Hyperglycemia is a marker for poor outcome in the postoperative

pediatric cardiac patient*

Andrew R. Yates, MD; Peter C. Dyke 2nd, MD; Roozbeh Taeed, MD; Timothy M. Hoffman, MD;
John Hayes, PhD; Timothy F. Feltes, MD; Clifford L. Cua, MD

Objective: Hyperglycemia in critical care populations has been
shown to be a risk factor for increased morbidity and mortality.
Minimal data exist in postoperative pediatric cardiac patients. The
goal of this study was to determine whether hyperglycemia in the
postoperative period was associated with increased morbidity or
mortality.
Design: Retrospective chart review.
Setting: Tertiary care, free-standing pediatric medical center
with a dedicated cardiac intensive care unit.
Patients: We included 184 patients <1 yr of age who under-
went cardiac surgery requiring cardiopulmonary bypass from
October 2002 to August 2004. Patients with a weight <2 kg, a
preoperative diagnosis of diabetes, preoperative extracorporeal
membrane oxygenation support, solid organ transplant recipients,
and preoperative renal or liver insufficiency were excluded.
Interventions: None.
Measurements and Main Results: Age was 4.3 ⴞ 3.2 months
and weight was 4.9 ⴞ 1.7 kg at surgery. Duration of hyperglyce-
mia was significantly longer in patients with renal insufficiency (p
ⴝ .029), liver insufficiency (p ⴝ .006), infection (p < .002), central
nervous system event (p ⴝ .038), extracorporeal membrane ox-
ygenation use (p < .001), and death (p < .002). Duration of
hyperglycemia was also significantly associated with increased
intensive care (p < .001) and hospital (p < .001) stay and longer
ventilator use (p < .001). Peak glucose levels were significantly
different in patients with renal insufficiency (p < .001), infection
(p ⴝ .002), central nervous system event (p ⴝ .01), and mortality
(p < .001).
Conclusions: Hyperglycemia in the postoperative period was
associated with increased morbidity and mortality in postopera-
tive pediatric cardiac patient. Strict glycemic control may improve
outcomes in this patient population. (Pediatr Crit Care Med 2006;
7:351–355)
KEY WORDS: congenital heart defects; postoperative care; hy-
perglycemia; mortality; morbidity; assessment; patient outcomes

H yperglycemia in the adult
critical care setting has
been shown to be a predic-
tor of increased morbidity
and mortality (1–3). Recent studies have
demonstrated that strict glycemic control
can decrease morbidity and mortality in
adult surgical and medical intensive care
settings in heterogeneous patient popu-
lations with or without the diagnosis of
diabetes (4 – 8).
*See also p. 397.
From the Department of Pediatrics, The Ohio State
University College of Medicine and Public Health and
Columbus Children’s Hospital Heart Center, Columbus,
OH.
The authors have not disclosed any potential con-
flicts of interest.
Address requests for reprints to: Andrew R. Yates,
MD, Pediatric Cardiology Fellow, Department of Pedi-
atrics, Section of Cardiology, Columbus Children’s
Hospital, Columbus, OH 43205-2696. E-mail:
yatesa@pediatrics.ohio-state.edu.
Copyright © 2006 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/01.PCC.0000227755.96700.98
In pediatric populations, it has been
known that hyperglycemia is associated
with poor outcomes for patients receiving
skin grafts for thermal injury, for patients
with neurologic trauma, and for neonates
with necrotizing enterocolitis (9 –12). Re-
cently, two studies have demonstrated
that hyperglycemia is also a predictor of
adverse outcomes in the pediatric inten-
sive care unit (13, 14). Srinivasan and
colleagues (14) demonstrated that 86% of
patients in their pediatric intensive care
unit had a glucose value ⬎126 mg/dL at
some point during their stay. In addition,
they showed that the duration of hyper-
glycemia and the peak glucose were also
associated with mortality. Faustino and
Apkon (13) demonstrated an association
between hyperglycemia and hospital
length of stay. The patient population an-
alyzed by Srinivasan et al. did not include
any postoperative cardiac patients.
Faustino and Apkon’s population in-
cluded cardiac patients in the postopera-
tive period, but there was no subanalysis
on this patient population.
We hypothesized that hyperglycemia
in patients ⬍1 yr of age who had under-
gone cardiac surgery using cardiopulmo-
nary bypass (CPB) would be associated
with increased morbidity and mortality in
the cardiac intensive care unit (CICU).
METHODS
The institutional review board approved
this retrospective chart review. All patients ⬍1
yr of age who underwent cardiac surgery re-
quiring CPB from October 2002 to August
2004 were reviewed. Patients with a weight ⬍2
kg, a preoperative diagnosis of diabetes, pre-
operative extracorporeal membrane oxygen-
ation (ECMO) support, solid organ transplant
recipients, and preoperative renal (creatinine
⬎1.5 mg/dL) or liver insufficiency (aspartate
aminotransferase or alanine aminotransferase
⬎250 units/dL) were excluded. All patients
were identified and tracked by their unique
medical record number.
After identification of patients, baseline de-
mographic information including age, weight,
gender, diagnosis, and type of surgery were
obtained. Surgical procedure was coded by the
risk assessment of congenital heart disease

