Continuing Medical Education Article

Outcome and prognostic factors in neonates with septic shock*

Elsa Kermorvant-Duchemin, MD, MSc; Sophie Laborie, MD; Muriel Rabilloud, MD, PhD;
Alexandre Lapillonne, MD, PhD; Olivier Claris, MD

LEARNING OBJECTIVES
On completion of this article, the reader should be able to:
1. Define the clinical and demographic factors associated with mortality in neonatal septic shock.
2. Identify the clinical and demographic factors associated with major morbidity in neonatal septic shock.
3. Describe the extreme vulnerability of very low birth weight infants to Gram-negative septic shock.
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education credit.

Objective: Few accurate data are available on the outcome of

septic shock in the neonatal period. The objective was to describe
outcome and to determine variables associated with death or
adverse outcome in neonates with septic shock.
Design: Retrospective cohort study.
Setting: A tertiary neonatal intensive care unit in a university
hospital.
Patients: All patients admitted to the neonatal intensive care
unit over a 6-yr period meeting the following criteria: hypotension
and/or need for intravenous fluid administration or vasoactive
drugs, in the presence of proven or highly probable infection.
Interventions: None.
Measurements and Main Results: Main outcomes were 28-day
mortality and adverse outcome at 18 months of corrected age,
defined as death or severe sequelae (cerebral palsy, severe developmental delay, hearing impairment, blindness, or short bowel syndrome). Forty-eight infants were included. Follow-up data at 18
months were obtained for 46 of 48 infants. The 28-day mortality was
40% (19 deaths). Adverse outcome at 18 months of corrected age

*See also p. 236.

Pediatrician, Neonatologist, AP-HP, Hpital
Saint-Vincent de Paul, Paris, Universit Paris 5,
Paris, France (EKD); Pediatrician, Neonatologist, Attending Physician, Edouard Herriot Hospital, Lyon,
France (EKD; SL); Associate Professor in Biostatistics, Hospices Civils de Lyon, Universit Claude

186

was observed in 24 of 46 infants (52%; death 19, severe sequelae

5). Twenty-eight percent of the infants were alive and had a
normal examination at 18 months. Infants with adverse outcome
had significantly lower gestational age, birth weight, Apgar score,
weight at onset of sepsis, and pH and more often had Gramnegative infection, fetal growth restriction, hypoglycemia, and
thrombocytopenia. Significant predictors (multivariate analysis)
of 28-day mortality and of adverse outcome at 18 months of
corrected age were weight (kg) at the onset of sepsis (odds ratio
0.14, 95% confidence interval 0.03 0.55; odds ratio 0.21, 95%
confidence interval 0.06 0.74, respectively) and Gram-negative
infection (odds ratio 10.1, 95% confidence interval 1.5 65.7; odds
ratio 45.5, 95% confidence interval 3 637, respectively).
Conclusions: Septic shock in the neonatal period has a very
poor outcome. Data underscore the extreme vulnerability of very
low birth weight infants to septic shock, particularly to Gramnegative species. (Pediatr Crit Care Med 2008; 9:186 191)
KEY WORDS: septic shock; newborn infants; preterm infants;
mortality; prognosis; Gram-negative bacteria

Bernard Lyon 1, Lyon, France (MR); Professor of

Pediatrics, Paris Descartes University, Department
of Neonatology, Saint-Vincent de Paul, Paris, France
(AL); Professor, Department of Neonatology, Hpital
Edouard Herriot, Lyon, France (OC).
For information regarding this article, E-mail:
elsa.kermorvant@svp.aphp.fr

