Cumulative Influence of Organ Dysfunctions and Septic
State on Mortality of Critically Ill Children
Francis Leclerc, Stéphane Leteurtre, Alain Duhamel, Bruno Grandbastien, François Proulx, Alain Martinot,
France Gauvin, Philippe Hubert, and Jacques Lacroix
Pediatric Intensive Care Unit, Jeanne de Flandre University Hospital; Department of Biostatistics, CERIM, Faculty of Medicine, Université de
Lille; Department of Epidemiology and Public Health, Calmette University Hospital, Lille; and Pediatric Intensive Care Unit, Necker-Enfants
Malades University Hospital, Paris, France; and Pediatric Intensive Care Unit, Sainte-Justine Hospital, Université de Montréal, Montréal,
Quebec, Canada
The interaction between sepsis and multiple organ dysfunction syn-
drome is poorly defined in children. We analyzed by Cox regression
models the cumulative influence of organ dysfunctions, using the
pediatric logistic organ dysfunction (PELOD) score, and septic state
(systemic inflammatory response syndrome or sepsis, severe sepsis,
and septic shock) on mortality of critically ill children. We included
593 children (mortality rate: 8.6%) from three pediatric intensive
care units; 514 patients had at least a systemic inflammatory re-
sponse syndrome and 269 had two or more organ dysfunctions.
Hazard ratio of death significantly increased with the severity of
organ dysfunction, as estimated by the PELOD score, and the worst
diagnostic category of septic state. Each increase of one unit in the
PELOD score multiplied the hazard ratio by 1.096 (p ⬍ 0.0001);
hazard ratio of diagnostic category was 9.039 (p ⫽ 0.031) for sys-
temic inflammatory response syndrome or sepsis, 18.797 (p ⫽
0.007) for severe sepsis and 32.572 (p ⬍ 0.001) for septic shock.
Cumulative hazard ratio of death ⫽ (hazard ratio of PELOD score) ⫻
(hazard ratio of diagnostic category). We conclude that there is a
cumulative accrual of the risk of death both with an increasing
severity of organ dysfunction and an increasing severity of the
diagnostic category of septic state.
Keywords: child; critical care; multiple organ dysfunction syndrome;
sepsis; septic shock
Sepsis remains an important health problem in children, as it is
in adults (1). A recent survey in the United States reported an
annual incidence of severe sepsis of 0.56 cases/1,000 children
with an overall mortality of 10.3% (2). Systemic inflammatory
response syndrome (SIRS), sepsis, severe sepsis, and septic
shock, as defined by the American College of Chest Physicians/
Society of Critical Care Medicine expert panel (3) with adapta-
tion to children by Hayden (4, 5), are frequently observed in
the pediatric intensive care unit (PICU). SIRS has been reported
with an incidence up to 82% in the PICU (6–8). Moreover, infec-
tion may lead to multiple organ dysfunction syndrome (MODS;
defined as more than two organ dysfunctions); this is particularly
true in children with septic shock who receive delayed treatment
or have primary or acquired immunodeficiency (9). Only a few
pediatric studies have reported that mortality of sepsis was linked
to MODS (2, 10, 11), whereas Wilkinson and colleagues failed
(Received in original form May 17, 2004; accepted in final form October 26, 2004)
Supported by the French Ministry of Health (Program Hospitalier de Recherche
Clinique no. 1,997/1922).
Correspondence and requests for reprints should be addressed to Francis Leclerc,
M.D., Service de Réanimation Pédiatrique, Hôpital Jeanne de Flandre, 59037, Lille,
France. E-mail: fleclerc@chru-lille.fr