Pediatr Crit Care Med 2006 Vol. 7, No. 4 351

Table 1. Characteristics of study patients (n ⫽ 184) mographic differences between nonsurvi-
vors and survivors were weight and
Total Nonsurvivors Survivors p
RACHS-1 score (Table 1). Age, gender,
No. (%) 184 21 (11.3) 163 (88.7)
and palliative pathway were not signifi-
Age, mos 4.30 ⫾ 3.17 3.81 ⫾ 4.03 4.39 ⫾ 3.04 NS cantly different when analyzing the de-
Weight, kg 4.86 ⫾ 1.69 4.14 ⫾ 1.39 4.98 ⫾ 1.70 .03 mographic differences with either Stu-
Gender, n (%) dent’s t-test or chi-square. There
Male 105 (57.1) 15 (14.3) 90 (85.7) NS remained an inverse relationship between
Female 79 (42.9) 6 (7.6) 73 (92.4)
Single-ventricle palliation, n (%) 37 (20.1) 6 (16.2) 31 (83.8) NS weight and each morbidity marker as well
Two-ventricle repair, n (%) 147 (79.6) 15 (10.2) 132 (89.8) as composite morbidity (p ⬍ .001).
RACHS-1 3.29 ⫾ 1.00 4.05 ⫾ 0.92 3.19 ⫾ 0.98 <.001 Longer CPB time was associated with
higher mortality (p ⬍ .001) (Table 2).
NS, not significant; RACHS, risk assessment of congenital heart disease score. Composite morbidity was also associated
with longer CPB time (p ⬍ .001) and
Table 2. Operative data and cardiac intensive care unit (CICU) glucose values for survivors and longer cross-clamp time (p ⫽ .005). CPB
nonsurvivors time was also associated with dialysis use
(p ⬍ .001), renal insufficiency (p ⬍ .001),
Nonsurvivors Survivors p liver insufficiency (p ⬍ .001), central ner-
vous system events (p ⫽ .007), and ECMO
CPB times
Total CPB time, mins 216.76 ⫾ 89.02 158.04 ⫾ 71.35 <.001 support (p ⬍ .001). Cross-clamp times
Cross-clamp time, mins 83.90 ⫾ 72.16 81.56 ⫾ 48.12 NS were also associated with ECMO support
Bypass glucose, values (p ⫽ .05), renal insufficiency (p ⫽ .004),
Prebypass, mg/dL 105.95 ⫾ 61.24 101.70 ⫾ 38.91 NS and composite morbidity (p ⫽ .005). The
10 mins after initiation, mg/dL 139.33 ⫾ 68.47 129.47 ⫾ 61.32 NS
Postbypass, mg/dL 169.95 ⫾ 75.66 195.82 ⫾ 63.56 NS
glucose levels before CPB, 10 mins after
CICU glucose values initiation, and after CPB were not statis-
Initial glucose, mg/dL 151.14 ⫾ 84.52 148.53 ⫾ 65.28 NS tically significantly different between
3-day average, mg/dL 140.30 ⫾ 76.99 120.23 ⫾ 30.78 NS nonsurvivors and survivors (Table 2).
10-day average, mg/dL 129.20 ⫾ 51.40 116.87 ⫾ 23.09 NS During the first 72 hrs there were 1.6
Peak glucose, mg/dL 255.86 ⫾ 195.59 179.26 ⫾ 86.98 <.001
Duration, days ⬎126 mg/dL 2.95 ⫾ 2.28 1.19 ⫾ 1.30 <.001 glucose measurements per day in the en-
tire group. There was a difference in the
CPB, cardiopulmonary bypass; NS, not significant. number of daily glucose measurements
when comparing survivors to nonsurvi-
score (RACHS)-1 (15). Operative data recorded Statistical Analysis. Data were described vors (1.5 ⫾ 1.1 vs. 2.6 ⫾ 2.0, p ⬍ .001).
included length of bypass, cross-clamp time, with means and standard deviations for con- There was a significant difference in the
and glucose values during the case. Continu- tinuous variables and percentages for categor- peak glucose when comparing nonsurvi-
ous variables regarding the hospital course ical variables. Simple comparisons between vors vs. survivors. Duration of hypergly-
consisted of CICU length of stay, hospital mortality and morbidity were made with chi- cemia was also longer in nonsurvivors
