Invited Review Articles

The pediatric multiple organ dysfunction syndrome

François Proulx, MD; Jean Sébastien Joyal, MD; M. Michele Mariscalco, MD; Stéphane Leteurtre, MD;
Francis Leclerc, MD; Jacques Lacroix, MD

Objectives: To review the epidemiology of pediatric multiple
organ dysfunction syndrome (MODS) and summarize current con-
cepts regarding the pathophysiology of shock, organ dysfunction,
and nosocomial infections in this population.
Data Source: A MEDLINE-based literature search using the
keywords MODS and child, without any restriction to the idiom.
Main Results: Critically ill children may frequently develop
multisystemic manifestations during the course of severe infec-
tions, multiple trauma, surgery for congenital heart defects, or
transplantations. Descriptive scores to estimate the severity of
pediatric MODS have been validated. Young age and chronic
health conditions have also been recognized as important con-
tributors to the development of MODS. Unbalanced inflammatory
processes and activation of coagulation may lead to the devel-
opment of capillary leak and acute respiratory distress syndrome.
Neuroendocrine and metabolic responses may result in insuffi-
cient adaptive immune response and the development of noso-
comial infections, which may further threaten host homeostasis.
Conclusions: Over the last 20 yrs, there has been an increasing
knowledge on the epidemiology of pediatric MODS and on the
physiologic mechanisms involved in the genesis of organ dys-
function. Nevertheless, further studies are needed to more clearly
evaluate what is the long-term outcome of pediatric MODS.
(Pediatr Crit Care Med 2009; 10:12–22)
KEY WORDS: child; epidemiology; systemic inflammatory re-
sponse syndrome; sepsis; multiple organ dysfunction syndrome;
shock; capillary leak syndrome; hypermetabolism; cytokines; im-
munoparalysis; nosocomial infections

T he concept that medical ther-
apy may alter disease expres-
sion and progression was sup-
ported by the emergence of
multiple organ failure with improve-
ments in the treatment of shock states
over the latter half of the 20th century (1,
2). During the late 60s, “high output re-
spiratory failure” has been recognized
among adults with peritonitis (3). A se-
quential pattern of organ failures was
then identified among adults with rup-
tured aortic aneurysms (4). Large epide-
miologic studies performed in critically
ill adults admitted to American or French
intensive care units (ICU) showed a rela-
tionship between an increasing number
of failing organs and mortality (5). As the
number of deaths also steadily increased
From the Division of Critical Care Medicine (FP,
JSJ, JL), Department of Pediatrics, Sainte-Justine Hos-
pital, University of Montreal, Montreal, Canada; De-
partment of Pediatrics (MMM), Section of Critical Care
Medicine, Baylor College of Medicine, Houston, TX;
and Department of Pediatrics (SL, FL), Service de
Réanimation Pédiatrique, Hôpital Jeanne de Flandre,
Lille, France.
The authors have not disclosed any potential con-
flicts of interest.
For information regarding this article, E-mail:
fproulx_01@yahoo.ca
Copyright © 2009 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/PCC.0b013e31819370a9
during and after the first week of ICU
admission (5), multiple organ failure was
viewed as the inexorable pathway to
death. In the 90s, diagnostic criteria for
adults with the systemic inflammatory
response syndrome (SIRS), sepsis, and
organ dysfunction have been proposed
(6), and these were recently revisited (7).
Most importantly, it has been recognized
that regardless of age, organ dysfunction
represents a continuum of physiologic
abnormalities rather than a dichotomous
state (normal vs. failure) that may occur
with or without any identifiable source of
infection (6).
Epidemiology of Pediatric
Multiple Organ Dysfunction
Syndrome
Wilkinson et al (8, 9) initially proposed
diagnostic criteria for organ failures in
critically ill children and defined multiple
organ failure as the simultaneous occur-
rence of at least 2 organ systems. They
found an association between an increas-
ing number of organ failures and pediat-
ric ICU (PICU) mortality (8, 9), which has
been confirmed repeatedly. Several
groups reported that the number of chil-
dren who die in PICU without reaching
criteria for multiple organ dysfunction
syndrome (MODS) is low (9 –11). As sum-
marized in Table 1, the epidemiology of
MODS has been described in various clin-
ical settings, such as general PICU popu-
lation, children with sepsis, congenital
heart diseases, trauma, liver, or bone
marrow transplantations. The incidence
and mortality rate of MODS varied largely
between clinical studies possibly due to
some variations in case-definition and
case-mix. One recent study demonstrated
a relationship between MODS, the length
of stay in PICU, and increased resource
use (26).
Factors that increase the risk of devel-
oping MODS in adults included delayed
or inadequate resuscitation, persistent
infectious or inflammatory focus, surgi-
cal misshaps, advancing age, and chronic
health conditions, such as alcoholism,
malnutrition, or cancer (27, 28). The pre-
disposing factors for pediatric MODS are
less clear. In one study, MODS most fre-
quently occurred under 1 yr of age, par-
ticularly among males (26). To evaluate
the association between age and organ
failure, we analyzed the distribution of
the Pediatric Logistic Organ Dysfunction
(PELOD) score against patient’s age us-
ing a previously published cohort (11). As
seen in Figure 1, there is a significantly
higher PELOD score in neonates, when
compared with infants, children, and ad-
olescents. Although it is unclear whether
PELOD score definitions hold the same
descriptive power in the neonatal popu-

12 Pediatr Crit Care Med 2009 Vol. 10, No. 1

Table 1. Epidemiology of pediatric MODS was inversely related to serum levels of
cytokines and the severity of MODS (32).
Patients Incidencea (%) Mortalityb (%)
Early work by Wilkinson et al (9)
General pediatric ICU population
showed that one fourth of children with
Wilkinson et al (9) 831 27 26 MODS may have chronic diseases. Most
Proulx et al (12) 777 11 51 recently, a comorbid condition was noted
Tan et al (13) 283 6 56 among 64% of children admitted to the
Leteurtre et al (14) 594 45 19 PICU (16). Congenital neurodevelopmen-
Tantalean et al (10) 276 57 42
Leteurtre et al (11) 1,806 53 12 tal delay may frequently be noted (33).
Khilnani et al (15) 1,722 17 26 Compared with previously healthy chil-
Typpo et al (16) 44,693 19 10 dren, those with chronic health condi-
Sepsis tions had a two-fold increased risk of un-
Wilkinson et al (8) 726 24 47 scheduled admission to the PICU (34).
Proulx et al (17) 1,058 18 36 The incidence of MODS, as defined by the
Goh et al (18) 495 17 57
Kutko et al (19) 80 73 19 International Pediatric Sepsis Consensus
Leclerc et al (20) 593 45 19 Conference (35), was two-fold greater
Congenital heart diseases among patients with comorbid condition,
Seghaye et al (21) 460 4 56 which independently increased the risk of
Trauma death by 60% when controlling for the
Calkins et al (22) 534 3 17 number of dysfunctional organs (16).
Liver or bone marrow transplantation
Feickert et al (23) 114 27 72
Keenan et al (24) 121 55 94
Descriptive Scores to Estimate
Lamas et alc (25) 49 90 69 the Severity of MODS

MOD, multiple organ dysfunction syndrome; ICU, intensive care unit. MODS scoring systems have been de-
a
Incidence of MODS; b mortality rate of MODS; c MODS was defined as three organ dysfunctions. veloped to be used in clinical trials as
outcome measures because mortality rate
remains overall relatively low in critically
ill children. Leteurtre et al (11, 14) devel-
oped and validated the PELOD score, a
scoring system based on the following
physiologic variables: Glasgow Coma
Scale score/pupillary reaction (neuro-
logic); heart rate/blood pressure (cardio-
vascular); serum creatinine (renal); PaO2/
FIO2 ratio, PaCO2, mechanical ventilation
(respiratory); white blood cell and plate-
let counts (hematologic); aspartate
transaminase level, and prothrombin
time or international normalized ratio
(hepatic) (11). Most recently, Graciano et
al (36) developed the pediatric-MODS
score that is based exclusively on labora-
tory values including lactic acid (cardio-
vascular); PaO2/FIO2 ratio (respiratory);
bilirubin (hepatic); fibrinogen (hemato-
Figure 1. Box plot of the Pediatric Logistic Organ Dysfunction (PELOD) score according to age in
critically ill children. Ranges (°), deciles 1 and 9 (⬜, ⳕ), quartiles 1 and 3 (䡺), medians (–), and means
logic); and blood urea nitrogen (renal).
(⫹) are indicated. The figure shows that significantly higher PELOD scores were noted in neonates Both scores presented good discrimina-
(⬍1 month), compared with infants (1–12 months), children (1–12 yrs), and adolescents (12–18 yrs) tive values and may be used to describe
(*p ⬍ 0.0001, Bonferoni correction). The highest number of organ dysfunction was also found in this severity of illness in critically ill children,
group (data not shown; p ⬍ 0.0001). Finally, neonates presented the highest rate of mortality: although neurologic dysfunction is not
neonates (25/171; 14.6%); infants (35/525; 6.7%); children (40/853; 4.7%); adolescents (15/257; 5.8%); evaluated with the pediatric-MODS score
p ⬍ 0.0001. (11, 36).

