Editorials
A long-acting vasopressin analog for septic shock: Brilliant idea or
dangerous folly?*
T his issue of Pediatric Critical
Care Medicine includes two
case reports regarding the
successful use of terlipressin
for catecholamine-dependent and cate-
cholamine-resistant septic shock in chil-
dren (1, 2). As a pediatric intensivist, my
first question is, What is terlipressin? My
next questions are, What are the advan-
tages and disadvantages of this agent, and
similar agents, in catecholamine-depen-
dent and catecholamine-resistant septic
shock? Finally, do I have enough infor-
mation to decide whether I should use
the medication for my patients?
Terlipressin (triglycyl lysine vasopres-
sin) is a long-acting vasopressin analog (3–
8). In part, it is a prodrug that is slowly
cleaved in vivo to lysine vasopressin by
endo- and exopeptidases in the liver and
kidney over 4 – 6 hrs, thereby allowing pro-
longed effects by intermittent intravenous
injections rather than continuous intrave-
nous infusion. However, it has some other
characteristics suggesting independent
pharmacological effects. Vasopressin and
terlipressin stimulate vascular V1a recep-
tors and renal tubular V2 receptors result-
ing in vasoconstriction and renal free water
reabsorption, respectively. Terlipressin has
relatively higher affinity for the vascular
V1a receptor and lower affinity to the V2
receptor than vasopressin (7). In addition,
terlipressin does not appear to increase fi-
brinolytic activity, whereas vasopressin
does (8). Because of the interplay between
the coagulation/fibrinolytic systems and
the inflammatory system, these differential
effects on fibrinolytic activity may be perti-
nent for treatment of septic shock. Both
vasopressin and terlipressin increase left
ventricular afterload and decrease splanch-
nic blood flow. In an endotoxemic sheep
model, terlipressin resulted in increased
*See also pages 112 and 116.
Keywords: terlipressin; vasopressin; septic shock;
vasodilatory shock; catecholamines; pediatric; child;
infant
Copyright © 2004 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/01.PCC.0000121301.62216.0D
188
pulmonary vascular resistance, whereas va-
sopressin does not cause pulmonary vaso-
constriction (6).
Terlipressin has been extensively used
and studied in adults with acute esopha-
geal variceal bleeding and the hepatore-
nal syndrome (9, 10). Although numer-
ous pharmacological agents have been
used for acute esophageal variceal bleed-
ing, terlipressin is the only one shown to
reduce mortality rate compared with pla-
cebo, with an impressive 34% relative
risk reduction in mortality rate (3, 4).
Terlipressin is well studied and com-
monly used in adults throughout the
world for this indication but is not pres-
ently available in the United States.
Vasopressin and/or vasopressin ana-
logs may have a role in the treatment of
vasodilatory shock states, including sep-
tic shock (5, 11–14). Plasma vasopressin
concentrations initially increase substan-
tially with acute hemorrhage or sepsis
(11, 12). However, adults with vasodila-
tory hypotensive septic shock receiving
catecholamine infusions have low plasma
vasopressin concentrations (i.e., relative
vasopressin deficiency), although the
concentrations are not low enough to
precipitate diabetes insipidus (11). The
low plasma vasopressin concentrations in
vasodilatory septic shock are generally at-
tributed to a hormonal deficiency syn-
drome due to neurohypophysial vasopres-
sin depletion or depressed release.
Interestingly, these patients have hyper-
sensitive vasopressor responses to vaso-
pressin infusions. Although vasopressin
infusions of 0.2–2 units/min rarely affect
the blood pressure in adults with gastro-
intestinal hemorrhage (or in normal sub-
jects), low-dose infusions of 0.01– 0.07
units/min substantially increase the mean
arterial pressure and decrease catechol-
amine requirements in patients with vaso-
dilatory septic shock (11-13). This hyper-
sensitivity to the pressor action of
vasopressin has also been observed in other
vasodilatory shock states (e.g., late-phase
hemorrhagic shock, severe heart failure
treated with a ventricular assist device, and
postcardiopulmonary bypass) (11–14).
These two case reports on the use of
terlipressin for pediatric septic shock in
this issue of Pediatric Critical Care Medi-
cine are consistent with a small series in
adult patients with septic shock: Ter-
lipressin can also increase the mean arterial
pressure and decrease catecholamine re-
quirements; however, the vasoconstriction
can result in lower cardiac output (1, 2, 5).
An 11-year-old child was demonstrated to
be in hyperdynamic norepinephrine-depen-
dent vasodilatory septic shock (1). Intrave-
nous administration of 0.5 mg terlipressin
(~0.14 mg/kg) promptly increased his sys-
temic vascular resistance, thereby allowing
rapid weaning of his norepinephrine infu-
sion. However, his cardiac index promptly
decreased. The duration of the vasocon-
strictor effect with each terlipressin bolus
was ~6 hrs. The use of terlipressin in an
anuric 8-day-old neonate was especially
bold (2). The baby improved while receiving
7 ␮g/kg of intravenous terlipressin every 12
hrs. To my knowledge, terlipressin pharma-
cology had not been previously studied in
neonates. It is conceivable that differences
in neonatal hepatic function could result in
substantial pharmacokinetic differences. It
is somewhat reassuring that terlipressin
had been used extensively in adults with
hepatorenal syndrome and acute gastroin-
testinal hemorrhage associated with portal
hypertension and severe hepatic dysfunc-
tion and that adverse effects seemed to be
rare (3, 4, 9, 10).
The use of terlipressin for hyperdynamic
vasodilatory septic shock is intriguing.
However, most children in septic shock
have hypodynamic cardiac function with
high systemic vascular resistance (15, 16).
In this setting, a vasoconstrictor may fur-
ther impede myocardial function and de-
crease tissue perfusion. Moreover, the well-
known decrease in splanchnic perfusion
with both vasopressin and terlipressin is
worrisome; splanchnic ischemia is associ-
ated with continued systemic inflammatory
response syndrome and multiple-organ
system failure. In addition, children in sep-
tic shock often change hemodynamic pro-
files (15, 16). For example, a child with
vasodilatory shock at one moment may
transform to a hypodynamic shock with
Pediatr Crit Care Med 2004 Vol. 5, No. 2
high systemic vascular resistance as the
disease progresses. A long-acting drug like
terlipressin cannot be easily titrated as the
disease process changes. This inflexibility is
potentially quite problematic.
Do I have enough information to decide
if and when I should use terlipressin in my
patients (if it were available in the United
States)? Because there are abundant adult
data indicating that terlipressin is a safe
and effective agent for the treatment of
acute esophageal variceal bleeding, I be-
lieve there is sufficient information to use
terlipressin for adolescents with this dis-
ease process. In contrast, the data are less
convincing for septic shock. At this time,
the concept of low-dose vasopressin “hor-
monal replacement” therapy for cate-
cholamine-resistant vasodilatory shock or
for decreasing high-dose catecholamine us-
age in catecholamine-dependent vasodila-
tory shock is alluring. However, there is no
evidence that the hemodynamic benefits
translate into better outcomes. Moreover,
the potential decreases in splanchnic flow
and myocardial function are concerning. A
long-acting agent like terlipressin may be
inherently more dangerous during septic
shock, especially for children with their un-
predictable and rapidly changing hemody-
namic profiles. Finally, I would prefer more
pharmacokinetic and pharmacodynamic
information in neonates and young chil-
dren before adding terlipressin to my thera-
peutic armamentarium in these age groups.
These two case reports highlight the
potential benefits of terlipressin, a long-
acting vasopressin analog, for cate-
cholamine-dependent and/or catechol-
amine-resistant vasodilatory septic
Pediatric patient safety: Identification and characterization of
adverse events, adverse drug events, and medical error*
A dverse events involving pa-
tients, particularly the criti-
cally ill and medically fragile,
occur at an alarming frequency
(1, 2). An adverse event is defined as an
*See also pages 119 nd 124.
Key Words: medical error; adverse drug event;
medication errors; patient safety; pediatrics; pediatric
intensive care unit; neonatal intensive care unit
Copyright © 2004 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/01.CCM.0000113928.24594.94
Pediatr Crit Care Med 2004 Vol. 5, No. 2
shock. They also highlight the need for
delineation of terlipressin pharmacology
in neonates, infants, and other young
children. Finally, the time has come for
further studies of low-dose vasopressin
and/or terlipressin hormonal replace-
ment therapy for catecholamine-resistant
vasodilatory septic shock and other vaso-
dilatory shock states in children.
Robert A. Berg, MD
The University of Arizona
Steele Memorial Children’s
Research Center
Tucson, AZ
REFERENCES
1. Peters MJ, Booth RA, Petros AJ. Terlipressin
bolus induces systemic vasoconstriction in
septic shock. Pediatr Crit Care Med 2004;
5:112–115
2. Matok I, Leibovitch L, Vardi A, et al: Terlip-
ressin as rescue therapy for intractable hypo-
tension during neonatal septic shock. Pedi-
atr Crit Care Med 2004; 5:116 –118
3. Ioannou GN, Doust J, Rockey DC: Systematic
review: Terlipressin in acute oesophageal
variceal haemorrhage. Aliment Pharmacol
Ther 2003; 17:53– 64
4. Ioannou G, Doust J, Rockey DC: Terlipressin
for acute esophageal variceal hemorrhage. Co-
chrane Database Syst Rev 2003;1(CD002147)
5. O’Brien A, Clapp L, Singer M: Terlipressin for
norepinephrine-resistant septic shock. Lan-
cet 2002; 359:1209 –1210
6. Westphal M, Stubbe H, Sielenkämper AW, et
al: Terlipressin dose response in healthy and
endotoxemic sheep: Impact on cardiopulmo-
nary performance and global oxygen trans-
port. Intensive Care Med 2003; 29:301–308
7. Bernadich C, Bandi JC, Melin P, et al: Effects
of F-180, a new selective vasoconstrictor pep-
injury resulting from a medical interven-
tion or the “the failure to complete a
planned action as intended or the use of a
wrong plan to achieve an aim” (1, 2). The
goal of all thoughtful and conscientious
caregivers is to provide the best care pos-
sible without exposing patients to addi-
tional harm and suffering by experienc-
ing an adverse event. Unfortunately,
adverse events are a substantial safety
concern in health care. The increasing
complexity in patient care, as well as the
public’s increasing scrutiny of the health
care system, underscores the need to
tide, compared with terlipressin and vaso-
pressin on systemic and splanchnic hemody-
namics in a rat model of portal hypertension.