length of stay, and number of hours of me- square or Student’s t-tests (Wilcoxon’s rank- (Table 2).
chanical ventilation. Outcome measurements sums in the case of highly skewed data). Lo- The use of inotropes in the postoper-
of liver insufficiency, renal insufficiency, dial- gistic regression was used to test the ative period was standardized by use of
ysis use, documented bacterial infection, cen- relationship between mortality and morbidity the inotrope score as previously described
measures and glucose measures while adjust-
tral nervous system event (seizure or change (16, 17). The inotrope scores of survivors
ing for weight. The weight-adjusted odds ra-
documented by radiologic imaging), ECMO and nonsurvivors were not significantly
tios were reported from the logistic regres-
support, and mortality were obtained. We different on admission to the CICU (0.63
sions and the models were illustrated with
combined those patients with any morbidity figures. Alpha was set at p ⬍ .05. There was no ⫾ 1.68 vs. 1.64 ⫾ 3.20, p ⫽ .08). There
marker (liver or renal insufficiency, dialysis adjustment for multiple tests; however, the was a significant difference in the ino-
use, bacterial infection, central nervous sys- actual p values are given. Analyses were per- trope score between nonsurvivors and
tem event, and ECMO support) to obtain a formed with SPSS (SPSS, Chicago, IL, version survivors when measured at 24 hrs (3.09
composite morbidity category. We recorded 13). ⫾ 3.75 vs. 1.38 ⫾ 2.48, p ⫽ .009), 48 hrs
every glucose value obtained during the first
(2.74 ⫾ 2.89 vs. 0.93 ⫾ 2.10, p ⬍ .001),
240 hrs after surgery. We also documented the
RESULTS and 72 hrs (1.60 ⫾ 2.30 vs. 0.74 ⫾ 1.86,
use of steroids, insulin requirement, and the
p ⫽ .01). In addition, the average ino-
use of inotropes using an inotrope score (do-
butamine [␮g/kg/min] ⫹ dopamine [␮g/kg/
One hundred and ninety-five patients trope score for the first 72 hrs of admis-
min] ⫹ 100 ⫻ epinephrine [mg/kg/min] ⫹ under a year of age who underwent car- sion was also significantly different (non-
100 ⫻ norepinephrine [mg/kg/min]) at 6-hr diac surgery requiring CPB during this survivors 2.60 ⫾ 2.42 vs. survivors 1.12
intervals for the first 72 hrs of the hospital period were evaluated. Eleven patients ⫾ 2.08, p ⫽ .008).
course (16, 17). For the purpose of this study, were excluded because their weight was There was a statistically significant
we defined hyperglycemia as a glucose ⱖ126 ⬍2 kg. No other patients met exclusion difference between the ten nonsurvivors
mg/dL based on the 2005 American Diabetes criteria; therefore, this study consisted of (46%) and the 20 survivors (12.3%) who
Association definition (18). We defined the du- 184 patients. received postoperative steroids during
ration of hyperglycemia as the number of days Twenty-one patients (11.3%) died be- the CICU stay (p ⫽ .005). Steroids admin-
with at least one glucose value ⱖ126 mg/dL. fore discharge. The only significant de- istered were adjusted to hydrocortisone

352 Pediatr Crit Care Med 2006 Vol. 7, No. 4

Table 3. Glucose and morbidity markers

Duration of
3-Day Average, 10-Day Average, Hyperglycemia,
Initial Glucose, mg/dL Peak Glucose, mg/dL mg/dL mg/dL Days