Copyright 2008 by the Society of Critical Care

Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0b013e31816689a8

Pediatr Crit Care Med 2008 Vol. 9, No. 2

epsis is a major cause of morbidity and death in the neonatal period, affecting 1 8 per
1,000 of all neonates (1). The
incidence of sepsis is higher in very low
birth weight infants, ranging from 1.9%
to 21% depending on age of onset of sepsis
(2, 3). Reported fatality rates range from
10% to 18% depending on birth weight and
age at onset of sepsis (2 4).
When sepsis is associated with cardiovascular dysfunction leading to septic
shock, survival is further compromised. In
children, severe sepsis and septic shock,
with a mortality rate of 10% to 40%, account for to 7% of all deaths among children annually (1, 4).
In neonates, it is generally accepted
that septic shock is also associated with
high mortality and morbidity, but very
few data on its epidemiology are available
in the literature. Watson and colleagues
(4) in a population-based study in children with severe sepsis (infection with at
least one acute organ dysfunction), but
not septic shock per se, reported a mortality rate of 10.3% in neonates. Other
attempts to describe the outcome of neonatal septic shock were restricted to necrotizing enterocolitis (NEC) with shock
(5) or group B Streptococcus septic shock
(6). No data are available on the longterm outcome and prognostic factors of
septic shock in neonatal intensive care
units (NICUs).
The objectives of this study were to
describe the short- and long-term outcomes of neonates with septic shock and
to identify factors affecting survival and
adverse outcome at 18 months of corrected age.

Based on the 2002 Consensus Conference

on definitions for sepsis and organ dysfunction
in pediatrics (7), sepsis was defined as proven
when a blood culture or bacterial culture from
a normally sterile site was positive for a likely
pathogen and, if bacterial cultures were negative, as highly probable in the presence of a
clinical and biological syndrome associated
with infection. Clinical and biological evidence of sepsis included presence of NEC defined according to Bells classification (8): hyperleukocytosis, defined by a leukocyte blood
count 25,000/mm3; leukopenia, defined as a
leukocyte blood count 5000/mm3; neutropenia, defined as a neutrophil blood count
1300/mm3 (9); thrombocytopenia, defined
as a platelet count 150,000/mm3; hyperglycemia, defined as glycemia 7 mmol/L; and
C-reactive protein 20 g/L.
Since universal agreement on the definition of neonatal septic shock does not exist,
and since diagnostic criteria for organ dysfunction from the 2002 International Pediatric
Sepsis Consensus Conference have not been
validated in premature infants (7), septic
shock was defined in our study as sepsis in the
presence of cardiovascular dysfunction, defined as hypotension or need for vasoactive
drugs or intravenous fluid administration
(normal saline, albumin, or fresh frozen
plasma). Hypotension was defined as a mean
blood pressure value 10th percentile of gestational-age- and postnatal-age-dependent
blood pressure values published in the literature (10 12) and was determined using oscillometric method with size-adapted cuffs (Philips). Infants who received intravenous fluids
but had neither hypotension nor signs of circulatory compromise (capillary refill time 3
secs, increased heart rate 160 beats/min,
cool extremities, decreased urinary output)
were not included in the study.

Data Collection
MATERIALS AND METHODS
Study Population and Definition
of Septic Shock
The study population included all newborn
infants with septic shock cared for in the NICU
of Edouard Herriot Hospital in Lyon, France,
over a 6-yr period. This NICU is located in a
tertiary care center where high-risk patients
are cared for; premature infants represent
60% of all admissions. The diagnoses of all
neonates admitted to the NICU during the
study period were prospectively entered in a
computerized database, and patients with septic shock were identified by retrospective review of the charts and hospital records of all
newborns with the definite diagnosis of sepsis,
septicemia, maternal-fetal infection, or NEC
and of all those who died.

Pediatr Crit Care Med 2008 Vol. 9, No. 2

The primary outcome measures were 28day mortality rate and adverse outcome rate,
defined as death or severe sequelae, at 18
months of corrected age. Severe sequelae were
classified as neurodevelopmental sequelae if
cerebral palsy (spastic diplegia, hemiplegia,
quadriplegia), severe developmental delay (not
ambulating at 18 months of corrected age), or
hearing impairment requiring amplification
or uni- or bilateral blindness were observed
and as digestive sequelae in the presence of a
short bowel syndrome requiring parenteral
nutritional support or enteral feeding via enterostomy.
The secondary end points were presence of
intraventricular hemorrhages or periventricular leukomalacia, graded according to the
method of de Vries et al. (13, 14), minor neurodevelopmental sequelae (psychomotor instability, mild language delay, moderate vision