This article has an online supplement, which is accessible from this issue’s table
of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 171. pp 348–353, 2005
Originally Published in Press as DOI: 10.1164/rccm.200405-630OC on October 29, 2004
Internet address: www.atsjournals.org
to demonstrate that sepsis significantly increased mortality in
children with multiple organ failure (12).
In previous pediatric studies on sepsis and MODS, each organ
failure or dysfunction was defined by its presence or absence (2, 6,
7, 10–17). However, organ dysfunction is an ordinal process,
and thus a score based on scaled and weighted rather than
dichotomous variables should be more informative (3, 18–21).
Two scaled MODS scores have been proposed for critically ill
children: the pediatric logistic organ dysfunction (PELOD) score
(18, 22) and the pediatric multiple organ dysfunction score (pub-
lished as an abstract) (23). Also, Johnston and colleagues used
the International Classification of Diseases, ninth revision, clini-
cal modification diagnostic and procedure codes to evaluate or-
gan dysfunction in pediatric hospitalizations (24).
The purpose of this study was to analyze the cumulative
influence of organ dysfunctions and septic state (SIRS, sepsis,
severe sepsis, and septic shock) on mortality of critically ill chil-
dren using the PELOD scoring system to estimate the severity
of cases of MODS (18, 22). Some of the results of this study
have been previously reported in the form of abstracts (25, 26).
METHODS
Patients
The study was run in three multidisciplinary tertiary care PICUs of
university-affiliated hospitals (two French, one Canadian) (Table 1).
The study was approved by the Ethics Committee of Ste-Justine Hospi-
tal and by the Comité Consultatif de Protection des Personnes dans la
Recherche Biomédicale de Lille. The number of patients needed to
develop the PELOD score was estimated to be 494 (18).
Between January 1997 and May 1997, all consecutive patients admit-
ted to the participating PICUs were prospectively included, unless they
met the following exclusion criteria: (1 ) age 18 years or older; (2 )
premature at entry into PICU; (3 ) pregnant; (4 ) length of stay in
the PICU less than 4 hours; (5 ) admission in a state of continuous
cardiopulmonary resuscitation without achieving stable vital signs for
at least 2 hours; (6 ) transfer to another PICU; or (7 ) admission for
scheduled procedures.
Data
Data were prospectively collected by research assistants or site investi-
gators on a standardized case report form: age; sex; emergency admis-
sion to PICU; Pediatric Risk of Mortality III score (27); immunodefi-
ciency; operative status; length of PICU stay; variables included in
the PELOD score (18, 22) (see Table E1 in the online supplement);
diagnostic criteria of SIRS, sepsis, severe sepsis, and septic shock as
proposed by American College of Chest Physicians/Society of Critical
Care Medicine consensus conference (3) and adapted to children by
Hayden (4, 5) (Table E2); and PICU outcome (survival or death).
Physiologic data from the preterminal period (the last 2 hours of life)
were excluded. Patients were monitored daily until they died or were
discharged from the PICU. Variables of the PELOD score were mea-
sured and collected as indicated in Table E1. Diagnostic criteria for
SIRS, sepsis, severe sepsis, and septic shock were daily recorded during
PICU stay, allowing identification of the worst diagnostic category
reached by each patient.
Leclerc, Leteurtre, Duhamel, et al.: Organ Dysfunction and Sepsis in Children 349