Liver insufficiency (n ⫽ 21) Yes 146.2 ⫾ 66.2 209.2 ⫾ 101.2 120.9 ⫾ 26.8 113.1 ⫾ 17.9 2.2 ⫾ 2.1
No 151.0 ⫾ 68.0 185.7 ⫾ 108.7 122.8 ⫾ 40.8 119.0 ⫾ 29.1 1.3 ⫾ 1.4
p NS NS NS NS .009
Renal insufficiency (n ⫽ 12) Yes 198.8 ⫾ 110.1 308.3 ⫾ 150.6 132.7 ⫾ 35.8 122.8 ⫾ 20.3 2.8 ⫾ 2.3
No 147.3 ⫾ 63.1 180.3 ⫾ 100.3 122.0 ⫾ 39.8 118.1 ⫾ 28.6 1.3 ⫾ 1.5
p .01 <.001 NS NS <.001
Dialysis (n ⫽ 4) Yes 120.7 ⫾ 38.4 464.5 ⫾ 378.7 183.8 ⫾ 136.2 185.9 ⫾ 107.0 3.0 ⫾ 1.1
No 151.2 ⫾ 68.1 182.5 ⫾ 88.4 121.3 ⫾ 34.6 116.9 ⫾ 22.6 1.4 ⫾ 1.6
p NS NS NS NS .038
Infection (n ⫽ 20) Yes 172.1 ⫾ 91.6 256.7 ⫾ 144.2 131.5 ⫾ 30.5 122.4 ⫾ 18.6 3.1 ⫾ 2.3
No 146.8 ⫾ 62.1 179.3 ⫾ 99.7 121.5 ⫾ 40.5 117.8 ⫾ 29.2 1.2 ⫾ 1.2
p NS .002 NS NS <.001
CNS event (n ⫽ 10) Yes 184.5 ⫾ 120.6 270.4 ⫾ 156.7 131.8 ⫾ 35.6 123.0 ⫾ 24.8 3.2 ⫾ 2.0
No 149.1 ⫾ 63.4 184.3 ⫾ 103.6 122.3 ⫾ 39.8 118.1 ⫾ 28.4 1.3 ⫾ 1.5
p NS .01 NS NS <.001
ECMO (n ⫽ 11) Yes 136.3 ⫾ 46.7 291.5 ⫾ 250.5 143.9 ⫾ 82.8 141.8 ⫾ 69.0 3.9 ⫾ 1.6
No 151.5 ⫾ 68.7 182.1 ⫾ 89.9 121.3 ⫾ 35.1 116.9 ⫾ 23.0 1.2 ⫾ 1.4
p NS NS NS NS <.001
Composite morbidity (n ⫽ 58) Yes 165.7 ⫾ 83.3 237.0 ⫾ 151.1 127.8 ⫾ 44.7 121.4 ⫾ 34.5 2.5 ⫾ 2.1
No 141.3 ⫾ 52.9 164.2 ⫾ 68.6 118.7 ⫾ 31.1 116.8 ⫾ 25.0 0.9 ⫾ 0.7
p .02 <.001 NS NS <.001

CNS, central nervous system; NS, not significant; ECMO, extracorporeal membrane oxygenation.