impairment, such as strabismus or need for

correcting lenses), or growth restriction
(weight or length 10th percentile for gender
and age). Postnatal growth data were analyzed
using the French standardized growth charts
(15).
To identify factors affecting survival and
long-term outcome, clinical, biological, and
microbiological data were obtained from each
infants medical records. Documented data of
pregnancy included number of fetuses, use of
antenatal steroids or antenatal antibiotics, and
presence of prolonged rupture of membranes.
Documented clinical data of the newborn included gestational age, birth weight, Apgar
and Clinical Risk Index for Babies scores, presence of a congenital malformation (when lethal in the absence of surgical repair), weight
and postnatal age at the onset of sepsis, heart
rate, blood pressure, presence of a patent ductus arteriosus (PDA) confirmed by echocardiography, presence of a recent surgical procedure (6 hrs before the onset of shock),
temperature, and origin of sepsis. Gestational
age was determined by the first-term ultrasonography when available or with date of last
menstrual period. Small for gestational age
infants were defined as birth weight 2 SD
below the mean for gestational age from Ushers charts (16). Early-onset sepsis was defined
as sepsis occurring within 72 hrs of age. Hypothermia was defined as a central temperature 36C. Maternal-fetal infection was diagnosed if the mother had a positive bacterial
culture and/or clinical symptoms associated
with infection (premature labor, fever 38C,
tainted amniotic fluid) with a likely pathogen
(Escherichia coli, group B Streptococcus, or
Listeria monocytogenes). Documented biological and bacteriologic data included blood
cell count, glycemia, minimal blood pH, and
pathogen.
Outcome data were obtained from follow-up clinic reports. When follow-up was incomplete for a corrected age 18 months, the
infants parent or family physician was interviewed by phone to obtain information about
age of onset of walking, schooling, growth,
speech or hearing impairment, psychological
difficulties, or other problems requiring specialized care.
The institutional review board of the hospital waived the need to review the study according to French law, which does not require
informed consent in noninterventional, retrospective cohort studies.

Statistical Methods
Statistical analyses were done with the software package SPSS 10.0 for Windows (SPSS,
Chicago, IL). For univariate analysis, continuous
data (e.g., gestational age, birth weight) were
discretized to obtain groups of similar size. Univariate analyses were performed with chi-square

187

test or Fishers exact test as appropriate. Logistic

regression models were developed to quantify
the associations between 28-day mortality or adverse outcome at 18 months corrected for gestational age, and covariates that were believed to
be important from univariate analyses, after adjustment for potentially confounding factors.
Continuous independent variables were introduced in the models as continuous variables,
and the linearity hypothesis was tested. We considered p .05 to be significant.

RESULTS
Study Population
Forty-eight neonates of the 3,800 infants admitted in the NICU during the 6-yr
study period satisfied the inclusion criteria
(1.3%) and had a total of 51 episodes of
septic shock (incidence rate 2.2 per 1,000
admissions per year). Information about
the study population is presented in Table
1. The median gestational age and the median birth weight were 29 wks (25th75th
percentile, 2734 wks) and 1135 g (25th
75th percentile, 9052460 g), respectively.
Forty (83%) of the 48 newborns were born
premature (i.e., gestational age 37 wks).
The median postnatal age at the onset of
sepsis was 14 days (25th75th percentile,
127 days). Hypotension was observed in
41 patients (80%), and all infants but one
had increased heart rate 160 beats/min.
All infants but one received cardiovascular
support. Vasoactive drugs were administered in 33 (65%) patients and intravenous
fluid boluses in 42 (82%) patients. The infant who did not receive any treatment had
a fulminant evolution; the diagnosis of septic shock was confirmed by two postmortem blood cultures positive for Enterobacter cloacae. Forty-three infants had
ventilatory support (84%). Thirty-four infants received at least one transfusion of red
blood cells (67%); ten infants received at
least one platelet transfusion (20%), and 19
received fresh frozen plasma (37%).