Hepatology 1998; 27:351–356
8. Douglas JG, Forrest JA, Prowse CV, et al:
Effects of lysine vasopressin and glypressin
on the fibrinolytic system in cirrhosis. Gut
1979; 20:565–567
9. Solanki P, Chawla A, Garg R, et al: Beneficial
effects of terlipressin in hepatorenal syn-
drome: A prospective, randomized placebo-
controlled clinical trial. J Gastroenterol
Hepatol 2003; 18:152–156
10. Colle I, Durand F, Pessione F, et al: Clinical
course, predictive factors and prognosis in
patients with cirrhosis and type 1 hepatore-
nal syndrome treated with Terlipressin: A
retrospective analysis. J Gastroenterol Hepa-
tol 2002; 17:882– 888
11. Landry DW, Levin HR, Gallant EM, et al:
Vasopressin deficiency contributes to the va-
sodilation of septic shock. Circulation 1997;
95:1122–1125
12. Robin JK, Oliver JA, Landry DW: Vasopressin
deficiency in the syndrome of irreversible
shock. J Trauma 2003; 54:S149 –S154
13. Tsuneyoshi I, Boyle WA. Vasopressin: New
uses for an old drug. Contemp Crit Care
2003; 1:1–11
14. Morales DL, Garrido MJ, Madigan JD, et al: A
double-blind randomized trial: Prophylactic
vasopressin reduces hypotension after car-
diopulmonary bypass. Ann Thorac Surg
2003; 75:926 –930
15. Carcillo JA, Fields AI: Clinical practice pa-
rameters for hemodynamic support of pedi-
atric and neonatal patients in septic shock.
Crit Care Med 2002; 30:1365–1378
16. Ceneviva G, Paschall JA, Maffei F, et al: He-
modynamic support in fluid-refractory pedi-
atric septic shock. Pediatrics 1998; 102:e19
make patient safety and the reduction of
adverse events an issue of highest priority
(3).
According to a national poll conducted
by the National Patient Safety Founda-
tion, nearly half of respondents, includ-
ing physicians (35%) and members of the
public (42%), reported errors in their
own or a family member’s medical care.
Almost a third (32%) of the respondents
indicated that the error had a permanent
negative effect on the patient’s health (4).
Advances are being made to improve sur-
189
veillance of medical errors and occur-
rence of patient harm (5–7). Identifying
and characterizing adverse events and
medical errors comprise a necessary first
step to effectively target efforts to de-
crease the risk of adverse events to our
patients (8, 9). Current efforts to enhance
patient safety must include progress in
the capture and characterization of ad-
verse events, the occurrence of harm, and
the degree of preventability of harm. No-
where is this more important than in the
pediatric intensive care unit (PICU).
In this month’s issue of Pediatric Crit-
ical Care Medicine, two groups of re-
searchers have tackled this challenging
task (10, 11). In 1984, the rate of adverse
events among newborns in New York
State was 1.4 in 100 hospitalizations with
an associated 20.8% rate of negligence
(12). Nearly 20 yrs later, Dr. Kanter and
colleagues (10) have found very little
progress. Their study determined the rate
and characteristics of hospital-reported
medical errors involving premature neo-
nates (n ⫽ 824). They reported a national
medical error rate of 1.2 per 100 dis-
charges using the Healthcare Cost and
Utilization Project (HCUP) 1997 dis-
charge database. This national adminis-
trative database represents discharges
from nearly 900 hospitals, consisting of
the International Classification of Diseas-
es-9 discharge diagnosis of 996 –999 for
medical error (10).
HCUP is a family of health care data-
bases and related software tools devel-
oped through a federal-state-industry
partnership and sponsored by the Agency
for Healthcare Research and Quality (13).
In a previous study, Slonim et al. used the
same database and methods and identi-
fied 1.81–2.96 medical errors per 100 dis-
charges of pediatric hospitalized patients
(14). Adult studies of medical errors have
ranged from 3.7 to 16.6 adverse events
per 100 admissions (12, 15, 16). There are
many strengths and limitations to admin-
istrative databases. One concern is the
underrecognition and underreporting of
adverse events (1, 17, 18). Miller et al.
cited significant underreporting of pa-
tient safety events as a limitation in their
study using the 1997 HCUP database
(18). Although existing administrative da-
tabases can reasonably be used to define the
epidemiology of adverse events and medical
errors as done by Dr. Kanter and colleagues
(10), the data provide limited clinical infor-
mation, little insight into timing of events,
and no ability to assess causality, and they
probably result in underreporting (14, 18).
190
The HCUP database also is limited to hos-
pitalized patients who survive to discharge
and does not include medication errors
(18). In the Kanter study of premature ne-
onates, a limitation of the HCUP database is
its inability to discriminate between ad-
verse events due to medical care and events
due to birth trauma (10). Birth trauma has
been reported to be at a frequency of 1.5
cases per 100 births (18). Strengths in us-
ing HCUP include ready availability, low
cost, and coverage of large populations
(15).
The study by Dr. Kanter and col-
leagues (10) contributes to the develop-
ing field of patient safety by providing a
descriptive epidemiology of medical er-
rors in the population of premature new-
borns sampled from a diverse range of
hospital settings. Despite the limitations
of administrative databases, the findings
of Dr. Kanter and colleagues are likely to
be generalizable to the national popula-
tion of premature infants given the large
data set and representative sampling of
hospitals in the HCUP database.
The next step in creating a safe envi-
ronment is the development of targeted
patient safety interventions. The second
patient safety-related article in this issue
focuses on adverse drug events occurring
in the PICU. Dr. Cimino and colleagues
(11) successfully developed a method to
assess the rate of prescribing errors in
nine freestanding PICUs. Dr. Cimino and
colleagues identified medication errors
prospectively for categorization and eval-
uation, and they assessed the impact of
initiatives to reduce medication error se-
verity and rates. The main goal of the
study was to assess the overall rate of
prescribing errors in nine PICUs partici-
pating in Child Health Accountability Ini-
tiative (CHAI) network (19) and to test
the effectiveness of a variety of hospital-
specific interventions to reduce medica-
tion-associated adverse events (11).
Using a pretest, posttest design,
12,026 PICU medication orders at base-
line and 9,187 orders postintervention
were evaluated for prescribing errors, ex-
cluding resuscitation orders. Medication
errors were defined as errors in drug or-
dering, transcribing, dispensing, admin-
istering, or monitoring. Adverse drug
events are injuries that result from the
use of a drug. The authors found a 31%
reduction (11.1–7.6% of orders) in pre-
scribing errors. Preventable adverse drug
events were uncommon (0.13% of all
medication errors at baseline, 0.03% dur-
ing the postintervention period) and of
low severity at baseline. Previous studies
have found comparably low rates of pre-
ventable adverse drug events (17).
Dr. Cimino and colleagues (11) ad-
dress the lack of measurement standards
or a consistent benchmark for adverse
drug events by demonstrating the useful-
ness of a generalizable method employed
to identify, document, and analyze pre-
scribing errors across a broad range of
PICUs. The technique is labor intensive
but yielded consistent results across the
PICUs and correlated with other pub-
lished studies (17). This method of ana-
lyzing prescribing errors captures error
and harm associated with medication
use. However, there was considerable
variation in the methods used to reduce
error rates, and the study design did not
allow for testing of any specific interven-
tion. In addition, there was the puzzling
finding of two institutions reporting an
increase in identified prescribing errors.
One of the most important aspects of this
study was the establishment of a baseline
rate for medication prescribing errors,
thus providing a benchmark for other
PICUs.
The published literature focusing on
the occurrence of medical errors in pedi-
atrics is limited and concludes that hos-
pitalized children experience significant
numbers of adverse medical events (17,
18). The authors of these two articles
have taken an important step to advance
the understanding of the incidence and
character of medical errors and adverse
events occurring in hospitalized children.
The first step in designing a health care
system to prevent medical injury is to
identify errors and their pattern of occur-
rence within delivery systems to reduce
the likelihood of adverse events (3). Re-
ducing the rate of medical errors and
adverse events experienced by our pa-
tients should be one of the main goals of
providing optimal health care for children.
Gitte Larsen, MD
Mary Jo C. Grant, PNP, PhD
Pediatric Intensive Care Unit
Primary Children’s Medical Center
University of Utah
Salt Lake City, UT
REFERENCES
1. Institute of Medicine: To Err Is Human:
Building a Safer Health System. National
Academy Press, Washington, DC, 2000
2. Committee on Quality of Health Care in
America. Crossing the Quality Chasm: A New
Health System for the 21st Century. National
Academy Press, Washington, DC, 2001
Pediatr Crit Care Med 2004 Vol. 5, No. 2
 3. American Academy of Pediatrics. Principles
of patient safety in pediatrics. Pediatrics
2001; 107:1473–1475
4. Blendon RJ, DesRoches CM, Brodie M, et al:
Views of practicing physicians and the public
on medical errors. N Engl J Med 2002; 347:
1933–1940
5. Barach P, Small SD: Reporting and prevent-
ing medical mishaps: Lessons from non-
medical near miss reporting systems. BMJ
2000; 320:759 –763
6. Kivlahan C, Sangster W, Nelson K, et al:
Developing a comprehensive electronic ad-
verse event reporting system in an academic
health center. J Qual Improv 2002; 28:
583–594
7. Weingart S: A physician-based voluntary re-
porting system for adverse events and medi-
cal errors. J Gen Intern Med 2001; 16:
809 – 814
Mechanical ventilation of the intubated asthmatic: How much do
we really know?*
I n this issue of Pediatric Critical
Care Medicine, Dr. Sarnaik and
colleagues (1) review their 5-yr ex-
perience using pressure-con-
trolled ventilation in pediatric patients
with status asthmaticus and respiratory
failure. Although this is a retrospective
review, the patients undergoing mechan-
ical ventilation were treated by a prede-
termined protocol. The 40 patients, who
underwent 51 episodes of mechanical
ventilation, had a low incidence of baro-
trauma and no mortality, despite the in-
vestigators’ efforts at achieving and main-
taining normal Pa CO 2 levels in the
patients.