Table 4. Duration of hyperglycemia and out- .001). No patients in the study group re-
comes ceived insulin during the hospital stay.
The initial glucose on arrival to the
Odds Ratioa p
CICU was significantly higher for those
Renal 1.36 .029 patients who developed renal insuffi-
insufficiency ciency or who had a composite morbidity
Liver insufficiency 1.39 .006 (Table 3). There was no significant differ-
Infection 1.48 .002 ence in the initial glucose values in those
CNS event 1.34 .038
ECMO 1.59 .001
patients who developed liver insuffi-
Dialysis 1.33 NS ciency, central nervous system complica-
Composite 1.62 <.001 tions, or infections or those who were
morbidity initiated on dialysis or ECMO. There was
Mortality 1.48 .002
no statistically significant association be-
tween the 3- and 10-day average glucose
CNS, central nervous system; ECMO, extracor-
poreal membrane oxygenation; NS, not significant. values for any of the morbidity markers.
a The peak glucose value recorded over the
Weight-adjusted odds ratio.
10-day period was not significantly re-
lated to liver insufficiency, dialysis, or
equivalents to compare glucocorticoid
potency. There was no difference in hy- ECMO use. There was a significant differ-
ence between patients with renal insuffi-
drocortisone equivalents administered to
ciency, documented infections, central
those patients who lived compared with
those who died (7.1 ⫾ 5.2 mg/kg vs. 5.7 nervous system events, and the compos-
⫾ 5.0 mg/kg, p ⫽ .48). In addition, there ite morbidity for the peak glucose levels
was no significant difference in the 10- (Table 3).
day average (119.4 ⫾ 21.7 vs. 117.9 ⫾ The duration of hyperglycemia was
29.3, p ⫽ .81), 3-day average (125.0 ⫾ significantly associated with all the re-
53.9 vs. 120.6 ⫾ 36.1, p ⫽ .15), or peak corded morbidities and mortality (Table
glucose (201.3 ⫾ 99.2 vs. 182.3 ⫾ 107.2, 3). When we adjusted for weight by mul-
p ⫽ .22) when comparing all patients tivariable logistic regression, there con-
who received steroids to those who did tinued to be a significant risk for adverse
not receive steroids. There was a differ- events with increased duration of hyper-
ence in the duration of hyperglycemia in glycemia for all outcome measures except
those patients who did not receive ste- dialysis (Table 4). Using the mathemati-
roids compared with those who received cal model from the logistic regression, we
steroids (1.2 ⫾ 1.3 vs. 2.1 ⫾ 2.3, p ⬍ could generate probability curves for
mortality (Fig. 1) and composite morbid-
ity (Fig. 2). Figure 1 demonstrates the
increasing probability of mortality with
increased duration of hyperglycemia.
Overall mortality (11.3%) for our cohort
was predicted to double with 4 days of
hyperglycemia based on a mathematical
model, standardized for weight. Figure 2
also shows the increasing probability of
an adverse event with increasing duration
of hyperglycemia. The observed compos-
ite morbidity (31.5%) for our cohort was
also predicted to double with approxi-
mately 4 days of hyperglycemia based on
a similar model.
In addition to the discrete outcomes
measured, hyperglycemia was also asso-
ciated with several continuous variables.
The duration of hyperglycemia was cor-
related with a longer length of hospital
stay (p ⬍ .001, R2 ⫽ .21) and a longer
length of CICU stay (p ⬍ .001, R2 ⫽ .13)
by linear regression. There was also an
association between the duration of hy-
perglycemia and the length of mechani-
cal ventilation (p ⬍ .001, R2 ⫽ .10).
DISCUSSION
Two recent studies have demonstrated
that hyperglycemia is a predictor of ad-
verse outcomes in the pediatric intensive
care unit (13, 14). To our knowledge,
these are the first data showing increased
morbidity and mortality with hyperglyce-
mia in high-risk neonates and infants un-