Bacteriology
Sepsis was proven in 42 of 51 patients
(82%). Pathogen distribution in bacteriologically documented septic shocks is reported in Table 2. Gram-negative pathogens accounted for 16 of 42 (38%)
bacteriologically-documented septic
shocks. No strains were resistant to antibiotics.
The nine patients with culture-negative sepsis remained in the study since
they all had a clinical syndrome associ188

ated with a high probability of infection

as defined by the 2002 Consensus Conference on definitions for sepsis and organ dysfunction in pediatrics (7). Indeed,
two infants had received antibiotics before bacterial culture, and one infant developed shock 24 hrs after his twin
brother died of early-onset E. coli septic
shock. NEC was diagnosed in six of nine
patients, digestive perforation was diagnosed in two of nine patients, and one
infant had a hepatic abscess at autopsy.
Hyperleukocytosis or leukopenia was observed in seven of nine patients, thrombopenia in five of nine patients, and hyperglycemia in five of nine patients, and
C-reactive protein was 20 mg/L in six of
nine patients.
Sepsis was associated with NEC, digestive perforation, or intra-abdominal abscess in 25 patients (49%). The culture of
the catheter was positive in eight patients
(16%), and maternal-fetal infection was
diagnosed in 14 patients (27%).

Outcome
28-Day Mortality. Nineteen infants
died within 28 days after onset of sepsis
(28-day mortality rate 40%). Sixteen
(84%) deaths occurred within the 72 hrs
after onset of shock. Six of nine infants
with PDA died. Gram-negative organisms
were responsible for ten (53%) deaths
(mortality rate 62%). Nosocomial pathogens (Staphylococcus aureus, coagulasenegative staphylococci [CONS], and Enterobacter cloacae) were isolated in eight
(42%) patients with fatal septic shock.
Adverse Outcome at 18 Months of
Corrected Age. No infant died after the
first 28 days of onset of shock. Follow-up
data at 18 months of corrected age were
available for 27 of the 29 survivors (93%).
These data were obtained from follow-up
clinics reports for 19 infants (70%) and
were collected by phone interview of the
family physician for three infants and of
the parents for the five others. The two
infants who were lost to follow-up had a
normal clinical examination at 6 months
of corrected age but were excluded from
the statistical analysis. Five infants among
the 27 followed-up survivors had severe sequelae (19%). Two infants had severe neurodevelopmental sequelae: One had severe
developmental delay, visual impairment,
and growth failure, and the other had cerebral palsy, epilepsy, and severe developmental delay. The other three infants had
short bowel syndrome, related to NEC in
one patient. One of these infants also had

Table 1. Characteristics of the 48 neonates with

septic shock

Variable

No. (%) of
Children

Gestational age, wks

28
20 (42)
2832
11 (23)
32
17 (35)
Birth weight, g
1000
17 (35)
10001500
14 (30)
1500
17 (35)
Gender ratio, M/F
25/23 (52/48)
Outborn
19 (40)
Multiple birth
15 (31)
Small for gestational age
5 (10)
Antenatal steroid therapy
24 (53)
Antenatal antibiotics
17 (39)
PROM 18 hrs
15 (36)
Apgar score 6 at 5 mins
12 (26)
CRIB score
2
18 (42)
3
10 (23)
4
15 (35)
Congenital malformationa
7 (15)
Age at the onset of sepsis 72 hr
15 (31)
PROM, prolonged rupture of membranes;
CRIB, Clinical Risk Index for Babies.
a
Esophageal atresia (1), Hirschsprung disease (2), meconium ileus (1), meconium cyst (1),
congenital diaphragmatic hernia (2).
Table 2. Pathogen distribution in bacteriologically
documented neonatal septic shocks (n 42)

Pathogen
Group B Streptococcus
Coagulase-negative
Staphylococcus
Staphylococcus aureus
Streptococcus pneumoniae
Group D Streptococcus
Enterococcus faecalis
Escherichia coli
Enterobacter cloacae
Clostridium clostridiformis
Klebsiella pneumoniae
Listeria monocytogenes
Candida albicans

No.
(%)a

Death,
No.b

6 (14)
12 (29)