The authors indicate that pressure-
controlled ventilation may represent a
safe alternative to the “traditional” mode
used in these patients, which the authors
believe to be volume-controlled ventila-
tion. Although volume-controlled venti-
lation may be the most commonly used
mode in reported series in children (2, 3)
and adults (4 – 6), some series do not
*See also p. 133.
Key Words: pressure-controlled ventilation; status
asthmaticus; respiratory failure
Copyright © 2004 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/01.CCM.0000113929.14813.51
Pediatr Crit Care Med 2004 Vol. 5, No. 2
8. Layde PM, Maas LA, Teret SP, et al: Patient
safety efforts should focus on medical inju-
ries. JAMA 2002; 287:1993–1997
9. McNutt RA, Abrams R, Aron DC: Patient
safety efforts should focus on medical errors.
JAMA 2002; 287:1997–2001
10. Kanter DE, Turenne W, Slonim AD: Hospital-
reported medical errors in premature neo-
nates. Pediatr Crit Care Med 2004; 5:119–123
11. Cimino MA, Kirschbaum MS, Brodsky L, et
al: Assessing medication prescribing errors
in pediatric intensive care units. Pediatr Crit
Care Med 2004; 5:124 –132
12. Brennan TA, Leape LL, Laird NM, et al: In-
cidence of adverse events and negligence in
hospitalized patients: Results of the Harvard
Medical Practice Study I. N Engl J Med 1991;
324:370 –376
13. Agency for Healthcare Research and Qual-
ity: Healthcare Cost and Utilization
Project. Available at http://www.ahrq.gov/
mention the specific modes of ventilation
used in the patients reported (7). Case
reports of the use of pressure support (8),
noninvasive ventilation (9, 10), and high-
frequency oscillatory ventilation (11)
suggest that physicians are using many of
the numerous modes available on today’s
sophisticated ventilators. This phenome-
non probably indicates a lack of content-
ment with the traditional approach to
mechanically ventilating these critically
ill patients and the continual search for a
better way. There have been previous
suggestions in the literature that pres-
sure control may be a rational alternative
to volume control (12, 13), but Dr. Sar-
naik and colleagues (1) are the first to
demonstrate its safety and effectiveness
in a relatively large group of patients.
How likely is it that the data presented
in Dr. Sarnaik and colleagues’ article will
be applicable to the practice of the read-
ers of this journal? To answer that ques-
tion, one would need to know the preva-
lent approach to status asthmaticus in
pediatric intensive care units across the
nation or throughout the world. At this
point, it is impossible to state what the
standard is for initiating mechanical ven-
tilation in critically ill pediatric patients
with status asthmaticus, let alone to
know what the standard approach is once
the patients are intubated. We know that
data/hcup/hcupnet.htm. Accessed October
24, 2003
14. Slonim AD, LaFleu BJ, Ahmed W, et al: Hos-
pital-reported medical errors in children. Pe-
diatrics 2003; 111:617– 621
15. Weingart SN, Iezzoni LI: Looking for medical
injuries where the light is bright. JAMA 2003;
290:1917–199
16. Wilson RM, Runciman WB, Gibberd RW, et
al: The quality in Australian health care
study. Med J Aust 1995; 163:458 – 471
17. Kaushal R: Medication errors and adverse
drug events in pediatric inpatients. JAMA
2001; 286:915–916
18. Miller MR, Elixhauser A, Zhan C: Patient
safety events during pediatric hospitaliza-
tions. Pediatrics 2003; 111:1358 –1366
19. Child Health Corporation of America. Child
Health Accountability Initiative. Available at:
http://www.chca.com/servpediat.html. Ac-
cessed on October 24, 2003
the frequency of intubation in these pa-
tients is very different in different cen-
ters. Roberts et al. (14) previously showed
that the approach of the pediatric critical
care community varies widely with re-
spect to frequency of the use of invasive
monitoring, blood gas determination,
and use of mechanical ventilation. Some
centers were classified as “high-use”
(⬎20% of admitted patients with status
asthmaticus went on to intubation) and
patients at these centers had a more than
two-fold higher risk of intubation, after
adjustment for severity of illness, than
patients at “low-use” institutions (where
⬍20% of their patients with status asth-
maticus were intubated). Patients at
high-use centers had a longer pediatric
intensive care unit and hospital length of
stay than patients at the low-use centers,
but mortality rates were not different be-
tween the two types of centers. In Roberts
et al.’s (14) database interrogation study,
the overall rate of intubation and me-
chanical ventilation for status asthmati-
cus was 17%, but the incidence ranged
from a low of 3% to a high of 46%.
Twenty percent of the patients cared
for by Dr. Sarnaik and colleagues (1) re-
ceived mechanical ventilation, putting
their center at the breakpoint between
the high- and low-use centers described
by Roberts et al. (14). What does this tell
191
us about the practice of this group of
investigators? Most of their patients were
intubated for respiratory arrest or respi-
ratory acidosis, but 22% were intubated
for the “clinical impression of fatigue.”
This latter group of patients proves prob-
lematic in its evaluation and emphasizes
the subjective nature of our approach to
this disease. It therefore makes it even
more difficult to compare the reported
population to that in other intensive care
units or to compare the results in this
article to other reported series of patients
ventilated for status asthmaticus.
Despite these problems, the strength of
the current research lies in the nature of
the initial approach to these patients’ respi-
ratory failure. Once intubated, the peak in-
spiratory pressure was adjusted in a tightly
controlled manner, to achieve normal PCO2
values as quickly as possible. When ready
for weaning, patients were handled in a
variety of ways, clearly at the discretion of
the treating physician. The median length
of mechanical ventilation was 29 hrs, com-
paring favorably with previous reports in
children (2) and adults (5, 15). There was
no mortality, and the incidence of baro-
trauma was low, in most cases predating
the initiation of mechanical ventilation.
There are no randomized controlled
trials comparing different modes of me-
chanical ventilation in asthma. Nor are
there likely to ever be any. There is no
single gold standard of how, when, and
why to initiate mechanical ventilation in
this disease. Newer therapeutic options
have been embraced by many, including
the use of noninvasive ventilation to
avoid some of the perils of intubation (9,
10). Despite the availability of National
Institutes of Health guidelines on the
treatment of asthma, many patients re-
ceive nonstandard care. In the population
presented by Dr. Sarnaik and colleagues
(1), a varying percentage of patients were
treated with heliox, isoproterenol, the-
ophylline, magnesium, ketamine, and
192
terbutaline. These are all agents that have
been reported but not proven to be of
benefit in the intensive care unit. Any of
these adjunctive measures may have af-
fected the course of the patients pre-
sented.
The use of inhaled ipatropium, al-
though recommended by both National
Institutes of Health panels (16, 17), was
only used in 47% of the patients. The
reasons for this variation are not clear,
nor are they addressed in the article.
Does this article prove the safety of pres-
sure-controlled ventilation in caring for
children with status asthmaticus? No. It
suggests that in the hands of this particular
group of physicians, with this particular
population, pressure-controlled ventilation
has been successful. It does not preclude
the safe use of other modes of ventilation in
other people’s hands. It does not address
the issues of how long one can safely wait
for medical therapies to work, without re-
sorting to mechanical ventilation. As pedi-
atric critical care practitioners read this ar-
ticle, they should compare the results to
their own practice and consider letting the
rest of the world know how they care for
such patients in their own institutions. Addi-
tional reports of well-described approaches to
this care would be most helpful.
Alice D. Ackerman, MD, FCCM
University of Maryland Medical
System
Baltimore, MD
REFERENCES
1. Sarnaik AP, Daphtary KM, Meert KL, et al:
Pressure-controlled ventilation in children
with severe status asthmaticus. Pediatr Crit
Care Med 2004; 5:133–138
2. Cox RG, Barker GA, Bohn DJ: Efficacy, re-
sults and complications of mechanical venti-
lation in children with status asthmaticus.
Pediatr Pulmonol 1991; 11:120 –126
3. Abd-Allah SA, Rogers MS, Terry M, et al:
Helium-oxygen therapy for pediatric acute
severe asthma requiring mechanical ventila-
tion. Pediatr Crit Care Med 2003; 4:353–357
4. Mutlu GM, Factor P, Schwartz DE, et al:
Severe status asthmaticus: Management with
permissive hypercapnia and inhalation anes-
thesia. Crit Care Med 2002; 30:477– 480
5. Afessa B, Morales I, Cury JD: Clinical course
and outcome of patients admitted to an ICU
for status asthmaticus. Chest 2001; 120:
1616 –1621
6. Georgopoulos D, Kondili E, Prinianakis G:
How to set the ventilator in asthma. Monaldi
Arch Chest Dis 2000; 55:74 – 83
7. Malmstrom K, Kaila M, Korhonen K, et al:
Mechanical ventilation in children with se-
vere asthma. Pediatr Pulmonol 2001; 31:
405– 411
8. Wetzel RC: Pressure-support ventilation in
children with severe asthma. Crit Care Med
1996; 24:1603–1605
9. Fernandez MM, Villagra A, Blanch L, et al:
Non-invasive mechanical ventilation in sta-
tus asthmaticus. Intensive Care Med 2001;
27:486 – 492
10. Meduri GU, Cook TR, Turner RE, et al:
Noninvasive positive pressure ventilation
in status asthmaticus. Chest 1996; 110:
767–774
11. Duval EL, van Vught AJ: Status asthmati-
cus treated by high-frequency oscillatory
ventilation. Pediatr Pulmonol 2000; 30:
350 –353
12. Werner HA: Status asthmaticus in children.
A review. Chest 2001; 119:1913–1929
13. Lopez-Herce J, Gari M, Bustinza A, et al: To
the editor: On pressure-controlled ventila-
tion in severe asthma. Pediatr Pulmonol
1996; 21:401– 403
14. Roberts JS, Bratton SL, Brogan TV: Acute
severe asthma: Differences in therapies and
outcomes among pediatric intensive care
units. Crit Care Med 2002; 30:581–585
15. Braman SS, Kaemmerlen JT: Intensive care
of status asthmaticus: A 10-year experience.
