intensive Care Medicine will be held 
at the Free University of Brussels at 
Campus Erasme. 

Contact: Ana Maria de Campos at 
32,2 555 3215 ore-mail 

January 21-23, \999— Washington. DC 
The AARC is cosponsoring Health 
Action "99: Putting the Pieces 
Together. This national grassroots 
conference of health advocates will 
be held at the Renaissance 
Mayflower Hotel. Topics include 
Medicare, children's health 
insurance, managed care reforms, 
and universal coverage. 
Contact: Families USA at 
(202)628-3030, info®, or 

February 13-20, 1999— 5r. Moritz. 

The Seventh Winter Symposium on 
Intensive Care Medicine will be held 
in St. Moritz and is jointly 
sponsored by the European Society 
of Intensive Care Medicine and the 
Society of Critical Care Medicine 

Contact: Ana Maria de Campos at 
32.2 555 3215 ore-mail 

March 14-17, \999— Orlando. Florida 
Noninvasive Ventilation, the 
seventh international conference of 
the Amerincal College of Chest 
Physicians, Independent Ventilator 
Users Network, and the AARC, is 
scheduled for the Caribe Royale 
Resort Suites. Topics include 
noninvasive ventilatory assistance in 
the home, ICU, ER, and long-term 
care sites: nutritional issues for 
ventilated patients; diagnosis and 
diagnostic methods: ethical issues; 
and telemonitoring in the home. 
Continuing education credits 
Contact: (800)343-2227 

March 16-19, \999— Brussels. 

The 19th International Symposium 
on Intensive Care and Emergency 
Medicine will be head at the 
Congress Center in Brussels. 
Contact: Ana Maria de Campos at 
32.2 555 3215 or e-mail 

April 20-23, 1999— Clearwater Beach. 

All Children's Hospital of St. 
Petersburg, FL, will host their 1999 
Neonatal/Pediatric Transport 
Conference at the Hilton Clearwater 
Beach Resort. The conference, titled 
Redefining State of the Art, 
includes a pre-conference lab and 
offers 23 CEUs. 
Contact: Connie Spadaccino at 

( 727 ) 892-4240 or ( 800 ) 456-4543. 
ext. 4240. 

Junel2-16, 1999 — International 
Society for Aerosols in Medicine 
12th International Congress at the 
Austria Center in Vienna, Austria. 
Topics include aerosol drug 
delivery, aerosol deposition and 
clearance, cellular and molecular 
interactions, environmental 
aerosols, standardization, aerosol 
diagnostics, and aerosol therapy. 
Contact: Vienna Academy of 
Postgraduate Medical Education 
and Research. Alser Strasse 4, 
A- 1090 Vienna, Austria. Phone 
(-^43/1) 405 13 83-22, 
fax (-1-43/1) 405 13 83-23, 

Respiratory Care • November 1998 Vol 43 No 1 1 



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4 5^" I NTERN ATia N AU 

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— Current job listings 

— American Respiratory Care Foundation 
fellowships, grants, & awards 

— Clinical Practice Guidelines 

National Board for Respiratory Care 


— 1 997 Subject and Author Indexes 

— Contact the editorial staff 

The American College 
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The National Board for Respiratory Care — 1999 Examination Dates and Fees 


CRT Examination 

RRT Examinalion 

CPFT Examination 

Examination Date 

March 13. 1999 

Application Deadline: January I. 1999 

June 5. 1999 

Application Deadline: February 1. 1999 

Junes, 1999 

Application Deadline. April 1, 1999 

Examination Fee 

SI 20 (new applicant) 

80 (reapplicant) 

120 written only (new applicant) 

80 written only (reapplicant) 

130 (new applicant) 

150 (reapplicant) 

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February 1999 
MARCH 1999 

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11. Known Bondholders, Morgagees, and Other Security Holders Owning or Holding 1 Percent or More ol Total 
Amount of Bonds, Mortgages, or Other Secundes: None 

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poses has not changed dunng preceding 12 months. 