0
2

3 (7)
1 (2)
1 (2)
5 (12)
9 (21)
5 (12)
1 (2)
1 (2)
1 (2)
1 (2)

2
0
0
2
5
4
0
1
0
0

Total of pathogens exceeds 100% because of

four co-infections; bnegative bacterial cultures:
three deaths.

psychomotor instability. The adverse outcome rate (death or severe sequelae at 18

months) was 24 of 46 (52%).
Grade IIb or III intraventricular hemorrhages were diagnosed in nine neonates (19%). All these infants died. Four
patients had periventricular leukomalacia: Two infants died, and the other two
had severe neurodevelopmental impairment.
Pediatr Crit Care Med 2008 Vol. 9, No. 2

Eight children had minor sequelae,

with psychomotor instability in four patients and mild language delay in four
others. Six infants had a weight and
length growth failure. Thirteen of the 46
neonates with complete follow-up were
alive and considered normal at 18
months of corrected age (28%).

Prognostic Factors
28-Day Mortality. By univariate analysis, newborns with low gestational age, low
birth weight and low weight at onset of
sepsis, low Apgar score, and low pH and
those with Gram-negative infection were
more likely to die before day 28 of life
(Table 3). No significant difference was
found between survivors and nonsurvivors
for gender, antenatal steroid therapy, prolonged rupture of membranes, antenatal
antibiotics, Clinical Risk Index for Babies
score, age at onset of sepsis, origin of sepsis,
presence of a PDA or surgical procedure 6
hrs before onset of shock, hypothermia,
leukopenia, neutropenia, or hypoglycemia.
There was a trend toward significance for
infants who were small for gestational age
(p .072) and those who had thrombocytopenia (p .072).
Multivariate logistic regression analysis indicated that the independent predictors of 28-day mortality were weight
at the onset of sepsis and Gramnegative infection (Table 4). When the
type of pathogen was removed from the
model, the independent predictors of
28-day mortality remained weight at
the onset of sepsis and low pH (pH unit,
odds ratio 0.65, 95% confidence interval
0.44 0.95, p .028), showing a strong
association between Gram-negative infection and low pH.
Adverse Outcome at 18 Months of
Corrected Age. Unadjusted comparisons
between survivors without major sequelae and infants with adverse outcome are shown in Table 5. Infants with
low gestational age, low birth weight or
low weight at onset of sepsis, low Apgar
score, low pH, hypoglycemia, thrombocytopenia, or Gram-negative infection
or those who were small for gestational
age were more likely to have an adverse
outcome at 18 months of corrected age.
Groups were not significantly different
for gender, antenatal steroid therapy,
antenatal antibiotics, prolonged rupture of membranes, Clinical Risk Index
for Babies score, age at onset of sepsis,
origin of sepsis, presence of a PDA or
surgical procedure 6 hrs before onset
Pediatr Crit Care Med 2008 Vol. 9, No. 2

Table 3. Results of univariate analysis of risk factors associated with 28-day mortality in 48 neonates
with septic shock

Variable
Gestational age, wks
28
2832
32
Birth weight, g
1000
10001500
1500
Apgar score 6 at 5 mins
Weight at onset of sepsis, g
1000
10001500
1500
Gram-negative infection
Minimal pH
7
77.2
7.2

Survivors, No. (%)

n 29

Nonsurvivors, No. (%)

n 19

6 (30)
7 (64)
16 (94)

14 (70)
4 (36)
1 (6)

4 (24)
9 (64)
16 (94)
3 (25)

13 (76)
5 (36)
1 (6)
9 (75)

4 (29)
7 (54)
18 (86)
6 (37)

10 (71)
6 (46)
3 (14)
10 (63)

4 (31)
13 (68)
10 (83)

9 (69)
6 (32)
2 (17)

p
.0001

.0001

.007
.002

.018
.025

Table 4. Results of univariate analysis of risk factors associated with adverse outcome (death or severe
sequelae at 18 months corrected for gestational age) in 48 neonates with septic shock