TABLE 1. STUDY SITES AND PATIENT CHARACTERISTICS

PICU A PICU B PICU C

Hospital pediatric beds, n* 530 456 260

Beds in PICU, n 22 15 14
Patient characteristics
Sample size, n 336 151 106
Deaths, n (%) 16 (4.7) 23 (15.2) 12 (11.3)
Age, mo, median (Q1⫺Q3)† 44 (11⫺105) 5 (1⫺63) 20 (6⫺70)
Nonpremature neonates, n 12 38 0
Surgical patients, n (%) 194 (58) 67 (44) 14 (13)
Ventilated patients, n (%) 139 (41) 108 (71) 42 (40)
Length of stay, d, median (Q1⫺Q3) 3 (25) 5 (3–11) 3 (2–9)
PRISM III score, median (Q1⫺Q3) 2 (0⫺5) 8 (4–15) 3 (0–8)

* n: number of patients.
†
Q1⫺Q3: interquartile.
Definition of abbreviations: PICU ⫽ pediatric intensive care unit; PRISM III ⫽ Pediatric Risk of Mortality III score.

Statistical Analysis
The validity of the database was checked by A.D. and B.G. before
statistical analyses were undertaken. Interobserver reliability was as-
sessed only during the validation step of the PELOD score, which
included the three participating centers of the development step; kappa
coefficients for organ dysfunction values ranged from 0.73 to 1 (22).
All statistical analyses were done with SAS software (SAS Institute,
Cary, NC). p Values ⬍ 0.05 were considered statistically significant.
Comparisons of frequencies were made using the chi-square or Fisher
exact probability test when appropriate, and multiple comparisons were
performed using the method described by Fleiss (28). Density of inci-
dence was defined as the number of new cases per unit person-time
(1,000 patient-days). Density of incidence was used to compute the
cumulative risk (R(t)) of acquiring SIRS, sepsis, severe sepsis, and
septic shock for each day after entry into PICU according the following
formula: R(t) ⫽ 1 ⫺ e⫺兺t DI(t ), where t is the current day after admission
in PICU. All patients were classified into the following independent
categories: no SIRS, SIRS, sepsis, severe sepsis, or septic shock ac-
cording to the worst septic state observed during their PICU stay.
Because no significant difference in mortality was found between the
SIRS and sepsis categories, these two groups were pooled in a same
category for further analysis. Cumulative influence of organ dysfunc-
tions and septic state on mortality was investigated by multivariate
survival analysis using the Cox proportional hazard model. Patients
may have had different lengths of stay. which is why the end point was
survival from the day of admission in PICU to discharge. The validity of
the proportional hazard assumption was assessed using time-dependent
coefficients as suggested by Cox (29). Because it was expected that the
delay reaching the worst septic state would be different across patients,
which might modulate survival, we performed a multivariate Cox re-
gression model using the PELOD score as fixed covariate and the
worst septic state as time-dependent covariate. Then, we investigated
separately by Cox regression models the influence of each organ dys-
function score (and also the number of organ dysfunctions) as fixed
covariate and the worst septic state as time dependent categorical covar-
iate (see the online supplement). Center effect was tested in each model
and hazard ratios were adjusted when necessary.
RESULTS
Population Characteristics
There were 594 patients who fulfilled the inclusion criteria. One
patient was excluded a posteriori because data were lacking with
respect to the septic state. The final sample involved 593 patients
with 51 deaths (8.6%). The readmission rate was 8%. The charac-
teristics of the population are given in Table 1. The sample
included 50 neonates (8%), 165 infants (28%), 300 children
(51%), and 78 adolescents (13%). The male:female ratio was
1:4, and the median age was 30 months (Q1-Q3: 5–93). There
were 275 (46%) surgical patients and 289 (48%) ventilated pa-
tients. Sixty-three patients (11%) were diagnosed as immunode-
ficient. The median Pediatric Risk of Mortality III score was 3
(Q1-Q3: 0–8), the median length of PICU stay was 3 days (Q1-Q3:
2–7), and the median PELOD score was 10 (Q1-Q3: 1–11). Two
hundred and sixty nine patients (45%) had MODS defined as
two or more organ dysfunction: 12 without SIRS and 257 with
SIRS, sepsis, severe sepsis, or septic shock (Table 2).

TABLE 2. MORTALITY RATE OF CHILDREN WITH SIRS, SEPSIS, SEVERE SEPSIS, AND SEPTIC
SHOCK DEPENDING ON THE NUMBER OF ORGAN DYSFUNCTIONS
No SIRS SIRS Sepsis Severe Sepsis Septic Shock

Patients with no OD 49 105 17 3 0

(% of deaths) 0 0 0 0 —
Patients with 1 OD 18 112 18 1 1
(% of deaths) 0 0 0 0 0
Patients with 2 OD 9 107 36 2 2
(% of deaths) 0 4 3 50 50
Patients with 3 OD 3 35 23 7 7
(% of deaths) 33 14 22 29 43
Patients with 4 OD 0 11 6 4 6
(% of deaths) — 73 33 75 100
Patients with 5 OD 0 5 2 0 2
(% of deaths) — 100 0 — 100
Patients with 6 OD 0 1 1 0 0
(% of deaths) — 100 100 — —

Definition of abbreviations: OD ⫽ organ dysfunction; SIRS ⫽ systemic inflammatory response syndrome.