JAMA 1990; 264:366 –368
16. National Heart Lung and Blood Institute:
The Expert Panel Report: Guidelines for the
Diagnosis and Treatment of Asthma. Be-
thesda, MD, National Institutes of Health,
1991
17. National Heart Lung and Blood Institute:
The Expert Panel Report 2: Guidelines for
the Diagnosis and Management of Asthma.
Bethesda, MD, National Institutes of Health,
1997
Pediatr Crit Care Med 2004 Vol. 5, No. 2
Don’t forget the “single chromosome polymorphism”: A need for
gender-stratification in pediatric patients?*
A ppropriately, a recent flurry of
clinical study has been directed
toward genetic associations and
disease (1). With ⬎1 million
genetic polymorphisms (2), this becomes of
clear significance given that many future
therapies are likely to be genotype-directed
and many studies genotype-stratified. The
simplest polymorphism is referred to as a
single nucleotide polymorphism. These
genetic polymorphisms can significantly
influence susceptibility and/or outcome in
manydiseasestates,forinstance,theapolipo-
protein E allele, which is important in
Alzheimer’s disease (3) and traumatic brain
injury (TBI) (4). In this issue of Pediatric
Critical Care Medicine, Dr. Morrison and
colleagues (5) attempt to determine
whether there is an association between
a much more common “polymorphism”
after TBI, namely the Y-chromosome.
TBI is unarguably a major public
health problem in the United States, il-
lustrated by the fact that TBI is the lead-
ing cause of death and disability in in-
fants and children. Among children aged
0 –14 yrs in the United States, there are
3,000 deaths, 29,000 hospitalizations, and
400,000 emergency department visits an-
nually associated with TBI (6). Studies
have shown that the highest pediatric age
incidence of TBI is among persons aged
15–24 yrs followed by ages 5 and
younger, and males are more than twice
as likely as females to become victims of
TBI. Current understanding suggests
that being of female gender (XX) imparts
a degree of protection from the sequelae
of TBI compared with male gender (XY).
This experimental evidence is based en-
tirely on carefully controlled studies in
reproductive-aged animals using hor-
mone replacement therapy, and as such
*See also p. 145.
Key Words: child abuse; gender; head injury; pe-
diatric; sex hormones; traumatic brain injury
Copyright © 2004 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/01.PCC.0000115621.73210.B9
Pediatr Crit Care Med 2004 Vol. 5, No. 2
many of the beneficial effects seen in fe-
males are attributed to the influence of
sex hormones. Estrogen has been shown
to preserve cerebral blood flow after TBI
in rats, and endogenous and injected pro-
gesterone reduced cerebral edema in fe-
male rats after TBI (7, 8). Indeed, a clin-
ical trial in adult patients using
progesterone as a neuroprotective agent
after TBI is underway.
Not discounting an important role for
sex hormones in the pathophysiology and
outcome after TBI, it remains possible, or
even likely, that innate, sex hormone-
independent gender effects also contrib-
ute. This may be of particular importance
in terms of TBI patients outside of the
reproductive years (i.e., children and the
elderly), when the influence of circulat-
ing sex hormones is less dominant. In-
deed, these age-group subpopulations are
known to have unfavorable outcomes af-
ter TBI (9, 10). Furthermore, boys are
believed to have poorer memory function
(11) and a higher incidence of neuropsy-
chiatric sequelae (12) than girls after TBI.
This issue’s report by Dr. Morrison
and colleagues (5) is important because it
attempts to correlate gender and age with
intensive care unit length of stay, hospi-
tal length of stay, survival, and neuro-
logic outcome after TBI in a pediatric
population. Importantly, it begins to di-
rect our attention to the possible need for
“gender-stratification” in terms of treat-
ment and study design in pediatric pa-
tients with acute brain injury cared for in
our pediatric intensive care units. In con-
trast to the previously mentioned studies
(11, 12), there was no gender difference
in neurologic outcome in the current
study by Dr. Morrison and colleagues (5).
There was, however, a shorter intensive
care unit length of stay for boys vs. girls.
The impact of gender in pediatric inten-
sive care unit patient populations extends
beyond TBI, as gender differences are
seen in either outcomes or responses to
therapy in children with stroke (13), pre-
maturity (14), and cancer (15,16).
As with previous studies, Dr. Morrison
and colleagues (5) found that younger
age was a significant risk factor for death
after TBI (9). This may be related to the
predominance of inflicted trauma (child
abuse) in infants and toddlers. These pa-
tients often present for medical care after
a significant time delay after injury and
perhaps after repeated insults, and they
have notoriously poor outcomes com-
pared with TBI due to noninflicted (acci-
dental) trauma (17). Thus, the presence
of inflicted TBI in the younger age group
may have contributed to the higher mor-
tality rate. Biochemical differences also
exist in these two patient populations
(18 –20).
Although the study by Dr. Morrison
and colleagues (5) disproved their origi-
nal hypothesis that boys would fare worse
than girls after TBI, this and other pedi-
atric studies support the notion that the
influence of gender should be considered
in the study design, clinical management,
and outcome assessment in pediatric in-
tensive care unit patients. Just as futur-
istic approaches to intensive care unit
medicine will likely include genotype-
and phenotype-specific management and
therapy, perhaps present-day approaches
to intensive care unit medicine should
begin to identify pathologic processes re-
quiring gender-, age-, and mechanism-
specific treatment.
Ericka L. Fink, MD
Robert S. B. Clark, MD
University of Pittsburgh School of
Medicine and Children’s
Hospital of Pittsburgh
Pittsburgh, PA
REFERENCES
1. Ioannidis JP, Trikalinos TA, Ntzani EE, et al:
Genetic associations in large versus small
studies: An empirical assessment. Lancet
2003; 361:567–571
2. Sachidanandam R, Weissman D, Schmidt
SC, et al: A map of human genome sequence
variation containing 1.42 million single nu-
cleotide polymorphisms. Nature 2001; 409:
928 –933
3. Fallin D, Cohen A, Essioux L, et al: Genetic
193
 analysis of case/control data using estimated
haplotype frequencies: Application to APOE
locus variation and Alzheimer’s disease. Ge-
nome Res 2001; 11:143–151
4. Crawford FC, Vanderploeg RD, Freeman MJ,
et al: APOE genotype influences acquisition
and recall following traumatic brain injury.
Neurology 2002; 58:1115–1118
5. Morrison WE, Arbelaez JJ, Fackler JC, et al:
Gender and age effects on outcome after pe-
diatric traumatic brain injury. Pediatr Crit
Care Med 2004; 5:145–151
6. Traumatic Brain Injury in the United States:
Assessing Outcomes in Children. Atlanta,
Centers for Disease Control and Prevention,
2000
7. Roof RL, Hall ED: Estrogen-related gender
difference in survival rate and cortical blood
flow after impact-acceleration head injury in
rats. J Neurotrauma 2000; 17:1155–1169
8. Roof RL, Hoffman SW, Stein DG: Progester-
one protects against lipid peroxidation fol-
lowing traumatic brain injury in rats. Mol
Chem Neuropathol 1997; 31:1–11
9. Levin HS, Aldrich EF, Saydjari C, et al: Se-
vere head injury in children: Experience of
Incidence and risk factors for oropharyngeal aspiration in
mechanically ventilated infants and children*
M echanically ventilated in-
fants and children are at
risk for aspiration of oro-
pharyngeal and gastric
contents into their tracheobronchial tree.
Although aspiration can be clinically si-
lent, aspiration of large volumes or recur-
rent aspiration of small volumes can lead
to lower respiratory tract disease. Aspira-
tion pneumonitis is a chemical injury
caused by the inhalation of sterile gastric
acid, whereas aspiration pneumonia is an
infectious process caused by the inhala-
tion of oropharyngeal secretions or gas-
tric contents colonized with pathogenic
bacteria (1). The incidence of aspiration
in critically ill patients is difficult to as-
certain from the literature, with reported
values ranging from 0.8 to 95% (2– 6).
*See also p. 152.
Key Words: aspiration; intubation; mechanical ven-
tilation; infant; child
Copyright © 2004 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/01.PCC.0000113267.04557.7D
194
the traumatic coma data bank. Neurosurgery
1992; 31:435– 444
10. Susman M, DiRusso SM, Sullivan T, et al:
Traumatic brain injury in the elderly: In-
creased mortality and worse functional out-
come at discharge despite lower injury sever-
ity. J Trauma 2002; 53:219 –223
11. Donders J, Hoffman NM: Gender differences
in learning and memory after pediatric trau-
matic brain injury. Neuropsychology 2002;
16:491– 499
12. Poggi G, Liscio M, Adduci A, et al: Neuropsy-
chiatric sequelae in TBI: A comparison
across different age groups. Brain Injury
2003; 17:835– 846
13. Hurvitz EA, Beale L, Ried S, et al: Functional
outcome of paediatric stroke survivors. Pedi-
atr Rehabil 1999; 3:43–51
14. Hindmarsh GJ, O’Callaghan MJ, Mohay HA,
et al: Gender differences in cognitive abilities
at 2 years in ELBW infants. Extremely low
birth weight. Early Hum Dev 2000; 60:
115–122
15. Weil MD, Lamborn K, Edwards MS, et al:
Influence of a child’s sex on medulloblas-
toma outcome. JAMA 1998; 279:1474 –1476
16. Ishii E, Eguchi H, Matsuzaki A, et al: Out-
The wide range in reported incidence is
likely due to differences in the methods
used to detect aspiration and in the pop-
ulations studied. In this issue of Pediatric
Critical Care Medicine, Dr. Amantea and
colleagues (7) take on the challenge of
estimating the incidence and describing
the risk factors for oropharyngeal aspira-
tion in a group of 50 mechanically venti-
lated infants and children. The overall
incidence of oropharyngeal aspiration
was 28%. Among the risk factors identi-
fied were frequent swallowing move-
ments detected by surface electromyogra-
phy, the presence of an oral endotracheal
tube, and lack of adequate sedation (in-
creased wakefulness).