Variable

Survival Without
Major Sequelae, No. (%)
n 22a

Death or Major
Sequelae, No. (%)
n 24

5 (25)
6 (55)
11 (73)

15 (75)
5 (45)
4 (27)

3 (18)
8 (57)
11 (73)
0 (0)
2 (17)

14 (82)
6 (43)
4 (27)
5 (100)
10 (83)

3 (21)
6 (46)
13 (68)
2 (13)
1 (10)

11 (79)
7 (54)
6 (32)
13 (87)
9 (90)

2 (15)
13 (68)
5 (50)
0 (0)
2 (17)
5 (29)

11 (85)
6 (32)
5 (50)
5 (100)
10 (83)
15 (71)

Gestational age, wks

28
2832
32
Birth weight, g
1000
10001500
1500
Small for gestational age
Apgar score 6 at 5 mins
Weight at onset of sepsis, g
1000
10001500
1500
Gram-negative infection
Hypoglycemia 2.4 mmol/L
Minimal pH
7
77.2
7.2
Thrombocytopenia 20,000/mm3
Thrombocytopenia 50,000/mm3
Thrombocytopenia 100,000/mm3
a

p
.014

.004

.05
.02
.027

.001
.012
.012

.05
.02
.007

Follow-up data at 18 months corrected age were not available for two infants.

Table 5. Predictors of 28-day mortality or adverse outcome (death or severe sequelae at 18 months
corrected for prematurity) in 48 neonates with septic shock by logistic regression
28-Day Mortality

Adverse Outcome

Predictor

OR (95% CI)

OR (95% CI)

Weight (kg) at onset of sepsis

Gram-negative infection

0.14 (0.03 0.55)

10.1 (1.5 65.7)

.005
.015

0.21 (0.06 0.74)

45.5 (3 637)

.015
.005

OR, odds ratio; CI, confidence interval.

189

of shock, hypothermia, leukopenia, or

neutropenia.
Significant independent predictors of
adverse outcome at 18 months of corrected age were weight at the onset of
sepsis and Gram-negative infection (Table 4). Presence of hypoglycemia or
thrombocytopenia also appeared important but did not reach significance in the
multivariable analysis (p .063 and p
.075, respectively).

DISCUSSION
This is the first study to describe the
28-day mortality and rate of adverse outcome at 18 months of corrected age in a
population of neonates with septic shock.
Furthermore, we have identified factors
affecting survival and long-term outcome. Of note, the vast majority of deaths
occurred within 72 hrs of shock. Beyond
the first 3 days, the risk of fatal outcome
seemed to decrease considerably. The 28day mortality rate (40%) in our study was
much higher than the mortality rate usually described in newborns with sepsis
(2 4, 17, 18), demonstrating the extreme
severity of septic shock in these infants,
even though our strategy for case identification, including the review of the
charts of all deaths, might have slightly
overestimated mortality. Because of the
retrospective nature of the study, a few
cases of sepsis might have been underdiagnosed. Therefore, the possibility that
the true number of patients who had sepsis with shock and a good outcome might
have been slightly underestimated cannot
be excluded.
Twenty-eight-day mortality was inversely related to weight at onset of sepsis, reaching 71% for neonates weighing
1000 g. Furthermore, weight at the onset of sepsis appeared to be an important
independent predictor not only of 28-day
mortality but also of adverse outcome.
The specific pathophysiology of sepsis in
premature infants, including early dysfunction of the immature myocardium,
immaturity of the neonatal immune system, and immaturity of the autonomic
nervous system, likely explains these results (10, 19).
Gram-negative organisms had the
highest mortality rate (62%) and were
responsible for 53% of fatal septic shock
and 54% of adverse outcome. Logistic
regression analysis showed that Gramnegative infection is one of the most important independent predictors of 28-day
mortality and adverse outcome in neona190