The Course of SIRS, Sepsis,

lation, the observed rate of mortality was
also higher in this group. There may exist
a different pattern of organ dysfunction
in the neonatal population (29, 30). In-
deed, there are important developmental
changes during the first year of life in
physiologic factors influencing the mat-
uration of renal, hepatic, gastrointestinal,
and central nervous system (31). Signifi-
cant variations in extracellular body wa-
ter, glomerular filtration rate, and iso-
forms of cytochrome P-450 have also
been noted (31). In this regard, drug me-
tabolism mediated by cytochrome P-450
and Organ Dysfunction
SIRS refers to any combination of fe-
ver or hypothermia, tachycardia; tachy-
pnea or hypocapnia; and leukocytosis or
leukopenia (6). The host response is
called “sepsis” when these symptoms are

Pediatr Crit Care Med 2009 Vol. 10, No. 1 13

suspected to be triggered by an infection.
Nearly, 70%– 80% of children admitted to
PICUs met diagnostic criteria for SIRS
(17, 37). Increased mortality has also
been noted in children with sepsis com-
pared with those with noninfectious SIRS
(37). In children, MODS usually devel-
oped rapidly after ICU admission (10, 12,
18). In one study, the maximal number of
organ failures was noted within 72 hrs in
the majority of patients (12). However,
some children still had evidence of organ
damages 1 wk or more after pediatric ICU
admission and/or developed a sequential
pattern of organ dysfunction (17). Com-
pared with children with a primary onset
of organ dysfunction, those with second-
ary MODS showed an increased length of
ICU stay and a higher mortality rate (17).
Sequential organ dysfunction has also
been associated with increasing circulat-
ing levels of cytokines (38, 39).
Severe Infections
An increased severity of organ dys-
function has been noted among children
with sepsis, severe sepsis, and septic
shock (10, 18). The risk of death steadily
increased when taking into account both
the severity of organ dysfunction and sep-
sis diagnostic categories enumerated ear-
lier (20). Mortality also varied with co-
morbid illnesses (40). Although there has
been a consensus definition for sepsis,
severe sepsis, and septic shock in adults
since the early 1990s, it has been difficult
to apply them to children because of de-
velopmental differences in physiologic
parameters (41). To address this concern,
an International Pediatric Sepsis Consen-
sus Conference was convened in 2002;
SIRS criteria for children were modified,
definitions of severe sepsis and septic
shock for the pediatric population was
revised, and organ system dysfunction
was defined (42).
Congenital Heart Diseases
Children with congenital heart dis-
eases may develop organ dysfunction in
the preoperative phase, when good bal-
ance between pulmonary and systemic
cardiac output has not been established.
In children with hypoplastic left heart
syndrome and pulmonary overcircula-
tion, prostaglandin infusion with after-
load reduction reduced the severity of
hepatic, renal, and gastrointestinal dys-
functions preoperatively (43). In one
study, 80% of deaths during the first
14
week after surgery for congenital heart
diseases were caused by MODS (44).
Thereafter, sepsis was estimated to be the
cause of death in 20% of cases (44). Early
MODS may occur after cardiopulmonary
bypass as a result of cardiovascular insta-
bility and inflammation (21). During ex-
tracorporeal membrane oxygenation sup-
port, persistent renal failure has been
repeatedly associated with a poor out-
come (45– 47). In the perioperative pe-
riod, organ dysfunction may develop as a
result of circulatory derangements asso-
ciated with a residual lesions, palliative
surgery, or procedures for single ventri-
cle physiology (43, 48). Children with
congenital heart diseases may be prone to
“classic” adult-type MODS, with the con-
cept of preconditioning, development of
immune paralysis (49), and susceptibility
to a second-hit phenomenon (44).
Multiple Trauma
Calkins et al (22) reported that none
of 334 children admitted to the PICU
for isolated head injury developed
MODS. Only 3% of children with mul-
tiple traumatic injury developed MODS
after 2 days in the PICU (22). Compared
with adults, the mortality rate was
three-fold lower in the pediatric popu-
lation (22). It is unclear whether this
may be due to differences in comorbid
conditions or a different inflammatory
response in children (50).
Transplantation of Solid Organs
MODS has been found to be a major
determinant for early mortality after pe-
diatric orthotopic liver transplantation
because of primary graft nonfunction,
vascular thrombosis, sepsis, or as a result
of pretransplant status (23). As measured
by the amount of fresh frozen plasma
administered, the extend of damage to
the engrafted liver was a major contrib-
utor to organ dysfunction. In this regard,
hepatic vascular thrombosis may lead to
severe hemorrhagic shock and acute re-
nal failure. This may then lead to polymi-
crobial sepsis caused by intestinal perfo-
ration and malnutrition. It has been
shown that severe rejection rarely occurs
early after liver transplantation. Con-
versely, patients with rejection episodes
were noted to less frequently develop
MODS in the postoperative phase (23).
Long-term survival depended on the un-
derlying disease, the presence of MODS
in the postoperative phase, or late sepsis
(23). The development of chronic graft
failure or lymphoproliferative disease was
also major determinant of outcome (23).
Bone Marrow Transplantation
The approach to organ dysfunction in
this population is based on the concept
that pretransplant conditioning leads to
potentially reversible cytoxicity, includ-
ing pancytopenia, capillary leak syn-
drome, acute graft vs. host disease, and
hepatic veno-occlusive disease. In one
large prospective study, MODS was the
only variable that had a negative impact
on the outcome (51). An increased mor-
tality rate has been noted in children who
develop septic shock and MODS after
bone marrow transplantation but not
among those suffering from neoplasic
disorders who did not have transplanta-
tion (19). In the former group, pulmo-
nary or neurologic dysfunctions were im-
portant determinants of patient survival
(52). Respiratory insufficiency may be
secondary to opportunistic infections,
bronchiolitis obliterans, pulmonary
edema, or toxicity. Combined neuro-
logic and renal dysfunction may occur
with cyclosporine or tacrolimus toxicity
and related bone marrow transplant
thrombotic microangiopathy.
Overview of the
Pathophysiology of Shock and
Organ Dysfunction
An overview of clinical conditions re-
ported in critically ill children with
MODS is presented in Figure 2. During
shock, sympathetic stimulation preferen-
tially directs blood flow toward brain and
myocardium, diverting it from the
splanchnic circulation. A higher rate of
mortality has been noted in critically ill
children with increased lactate concen-
trations (53, 54). In contrast to adults,
most studies performed in critically ill
children did not find the gastric pH to be
predictive of developing MODS or death
(53, 55–58). However, decreased intesti-
nal pH in very low birth weight infants
was associated with a higher risk of de-
veloping necrotizing enterocolitis (59).
Hemodynamic profiles noted in critically
ill children with septic shock were more
unpredictable than it has been initially
recognized (60 – 62). Indeed, only 20% of
children with fluid refractory septic
shock presented the classic picture of
high cardiac index and low systemic vas-
cular resistance (63). Nearly, 60% of pa-
Pediatr Crit Care Med 2009 Vol. 10, No. 1
 ary conserved system that provides im-
mediate defense against pathogens (73–
76). In critically ill children, higher levels
of pro- and anti-inflammatory mediators,
as well as increased prothrombotic and
antifibrinolytic plasma activities have
been associated with the severity of
MODS and mortality (38,39,64, 65,77–
81). Activation of tissue factor pathway is
a central event in the genesis of micro-
thrombosis. The expression of tissue fac-
tor by lipopolysaccharide, tumor necrosis
factor (TNF)-␣, and interleukin (IL)-1
cause activation of factor VII, X, and V,
thereby increasing thrombin generation
and fibrin deposition (82). Children who
died of meningococcal sepsis presented
higher concentrations of several proin-
flammatory mediators, as well as in-
Figure 2. Overview of the pathophysiology of multiple organ dysfunction syndrome. The host response creased serum levels of IL-10 and soluble
to injury or infection is central to the development of multiple organ dysfunction syndrome. Shock TNF receptors, which have anti-inflam-
states are characterized by abnormal microcirculatory blood flow, with variable degree of peripheral matory activity (83, 84). The outcome of
vasoplegia and myocardial depression that may cause acute renal failure. The latter may aggravate children with meningococcemia was
capillary leak syndrome. Renal failure itself may result in worse lung injury or other organ failure.
found to be related to polymorphisms in
Inflammatory processes, including the cytokine and chemokine response, lead to endothelial cell
activation, which is clinically recognized as disseminated intravascular coagulation, capillary leak, and
the plasminogen activator inhibitor gene
acute respiratory distress syndrome. Hypermetabolism, also called “septic autocannibalism,” may in response to TNF-␣ activation (84). Im-
result in a state of severe malnutrition, which is associated with secondary immunoparalysis. Overall, paired coagulation may also have oc-
impaired mechanisms of tissue repair may lead to the development of nosocomial infections, usually curred due to an age-dependent relative
7–10 days later. The biological significance of other clinical conditions highlighted earlier remains to liver immaturity (85, 86).