Research on the epidemiology of aspi-
ration has been complicated by the lack
of sensitive and specific bedside markers
to detect aspiration. In the study by Dr.
Amantea and colleagues (7), aspiration of
oropharyngeal secretions is assessed by
the application of blue dye to the base of
the tongue and subsequent testing of tra-
cheal secretions for the dye’s presence.
No data are available to show that results
come of acute lymphoblastic leukemia in
children with AL90 regimen: Impact of re-
sponse to treatment and sex difference on
prognostic factors. Med Pediatr Oncol 2001;
37:10 –19
17. Duhaime AC, Christian CW, Rorke LB, et al:
Nonaccidental head injury in infants—the
“shaken-baby syndrome.” N Engl J Med 1998;
338:1822–1829
18. Kochanek PM, Clark RS, Ruppel RA, et al:
Biochemical, cellular, and molecular mech-
anisms in the evolution of secondary damage
after severe traumatic brain injury in infants
and children: Lessons learned from the bed-
side. Pediatr Crit Care Med 2000; 1:4 –19
19. Clark RS, Kochanek PM, Adelson PD, et al:
Increases in bcl-2 protein in cerebrospinal
fluid and evidence for programmed cell
death in infants and children after severe
traumatic brain injury. J Pediatr 2000; 137:
197–204
20. Ruppel RA, Kochanek PM, Adelson PD, et al:
Excitatory amino acid concentrations in ven-
tricular cerebrospinal fluid after severe trau-
matic brain injury in infants and children:
The role of child abuse. J Pediatr 2001; 138:
18 –25
from the dye method correlate with those
from established diagnostic methods to
detect aspiration. To the contrary, how-
ever, there are data to show that the dye
method lacks sensitivity. For example,
Thompson-Henry et al. (8) demonstrated
that dye added to small volumes of oral
liquid and semisolid feedings failed to de-
tect aspiration in tracheotomized adults
in whom aspiration was confirmed by
modified barium swallow or fiberoptic
endoscopic evaluation. Other studies in
which blue dye was used to color enteral
formulas delivered through nasogastric
feeding tubes also have shown that blue
dye lacks sensitivity in detecting aspira-
tion (9, 10). Considering the methods
used by Dr. Amantea and colleagues (7),
their findings suggest that the incidence
of aspiration in their population is
ⱖ28%.
Risk factors for aspiration in critically
ill patients are numerous; most com-
monly cited are decreased level of con-
sciousness, supine positioning, presence
of a nasogastric or endotracheal tube, in-
termittent feeding delivery methods, and
Pediatr Crit Care Med 2004 Vol. 5, No. 2
high-risk conditions such as neurologic
disorders (11). A randomized trial of su-
pine vs. semirecumbent body positioning
conducted by Drakulovic et al. (12) dem-
onstrated that the frequency of clinically
suspected and microbiologically con-
firmed nosocomial pneumonia was sig-
nificantly greater in supine positioned pa-
tients. The incidence of nosocomial
pneumonia was highest for patients re-
ceiving enteral nutrition in the supine
position. Mechanical ventilation for ⱖ7
days and decreased level of consciousness
(Glasgow Coma Scale ⬍9) were addi-
tional risk factors. In a prospective obser-
vational study, Adnet and Baud (13) dem-
onstrated an increased frequency of
suspected aspiration pneumonia on in-
tensive care unit admission in adults with
impaired consciousness at the time of
initial contact with prehospital person-
nel. Most investigators agree that supine
positioning and impaired consciousness
are major risk factors for aspiration.
Dr. Amantea and colleagues (7) evalu-
ated the contribution of various risk fac-
tors for aspiration using both univariate
and multivariate analyses. On univariate
testing, inadequate sedation (i.e., in-
creased wakefulness), increased fre-
quency of swallowing movements, and
oral intubation were associated with in-
creased aspiration risk. On multivariate
testing, inadequate sedation was not an
independent risk factor, presumably due
to the high correlation between level of
sedation and frequency of swallowing
movements. These findings are in con-
trast with previous studies of both intu-
bated and nonintubated patients in which
decreased levels of consciousness were
found to contribute to aspiration risk (12,
13). The contrasting findings may be ex-
plained by the nature of the impaired
consciousness, whether pharmacologi-
cally induced in the critical care setting
or due to preexisting neurologic compro-
mise before endotracheal intubation. It is
also possible that the questionable effi-
cacy of the detection method used in the
study partially explains why risk factors
identified by the investigators are incon-
gruent with what is typically reported in
the literature.
Dr. Amantea and colleagues (7) spec-
ulate that the presence of an oral endo-
tracheal tube impairs tongue movement
and laryngeal closure, and that children
who swallow frequently expose their air-
ways to oropharyngeal secretions more
often than sedated children who swallow
less. The latter speculation is not sup-
Pediatr Crit Care Med 2004 Vol. 5, No. 2
ported by a comprehensive review of the
physiology and pathophysiology of upper
airway reflexes by Nishino (14). Accord-
ing to Nishino, the main function of the
swallowing reflex is to propel food and
secretions from the oral cavity to the
stomach, thereby keeping the oropharynx
clear of foreign materials. Lack of swal-
lowing thus could be expected to result in
accumulation of colonized secretions in
the oropharynx, predisposing the patient
to aspiration pneumonia, the presence of
an endotracheal tube not withstanding.
The integrity of the barrier preventing
oropharyngeal secretions from gaining
access to the tracheobronchial tree is
markedly influenced by the interaction
between the swallowing reflex and the
respiratory cycle. Awake swallowing oc-
curs during the expiratory phase of res-
piration, thus serving as a protective
mechanism that prevents low-grade aspi-
ration from occurring. Swallowing in the
unconscious state, on the other hand,
occurs equally during inspiration and ex-
piration, rendering the patient suscepti-
ble to aspiration.
All of the patients studied by Dr.
Amantea and colleagues (7) were me-
chanically ventilated with uncuffed endo-
tracheal tubes and were evaluated for as-
piration in the supine body position.
These features make their findings diffi-
cult to apply to those intensive care units
where patients are routinely cared for in
the semirecumbent position and cuffed
endotracheal tubes are frequently used.
Several studies have found the use of
cuffed endotracheal tubes to be protective
against aspiration (4, 15–16). Due to the
anatomy of the infant’s airway, practitio-
ners are cautious about using cuffed en-
dotracheal tubes in these patients (17).
The infant’s airway is narrowest at the
laryngeal subglottis, which is surrounded
by a rigid cartilaginous complete cricoid
ring. Compression of the respiratory mu-
cosa by a tight-fitting endotracheal tube
can cause subglottic edema. Short-term
complications include postextubation
stridor, whereas in the long term tracheal
stenosis can develop. Recent studies in
both the pediatric intensive care unit and
operating room settings have demon-
strated the safety and efficacy of cuffed
endotracheal tubes in infants and young
children. Deakers et al. (15) studied 282
consecutive tracheal intubations in a pe-
diatric intensive care unit to compare the
outcomes of patients with cuffed and un-
cuffed endotracheal tubes. The overall in-
cidence of postextubation stridor was
15% with no significant difference be-
tween the two endotracheal tube groups
even after controlling for age, duration of
intubation, trauma, leak around the en-
dotracheal tube before extubation, and
Pediatric Risk of Mortality Score. No pa-
tient experienced any long-term airway
complications. Khine et al. (16) com-
pared the use of cuffed vs. uncuffed en-
dotracheal tubes in 488 children mechan-
ically ventilated during anesthesia.
Cuffed tubes prevented the need for re-
peat intubations due to airleak, allowed
the use of lower rates of fresh gas flow,
and reduced the concentration of anes-
thetics in the operating room atmo-
sphere. The incidence of postextubation
stridor was low and similar between
groups. These studies suggest that cuffed
endotracheal tubes can be safely used in
young children as long as cuff pressures
are carefully followed.
It is clear that pulmonary aspiration in
infants and children is a multifactorial
process. Less clear, however, are the find-
ings from this study concerning the in-
fluence of sedation and swallowing ability
on aspiration in critically ill children. As-
sessing the adequacy of sedation requires
clinical judgment; furthermore, decisions
must be based on the underlying disease
process, planned interventions, antici-
pated outcomes, and patient preferences.
Practitioners would be amiss to conclude
that sedation is inadequate in mechani-
cally ventilated children unless swallow-
ing reflexes are inhibited. The degree of
sedation required to suppress swallowing
may be associated with other unwanted
outcomes such as prolonged mechanical
ventilation, suppression of cough and
predilection for atelectasis, and hemody-
namic instability. An important finding of
this study is the benefit of nasal intuba-
tion compared with oral intubation in
reducing aspiration risk. The relationship
between route of intubation and clinically
significant pulmonary aspiration needs to
be further addressed in a randomized
controlled trial.
Kathleen L. Meert, MD
Norma A. Metheny, PhD
Department of Pediatrics
Children’s Hospital of Michigan
Wayne State University School of
Medicine
Detroit, MI
St. Louis University School of
Nursing
St. Louis, MO
195
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1. Marik PE: Aspiration pneumonitis and aspi-
ration pneumonia. N Engl J Med 2001; 344:
665– 671
2. Winterbauer RH, Durning RB, Barron E, et
al: Aspirated nasogastric feeding solution de-
tected by glucose strips. Ann Intern Med
1981; 95:67– 68
3. Cataldi-Betcher E, Seltzer MH, Slocum BA,
et al: Complications occurring during en-
teral nutrition support: A prospective study. J
Parenter Enteral Nutr 1983; 7:546 –552
4. Browning DH, Graves SA: Incidence of aspi-
ration with endotracheal tubes in children.