350 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005

Figure 1. Cumulative risk over time (length of stay in a pediatric inten-

sive care unit) of acquiring systemic inflammatory response syndrome
(no symbol), sepsis (open circle), severe sepsis (open triangle), and septic
shock (x). Example: at Day 10, the cumulative risk of sepsis is 0.4 (40%).

Incidence of SIRS, Sepsis, Severe Sepsis, and Septic Shock

Among the 593 children, 514 (87%) was in a SIRS or a septic
state: there were 376 cases of SIRS (63%), 103 cases of sepsis Figure 2. Observed cumulative hazard ratios (HR) of death of the PELOD
(17%), 17 cases of severe sepsis (3%), and 18 cases of septic shock score (which may range from 0 to 71) and the diagnostic category of
(3%). The proportion of patients who reached their worst diag- septic state in the study population (593 children); HR of death is
nostic category of the septic state during the first day in the calculated by multiplying HR of the pediatric logistic organ dysfunction
PICU was 75% and the proportion was 88% within 48 hours (PELOD) score (1.096PELOD score) by HR of diagnostic category: no systemic
after admission. inflammatory response syndrome (SIRS) (diamond ); SIRS, sepsis (dash);
severe sepsis (triangle); and septic shock (square).
Cumulative Risk Over Time of Acquiring SIRS, Sepsis,
Severe Sepsis, and Septic Shock
The risk over time of acquiring SIRS, sepsis, severe sepsis, or
septic shock is shown in Figure 1. TABLE 3. HAZARD RATIOS OF DEATH OF EACH ORGAN
DYSFUNCTION AND DIAGNOSTIC CATEGORIES OF
Mortality Rate of Children with SIRS, Sepsis, Severe Sepsis, SEPTIC STATE
and Septic Shock
Hazard Ratio CI 95% CI 95% p Value
The observed mortality rates were 1% when SIRS was absent,
6% for SIRS, 8% for sepsis, 35% for severe sepsis, and 67% Cardiovascular OD 1.179 1.113 1.249 ⬍ 0.0001
SIRS or sepsis 9.085 1.223 66.963 0.0304
for septic shock (SIRS versus sepsis: p ⫽ 0.34; sepsis versus Severe sepsis 37.429 4.445 315.161 0.0009
severe sepsis: p ⫽ 0.007; severe sepsis versus septic shock: p ⬍ Septic shock 54.154 6.970 420.783 0.0001
0.0001; SIRS and sepsis versus severe sepsis: p ⬍ 0.0001). The Neurological OD* 1.163 1.124 1.203 ⬍ 0.0001
hazard ratio of death of each diagnostic category, without adjust- SIRS or sepsis 6.180 0.835 45.735 0.0745
ment with the PELOD score, was 7.43 (95% confidence interval Severe sepsis 11.682 1.336 102.177 0.0263
Septic shock 26.012 3.167 213.657 0.0024
[CI]: 1.01–54.81; p ⫽ 0.049) for SIRS or sepsis, 27.40 (3.26–230.44;
Respiratory OD 1.113 1.040 1.191 0.0020
p ⫽ 0.002) for severe sepsis and 61.74 (7.84–486.11; p ⬍ 0.0001) SIRS or sepsis 8.727 1.181 64.512 0.0338
for septic shock. Severe sepsis 29.343 3.500 246.001 0.0018
Septic shock 53.022 6.745 416.831 0.0002
Cumulative Influence of MODS and Septic State on Mortality Renal OD 1.139 1.078 1.204 ⬍ 0.0001
(Cox Models) SIRS or sepsis 6.987 0.947 51.547 0.0566
Severe sepsis 23.117 2.754 194.026 0.0038
No center effect was found for the different Cox models apart Septic shock 59.065 7.546 462.338 0.0001
from the neurologic organ dysfunction (Wald test, p ⫽ 0.03). Hematological OD 1.225 1.116 1.344 ⬍ 0.0001
PELOD score. Each increase of one unit in the PELOD score SIRS or sepsis 7.603 1.033 55.976 0.0464
multiplied the hazard ratio by 1.096 (95% CI: 1.077–1.116; p ⬍ Severe sepsis 11.899 1.318 107.454 0.0274
Septic shock 56.576 7.195 444.894 0.0001
0.0001), and, thus the hazard ratio of a given PELOD score was
Hepatic OD 2.692 1.023 7.088 0.0449
1.096PELOD score. Adjusted hazard ratio of each diagnostic category, SIRS or sepsis 7.518 1.019 55.459 0.0479
taking into account the PELOD score, was 9.039 (95% CI: 1.227– Severe sepsis 29.031 3.448 244.471 0.0019
66.620; p ⫽ 0.031) for SIRS or sepsis, 18.797 (2.241–157.693; p ⫽ Septic shock 54.885 6.965 432.482 0.0001
0.007) for severe sepsis, and 32.572 (4.179–253.890; p ⬍ 0.001)
Definition of abbreviations: CI ⫽ confidence interval; HR ⫽ hazard ratio; OD ⫽
for septic shock. The cumulative influence of the PELOD score
organ dysfunction; SIRS ⫽ systemic inflammatory response syndrome.
and diagnostic categories in our population is depicted in * Neurologic hazard ratio was adjusted because center effect was significant
Figure 2. As an example, a child with a PELOD score of 24 and for this OD (Wald test, p ⫽ 0.0315). For all other analysis, no significant center
severe sepsis had a hazard ratio of death ⫽ (1.09624) ⫻ (18.797) ⫽ effect was detected.
169.64. Cumulative HR of death ⫽ (HR of OD score) ⫻ (HR of diagnostic category of
septic state). Example for renal OD score of 10 in a child with severe sepsis: HR
Score of each organ dysfunction. Each increase of one unit in
of death ⫽ (1.13910) ⫻ (23.117) ⫽ 84.95 (see Table E3 in the online supplement).
organ dysfunction scores multiplied the hazard ratio by a value Diagnostic category of septic state: SIRS or sepsis, severe sepsis, septic shock.
i, ranging from 1.113 to 2.692 (all p ⬍ 0.05), depending on the HR given for each OD corresponds to HR of death for each increase of one unit
considered organ dysfunction (Table 3); thus, the hazard ratio in the OD score.
Leclerc, Leteurtre, Duhamel, et al.: Organ Dysfunction and Sepsis in Children 351