tal septic shock. These data are in agreement with the known severity of Gramnegative sepsis in very low birth weight
infants. Stoll et al. (2) reported a greater
risk of death among very low birth weight
infants with late-onset Gram-negative
sepsis compared with other organisms
(36% died, corresponding to the highest
mortality rate; odds ratio for death,
Gram-negative vs. other organisms, 3.5
[2.5 4.9], p .001). Karlowicz et al. (20)
also showed that Gram-negative bacteria
were the most frequent pathogens causing fulminant late-onset sepsis (i.e., causing death in 48 hrs of onset of illness)
in a 10-yr retrospective study in a NICU,
causing 69% of all cases. There are concerns that Gram-negative sepsis frequency may be increasing in neonates
(20, 21). We speculate that efforts to decrease the risk of these infections, for
example, avoiding broad-spectrum antibiotic therapies, may have a measurable
impact on septic shock mortality rates.
CONS was the most common isolated
organism, and this could be surprising
because this pathogen is usually not associated with severe sepsis syndrome.
This can be explained by the high number
of premature infants in the cohort (83%),
who are more prone to CONS sepsis than
term infants, and the relatively high rate
of CONS infections in the unit (15 of
1000 catheter-days). Nevertheless, the incidence of CONS septic shock appears to
be rare considering the number of infants
admitted during the study period (incidence 12 of 3,800 0.3%).
Interestingly, we found relatively few severe neurologic sequelae among survivors,
considering the known association between
systemic hypotension, infection, and adverse neurodevelopmental outcome (22
24). This may be explained by the high
death rate (11 of 13) among infants diagnosed with severe intraventricular hemorrhage or periventricular leukomalacia.
Conversely, the number of digestive sequelae should not be surprising, given the
susceptibility of the growing immature
bowel to hemodynamic compromise and
inflammation. They were all observed in
sepsis of digestive origin, and proven NEC
was responsible for one patient.
Our data show that septic shock is not
a frequent event among neonates. This is
responsible for the relatively small number of patients identified and calls into
question some nonsignificant results. We
chose to include patients from a single
center and to limit the study period to
avoid management bias. PDA could have

been expected to significantly affect outcome, since it can be responsible for

greater hemodynamic impairment. Six of
the nine infants with PDA died, but the
association was not significant.
Thrombocytopenia and disseminated
intravascular coagulation have been shown
to be predictors of adverse outcome in
adult septic shock (1, 25). Similarly, thrombocytopenia could be associated with an
increased risk of adverse outcome during
septic shock in neonates, even if this factor
did not remain significant in the multivariate analysis.
Hypoglycemia 2.4 mmol/L, although
not significant in multivariate analysis, also
appeared to be a marker of adverse outcome in our cohort. Some studies suggest
that hypoglycemia, even moderate, is a risk
factor for neurodevelopmental impairment
in the newborn infant (26, 27). Infection is
also a known risk factor of hypoglycemia
(28), especially in premature infants in
whom glycogen stores are reduced.
Low arterial pH (7.33) has been found
to be an independent predictor of an increased early mortality rate in adults (25).
In neonates, Goldstein et al. (23) showed
that no infant survived after exposure to a
pH 7.15 for 5 hrs in a cohort of 191
very low birth weight infants. In our study,
11 of the 13 infants (85%) with a blood pH
7 had an adverse outcome. Nevertheless,
pH did not reach significance in the regression analysis, and this is likely explained by
the significant association between Gramnegative pathogens and low blood pH in the
model.

CONCLUSIONS
Septic shock remains a major challenge
in the NICU. Less than a third of the infants
of our cohort were alive and considered
normal at 18 months of corrected age. Adverse outcome was mainly dependent on
mortality, and death occurred in the first 3
days of onset of shock for most neonates.
Severe neurologic sequelae were rare
among survivors.
We have shown that the outcome of
septic shock in neonates is mainly determined by weight at the onset of sepsis
and type of infecting organism. Our study
has pointed out the extreme vulnerability
of preterm infants to this serious complication of sepsis, especially those of very
low birth weight. Our data also showed
that presence of a Gram-negative infection has a major impact on outcome.
Efforts toward furthering our understanding the pathophysiology of neonatal
Pediatr Crit Care Med 2008 Vol. 9, No. 2

septic shock and its early recognition and

reversal should have a measurable effect
on outcome.

REFERENCES
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