J Pediatr 1983; 102:582–584
5. Kingston GW, Phang PT, Leathley MJ: In-
creased incidence of nosocomial pneumonia
in mechanically ventilated patients with sub-
clinical aspiration. Am J Surg 1991; 161:
589 –592
6. Strong RM, Condon SC, Solinger MR, et al:
Equal aspiration rates from postpyloric and
Nitric oxide: To inhale or not to inhale*
C ardiopulmonary bypass (CPB)
is an iatrogenic hierarchical
kill of vital organ perfusion. It
is associated with a defined
period of altered perfusion of lung and
myocardium. After CPB, increases in pul-
monary artery pressure and pulmonary
vascular resistance may lead to deteriora-
tion in the postoperative period. Inhaled
nitric oxide (INO) has been proposed as a
likely candidate to ameliorate these un-
toward effects. However, the effect of INO
in decreasing the deranged physiology of
ischemic reperfusion injury has met with
contrasting results. Most of the studies
examining INO effects on pulmonary
pathophysiology were performed in iso-
lated lung models (1–5) and in situ lung
models, which do not mimic the clinical
scenario after CPB (6 –7).
In an attempt to settle the score, Dr.
Hubble and colleagues (8) conducted ex-
periments in an in vivo ischemic reper-
fusion lung injury model, reported in this
*See also p. 157.
Key Words: nitric oxide; inhaled nitric oxide; car-
diopulmonary bypass; ischemic reperfusion injury; pul-
monary hypertension
Copyright © 2004 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/01.CCM.0000113927.64484.C0
196
intragastric-placed small bore nasoenteric
feeding tubes: A randomized, prospective
study. J Parenter Enteral Nutr 1992; 16:
59 – 63
7. Amantéa SL, Piva JP, Sanches P, et al: Oro-
pharyngeal aspiration in pediatric patients
with endotracheal intubation. Pediatr Crit
Care Med 2004; 5:152–156
8. Thompson-Henry S, Braddock B: The modi-
fied Evan’s blue dye procedure fails to detect
aspiration in the tracheotomized patient:
Five case reports. Dysphagia 1995; 10:
172–174
9. Potts RG, Zaroukian MH, Guerrero PA, et al:
Comparison of blue dye visualization and
glucose oxidase test strip methods for detect-
ing pulmonary aspiration of enteral feedings
in intubated adults. Chest 1993; 103:117–121
10. Metheny NA, Dahms TE, Stewart BJ, et al:
Efficacy of dye-stained enteral formula in de-
tecting pulmonary aspiration. Chest 2002;
122:276 –281
issue of Critical Care Medicine. Their el-
egant experiments in a piglet model of
CPB compared the effects of INO on car-
diopulmonary status when INO was ad-
ministered during ischemia only, during
reperfusion only, and during both isch-
emia and reperfusion (8). They found that
administering INO during the ischemic
period of CPB worsens post-CPB hemo-
dynamic status, whereas administration
of INO after CPB only may be beneficial;
INO during both ischemia and reperfu-
sion yielded intermediate benefits.
These findings are puzzling in that
intuitively we would expect that if INO
administered after CPB is beneficial,
there should be, at a minimum, no ad-
verse effects on hemodynamic status if
given during CPB. The finding of NO be-
ing good and bad in differing amounts or
circumstances has posed a dilemma for
investigators. The seemingly good and
bad effects on a single organ are amply
demonstrated in the lung, in which basal
concentrations of NO are important for
normal lung physiology (bronchodilation
and maintenance of normal arterial tone)
but the large amounts produced during
asthma exacerbations may increase lung
edema and mucus secretion (9). In fact,
the beneficial effects of steroids used in
asthma may be partly due to decreased
NO production. Similarly, basal NO pro-
11. Metheny NA: Risk factors for aspiration. J
Parenter Enteral Nutr 2002; 26:S26 –S33
12. Drakulovic MB, Torres A, Bauer TT, et al:
Supine body position as a risk factor for
nosocomial pneumonia in mechanically ven-
tilated patients: A randomized trial. Lancet
1999; 354:1851–1858
13. Adnet F, Baud F: Relation between Glasgow
Coma Scale and aspiration pneumonia. Lan-
cet 1996; 348:123–124
14. Nishino T: Physiological and pathophysiolog-
ical implications of upper airway reflexes in
humans. Jpn J Physiol 2000; 50:3–14
15. Deakers TW, Reynolds G, Stretton M, et al:
Cuffed endotracheal tubes in pediatric inten-
sive care. J Pediatr 1994; 125:57– 62
16. Khine HH, Corddry DH, Kettrick RG, et al:
Comparison of cuffed and uncuffed endotra-
cheal tubes in young children during general
anesthesia. Anesthesiology 1997; 86:627– 631
17. Erb T, Frei FJ: The use of cuffed endotracheal
tubes in infants and small children. Anaes-
thesist 2001; 50:395– 400
duction is needed to maintain normal
vascular tone whereas large amounts, as
seen in septic shock, are detrimental.
An explanation of the detrimental ef-
fect of INO during CPB is elusive. It is
possible that the study (90 mins) may not
be of sufficient duration to determine the
full extent of the effect of INO on the
cardiopulmonary variables in piglets. It is
also possible that the authors found no
difference in lung damage using dry
lung-weight ratio, myeloperoxidase, and
histologic evaluation because of the short
time frame or because the histologic eval-
uation is crude and subjective (hemor-
rhage, neutrophil number, and alveolar
destruction on a score of 0 for best to 3
for worst for each of category). However,
what are likely explanations if these find-
ings of worsening hemodynamics are
real?
The authors offered several plausible
explanations; however, none can fully
explain the phenomenon seen. It is pos-
sible that accumulation of NO in the
lung tissue of the piglets that received
INO during the ischemic phase of CPB
may set up the milieu for the genera-
tion of potentially toxic substances un-
der hyperoxic study conditions. An-
other explanation was the up-
regulation of endothelin with a
concomitant down-regulation of intrin-
Pediatr Crit Care Med 2004 Vol. 5, No. 2
sic NO synthesis resulting in the eleva-
tion of pulmonary vascular resistance
and pulmonary hypertension. However,
both theories go adrift because worse
hemodynamics than the control group
(no INO) would be expected but did not
occur in the group that received INO
only during CPB. It is also possible that
dosing of INO during CPB altered the
response to post-CPB INO without up-
regulation of endothelin. This is likely
to explain the hemodynamic values
seen in the INO during CPB only group
and also may explain the blunted re-
sponse to INO in the group receiving
INO both during and after CPB.
An examination of endogenous NO
generation in lung ischemic reperfusion
injuries may provide the physiologic un-
derpinning of the seemingly contradic-
tory findings. Nitric oxide is produced by
many cells within the lung (albeit in
small amounts—parts per billion) and
appears to play a critical role in the
pathophysiology of the pulmonary vascu-
lar bed and airways (10 –12). Endothelial
cells constitutively express a relatively
low output of NO via NO synthase I en-
zymatic pathway, and airway epithelial
cells normally produce NO via the NO
synthase III pathway. Output of NO via
NO synthase II, which could be further
induced by inflammatory mediators, pro-
duces larger quantities of NO (13, 14).
Endogenous NO production and bio-
activity are subject to great alterations
due to hypoxia, ischemia, and reperfu-
sion. Experiments in both cell culture in
animal and human lungs have shown
that enzymatic NO production exhibits a
characteristic oxygen dependence and
thus hypoxia reduces enzyme activity to
synthesize NO (15–18). Hypoxia, how-
ever, might increase NO generation from
nonenzymatic sources involved in the re-
duction of inorganic nitrate to NO, a re-
action that takes place predominantly
during acidic/reducing conditions as may
be seen during ischemic reperfusion in-
jury (19, 20). Although the potential rel-
evance of this phenomenon to lung pa-
thology has been demonstrated by
showing alteration of acid-base balance
and increase in NO production from ni-
trate and acidic pH in asthma (21), it also
has been suggested that pH changes as-
sociated with ischemia can trigger this
chemistry in the heart and aorta (22, 23).
Therefore, hypoxia and ischemia might
alter NO concentrations and bioactivity
by multiple and sometimes opposing
mechanisms.
Pediatr Crit Care Med 2004 Vol. 5, No. 2
Mechanical forces imposed on cells
by dynamically changing blood (pulsa-
tile vs. nonpulsatile flow) and air flow
(including positive end-expiratory pres-
sure) are also important contributors to
both microvascular and airway NO pro-
duction. During ischemia, these me-
chanical stimuli are reduced with the
potential effect of decoupling NO syn-
thesis from shear stresses. During isch-
emia and reperfusion, NO can serve
both as an antioxidant (by inhibiting
lipid free radicals) and as an oxidant (by
contributing to peroxynitrite forma-
tion), which both lead to its consump-
tion. These complex interactions are
likely to alter NO production. In fact,
NO production measured by exhaled NO
is reduced postoperatively and is thought to
be due to lung epithelial or pulmonary vas-
cular endothelial injury (24).
Based on these iterations, one can pre-
dict that ischemic reperfusion injury
would be associated with a complicated
picture of NOS expression, generation,
and consumption. An appreciation of the
complexity of NO physiology in lung in-
jury, however, although important, does
not enable us to fully explain the study
findings. The relative contribution of
each of these complex interactions will
need to be unraveled to fully explain the
observed phenomenon.