be clarified. TAMOF, thrombocytopenia-associated multiple organ failure. In the Recombinant Human Protein C
Worldwide Evaluation in Severe Sepsis
trial, the use of recombinant human ac-
tients showed low cardiac index with high Nitric oxide has been shown to mod- tivated protein C reduced mortality and
systemic vascular resistance and both pa- ulate cell signaling by readily decaying improved organ dysfunction among
rameters might even be decreased (63). into nitrite and a potent nitrosating spe- adults with severe sepsis (87). In the Re-
cies, dinitrogen trioxide, which are in- searching Severe Sepsis and Organ Dys-
Nitric Oxide volved in the nitrosylation of signaling function in Children: A Global Perspec-
proteins, membrane receptors, and ion tive trial, children with sepsis-induced
Nitric oxide may directly contribute to channels modulating cellular activity cardiovascular and respiratory failure
the genesis of organ damages through (67). Scavenging of free radicals by nitric were randomly assigned to receive pla-
dysregulation of regional vascular blood oxide are protective of cell survival. How- cebo or recombinant human activated
flow and by indirect mechanisms related ever, in the presence of superoxide radi- protein C (88). There was no difference
to the formation of peroxinitrites. The cals, large amount of nitric oxide pro- between treatment groups in either or-
severity of arterial hypotension among duced highly reactive peroxynitrites gan failure resolution or mortality (88).
children with sepsis and MODS corre- that may damage lipid membranes and Although overall bleeding events were
lated with serum concentrations of ni- DNA (68) or induce abnormal mito- not different between groups, there was
trites and nitrates (64). The constitutive chondrial activity (69). Peroxinitrites an increased incidence of central nervous
isoform of nitric oxide synthase has been have been shown to inhibit the mito- system bleeding in the treated group
shown to produce nanomolar concentra- chondrial cytochrome oxidase complex among children younger than 2 months.
tion of nitric oxide. However, activation (70), a phenomenon known as “cyto- Thus, recombinant human activated pro-
of the inducible nitric oxide synthase by pathic hypoxia” (71). tein C is not recommended in the treat-
lipopolysaccharide or cytokines leads to ment of children with severe sepsis.
nitric oxide concentrations within the Inflammation, Coagulation, and Nguyen et al (89) have described a
macromolar range (65). Nitric oxide con- Fibrinolysis specific subset of critically ill children
centrations in this range can produce ab- with thrombocytopenia-associated multi-
normal regional vascular blood flow be- The sepsis triad refers to activation of ple organ failure (Fig. 2). Autopsies of
cause of retrograde feedback inhibition of the coagulation system with inhibition of children dying from MODS demonstrated
the constitutive isoform (65). It has been fibrinolysis triggered by inflammatory microthromboses that stained positive
suggested that hypotension refractory to processes (72). The natural course of sep- for von Willebrand factor antigen and few
vasoactive agents might depend on de- sis and organ dysfunction has been stained for fibrin (89). von Willebrand
layed activation of the inducible nitric shown to vary with hereditary factors in factor is released from injured endothe-
oxide synthase isoform (66). innate immunity, an ancient evolution- lial cells as an ultralarge form, which

Pediatr Crit Care Med 2009 Vol. 10, No. 1 15

initiates the platelet plug after injury.
The von Willebrand factor cleaving pro-
tease, also known as ADAMTS-13, cleaves
the ultralarge form into smaller less ad-
hesive fragments. Severe enzymatic defi-
ciency of ⬍7%–10% ADAMTS-13 activity
results in thrombotic thrombocytope-
nic purpura. However, it has been re-
cently demonstrated that as many as
30% of children with severe sepsis
had moderately decreased protease ac-
tivity (ADAMTS-13 around 20%) (90).
ADAMTS-13 activity was also inversely
correlated with Pediatric Risk of Mor-
tality and PELOD scores and paralleled
the course of thrombocytopenia (90).
Capillary Leak and Acute
Respiratory Distress Syndrome
MODS has been associated with ab-
normal systemic vascular permeability
resulting in the development of the cap-
illary leak syndrome (91, 92). During me-
ningococcemia, the amount of circulat-
ing endotoxin determines the severity of
complement activation and capillary
leakage (93). Susceptibility to the devel-
opment of edema after cardiopulmonary
bypass (94, 95) or bone marrow trans-
plantation (96) is also related to activa-
tion of complement. In healthy individu-
als, Gamble et al (97) found the highest
vascular permeability coefficients values
among younger children. By the end of
the second decade of life, susceptibility to
vascular leakage was noted to be three- to
four-fold lower (97). These observations
might reflect the increased permeability of
growing capillary and changes in microvas-
cular density associated with growth (97).
In this regard, survivors from PICU had
lower percent fluid overload and were more
likely to attain their target dry weight dur-
ing continuous renal replacement therapy
(42, 98, 99). Acute renal failure was devel-
oped in 5% of children admitted to the
PICU (100). Requirement for renal replace-
ment therapy during MODS has been asso-
ciated with a 50% mortality rate (42, 101).
Pulmonary congestion with protein-
rich pulmonary edema has been recog-
nized as a cardinal feature of the acute
respiratory distress syndrome (ARDS)
(102), a clinical condition that has been
associated with a 20% mortality rate in
children (103). Abnormally increased vas-
cular pulmonary permeability has been
associated with platelet activation, neu-
trophils, and macrophage infiltration
(102), as well as with fibrin exudate re-
sulting in hyaline membrane formation
16
(102). During the early phase of pulmo-
nary injury, a restrictive pattern is noted
with a decrease in respiratory system
compliance and forced vital capacity
(104). The natural course of ARDS has
been characterized by inadequate gas ex-
changes requiring more aggressive me-
chanical ventilation. This leads to the
production of inflammatory mediators
that would further increase pulmonary
capillary permeability and generates del-
eterious mechanical forces that leads to
further damage of the alveolar-capillary
membrane (105).
Neuroendocrine Response
Nonsurvivors from meningococcal
sepsis showed adequate plasma rennin
activity, with variable aldosterone levels
(106, 107). They presented, however, with
significantly lower serum cortisol and a
severely decreased cortisol to adrenocor-
ticotropin hormone ratio, indicating a
state of adrenal insufficiency (106, 108,
109). This may have been secondary to an
inadequate perfusion of the adrenal cor-
tex or abnormal adrenocorticotropin hor-
mone receptor binding caused by lipo-
polysaccharide or TNF-␣ (110). These
patients also had evidence of the euthy-
roid sick syndrome, consisting of de-
creased concentrations of total T3 and T4,
increased levels of reverse T3, normal free
T4, and no change in thyrotropin stimu-
lating hormone (110 –112). In newborns,
dopamine was found to suppress the se-
cretion of growth hormone, thyrotropin
and prolactin, which could aggravate par-
tial hypopituitarism and the euthyroid
sick syndrome (113) A biphasic hypo-
thalamo-hypohyseal hormonal response
reaching a turning point 7–10 days after
the onset of critical illnesses has been
described. There was an abnormal pulsa-
tile secretion of growth hormone, thyro-
tropin and prolactin, whereas the non-
pulsatile secretion was maintained (114).
This phenomenon appeared to be of hy-
pothalamic origin (114).
Hypermetabolism
At the onset of severe infections or
thermal injury, a decreased metabolic
rate with hypothermia and stimulation of
the neuroendocrine response has been
referred to as the ebb phase (115). Hyper-
metabolism has then been noted during
the flow phase, usually about 24 hrs after
injury (116). Turi et al (117) found nor-
mal metabolic requirements in children
with SIRS or sepsis without any organ
dysfunction. In adults, hypermetabolism
occurs as a result of an increased oxida-
tion of glucose and fatty acids (118, 119),
as well as an increased rate of neoglu-
cogenesis through the use of lactate,
glycerol, or amino acids (alanine, glu-
tamine, serine, and glycine). Humoral
factors released by the wound have been
shown to trigger skeletal muscle proteol-
ysis. TNF-␣, also known as “cachectin,”
plays a major role along with IL-1 in the
development of “septic autocannibalism”
(118, 119). Decreased lipoprotein lipase
activity induced by TNF-␣ leads to in-
creased serum levels of triglycerides, cho-
lesterol, and hyperglycemia, a clinical
condition known as the “metabolic syn-
drome.” Glucose-lactate metabolism be-
tween skeletal muscle and liver is known
as the Cori cycle. Under hypoxic condi-
tions of tissue injury or infection, glucose
is transformed into lactate, which is fur-
ther converted within liver into glucose,
before returning to the injured area. This
process resulted in a net loss of 4 mol of
adenosine triphosphate per cycle, which
may explain in part the drainage of ener-
getic reserve. In the most severely ill
patients, muscle protein breakdown
with consumption of branched amino
acids and increased nitrogen urinary
losses may lead to muscular cachexia,
atrophy of intestinal epithelium, abnor-
mal wound healing, and secondary im-
mune dysfunction.