of a given organ dysfunction score was value iorgan dysfunction score.
Adjusted hazard ratios of each diagnostic category of septic state
for the corresponding organ dysfunction are given with their
95% CIs in Table 3. All theoretical values of cumulative hazard
ratio of death of each organ dysfunction score and diagnostic
categories are given in Table E3. As an example, a child with
a respiratory organ dysfunction score of 10 and septic shock had
a hazard ratio of death ⫽ (1.11310) ⫻ (53.022) ⫽ 154.67.
Number of organ dysfunctions. Each organ dysfunction
multiplied the hazard ratio by 2.374 (95% CI: 1.916–2.940; p ⬍
0.0001) and, thus the hazard ratio of organ dysfunction number
was 2.374organ dysfunction number. Adjusted hazard ratio of diagnostic
category was 8.916 (95% CI: 1.207–65.872; p ⫽ 0.032) for SIRS
or sepsis, 19.637 (2.345–164.433; p ⫽ 0.006) for severe sepsis,
and 47.039 (6.077–364.093; p ⫽ 0.0002) for septic shock. As an
example, a child with two organ dysfunctions had a hazard ratio
of death ⫽ (2.3742) ⫻ (8.916) ⫽ 50.25 in case of SIRS or sepsis
and a hazard ratio of death ⫽ (2.3742) ⫻ (47.039) ⫽ 265.11 in
case of septic shock.
DISCUSSION
This prospective multicenter study is the first that used a vali-
dated pediatric MODS score based on scaled and weighted vari-
ables (PELOD score) in children with sepsis. It showed that the
hazard ratio of death increased with the severity of MODS, as
estimated by the PELOD score (or each organ dysfunction
score) and the worst diagnostic category (from SIRS to septic
shock). These hazard ratios are multiplicative and, thus the final
hazard ratio is obtained by multiplying the hazard ratio of each
one unit increase in the PELOD (or organ dysfunction score)
by the hazard ratio of the diagnostic category of septic state.
Translated in practical terms, this means that an increase in the
PELOD score of 10 points was associated with a hazard ratio
of death of 2.50 (1.09610 ⫻ 1) in children without SIRS and of
81.46 (2.501 ⫻ 32.572) in children with septic shock. Further-
more, each increase of one unit in the total PELOD score (or
each organ dysfunction score) and the number of organ dysfunc-
tion significantly affected hazard ratio of death in the three
considered diagnostic categories. Finally, it can be seen in Table 3
that neurologic organ dysfunction demonstrated the lowest haz-
ard ratios of death for all septic states (sepsis, severe sepsis and
septic shock) as compared with all the other organ dysfunctions.
This could mean that death is less frequently attributable or
associated with an infectious process in patients with neurologic
dysfunction than in those with other dysfunctions.
In this study, we used the database that was prospectively
collected for the development phase of the PELOD score (18)
rather than the larger database collected while validating the
PELOD score (22) because the presence or absence of septic
states were annotated prospectively in the former, whereas it
was not at all in the latter. However, both collections of data were
quite similar with respect to mortality rate (6.4%), distribution of
ages and median age (24 months), median length of stay (2 days),
percentage of patients with MODS (53%),and median PELOD
score (10) (22). These findings also compare with those of previ-
ous studies among children admitted in PICUs as reviewed by
Johnston and colleagues (24).
We pooled patients with SIRS and those with sepsis, because
mortality rates were similar, as previously reported both in chil-
dren (11, 30) and adults (31, 32). Also, in statistical analysis, we
used the PELOD score value rather than probability of death
because MODS scoring systems were developed to be used as
outcome measures rather than predictive indexes (18, 20).
Two Main Questions of the Study
The first question is: does sepsis influence the risk of death
among children with MODS? In the series of Wilkinson and
colleagues, sepsis, as defined in the article (both bacteremia and
clinical sepsis syndrome), did not increase mortality rates in the
groups of children with organ system failure (46% versus 47%
in those without sepsis) (12). Three studies gave different results
(Table 4). Proulx and colleagues reported an incidence of sepsis,
severe sepsis, and septic shock of 23%, 4%, and 2% respectively
(7). In children having primary (n ⫽ 168) or secondary (n ⫽ 23)
MODS, a trend toward distinct mortality rates according to the
diagnostic categories (from no SIRS to septic shock: p ⫽ 0.057)