Regardless of the explanation, how
relevant are these findings to the clini-
cian? Does the piglet’s physiology ap-
proximate the human neonate in whom
CPB may be used? It is possible that the
basal NO production and response to
INO during CPB seen in healthy piglets
would be different from that seen in
neonates with congenital heart disease
in whom hypoxia, acidosis, increased or
decreased pulmonary blood flow, and
altered pulmonary mechanics may be
present before CPB. Several authors
have reported that preoperative pulmo-
nary hypertension and left to right
shunts seem to be related to postoper-
ative pulmonary vascular reactivity
(25–27). The findings of the study,
therefore, need to be verified under
conditions more likely to be seen in the
neonate undergoing CPB. Moreover, in
view of the complex relationships in NO
production during ischemic reperfu-
sion injury, control for the multitude of
factors involved will be needed to un-
ravel their relative contribution—a
daunting task indeed. In the meantime,
INO should be used with caution if at
all during CPB. The tantalizing data
remind us that too much of a good
thing may be good for nothing.
Niranjan Kissoon, MD, CPE
Division of Pediatric Critical Care
Medicine
University of Florida
HSC/Jacksonville
Jacksonville, FL
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after total cardiopulmonary bypass. J Thorac
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8. Hubble CL, Cheifetz IM, Craig DM, et al:
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lung preservation for transplantation.
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13. Guo FH, De Raeve HR, Rice TW, et al: Con-
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15. Dweik RA, Laskowski D, Abu-Soud HM, et al:
Nitric oxide synthesis in the lung. Regulation
by oxygen through a kinetic mechanism.
J Clin Invest 1998; 101:660 – 666
16. Phelan MW, Faller DV: Hypoxia decreases
constitutive nitric oxide synthase transcript
and protein in cultured endothelial cells.
J Cell Physiol 1996; 167:469 – 476
17. Nelin LD, Thomas CJ, Dawson CA: Effect of
hypoxia on nitric oxide production in neona-
tal pig lung. Am J Physiol 1996; 271:
H8 –H146
18. Ziesche R, Petkov V, Mosgoller W, et al:
Regulation of human endothelial nitric
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tion in human pulmonary arteries—
implications for the therapy of pulmonary
hypertension in COPD patients. Acta
Is it time to revisit a role for antithrombotic therapy in asphyxia
neonatorum?*
I t has been estimated that approx-
imately 130 million births occur
worldwide each year with four
million newborns suffering birth
asphyxia, of whom one million die and
one million have serious neurologic im-
pairment (1). A great deal of excitement
has been generated by recent studies that
suggest that hypoxic-ischemic brain in-
jury can be reversed or ameliorated by
the use of therapeutic postresuscitative
hypothermia. Independent groups in
Austria and Australia demonstrated, in a
randomized, controlled trial format, that
postresuscitative cooling led to a signifi-
cant improvement in neurologic out-
come in adults who, for the most part,
had ventricular fibrillation-induced car-
diac arrest (2, 3). Compagnoni and col-
leagues (4) simultaneously reported, in a
sequential series trial format from 1997
to 1999, that newborns with asphyxia
who were subjected to whole-body cool-
ing within 6 hrs of birth to a temperature
between 32°C and 34°C for 72 hrs had a
significant reduction in major neurologic
abnormalities and abnormal magnetic
*See also p. 163.
Copyright © 2004 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/01.PCC.0000121302.62216.D6
198
Anaesthesiol Scand Suppl 1996; 109:
97–98
19. Zweier JL, Samouilov A, Kuppusamy P: Non-
enzymatic nitric oxide synthesis in biological
systems. Biochim Biophys Acta 1999; 1411:
250 –262
20. Modin A, Bjorne J, Herulf M, et al: Nitrite-
derived nitric oxide: A possible mediator of
“acidic-metabolic” vasodilation. Acta Physiol
Scand 2001; 171:9 –16
21. Hunt JF, Fang K, Malik R, et al: Endogenous
airway acidification. Implications for asthma
pathophysiology. Am J Respir Crit Care Med
2000; 161:694 – 699
22. Zweier JL, Samouilov A, Kuppusamy P: Non-
enzymatic nitric oxide synthesis in biological
systems. Biochim Biophys Acta 1999; 1411:
250 –262
23. Modin A, Bjorne J, Herulf M, et al: Nitrite-
derived nitric oxide: A possible mediator of
resonance imaging findings. At the time
of the writing of this editorial, the results
of a multicenter, randomized, controlled
trial of postresuscitative hypothermia for
perinatal asphyxia are expected to be dis-
cussed at a “Hot Topics” conference in
neonatology. If therapeutic hypothermia
becomes a mainstay, then the next clini-
cal question is which approach can act
synergistically with this therapy to fur-
ther improve both survival and neuro-
logic outcome from asphyxia neonato-
rum?
In this issue of Pediatric Critical Care
Medicine, El Beshlawy et al. (5) demon-
strate that neonatal asphyxia is associated
with systemic thrombosis and depletion
of two important anticoagulant proteins:
antithrombin III and protein C. The au-
thors speculate that the use of antithrom-
bin III concentrate and protein C concen-
trate should be investigated in asphyxia
neonatorum. The link between perinatal
asphyxia, thrombosis, and “defibrination
syndrome” was first described in the
1960s. Leissring and Vorlecky (6) re-
ported autopsy findings of a term new-
born with asphyxia after breech delivery
for severe preeclampsia. The child had
vasoocclusive fibrin thrombi (consistent
with disseminated intravascular coagula-
tion pathophysiology) and hyaline
thrombi (platelet thrombi consistent
with thrombotic thrombocytopenic pur-
“acidic-metabolic” vasodilation. Acta Physiol
Scand 2001; 171:9 –16
24. Beghetti M, Silkoff PE, Caramori M, et al:
Decreased exhaled nitric oxide may be a
marker of cardiopulmonary bypass-in-
duced injury. Ann Thorac Surg 1998; 66:
532–534
25. Hoffman JIE, Rudolph AM, Heymann MA:
Pulmonary vascular disease with congenital
heart lesions: Pathologic features and causes.
Circulation 1958; 28:533–547
26. Del Nido PJ, Williams WG, Villamater J, et al:
Changes in pericardial surface pressure dur-
ing pulmonary hypertensive crises after car-
diac surgery. Circulation 1987; 76(Suppl III):
III-93–III-96
27. Meyrick B, Reid L: Ultrastructural findings in
lung biopsy material from children with con-
genital heart defects. Am J Pathol 1980; 101:
527–542
pura pathophysiology) occluding vessels.
Skyberg and Jacobsen (7) reported the
first successful treatment of this syn-
drome in an asphyxic term newborn in-
fant who presented with severe spasticity
and opisthotonus 5.5 hrs after birth. His
temperature was 35.8°C, he was in shock
with deep blue skin, and his cerebrospi-
nal fluid contained visible blood. He was
treated as defibrination syndrome with
one exchange transfusion of 500 mL of
heparinized whole blood (containing
2500 international units of heparin) plus
an 8-day course of corticosteroid therapy.
The child had a remarkable recovery and
was considered neurologically normal at
1 yr of life. The neonatal community was
favorably impressed by this report, and
several subsequent reports refer to treat-
ment with heparinized whole blood ex-
change transfusion as the established
therapy for asphyxia neonatorum. In
1973, Hambleton and Appleyard (8) per-
formed a controlled trial of fresh frozen
plasma infusion alone in asphyxiated low
birthweight infants (⬍2.5 kg) and found
no reduction in intraventricular hemor-
rhages with this treatment. They and oth-
ers concluded that although fresh frozen
plasma infusion was not effective, hepa-
rinized whole blood exchange transfusion
was “well established” as an effective
therapy for asphyxia with defibrination
syndrome in the term newborn (9). In
Pediatr Crit Care Med 2004 Vol. 5, No. 2
agreement with the findings of Hamble-
ton and colleagues, a 1996 randomized,
controlled trial similarly showed that
prophylactic treatment of preterm babies
with fresh frozen plasma had no effect on
outcomes (10).
Much has changed since the 1970s.
The collective memory for the use of hep-
arinized whole blood exchange has been
lost. Indeed, whole blood is no longer
available in much of the Western world
where blood is presently banked as com-
ponents. However, there has been a great
improvement in knowledge about antico-
agulant and procoagulant proteins and
their role in thrombotic microangio-
pathic syndromes. Three clinically im-
portant circulating anticoagulant pro-
teins have been identified, namely,
antithrombin III, protein C, and von Wil-
lebrand factor-cleaving protease, or
ADAM TS 13 (11). Antithrombin III is an
active anticoagulant only when it is com-
plexed with heparin. It is common prac-
tice in veterinary medicine today to treat
defibrination syndrome by infusing hep-
arin-treated fresh frozen plasma. The ra-
tionale given is that heparin “activates”
antithrombin III, preventing ongoing co-
agulation while the procoagulant factors
prevent bleeding from consumptive co-
agulopathy. Protein C is an active antico-
agulant when it is complexed with endo-
thelial thrombomodulin. Activated
protein C resistance (also known as factor
V Leiden deficiency) has been reported as
a cause of ischemic stroke in neonates
and infants (12, 13). Patients with acti-
vated protein C resistance can be success-
fully anticoagulated with warfarin or hep-
arin therapy. The von Willebrand factor-
cleaving protease ADAM TS 13 is always
active. Unlike antithrombin III and pro-
tein C, it is not thought to have any effect
on fibrin. Instead, this enzyme cleaves
thrombogenic large and ultralarge von
Willebrand factor multimers, preventing
uncontrolled platelet thrombosis (hyaline
thrombi). Absence or inhibition of ADAM
TS 13 is considered to be the cause of
thrombotic thrombocytopenic purpura-
mediated thrombotic microangiopathy
(11). Newborns have markedly reduced
levels of antithrombin III, protein C, and
ADAM TS 13 compared with adults (14,
15). Pathophysiologic processes that
cause endotheliopathy, including sepsis
(15) and perinatal asphyxia (5), consume
antithrombin III and protein C, leaving
the newborn with severe anticoagulant
protein deficiency and a proclivity to sys-
temic thrombosis (5, 15). Replacement of
Pediatr Crit Care Med 2004 Vol. 5, No. 2
these anticoagulant factors can be
achieved with plasma infusion or with
concentrates. Each 10 mL/kg of plasma
given replaces approximately 10% of nor-
mal activity. Antithrombin III and pro-
tein C can be more efficiently given as
commercially purified concentrates.