Adaptive Immunity and the
Development of Nosocomial
Infections
In contrast to the innate system, im-
mune receptors involved in adaptive
immunity are somatically derived and
are not predetermined to recognize any
particular antigen. Adaptive immunity
develops over several days and provide
specific defenses against pathogens.
The type of cytokines produced by
helper T cells has been shown to modify
the immune response to foreign anti-
gens. Activation of macrophages and
cellular immune response have been as-
sociated with the differentiation of
CD4⫹ helper T cells into proinflamma-
tory Th1 cells producing interferon-␥,
TNF-␣, lymphotactin, and IL-2. Con-
versely, the anti-inflammatory response
leading to an activation of B cells with
synthesis of immunoglobulins has been
linked to a Th2 phenotype secreting
Pediatr Crit Care Med 2009 Vol. 10, No. 1
IL-4, IL-5, IL-9, and IL-13. A lower rate
of graft rejection has been reported
among young children who had liver
transplantation and who also presented
a Th2 cytokine profile (120).
An increased risk of developing noso-
comial infections among critically ill
children has been linked to a state of
secondary immune paralysis with re-
duced monocyte HLA-DR expression
(121–124). However, immunoparalysis,
as defined by a diminished capacity of
leukocytes to secrete cytokines in re-
sponse to lipopolysaccharide, is not a
generalized phenomenon (125). In con-
trast to cells derived from blood or
spleen, those derived from tissues are ei-
ther fully responsive to ex vivo stimuli or
even primed, thereby, indicating a com-
partmentalization of inflammatory pro-
cesses (125). Therefore, it has been
thought that intracellular reprogram-
ming is responsible for the hyporeactivity
of circulating leukocytes. This may rep-
resent a physiologic adaptative mecha-
nism with protective effects. This obser-
vation is reminiscent of the phenomenon
of endotoxin tolerance, which has been
well described in models of sepsis (126 –
128). What is becoming increasingly
clear is that the interplay between classic
innate and adaptative immune system is
critical for the development of MODS.
Patients with activated cytotoxic T cells
and natural killer cells in severe sepsis/
septic shock had a higher mortality rate
and worse organ function compared with
those who do not have evidence of acti-
vation (129).
Prolonged lymphopenia and apopto-
sis-associated depletion of lymphoid or-
gans play a role in nosocomial infection-
related deaths among critically ill
children (130). An absolute lymphocyte
count of ⬍1000 for more than 7 days was
noted only in children with MODS. Lym-
phopenia was independently associated
with splenic or lymph node hypocellularity,
nosocomial infection, and death (130). Im-
munodepression with prolonged hypopro-
lactinemia was also more frequently noted
in children with MODS (130). Recent stud-
ies suggest that dying lymphocytes emit
signals triggering cell death in neighboring
cells, which do not express the antiapop-
totic protein Bcl-2 (131).
Gut Mucosal Barrier
Dysfunction and MODS
The role of gut injury and inflamma-
tion as the “motor” of MODS has been
Pediatr Crit Care Med 2009 Vol. 10, No. 1
postulated for a number of decades (132).
The mechanism was thought to be re-
lated to intestinal bacteria and/or endo-
toxin translocating to the systemic circu-
lation via the portal vein. However,
neither clinical studies nor animal stud-
ies demonstrated bacterial translocation
via the portal vein (133). Instead it seems
that mesenteric lymph translocates fac-
tors that activate neutrophils and injure
endothelial cells (133). In neonates, the
development of necrotizing enterocolitis
resulted in increased plasma endotoxin
levels (134). Endotoxemia was more se-
vere at the onset of illness among infants
with necrotizing enterocolitis and play a
critical role in the development of MODS
(134). Intraepithelial ␥␦ lymphocytes
maintain the integrity of intestinal epi-
thelial tight junctions in response to in-
fection (135). Gut ischemia-reperfusion
markedly reduces gut lymphoid tissue
and may lead to increased risk of infec-
tion (136). Thus, measures to improve
gut epithelial barrier may theoretically
improve or prevent MODS.
Other Manifestations of Organ
Dysfunction in Critically Ill
Children
MODS is a risk factor to develop upper
gastrointestinal bleeding (137–139).
Clinically, significant upper gastrointesti-
nal bleeding occurs in 2% of PICU admis-
sions (139). It is most frequently ob-
served among mechanically ventilated
patients with a Pediatric Risk of Mortality
score ⬎10 and with evidence of systemic
coagulopathy (139).
Neuromuscular syndromes, including
critical illness polyneuropathy, pure mo-
tor polyneuropathy, thick-filament my-
opathy, and necrotizing myopathy have
been described (140 –143). Prolonged
weakness has been identified in 2% of
critically ill children studied prospec-
tively, of whom 63% had MODS and 57%
had transplantation (144). SIRS has been
proposed as a common underlying patho-
genic process, which may have been po-
tentiated by the use of steroids or neuro-
muscular blocking agents (140).
Typically, patients showed flaccid quadri-
plegia with the inability to wean from
ventilatory support despite cardiopulmo-
nary recovery (140). In most severe cases,
deep tendon reflexes were abolished.
Electrophysiological abnormalities usu-
ally showed a pattern of axonal polyneu-
ropathy or abnormalities of neuromuscu-
lar transmission (140). Recovery in
strength most frequently occurred over a
period of weeks to months.
Outcome of Pediatric MODS
There are limited data on the long-
term outcomes of patients who survive to
discharge from the PICU. A normal qual-
ity of life with minimal health problems
is reported in 60% of children with
MODS, whereas 32% indicated a fair
quality of life with ongoing health, emo-
tional, social, physical, or cognitive prob-
lems that required some intervention or
hospitalization; 2% had a poor quality of
life (145). The return of organ function in
children who developed MODS has not
been examined in a systematic manner.
There are few small case series in chil-
dren with ARDS or those with MODS
after cardiac surgery (146, 147). In one
study, 78% of children who left the hos-
pital after acute renal failure in the ICU
survived beyond 24 months (148).
Therapy of Pediatric MODS and
Future Research Directions
How new or progressive MODS can be
prevented is still a matter of debate. Early
goal-directed therapy has been shown to
decrease mortality and the severity of
MODS in adults with sepsis (149). Guide-
lines developed from the American Col-
lege of Critical Care Medicine in 2002
proposed a time-dependent flow diagram
in the hemodynamic support of children
with sepsis (150). In a retrospective
study, it appears that those children who
receive resuscitation in accordance with
these guidelines faired better than those
that do not before transport (151). How-
ever, no study to date has determined
whether the end points proposed by the
guidelines are achievable in children, and
if so, whether they change outcome. He-
modynamic profiles during pediatric sep-
tic shock are clearly different from those
noted among adult patients (152). Al-
though inadequate oxygen delivery to tis-
sues results in organ dysfunction ini-
tially, MODS itself may well occur as a
result of mitochondrial dysfunction
(153). As children with septic shock have
better outcomes than adults, it is sugges-
tive that their mitochondrial functions
are relatively preserved compared with
that of adults. This is an exciting and
relatively unexplored area of research as
therapies are being developed to affect
mitochondrial function in sepsis (154).
17
 Control of infectious focus is as criti-
cal in children than it is in adults. There-
fore, antibiotic therapy should be started
early with appropriate resection of in-
fected or necrotic tissue. However, the
prolonged use of large spectrum antibi-
otic therapy should be avoided when cul-
tures are negative, and the risk-benefit of
invasive catheters be reevaluated period-
ically. Similar caution should be applied
when using nephrotoxic or hepatotoxic
drugs, with a special emphasis on timely
drug dosages, metabolic clearance, and
drug interaction. In the case of a trans-
planted patient with active systemic in-
fection, immunosuppressive therapy
should be minimized. Lymphopenia may
occur with the use of dopamine or steroids,
and prolonged lymphopenia has been asso-
ciated with secondary infection and MODS
(130). Results of the Corticosteroid Therapy
of Septic Shock trial in adults suggest that
although shock reversal may occur more
rapidly with steroids, overall survival is not
improved, apparently due to an increased
rate of infections (155).
Several other approaches are cur-
rently used with the aim of supporting
organ failure. These include lung protec-
tive strategies to minimize ventilator-
associated lung injury and renal replace-
ment therapy to control fluid overload
and therefore allow sufficient protein-
calorie intake with parenteral nutrition.
Early enteric feeding has been proposed
to prevent intestinal disuse with second-
ary mucosal atrophy, decreasing the sus-
ceptibility to bacterial translocation and
systemic inflammation. Indeed, the ca-
pacity to tolerate enteral feedings, as for
the mobilization of third space and pe-
ripheral edema, usually represent a trend
for clinical improvement.