TABLE 4. RELATIONSHIPS BETWEEN MODS AND SEPTIC STATES IN CHILDREN: DATA FROM LITERATURE

Influence of Septic State on Mortality of Children with MODS

Author (reference) Wilkinson (12) Proulx (7) Goh (15) Tantalean (17)
Total number of patients 726 1,058 495 276
Mortality (%) 11 — 10 25.7
Sepsis definition (reference) Wilkinson (13) Age-adapted ACCP/SCCM (3) Age-adapted ACCP/SCCM (3) From Jafari (33) and
ACCP/SCCM (3)
Incidence of septic states (%) 21–24 29 — 46
MODS definition Present study Modified Wilkinson Wilkinson Present study
Incidence of MODS (%) 24 18 17 57
Mortality (%) 47 36 57 42
Number of patients with MODS and septic state 84 72 44 87
Mortality (%) 46 32 66 52
Influence of MODS on Mortality of Children With Septic State
Author (reference) Saez-Llorens (14) Duke (10) Kutko (11)
Total number of patients 4,529 — 2,346
Mortality (%) — — —
Sepsis definition (reference) Present study Present study Adapted from Task Force (35)
Number of patients with septic state 815 31 147
MODS definition Present study Modified Wilkinson Modified Wilkinson
Incidence of MODS (%) — — —
Mortality (%) — — —
Number of patients with septic state and MODS 197 11 70
Mortality (%) 73 64 19