In the past, when neurologic outcome
was considered immutable after perinatal
asphyxia, little thought was given to
treating or reversing the associated
thrombotic microangiopathy. However,
now that brain injury appears to be at
least partly reversible with therapeutic
hypothermia, it is time to think about the
potential role of anticoagulant therapies
to further improve outcome and neuro-
logic function after perinatal asphyxia.
Preparatory studies will likely be needed.
First, because temperature itself has ef-
fects on coagulation, the effects of hypo-
thermia on thrombosis and fibrinolysis
will need to be considered. Coagulation is
decreased at 32°C; coagulation is not de-
creased at 35°C. Second, because some
patients with perinatal asphyxia have de-
fibrination syndrome whereas others do
not, patient selection will be important to
any study design. For example, patients
with consumptive coagulopathy may re-
quire anticoagulant therapy as well as
procoagulant replacement, whereas pa-
tients without “defibrination” may only
require anticoagulant therapies.
In summary, in this issue of Pediatric
Critical Care Medicine, El Beshlawy et al.
(5) provide a modern day evaluation of
the coagulopathy associated with As-
phyxia Neonatorum. Their findings sup-
port severe depletion of the anticoagulant
proteins antithrombin III and protein C
in the setting of systemic thrombosis.
Antithrombin III concentrate and protein
C concentrate are recommended thera-
pies for newborns with congenital anti-
thrombin III and protein C deficiency.
These therapies have little to no risk for
causing bleeding when administered in
the absence of heparin. Based on the
findings of El Beshlawy et al. (5), we
agree that it is time to investigate
whether antithrombin III concentrate
and protein C concentrate have a ther-
apeutic role in newborns with asphyxia
and acquired antithrombin III and pro-
tein C deficiency.
Robert Clark
Joseph A. Carcillo
Children’s Hospital of Pittsburgh
Pittsburgh, PA
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Non protein bound iron as early predictive
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2003; 126(Pt 5):1224 –1230
2. Bernard SA, Gray TW, Buist MD, et al: Treat-
ment of comatose survivors of cardiac arrest
with induced hypothermia N Engl J Med
2002; 346:557–563
3. The Hypothermia After Cardiac Arrest Study
Group. Mild hypothermia to improve neuro-
logic outcome after cardiac arrest. N Engl
J Med 2002; 346:549 –556
4. Compagnoni G, Pogliani L, Lista G, et al:
Hypothermia reduces neurologic damage in
asphyxiated newborn infants. Biol Neonate
2002; 82:222–227
5. El Beshlawy A, Hussein HA, Abou-Elew HH,
et al: Study of protein C, protein S, and
antithrombin III in hypoxic newborns. Pedi-
atr Crit Care Med 2004; 5:163–166
6. Leissring JC, Vorlicky LN: Disseminated in-
travascular coagulation in a neonate. Am J
Dis Child 1968; 115:105–111
7. Skyberg D, Jacobsen CD: Defibrination syn-
drome in a newborn and its treatment with
exchange transfusion. Acta Paediatr Scand
1969; 58:83– 86
8. Hambleton G, Appleyard WJ: Controlled trial
of fresh frozen plasma in asphyxiated low
birthweight infants. Arch Dis Child 1973; 48:
31–38
9. Kirsch W, Buttner M, Wenzel E: Diagnostic
therapeutic problems of defibrination syn-
drome in shock, sepsis, and neonatal hypoxia.
Monatsschr Kinderheilkd 1977; 125:621– 627
10. A randomized trial comparing the effect of
prophylactic intravenous fresh frozen
plasma, gelatin or glucose on early mortal-
ity and morbidity in preterm babies. The
Northern Neonatal Nursing Initiative
(NNNI) Trial Group Eur J Pediatr 1996;
155:580 –588
11. Nguyen T, Hall M, Han Y, et al: Microvascu-
lar thrombosis in pediatric multiple organ
failure: Is it a therapeutic target? Pediatr Crit
Care Med 2001; 2:187–186
12. Thorarensen O, Ryan S, Hunter J, et al: Fac-
tor V Leidien mutation: An unrecognized
cause of hemiplegic cerebral palsy, neonatal
stroke, and placental thrombosis Ann Neurol
1997; 42:372–375
13. Nowak-Gottl U, Strater R, Dubbers A, et al:
Ischaemic stroke in infancy and childhood:
Role of the Arg506 to Gln mutation in the
factor V gene. Blood Coagul Fibrinolysis
1996; 7:684 – 688
14. Kavakli K, Canciani MT, Mannucci PM:
Plasma levels of the von Willebrand Factor
Cleaving Protease in physiological and
pathophysiological conditions in children.
Pediatr Hematol Oncol 2002; 19:467– 473
15. Roman J, Velasco F, Fernandez F, et al:
Coagulation, fibrinolytic and kallikrein
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23:142–148
199
Surface properties and the meconium aspiration syndrome*
I n this issue of Pediatric Critical
Care Medicine, Dr. Fuloria and
colleagues (1) explore the physical
properties and interactions of sa-
line-suspended meconium, calf lung sur-
factant, and perflubron. The picture that
emerges may help to elucidate the patho-
physiology of the meconium aspiration
syndrome. It also illustrates the weakness
of the link between the behavior of meco-
nium and the disease it produces.
The authors show that, although
meconium reduces the surface tension of
saline, it interferes with the surface ten-
sion lowering effect of surfactant in pro-
portion to the concentration of the sus-
pension. This interaction has been
studied in vitro (2) and in intact animals
(3–5) and has generated interest in sur-
factant therapy as a treatment of meco-
nium aspiration (6, 7).
Dr. Fuloria and colleagues (1) further
show that meconium suspension spreads
poorly over Teflon but readily over per-
flubron. This ability to wet a perflubron
film is not directly correlated to the dis-
ease process, but the implication is that
perflubron, which itself spreads readily
over saline or Teflon, may enhance the
clearance of sticky meconium from air-
ways by making it more slippery.
Using a third technique, distraction
(de Nouy ring), the authors show that the
interfacial tension between a perflubron
layer and a meconium/saline suspension
is variable and is inversely related to the
logarithm of the meconium concentra-
tion. The greater the concentration of
meconium, the lower is the interfacial
surface tension. Of great interest here is
the finding that at very low meconium
concentration, a saline-perflubron inter-
face has surface tension near 40 dyne/cm,
roughly halfway between the surface ten-
sions of perflubron (at air) and water (at
air). But let’s come back to that.
*See also p. 167.
Key Words: saline-suspended meconium; calf lung
surfactant; perflubron; meconium aspiration
Copyright © 2004 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/01.PCC.0000115958.23002.D5
200
So which of these properties of meco-
nium are relevant to clinical meconium
aspiration syndrome? Clearly meconium
aspiration makes the lungs stiff. This
would appear to correlate with loss of
surfactant function. We are comfortably
familiar with this. The rationale for high-
dose surfactant instillation in meconium
aspiration syndrome is that giving more
surfactant may reverse or overwhelm this
interference. Polymers such as dextran
and polyethylene glycol can be added to
surfactant to make it more resistant to
this inhibition (8, 9), and surfactants hav-
ing higher concentrations of surfactant
proteins (A, B, and C) are more resistant
to inactivation (10), suggesting the po-
tential for “designer surfactants” of
greater resistance. Surfactant dysfunc-
tion is a widely recognized component of
other lung diseases, including acute re-
spiratory distress syndrome. Designer
surfactants might, therefore, have wide-
spread use.
Could perfluorocarbons like per-
flubron be used to reduce surface tension
in meconium aspiration syndrome? Dr.
Fuloria and colleagues (1) have shown
that the surface properties of perflubron
are not altered by exposure to meconium.
Laboratory and clinical experience argues
that perflubron might prove useful.
But at what interface does perflubron
reduce surface tension? Gas/perflubron
interfaces have modest surface tension
(18 dyne/cm). But what of the interface
between perflubron and immiscible alve-
olar tissue surface material? If that inter-
face had a surface tension of 40 dyne/cm,
like that of saline to perflubron, perfluo-
rocarbons could not be helpful. However,
even in the lung exposed to meconium,
the alveolar tissue is covered by a surface
of complex composition. Dr. Fuloria and
colleagues (1) have shown that at high
meconium concentration, a saline/meco-
nium-perflubron interface has a surface
tension near that of perflubron and gas.
The interface truly at issue during partial
or tidal liquid ventilation for meconium
aspiration is that of perflubron to a mix-
ture (in one phase) of surfactant and
meconium.
What of the other properties of meco-
nium? Meconium suspension does not
spread over Teflon. Perhaps this impairs
mucociliary clearance of meconium.
Might mucociliary clearance of meco-
nium be enhanced by perflubron lavage,
wetting surfaces to spread, lift, slip, and
mobilize droplets of meconium?
Meconium is “sticky” and relatively
“dry.” Perhaps meconium particles ob-
struct airways and are hard to dislodge by
“cough (air flow) transport.” Can such
particles be washed away? There is recent
interest in lavage using dilute surfactant
as a means to mobilize and remove meco-
nium (11, 12). Does the “wetting” prop-
erty of perflubron offer an opportunity
here?
Rubin et al. (13) discussed various
properties of meconium, describing it as
characterized by cohesiveness (“spinabil-
ity”), dryness, cough transportability, cil-
iary transportability, “wetability,” and
non-Newtonian interfacial adhesion ten-
sion. We know little of the relation of
these properties to the lung dysfunction
of meconium aspiration.
It is probably simplistic to think of
meconium aspiration syndrome as just
another surfactant dysfunction state, but
at least that aspect of it is tangible.
Bradley P. Fuhrman, MD
State University of New York at
Buffalo
Women’s and Children’s Hospital
of Buffalo
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