There is some evidence that blood glu-
cose control can improve mitochondrial
dysfunction in patients with sepsis (156).
What remains unclear at this point is
whether therapy aimed at reversing the
metabolic response is helpful in critically
ill patients (157). In medical or surgical
adult ICUs, tight glycemic control with
intensive insulin therapy has been re-
ported to decrease morbidity or mortal-
ity; however, other studies suggested no
benefit or potential harm because of hy-
poglycemia (158 –160). At least in infants
with bronchiolitis, hyperglycemia is not
associated with prolonged ICU length of
stay or mortality (161). Therefore, several
critical questions must be answered as we
design trials in children: What is the
threshold glucose level above which in-
18
creased morbidity and mortality are ob-
served? What other indicators identify
those patients with insulin resistance
who are at highest risk?
Transfusion of red cells was frequently
advocated as a mean to prevent MODS
and death in critically ill patient. A large-
scale multicenter clinical trial in PICU
patients who were hemodynamically sta-
ble, the Transfusion Requirements in the
Pediatric Intensive Care Unit (TRIPICU)
study, showed that a restrictive transfu-
sion strategy based on an hemoglobin
transfusion threshold of 70g/L was not
inferior to a liberal approach (threshold:
95g/L) with regard to the number of pa-
tients with “new or progressive MODS or
death” (162). The incidence rate of “new
and/or progressive MODS” in the TRI-
PICU study was 12%, whereas the death
rate was, as expected, only 4%. Using new
and/or progressive MODS as the primary
outcome measure, this trial decreased by
five-fold the sample size required to com-
plete the study. However, new and/or pro-
gressive MODS is a dichotomous out-
come measure, and it was possible that
the absence of difference between the two
groups (restrictive vs. liberal) can be at-
tributable to a lack of sensitivity. There-
fore, the investigators used the PELOD
score to see if there was any trend: the
increase of the PELOD score after ran-
domization (delta: 3.8 ⫾ 10.9 vs. 3.8 ⫾
9.9) was also similar in both groups
(162). The TRIPICU study showed that
red-cell transfusion is not an effective
mean to prevent new or progressive
MODS in stable critically ill children.
In the future, quantification of the se-
verity of cases of MODS throughout PICU
stay using a quantitative scoring system
such as the PELOD score may be helpful.
With this regard, it is to be determined
whether real-time acquisition of physi-
ologic data using computer-based sys-
tems may facilitate this process, be-
cause the number of patients rapidly
decreases after the first few days of pe-
diatric ICU admission. It is unclear
whether criteria reflecting physiologic
improvement should be the same as
those aimed to identify development of
organ dysfunction. In addition, as day 1
MODS is associated with significant
long-term morbidity as measured by
cognitive and overall performance
scores, perhaps this would be a mean-
ingful outcome measure in addition to
resolution of organ failure itself (16).
REFERENCES
1. Pinsky M: The definition and history of
multiple-system organ failure. In: Charbon-
neau P (Ed). Syndrome de défaillance mul-
tiviscérale, Paris, Exposition Scientifique
Française, 1991, pp 3–7
2. Fry D, Pearlstein L, Fulton R, et al: Multiple
system organ failure: The role of uncon-
trolled infection. Arch Surg 1980; 115:
136 –140
3. Burke J, Pontoppidan H, Welch C: High
output respiratory failure: An important
cause of death ascribed to peritonitis or
ileus. Ann Surg 1963; 158:581–595
4. Tilney NL, Bailey GL, Morgan AP: Sequen-
tial system failure after rupture of abdomi-
nal aortic aneurysms: An unsolved problem
in postoperative care. Ann Surg 1973; 178:
117–122
5. Knauss W, Wagner D: Multiple organ fail-
ure: Epidemiology and prognosis. Crit Care
Clin 1989; 5:221–232
6. American College of Chest Physicians, So-
ciety of Critical Care Medicine: American
College of Chest Physicians/Society of Crit-
ical Care Medicine Consensus Conference:
Definitions for sepsis and organ failure and
guidelines for the use of innovative thera-
pies in sepsis. Crit Care Med 1992; 20:
864 – 874
7. Levy M, Fink M, Marshall J, et al: 2001
SCCM/ESICM/ACCP/ATS/SIS International
Sepsis Definitions Conference. Crit Care
Med 2003; 31:1250 –1256
8. Wilkinson JD, Pollack MM, Glass NL, et al:
Mortality associated with multiple organ
system failure and sepsis in pediatric inten-
sive care unit. J Pediatr 1987; 111:324 –328
9. Wilkinson JD, Pollack MM, Ruttimann UE,
et al: Outcome of pediatric patients with
multiple organ system failure. Crit Care
Med 1986; 14:271–274
10. Tantalean JA, Leon RJ, Santos AA, et al:
Multiple organ dysfunction syndrome in
children. Pediatr Crit Care Med 2003;
4:181–185
11. Leteurtre S, Martinot A, Duhamel A, et al:
Validation of the paediatric logistic organ
dysfunction score: Prospective, observa-
tional, multicentre study. Lancet 2003; 362:
192–197
12. Proulx F, Gauthier M, Nadeau D, et al: Tim-
ing and predictors of death in pediatric pa-
tients with multiple organ system failure.
Crit Care Med 1994; 22:1025–1031
13. Tan G, Tan T, Goh D, et al: Risk factors for
predicting mortality in a paediatric inten-
sive care unit. Ann Acad Med Singapore
1998; 27:813– 818
14. Leteurtre S, Martinot A, Duhamel A, et al:
Development of a pediatric multiple organ
dysfunction score: Use of two strategies.
Med Decis Making 1999; 19:399 – 410
15. Khilnani P, Sarma D, Zimmerman J: Epi-
demiology and peculiarities of pediatric
multiple organ dysfunction syndrome in
Pediatr Crit Care Med 2009 Vol. 10, No. 1
 New Delhi, India. Intensive Care Med 2006;
32:1856 –1862
16. Typpo K, Petersen N, Hallman D, et al:
Impact of premorbid conditions on multiple
organ dysfunction syndrome in the PICU.
Pediatr Res 2007; electronic citations
17. Proulx F, Fayon M, Farrell CA, et al: Epide-
miology of sepsis and multiple organ dys-
function syndrome in children. Chest 1996;
109:1033–1037
18. Goh A, Lum L: Sepsis, severe sepsis and
septic shock in paediatric multiple organ
dysfunction syndrome. J Paediatr Child
Health 1999; 35:488 – 492
19. Kutko M, Calarco M, Flaherty M, et al: Mor-
tality rates in pediatric septic shock with
and without multiple organ system failure.
Pediatr Crit Care Med 2003; 4:333–337
20. Leclerc F, Leteurtre S, Duhamel A, et al:
Cumulative influence of organ dysfunctions
and septic state on mortality of critically ill
children. Am J Respir Crit Care Med 2005;
171:348 –353
21. Seghaye MC, Engelhardt W, Grabitz RG, et
al: Multiple system organ failure after open
heart surgery in infants and children. Tho-
rac Cardiovasc Surg 1993; 41:49 –53
22. Calkins CM, Bensard DD, Moore EE, et al:
The injured child is resistant to multiple
organ failure: A different inflammatory re-
sponse? J Trauma 2002; 53:1058 –1063
23. Feickert H, Schepers A, Rodeck B, et al:
Incidence, impact on survival, and risk fac-
tors for multi-organ system failure in chil-
dren following liver transplantation. Pedi-
atr Transplant 2001; 5:266 –273
24. Keenan HT, Bratton SL, Martin LD, et al:
Outcome of children who require mechan-
ical ventilatory support after bone marrow
transplantation. Crit Care Med 2000; 28:
830 – 835
25. Lamas A, Otheo E, Ros P, et al: Prognosis of
child recipients of hematopoietic stem cell
transplantation requiring intensive care.