Pediatr Crit Care Med 2006 Vol. 7, No. 4 353


Figure 1. Duration of hyperglycemia and probability of mortality. Line, mathematical model; dia-
monds, observed mortality. In(p/1-p) ⫽ ⫺1.61 ⫺ .25 ⫻ weight ⫹ .39 ⫻ number of hyperglycemic days.
Figure 2. Duration of hyperglycemia and probability of composite morbidity. Line, mathematical
model; diamonds, observed composite morbidity. In(p/1-p) ⫽ .019 ⫺ .29 ⫻ weight ⫹ .48 ⫻ number
of hyperglycemic days.
dergoing cardiac surgery. These data
demonstrate an association with initial
glucose, peak glucose, and duration of
hyperglycemia with increased incidence
of morbidity and mortality. In addition,
prolonged hyperglycemia was associated
with increased length of hospital stay,
length of CICU stay, and duration of me-
chanical ventilation.
In this patient population, hyperglyce-
mia may be a stress response, but it may
also be iatrogenic via catecholamine or
steroid administration. There was a sta-
tistically significant difference in the ino-
trope score between survivors and non-
survivors; however, the absolute value of
the inotrope score was equivalent to “re-
nal dose” dopamine, which is not com-
monly thought to contribute to meta-
bolic derangements (16, 17). At our
institution, steroids are not routinely ad-
ministered before CPB and are only given
354
in cases with circulatory arrest and then
at the discretion of the surgical team. If
this affected the glucose levels we would
have expected to see a significant differ-
ence in the initial glucose on arrival to
the CICU, which was not evident. The
elevated intraoperative glucose values are
consistent with previously observed gly-
cemic response during CPB (19). There
was a significant difference in the postop-
erative steroid administration between
nonsurvivors and survivors; however,
only one patient received stress dose ste-
roids for presumed cortisol deficiency. All
other steroid usage was related to airway
edema and was administered in the
periextubation period. Steroid use only
influenced the duration of hyperglycemia
and not the peak value and may thus
account for a portion of our findings. The
mortality rate related to steroid use may
be artificial and related to our strategy of
attempting to extubate all patients before
arrival to the CICU. Thus those patients
who were initially ill would have re-
mained intubated after surgery and
would subsequently be more likely to
have received steroids before extubation.
The etiology of hyperglycemia and
link to poor outcomes in this patient
population are still not known. There is
evidence in animal and human models
that hyperglycemia increases nitric ox-
ide generation resulting in myocyte
damage via peroxynitrite, increases
myocardial apoptosis via reactive oxy-
gen species, and increases angiotensin
II generation (20 –22). Hyperglycemia
has also been shown to decrease cardiac
output, cardiac index, and stroke vol-
ume with increased systemic vascular
resistance in rats (23). In cerebral isch-
emia, animal models have shown that
hyperglycemia worsens intracellular
acidosis, increases brain edema, and
disrupts the blood-brain barrier (24 –
26). Furthermore, hyperglycemia has
been shown to be detrimental to renal
tissue and to impair bacterial defense
mechanisms (27–29). Our data show a
similar association of the duration of
hyperglycemia and these morbidity
markers. If hyperglycemia is associated
with increased morbidity, this would
likely explain the longer CICU stay, hos-
pital stay, and ventilator time for these
patients.
Our lack of correlation between ini-
tial glucose and outcomes would con-
cur with studies in the adult setting
which have demonstrated that intraop-
erative insulin use does not decrease
the need for antiarrhythmic medica-
tions or inotropes after surgery (30).
We would, however, propose that strict
glycemic control in the postoperative
period may also affect outcomes similar
to adult studies (1, 7, 8, 31, 32).
Limitations of this study include its
retrospective nature with a heteroge-
neous patient population. Glucose mea-
surements were not standardized in the
postoperative care, and thus patients
considered ill had more frequent mon-
itoring of laboratory values resulting in
sample bias. RACHS-1 scores averaged
3.3 for all patients in our cohort, indi-
cating a high-risk patient population
with a predicted mortality between
9.5% (risk category 3) and 19.2% (risk
category 4), and our findings may not
translate to populations with lower
RACHS-1 scores, older patients, or
those not undergoing CPB. We cannot
Pediatr Crit Care Med 2006 Vol. 7, No. 4
comment on the etiology of hypergly-
cemia in our patient population, and we
realize that inotrope and postoperative
steroid use were significantly different
between nonsurvivors and survivors
and may have resulted in hyperglyce-
mia. We also did not account for glu-
cose administration via intravenous flu-
ids or parenteral nutrition. Finally, this
study only shows association of hyper-
glycemia with morbidity and mortality
and does not show causation.
CONCLUSION
The peak glucose and duration of
hyperglycemia in the immediate post-
operative period were associated with