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New Federal Register Notices Now Available 

The Center for Devices and Raidiological Health announces the 
publication of new Facts-on-Demand FOD notices in the 
Federal Register. The new publications: FOD#774 — Medical 
Devices: Preemption of State Product Liability Claims; 
Proposed Rule; FOD#6()7 — Rebuilders, Reconditioners, 
Services, and "As Is" Remarketers of Medical Devices; Review 
and Revision of Compliance Policy Guides and Regulatory 
Requirements; Request for Comments and Information; 
Proposed Rule: and FOD#513 — Medical Devices: Reports of 
Corrections and Removals; Stay of Effective Date of 
Information Collection Requirements; Stay of Effective Date 
of Final Regulation. For more information about Facts-on- 
Demand call (8001 899-0381 or (301) 826-0111. The FOD sys- 
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NAMES 1 999 Education, Conference 
Schedule Set 

The National Association for Medical Equipment Services 
(NAMES) announces its 1999 national conferences and 
regional education seminars. For information about 
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Web Site Link to Fellowships, Scholarships, 
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The American Association for Respiratory Care's web site con- 
tains important information about fellowships, scholarships, 
and research grants. International fellowships, education 
scholarships, research fellowships, and other grand programs 
are described in detail. The site also contains information 
about the $1,000,000 Research Fund, a restricted fund to 
sponsor research initiatives that document the clinical and 
economic impact of respiratory care professionals in the deliv- 
ery of health care. To apply, a "Research Plan Abstract" must 
be submitted to the AARC by Februai^ 1, 1999. To find out 
more about these programs, log on at 

year 2000 Date Problem Addressed by FDA 

On June 24, 1998, the Food and Drug Administration 
announced the availability of the document, "Guidance on 
FDA's Expectations of Medical Device Manufacturers Concern- 
ing the Year 2000 Date Problem." The document is available 
via telephone (800) 899-0381 or (301) 827-0111 or via the 
Internet at 

New Address for Asthma Group 

The Allergy and Asthma Network Mothers of Asthmatics Inc 
has moved. The organization's new address is 2751 Prosperity 
Avenue, Suite 150, Fairfax VA 22031. The telephone numbers 
are (800) 878-4403 or (703) 641-9595, Fax (703) 573-7794. 
Information about the group and their activities is available at 
their Internet address: 




in This Issue 

Anund, K J S 942 

Arnold. John H 961 

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Dallon. Heidi J 966, 978 

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Schexnayder, Steven M 995 

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Develop options such as h low-by and the /Zi>U" 
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avauaoie, you can ue sure mat iiiey win incorporate 
the characteristics common to all Nellcor Puritan 
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For more information call 1-800-NELLCOR. 




7200, Flow-by and 7250 are trademarks ol Nellcor Puritan Bennett Inc. ©1 997 Nellcor Puritan Bennett Inc. All rights reserved, A-FRM276-00 Rev A 

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C(ip\rif;hl O 1998. hy Daedalus Emerpris 

: Inc 


Rrspiratory Care • November 1998 Vol 4.^ No 1 1 


and still going 


7200 SERIES 


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7200, Flow-by and 7250 are trademarks of Nellcor Puritan Bennett Inc ©1 997 Nellcor Puritan Bennett Inc All rights reserved www.nellcorpb com A-FRM276-00 Rev A 

Circle 131 on reader service card 

It's easy to see whyTheraPEPis becoming 
the PEP therapy device of choice. 


Easy to use. 

COPD patients can master Positive Expiratory Pressure therapy quickly and maintain an effective continuum of care away from hospital. 
TheraPEP improves secretion clearance, tacilitates opening of airways and may be used for the treatment of atelectasis. 

Easy to tolerate. 

TheraPEP may reduce the need tor postural drainage, and is ideal for patients unable to tolerate conventional chest physiotherapy 

Easy to read. 

Highly \asible pressure indicator piwides immediate, visual feedback from any angle. 

Easy to adjust. 

Six fi.xed orifice options allow physicians to prescribe appropriate flow resistance levels for each parient. 

Easy to carry. 

Draw-string bag lets patients carry TheraPEP convenienriy and discreetly 

Easy to clean. 

Durable plastic construction, removible base, and linear, viK'ed resistor promotes easv cleaning. 

Easy to order. 

To order your TheraPEP or a free catalog of DHL) qualm' respiratory care products, call toll-free today 


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Positwe ExpiratoHf Pn-ssun- Jliempi/ Si/ste 



Inntnmiims Jiir respirakiry care. 

Cumu.t.i.NY Wn: USA (,M5) (.>I7-:22I FAX (.115) M7-8083 

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