Intensive Care Med 2003; 29:91–96
26. Johnston J, Yi M, Britto M, et al: Impor-
tance of organ dysfunction in determining
hospital outcomes in children. J Pediatr
2004; 144:595– 601
27. Baue AE: Multiple, progressive, or sequen-
tial systems failure. A syndrome of the
1970s. Arch Surg 1975; 110:779 –781
28. Zimmerman J, Knauss W, Wagner D, et al:
A comparison of risks and outcome for
patients with organ system failure:
1982–1990. Crit Care Med 1996; 24:
1633–1641
29. Avanoglu A, Ergun O, Bakirtas F, et al:
Characteristics of multisystem organ failure
in neonates. Eur J Pediatr Surg 1997;
7:263–266
30. Shah P, Riphagen S, Beyene J, et al: Multi
dysfunction in infants with post-asphyxial
hypoxic-ischaemic encephalopathy. Arch
Dis Child Fetal Neonatal Ed 2004; 89:
F152–F155
31. Kearns G, Abdel-Rahman S, Alander S, et al:
Developmental pharmacology: Drug dispo-
Pediatr Crit Care Med 2009 Vol. 10, No. 1
sition, action, and therapy in infants and
children. N Engl J Med 2003; 349:
1157–1167
32. Carcillo JA, Doughty L, Kofos D, et al: Cy-
tochrome P450 mediated-drug metabolism
is reduced in children with sepsis-induced
multiple organ failure. Intensive Care Med
2003; 29:980 –984
33. Graham RJ, Dumas HM, O’Brien JE, et al:
Congenital neurodevelopmental diagnoses
and an intensive care unit: Defining a pop-
ulation. Pediatr Crit Care Med 2004;
5:321–328
34. Dosa NP, Boeing NM, Ms N, et al: Excess
risk of severe acute illness in children with
chronic health conditions. Pediatrics 2001;
107:499 –504
35. Goldstein B, Giroir B, Randolph A: Interna-
tional pediatric sepsis consensus confer-
ence: Definitions for sepsis and organ dys-
function in pediatrics. Pediatr Crit Care
Med 2005; 6:2– 8
36. Graciano AL, Balko JA, Rahn DS, et al: The
Pediatric Multiple Organ Dysfunction Score
(P-MODS): Development and validation of
an objective scale to measure the severity of
multiple organ dysfunction in critically ill
children. Crit Care Med 2005; 33:
1484 –1491
37. Carvalho PR, Feldens L, Seitz EE, et al:
Prevalence of systemic inflammatory syn-
dromes at a tertiary pediatric intensive care
unit. J Pediatr (Rio J) 2005; 81:143–148
38. Whalen MJ, Doughty LA, Carlos TM, et al:
Intercellular adhesion molecule-1 and vas-
cular cell adhesion molecule-1 are in-
creased in the plasma of children with sep-
sis-induced multiple organ failure. Crit
Care Med 2000; 28:2600 –2607
39. Doughty L, Carcillo JA, Kaplan S, et al: The
compensatory anti-inflammatory cytokine
interleukin 10 response in pediatric sepsis-
induced multiple organ failure. Chest 1998;
113:1625–1631
40. Odetola F, Gebremariam A, Freed G: Pa-
tients and hospital correlates of clinical out-
comes and resources utilization in severe
pediatric sepsis. Pediatrics 2007; 119:
487– 494
41. Bone RC, Balk RA, Cerra FB, et al: Defini-
tions for sepsis and organ failure and guide-
lines for the use of innovative therapies in
sepsis. The ACCP/SCCM Consensus Confer-
ence Committee. American College of Chest
Physicians/Society of Critical Care Medi-
cine. Chest 1992; 101:1644 –1655
42. Goldstein SL, Somers MJ, Baum MA, et al:
Pediatric patients with multi-organ dys-
function syndrome receiving continuous
renal replacement therapy. Kidney Int
2005; 67:653– 658
43. Stieh J, Fischer G, Scheewe J, et al: Im-
pact of preoperative treatment strategies
on the early perioperative outcome in ne-
onates with hypoplastic left heart syn-
drome. J Thorac Cardiovasc Surg 2006;
131:1122–1129 e2
44. Ben-Abraham R, Efrati O, Mishali D, et al:
Predictors for mortality after prolonged me-
chanical ventilation after cardiac surgery in
children. J Crit Care 2002; 17:235–239
45. Baslaim G, Bashore J, Al-Malki F, et al: Can
the outcome of pediatric extracorporeal
membrane oxygenation after cardiac sur-
gery be predicted? Ann Thorac Cardiovasc
Surg 2006; 12:21–27
46. Huang SC, Wu ET, Chen YS, et al: Experi-
ence with extracorporeal life support in pe-
diatric patients after cardiac surgery. Asaio
J 2005; 51:517–521
47. Aharon AS, Drinkwater DC, Churchwell KB,
et al: Extracorporeal membrane oxygen-
ation in children after repair of congenital
cardiac lesions. Ann Thorac Surg 2001; 72:
2095–2101
48. Shime N, Kageyama K, Ashida H, et al:
Application of modified sequential organ
failure assessment score in children after
cardiac surgery. J Cardiothorac Vasc
Anesth 2001; 15:463– 468
49. Allen ML, Hoschtitzky JA, Peters MJ, et al:
Interleukin-10 and its role in clinical im-
munoparalysis following pediatric cardiac
surgery. Crit Care Med 2006; 34:2658 –2665
50. Thomas N, Lucking S, Dillon P, et al: Is the
injured child different or just treated differ-
ently with respect to the development of
multiple organ dysfunction syndrome.
J Trauma 2003; 55:181–184
51. Diaz M, Vicent M, Prudencio M, et al: Pre-
dicting factors for admission to an intensive
care unit and clinical outcome in pediatric
patients receiving hematopoietic stem cell
transplantation. Haematologica 2002; 87:
292–298
52. Rossi R, Shemie SD, Calderwood S: Prog-
nosis of pediatric bone marrow transplant
recipients requiring mechanical ventila-
tion. Crit Care Med 1999; 27:1181–1186
53. Duke TD, Butt W, South M: Predictors of
mortality and multiple organ failure in chil-
dren with sepsis. Intensive Care Med 1997;
23:684 – 692
54. Siegel LB, Dalton HJ, Hertzog JH, et al:
Initial postoperative serum lactate levels
predict survival in children after open heart
surgery. Intensive Care Med 1996; 22:
1418 –1423
55. Casado-Flores J, Mora E, Perez-Corral F, et
al: Prognostic value of gastric intramucosal
pH in critically ill children. Crit Care Med
1998; 26:1123–1127
56. Dugas MA, Proulx F, de Jaeger A, et al:
Markers of tissue hypoperfusion in pediatric
septic shock. Intensive Care Med 2000; 26:
75– 83
57. Calvo Rey C, Ruza Tarrio F, Delgado
Dominguez MA, et al: Effectiveness of he-
modynamic treatment guided by gastric in-
tramucosal pH monitoring. An Esp Pediatr
2000; 52:339 –345
58. de Souza RL, de Carvalho WB: Preliminary
study about the utility of gastric tonometry
during the weaning from mechanical ven-
tilation. Rev Assoc Med Bras 2002; 48:
66 –72
19
59. Campbell ME, Costeloe KL: Measuring in-
tramucosal pH in very low birth weight
infants. Pediatr Res 2001; 50:398 – 404
60. Pollack MM, Fields AI, Ruttimann UE: Se-
quential cardiopulmonary variables of in-
fants and children in septic shock. Crit Care
Med 1984; 12:554 –559
61. Pollack MM, Fields AI, Ruttimann UE: Dis-
tributions of cardiopulmonary variables in
pediatric survivors and nonsurvivors of sep-
tic shock. Crit Care Med 1985; 13:454 – 459
62. Mercier JC, Beaufils F, Hartmann JF, et al:
Hemodynamic patterns of meningococcal
shock in children. Crit Care Med 1988; 16:
27–33
63. Carcillo JA, Pollack MM, Ruttimann UE, et
al: Sequential physiologic interactions in
pediatric cardiogenic and septic shock. Crit
Care Med 1989; 17:12–16
64. Wong HR, Carcillo JA, Burckart G, et al:
Increased serum nitrite and nitrate concen-
trations in children with the sepsis syn-
drome. Crit Care Med 1995; 23:835– 842
65. Schwartz D, Mendonca M, Schwartz I, et al:
Inhibition of constitutive nitric oxide syn-
thase by nitric oxide generated by inducible
NOS after lipopolysaccharide administra-
tion provokes renal dysfunction in rats.
J Clin Invest 1997; 100:439 – 448
66. Matejovic M, Krouzecky A, Martinkova V, et
al: Selective inducible nitric oxide synthase
inhibition during long-term hyperdynamic
porcine bacteremia. Shock 2004; 21:
458 – 465
67. Broillet MC: S-nitrosylation of proteins.
Cell Mol Life Sci 1999; 55:1036 –1042
68. Burney S, Caulfield JL, Niles JC, et al: The
chemistry of DNA damage from nitric oxide
and peroxynitrite. Mutat Res 1999; 424:
37– 49
69. Inoue M, Sato EF, Park AM, et al: Cross-talk
between NO and oxyradicals, a supersystem
that regulates energy metabolism and sur-
vival of animals. Free Radic Res 2000; 33:
757–770
70. Fink MP: Bench-to-bedside review: Cyto-
pathic hypoxia. Crit Care 2002; 6:491– 499
71. Fink MP: Cytopathic hypoxia in sepsis: A
true problem? Minerva Anestesiol 2001; 67:
290 –291
72. Short M: Linking the sepsis triad of inflam-
mation, coagulation and suppressed fibri-
nolysis to infants. Adv Neonat Care 2004;
4:258 –273
73. Emonts M, Hazelzet JA, de Groot R, et al:
Host genetic determinants of Neisseria
meningitidis infections. Lancet Infect Dis
2003; 3:565–577
74. Viktorov VV, Viktorova TV, Mironov PI, et
al: Significance of hereditary factors in mul-
tiple organ dysfunction syndrome in chil-
dren with infections. Anesteziol Reanimatol
2000; 32–34
75. Medzhitov R, Janeway C Jr: Innate immu-
nity. N Engl J Med 2000; 343:338 –344
76. Mariscalco M: Innate immunity in critical
care. Semin Pediatr Infect Dis 2006; 17:
25–35
20
77. Doughty L, Carcillo JA, Kaplan S, et al:
Plasma nitrite and nitrate concentrations
and multiple organ failure in pediatric sep-
sis. Crit Care Med 1998; 26:157–162
78. Doughty LA, Kaplan SS, Carcillo JA: Inflam-
matory cytokine and nitric oxide responses
in pediatric sepsis and organ failure. Crit
Care Med 1996; 24:1137–1143
79. Hatherill M, Tibby SM, Turner C, et al:
Procalcitonin and cytokine levels: Relation-
ship to organ failure and mortality in pedi-
atric septic shock. Crit Care Med 2000; 28:
2591–2594
80. Han YY, Doughty LA, Kofos D, et al: Pro-
calcitonin is persistently increased among
children with poor outcome from bacterial
sepsis. Pediatr Crit Care Med 2003; 4:21–25
81. Green J, Doughty L, Kaplan SS, et al: The
tissue factor and plasminogen activator in-
hibitor type-1 response in pediatric sepsis-
induced multiple organ failure. Thromb
Haemost 2002; 87:218 –223
82. Anisimova IN, Shvets OL, Guliaev DV, et al:
Morphologic aspects of hemostasis distur-
bances in meningococcemia in children.
Arkh Patol 1993; 55:16 –22
83. Hazelzet JA, van der Voort E, Lindemans J,
et al: Relation between cytokines and rou-
tine laboratory data in children with septic
shock and purpura. Intensive Care Med
1994; 20:371–374
84. Kornelisse RF, Hazelzet JA, Savelkoul HF,
et al: The relationship between plasmino-
gen activator inhibitor-1 and proinflamma-
tory and counterinflammatory mediators in
children with meningococcal septic shock.
J Infect Dis 1996; 173:1148 –1156
85. Hazelzet JA, Risseeuw-Appel IM, Kornelisse
RF, et al: Age-related differences in out-
come and severity of DIC in children with
septic shock and purpura. Thromb Hae-
most 1996; 76:932–938
86. Andrew M: Developmental hemostasis: Rel-
evance to hemostatic problems during
childhood. Semin Thromb Hemost 1995;
74:415– 425
87. Bernard GR, Vincent JL, Laterre PF, et al:
Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Engl
J Med 2001; 344:699 –709
88. Nadel S, Goldstein B, Williams MD, et al:
Drotrecogin alfa in children with severe
sepsis: A multicentre phase III randomised
controlled trial. Lancet 2007; 369:836 – 843
89. Nguyen T, Hall M, Han Y, et al: Microvas-
cular thrombosis in pediatric multiple or-
gan failure: Is it a therapeutic target? Pedi-
atr Crit Care Med 2001; 2:187–196
90. Nguyen TC, Liu A, Liu L, et al: Acquired
ADAMTS-13 deficiency in pediatric patients
with severe sepsis. Haematologica 2007; 92:
121–124
91. Foley K, Keegan M, Campbell I, et al: Use of
single-frequency bioimpedance at 50 kHz to
estimate total body water in patients with
multiple organ failure and fluid overload.
Crit Care Med 1999; 27:1472–1477
92. Shime N, Ashida H, Chihara E, et al: Bioel-
ectrical impedance analysis for assessment
of severity of illness in pediatric patients
after heart surgery. Crit Care Med 2002;
30:518 –520
93. Hazelzet JA, de Groot R, van Mierlo G, et al:
Complement activation in relation to capil-
lary leakage in children with septic shock
and purpura. Infect Immun 1998; 66:
5350 –5356
94. Zhang S, Wang S, Li Q, et al: Capillary leak
syndrome in children with C4A-deficiency
undergoing cardiac surgery with cardiopul-
monary bypass: A double-blind, randomised
controlled study. Lancet 2005; 366:
556 –562
95. Zhang S, Wang S, Yao S: Evidence for de-
velopment of capillary leak syndrome asso-
ciated with cardiopulmonary bypass in pe-
diatric patients with the homozygous C4A
null phenotype. Anesthesiology 2004; 100:
1387–1393
96. Nurnberger W, Heying R, Burdach S, et al:
C1 esterase inhibitor concentrate for capil-
lary leakage syndrome following bone mar-
row transplantation. Ann Hematol 1997;
75:95–101
97. Gamble J, Bethell D, Day NP, et al: Age-
related changes in microvascular perme-
ability: A significant factor in the suscepti-
bility of children to shock? Clin Sci 2000;
98:211–216
98. Goldstein SL, Currier H, Graf C, et al:
Outcome in children receiving continu-
ous venovenous hemofiltration. Pediat-
rics 2001; 107:1309 –1312
99. Michael M, Kuehnle I, Goldstein S: Fluid
overload and acute renal failure in pediatric
stem cell transplant patients. Pediatr Neph-
rol 2004; 19:91–95
100. Bailey D, Phan V, Litalien C, et al: Risk
factors of acute renal failure in critically ill
children: A prospective descriptive epidemi-
ological study. Pediatr Crit Care Med 2007;
8:29 –35
101. Goldstein SL, Somers MJ, Brophy PD, et al:
The Prospective Pediatric Continuous Renal
Replacement Therapy Registry: Design, de-
velopment and data assessed. Int J Artif
Organs 2004; 27:9 –14
102. Matthay M, Zimmerman G: Acute lung in-
jury and the acute respiratory distress syn-
drome: Four decades of inquiry into patho-
genesis and rational management. Am J
Respir Cell Mol Biol 2005; 33:319 –327
103. Flori HR, Glidden DV, Rutherford GW, et al:
Pediatric acute lung injury: Prospective
evaluation of risk factors associated with
mortality. Am J Respir Crit Care Med 2005;
171:995–1001
104. Newth C, Stretton M, Deakers T, et al: As-
sessment of pulmonary function in the
early phase of ARDS in pediatric patients.
Pediatr Pulmonol 1997; 23:169 –175
105. Fishel RS, Are C, Barbul A: Vessel injury
and capillary leak. Crit Care Med 2003; 31:
S502–S511
106. den Brinker M, Joosten KF, Liem O, et al:
Adrenal insufficiency in meningococcal sep-
Pediatr Crit Care Med 2009 Vol. 10, No. 1
 sis: Bioavailable cortisol levels and impact
of interleukin-6 levels and intubation with
etomidate on adrenal function and mortal-
ity. J Clin Endocrinol Metab 2005; 90:
5110 –5117
107. Lichtarowicz-Krynska E, Cole T, Camacho-
Hubner, et al: Circulating aldosterone levels
are unexpectedly low in children with acute
meningococcal disease. J Endocrinol Metab
2004; 89:1410 –1414
108. Riordan F, Thomson A, Ratcliffe J, et al:
Admission cortisol and adrenocorticotro-
phic hormone levels in children with me-
ningococcal disease; evidence for adrenal
insufficiency? Crit Care Med 1999; 27:
2257–2261
109. De Kleijn ED, Joosten KF, Van Rijn B, et al:
Low serum cortisol in combination with
high adrenocorticotrophic hormone con-
centrations are associated with poor out-
come in children with severe meningococ-
cal disease. Pediatr Infect Dis J 2002; 21:
330 –336
110. Joosten KF, de Kleijn ED, Westerterp M, et
al: Endocrine and metabolic responses in
children with meningoccocal sepsis: Strik-
ing differences between survivors and non-
survivors. J Clin Endocrinol Metab 2000;
85:3746 –3753
111. den Brinker M, Joosten KF, Visser TJ, et al:
Euthyroid sick syndrome in meningococcal
sepsis: The impact of peripheral thyroid
hormone metabolism and binding proteins.
J Clin Endocrinol Metab 2005; 90:
5613–5620
112. den Brinker M, Dumas B, Visser TJ, et al:
Thyroid function and outcome in children
who survived meningococcal septic shock.
Intensive Care Med 2005; 31:970 –976
113. Van den Berghe G, de Zegher F, Lauwers P:
Dopamine suppresses pituitary function in
infants and children. Crit Care Med 1994;
22:1747–1753
114. Van den Berghe G, de Zegher F, Bouillon R:
Acute and prolonged critical illness as dif-
ferent neuroendocrine paradigms. J Clin
Endocrinol Metab 1998; 83:1827–1834
115. Herndon DN, Gore D, Cole M, et al: Deter-
minants of mortality in pediatric patients
with greater than 70% full-thickness total
body surface area thermal injury treated by
early total excision and grafting. J Trauma
1987; 27:208 –212
116. Frayn K: Hormonal control of metabolism
in trauma and sepsis. Clin Endocrinol 1986;
24:577–599
117. Turi RA, Petros AJ, Eaton S, et al: Energy
metabolism of infants and children with
systemic inflammatory response syndrome
and sepsis. Ann Surg 2001; 233:581–587
118. Cerra FB: Metabolic manifestations of mul-
tiple systems organ failure. Crit Care Clin
1989; 5:119 –131
119. Cerra FB: Hypermetabolism-organ failure
syndrome: A metabolic response to injury.