Definition of abbreviations: ACCP ⫽ American College of Chest Physicians; MODS ⫽ multiple organ dysfunction syndrome; SCCM ⫽ Society of Critical Care Medicine.
352 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005
was observed (7). Among the 84 children with MODS reported
by Goh and colleagues, 11% had sepsis, 24% severe sepsis, and
18% septic shock; the MODS index (total number of organ
dysfunction divided by 6 and expressed as percentage) varied
among the diagnostic categories (sepsis 36%; severe sepsis 46%;
septic shock 58%; p ⫽ 0.007) and the observed mortality also
varied according to the different categories (sepsis 22%, severe
sepsis 65%, septic shock 80%; p ⫽ 0.03) (15). In the series from
Tantalean and colleagues, the mortality rate of children with
MODS plus sepsis was greater than that of those without sepsis
(52% versus 29%; p ⬍ 0.001) (17). As underlined by Cengiz
and Zimmerman, the high prevalence of severe sepsis and septic
shock in the latter series of critically ill children cared for in
Lima might be explained by their nutrition status (malnutrition
was observed in 33%) (34). Our results also demonstrated that
mortality of children with MODS (more than two organ dysfunc-
tions) was modulated by the severity of the septic state (Table 2),
even though the number of patients in certain categories was
small. In fact, in our patients with MODS, the death rate signifi-
cantly increased with the increasing severity of the septic state
(from 8% in children without SIRS to 71% in those with septic
shock (Fisher exact test: p ⬍ 0.0001).
The second question is: does MODS increase the risk of death
among children with sepsis? Three series are to be considered
(Table 4). In a retrospective study, Saez-Llorens and colleagues
reported that the incidence of sepsis, severe sepsis, and septic
shock was 4%, 11%, and 3%, respectively; the incidence of
MODS in patients with sepsis was 24% (14). Children with septic
states and MODS had the worst prognosis with 66% (versus
32% in children without MODS; p ⬍ 0.0001) and 84% (versus
37%; p ⬍ 0.0001) of them dying from severe sepsis and septic
shock, respectively (14). In the series from Duke and colleagues,
64% of children with sepsis and septic shock and MODS at 48
hours after admission died, whereas 94% of those without
MODS survived (10). Recently, Kutko and colleagues reviewed
a subgroup of 80 children with 96 episodes of septic shock, of
whom 71% had an oncologic disease (11). Although the mortal-
ity rate was not different between oncologic and nononcologic
patients, it was higher in patients with MODS (19%; n ⫽ 70
episodes of shock) than in those without MODS (0%; n ⫽ 26
episodes of shock; p ⬍ 0.05). MODS was present in 100% of
the patients who died (11). These data, which suggest a link
between MODS and death in septic children, are in line with
those from an American survey that included 9,675 cases of
severe sepsis in which mortality ranged from 7% for children
with one organ system failure (definitions not given) to 53% for
those with more than four organ systems failure (2).
Furthermore, such a link between MODS and death has been
reported in many conditions in which children are at risk of
sepsis: children treated with high frequency oscillatory ventila-
tion (36), after cardiac surgery (37, 38), with malignancies (39, 40),
and after liver (41) and bone marrow (42) transplantation. Our
study confirmed that children had a worse prognosis when
MODS was present, whatever the diagnostic category of septic
state.
What are the limitations and strengths of our study? One
limitation may be that only three PICUs participated in the data
collection. However, incidence of SIRS, sepsis, severe sepsis,
septic shock, and MODS were in accordance to previous re-
ported studies in children, and mortality rates observed in the
three participating PICUs were in the range of that reported in
United States (27) and other countries (43). Another limitation is
the use of the PELOD score calculated from the most abnormal
values of variables measured during the entire PICU stay. Such
an approach is advocated by experts to create and validate
MODS scores against mortality (44), and maximum multiple
organ dysfunction scores accurately predicted outcome in criti-
cally ill adults (45, 46). In future studies, the PELOD score (total
and component scores) should be calculated daily or repeatedly
to describe the variation of organ dysfunction with time, and
obtain additional prognostic information (20, 47).
The representativity of the sample of patients collected in
this study is probably good for the following reasons. The sites
where the study was done are quite typical multidisciplinary
European and North American university–affiliated multidisci-
plinary tertiary care PICUs. The very high cumulative risk to
contract a septic state during PICU stay was comparable in the
collected sample to the risk reported by Proulx and colleagues
(7), with 87 and 82% of patients at least having SIRS, respec-
tively. Another strength of this study is the larger number of
patients as compared with other pediatric studies that focused
on the modulatory effect of MODS on mortality associated with
SIRS, sepsis, severe sepsis, and septic shock (10, 11, 14). More-
over, we collected prospectively and daily the criteria of SIRS,
sepsis, severe sepsis, and septic shock during the entire PICU
stay. Finally, this is the first study that used a clinimetric MODS
scale in children and analyzed the cumulative influence of organ
dysfunctions and septic state on mortality. Even though the in-
crease in the number of organ dysfunction was associated with
an increase in the hazard ratio of death, we think that the PELOD
score should be preferred to the number of organ dysfunction,
which does not take into account the severity level of each organ
dysfunction. Moreover, the 2001 Society of Critical Care Medicine/
European Society of Intensive Care Medicine/American College
of Chest Physicians/American Thoracic Society/Surgical Infection
Society international sepsis definitions conference suggested to
use the PELOD score to measure the severity of organ dysfunc-
tion developing over the course of critical illness of children (48, 49).
This study reinforces this suggestion by demonstrating that PELOD
quantification of MODS is an appropriate surrogate marker for
mortality in pediatric septic states.
Conclusions
This study showed that there is a cumulative accrual of the
risk of death both with an increasing severity of MODS—as
estimated by the PELOD score, organ dysfunction scores, or
the number of organ dysfunctions—and an increasing severity
of the worst septic state (SIRS-sepsis, severe sepsis, septic shock)
in critically ill children. This study also suggests that the PELOD
score is a valid scale to measure organ dysfunctions.
Conflict of Interest Statement : F.L. does not have a financial relationship with a
commercial entity that has an interest in the subject of this manuscript; S.L. does
not have a financial relationship with a commercial entity that has an interest in
the subject of this manuscript; A.D. does not have a financial relationship with a
commercial entity that has an interest in the subject of this manuscript; B.G. does
not have a financial relationship with a commercial entity that has an interest in
the subject of this manuscript; F.P. does not have a financial relationship with a
commercial entity that has an interest in the subject of this manuscript; A.M. does
not have a financial relationship with a commercial entity that has an interest in
the subject of this manuscript; F.G. does not have a financial relationship with a
commercial entity that has an interest in the subject of this manuscript; P.H. does
not have a financial relationship with a commercial entity that has an interest in
the subject of this manuscript; J.L. does not have a financial relationship with a
commercial entity that has an interest in the subject of this manuscript.
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