Crit Care Clin 1989; 5:289 –302
120. Ganschow R, Broering DC, Nolkemper D, et
al: Th2 cytokine profile in infants predis-
Pediatr Crit Care Med 2009 Vol. 10, No. 1
poses to improved graft acceptance after
liver transplantation. Transplantation
2001; 72:929 –934
121. Singh-Naz N, Sprague BM, Patel KM, et al:
Risk assessment and standardized nosoco-
mial infection rate in critically ill children.
Crit Care Med 2000; 28:2069 –2075
122. Singh-Naz N, Sprague BM, Patel KM, et al:
Risk factors for nosocomial infection in
critically ill children: A prospective cohort
study. Crit Care Med 1996; 24:875– 878
123. Peters M, Petros A, Dixon G, et al: Acquired
immunoparalysis in paediatric intensive
care: Prospective observational study. BMJ
1999; 319:609 – 610
124. Allen ML, Peters MJ, Goldman A, et al: Early
postoperative monocyte deactivation pre-
dicts systemic inflammation and prolonged
stay in pediatric cardiac intensive care. Crit
Care Med 2002; 30:1140 –1145
125. Cavaillon J, Adib-Conquy M, Cloez-Tayarani
I, et al: Immunodepression in sepsis and
SIRS assessed by ex vivo cytokine produc-
tion is not a generalized phenomenon: A
review. J Endotoxin Res 2001; 7:85–93
126. Adib-Conquy M, Moine P, Asehnoune K, et
al: Toll-like receptor-mediated tumor ne-
crosis factor and interleukin-10 production
differ during systemic inflammation. Am J
Respir Crit Care Med 2003; 168:158 –164
127. Adib-Conquy M, Adrie C, Moine P, et al:
NF-kappaB expression in mononuclear cells
of patients with sepsis resembles that ob-
served in lipopolysaccharide tolerance.
Am J Respir Crit Care Med 2000; 162:
1877–1883
128. Cavaillon J, Fitting C, Adib-Conquy M:
Mechnasims of immunodysregulation in
sepsis. Contrib Nephrol 2004; 144:76 –93
129. Zeerleder S, Hack CE, Caliezi C, et al: Acti-
vated cytotoxic T cells and NK cells in se-
vere sepsis and septic shock and their role
in multiple organ dysfunction. Clin Immu-
nol 2005; 116:158 –165
130. Felmet KA, Hall MW, Clark RS, et al: Pro-
longed lymphopenia, lymphoid depletion,
and hypoprolactinemia in children with
nosocomial sepsis and multiple organ fail-
ure. J Immunol 2005; 174:3765–3772
131. Schwulst SJ, Davis CG, Coopersmith CM, et
al: Adoptive transfer of dying cells causes
bystander-induced apoptosis. Biochem Bio-
phys Res Commun 2007; 353:780 –785
132. Fink MP, Delude RL: Epithelial barrier dys-
function: A unifying theme to explain the
pathogenesis of multiple organ dysfunction
at the cellular level. Crit Care Clin 2005;
21:177–196
133. Senthil M, Brown M, Xu DZ, et al: Gut-
lymph hypothesis of systemic inflammatory
response syndrome/multiple-organ dys-
function syndrome: Validating studies in a
porcine model. J Trauma 2006; 60:958 –965
134. Sharma R, Tepas JJ, Hudak ML, et al: Neo-
natal gut barrier and multiple organ failure:
Role of endotoxin and proinflammatory cy-
tokines in sepsis and necrotizing enteroco-
litis. J Pediatr Surg 2007; 42:454 – 461
135. Dalton JE, Cruickshank SM, Egan CE, et al:
Intraepithelial gammadelta⫹ lymphocytes
maintain the integrity of intestinal epithe-
lial tight junctions in response to infection.
Gastroenterology 2006; 13:818 – 829
136. Fukatsu K, Sakamoto S, Hara E, et al: Gut
ischemia-reperfusion affects gut mucosal
immunity: A possible mechanism for infec-
tious complications after severe surgical in-
sults. Crit Care Med 2006; 34:182–187
137. Lacroix J, Nadeau D, Laberge S, et al: Fre-
quency of upper gastrointestinal bleeding in
a pediatric intensive care unit. Crit Care
Med 1992; 20:35– 42
138. Gauvin F, Dugas MA, Chaibou M, et al: The
impact of clinically significant upper gas-
trointestinal bleeding acquired in a pediat-
ric intensive care unit. Pediatr Crit Care
Med 2001; 2:294 –298
139. Chaibou M, Tucci M, Dugas MA, et al: Clin-
ically significant upper gastrointestinal
bleeding acquired in a pediatric intensive
care unit: A prospective study. Pediatrics
1998; 102:933–938
140. Jordan I, Cambra FJ, Alcover E, et al: Neu-
romuscular pathology in a critical pediatric
patient. Rev Neurol 1999; 29:432– 435
141. Sheth RD, Bolton CF: Neuromuscular com-
plications of sepsis in children. J Child Neu-
rol 1995; 10:346 –352
142. Petersen B, Schneider C, Strassburg HM, et
al: Critical illness neuropathy in pediatric
intensive care patients. Pediatr Neurol
1999; 21:749 –753
143. Ohto T, Iwasaki N, Ohkoshi N, et al: A
pediatric case of critical illness polyneurop-
athy: Clinical and pathological findings.
Brain Dev 2005; 27:535–538
144. Banwell BL, Mildner RJ, Hassall AC, et al:
Muscle weakness in critically ill children.
Neurology 2003; 61:1779 –1782
145. Morrison AL, Gillis J, O’Connell AJ, et al:
Quality of life of survivors of pediatric inten-
sive care. Pediatr Crit Care Med 2002; 3:1–5
146. Fanconi S, Kraemer R, Weber J, et al: Long-
term sequelae in children surviving adult
respiratory distress syndrome. J Pediatr
1985; 106:218 –222
147. Ben-Abraham R, Weinbroum AA, Roizin H,
et al: Long-term assessment of pulmonary
function tests in pediatric survivors of acute
respiratory distress syndrome. Med Sci
Monit 2002; 8:CR153–CR157
148. Askenazi DJ, Feig DI, Graham NM, et al: 3–5
year longitudinal follow-up of pediatric pa-
tients after acute renal failure. Kidney Int
2006; 69:184 –189
149. Rivers E, Nguyen B, Havstad S, et al: Early
goal-directed therapy in the treatment of
severe sepsis and septic shock. N Engl J Med
2001; 345:1368 –1377
150. 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
151. Han YY, Carcillo JA, Dragotta MA, et al:
Early reversal of pediatric-neonatal septic
shock by community physicians is associ-
21
 ated with improved outcome. Pediatrics
2003; 112:793–799
152. Ceneviva G, Paschall JA, Maffei F, et al:
Hemodynamic support in fluid-refractory
pediatric septic shock. Pediatrics 1998;
102:e19
153. Singer M: Mitochondrial function in sepsis:
Acute phase versus multiple organ failure.
Crit Care Med 2007; 35:S441–S448
154. Piel DA, Gruber PJ, Weinheimer CJ, et al:
Mitochondrial resuscitation with exogenous
cytochrome c in the septic heart. Crit Care
Med 2007; 35:2120 –2127
155. Sprung CL, Annane D, Keh D, et al: Hy-
drocortisone therapy for patients with
22
septic shock. N Engl J Med 2008; 358:
111–124
156. Vanhorebeek I, De Vos R, Mesotten D, et
al: Protection of hepatocyte mitochon-
drial ultrastructure and function by strict
blood glucose control with insulin in crit-
ically ill patients. Lancet 2005; 365:53–59
157. Verbruggen SC, Joosten KF, Castillo L, et
al: Insulin therapy in the pediatric inten-
sive care unit. Clin Nutr 2007; 26:
677– 690
158. Van den Berghe G, Wilmer A, Hermans G,
et al: Intensive insulin therapy in the
medical ICU. N Engl J Med 2006; 354:
449 – 461
159. Van den Berghe G, Wouters P, Weekers F, et
al: Intensive insulin therapy in the critically
ill patients. N Engl J Med 2001; 345:
1359 –1367
160. Brunkhorst FM, Reinhart K: Sepsis therapy:
Present guidelines and their application.
Chirurg 2008
161. Branco RG, Tasker RC: Glycemic level in
mechanically ventilated children with bron-
chiolitis. Pediatr Crit Care Med 2007;
8:546 –550
162. Lacroix J, Hebert PC, Hutchison JS, et al:
Transfusion strategies for patients in pedi-
atric intensive care units. N Engl J Med
2007; 356:1609 –1619
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