increased morbidity and mortality in
postoperative pediatric cardiac patients
undergoing cardiopulmonary bypass. In
addition, prolonged hyperglycemia was
associated with increased length of hos-
pital stay, increased length of CICU
stay, and increased duration of mechan-
ical ventilation. Prospective, random-
ized investigation into strict glycemic
control in this patient population is
necessary to determine whether control
of hyperglycemia will result in de-
creased morbidity and mortality rates.
REFERENCES
1. Krinsley JS: Association between hyperglyce-
mia and increased hospital mortality in a
heterogeneous population of critically ill pa-
tients. Mayo Clin Proc 2003; 78:1471–1478
2. Wong VW, Ross DL, Park K, et al: Hypergly-
cemia: still an important predictor of adverse
outcomes following AMI in the reperfusion
era. Diabetes Res Clin Pract 2004; 64:85–91
3. Bochicchio GV, Sung J, Joshi M, et al: Per-
sistent hyperglycemia is predictive of out-
come in critically ill trauma patients.
J Trauma 2005; 58:921–924
4. Malmberg K: Prospective randomised study
of intensive insulin treatment on long term
survival after acute myocardial infarction in
patients with diabetes mellitus. DIGAMI (Di-
abetes Mellitus, Insulin Glucose Infusion in
Acute Myocardial Infarction) Study Group.
BMJ 1997; 314:1512–1515
5. Furnary AP, Zerr KG, Grunkemeier GL, et al:
Pediatr Crit Care Med 2006 Vol. 7, No. 4
Continuous intravenous insulin infusion reduces
the incidence of deep sternal wound infection
in diabetic patients after cardiac surgical pro-
cedures. Ann Thorac Surg 1999; 67:352–360
6. Van den Berghe G: How does blood glucose
control with insulin save lives in intensive
care? J Clin Invest 2004; 114:1187–1195
7. Krinsley JS: Effect of an intensive glucose
management protocol on the mortality of
critically ill adult patients. Mayo Clin Proc
2004; 79:992–1000
8. 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
9. Gore DC, Chinkes D, Heggers J, et al: Asso-
ciation of hyperglycemia with increased mor-
tality after severe burn injury. J Trauma
2001; 51:540 –544
10. Chiaretti A, Piastra M, Pulitano S, et al: Prog-
nostic factors and outcome of children with
severe head injury: An 8-year experience.
Childs Nerv Syst 2002; 18:129 –136
11. Cochran A, Scaife ER, Hansen KW, et al: Hyper-
glycemia and outcomes from pediatric traumatic
brain injury. J Trauma 2003; 55:1035–1038
12. Hall NJ, Peters M, Eaton S, et al: Hyperglycemia
is associated with increased morbidity and
mortality rates in neonates with necrotizing
enterocolitis. J Pediatr Surg 2004; 39:898 –901
13. Faustino EV, Apkon M: Persistent hypergly-
cemia in critically ill children. J Pediatr
2005; 146:30 –34
14. Srinivasan V, Spinella PC, Drott HR, et al:
Association of timing, duration, and intensity
of hyperglycemia with intensive care unit
mortality in critically ill children. Pediatr
Crit Care Med 2004; 5:329 –336
15. Jenkins KJ, Gavreau K, Newburger JW, et al:
Consensus-based method for risk adjustment
for surgery for congenital heart disease. J Thorac
Cardiovasc Surg 2002; 123:110 –118
16. Wernovsky G, Wypij D, Jonas RA, et al: Post-
operative course and hemodynamic profile
after the arterial switch operation in neo-
nates and infants: A comparison of low-flow
cardiopulmonary bypass and circulatory ar-
rest. Circulation 1995; 92:2226 –2235
17. Kulik TJ, et al: Outcome-associated factors in
pediatric patients treated with extracorporeal
membrane oxygenator after cardiac surgery.
Circulation 1996; 94(9 Suppl):II63–II68
18. American Diabetes Association: Diagnosis
and classification of diabetes mellitus. Dia-
betes Care 2005; 28(Suppl 1):S37–S342
19. Malatinsky J, Vigas M, Jezova D, et al: The
effects of open heart surgery on growth hor-
mone, cortisol and insulin levels in man.
Hormone levels during open heart surgery.
Resuscitation 1984; 11:57– 68
20. Ceriello A, Quagliaro L, D’Amico M, et al:
Acute hyperglycemia induces nitrotyrosine
formation and apoptosis in perfused heart
from rat. Diabetes 2002; 51:1076 –1082
21. Cai L, Li W, Wang G, et al: Hyperglycemia-
induced apoptosis in mouse myocardium:
Mitochondrial cytochrome C-mediated
caspase-3 activation pathway. Diabetes 2002;
51:1938 –1948
22. Modesti A, Bertolozzi I, Gamberi T, et al:
Hyperglycemia activates JAK2 signaling
pathway in human failing myocytes via an-
giotensin II-mediated oxidative stress. Diabe-
tes 2005; 54:394 – 401
23. DiPette DJ, Ward-Hartley KA, Jain RK: Effect
of glucose on systemic hemodynamics and
blood flow rate in normal and tumor tissues
in rats. Cancer Res 1986; 46:6299 – 6304
24. Anderson RE, Tan WK, Martin HS, et al:
Effects of glucose and PaO2 modulation on
cortical intracellular acidosis, NADH redox
state, and infarction in the ischemic penum-
bra. Stroke 1999; 30:160 –170
25. Pulsinelli WA, Waldman S, Rawlinson D, et
al: Moderate hyperglycemia augments isch-
emic brain damage: A neuropathologic study
in the rat. Neurology 1982; 32:1239 –1246
26. Dietrich WD, Alonso O, Busto R: Moderate
hyperglycemia worsens acute blood-brain
barrier injury after forebrain ischemia in
rats. Stroke 1993; 24:111–116
27. Kang BP, Frencher S, Reddy V, et al: High
glucose promotes mesangial cell apoptosis by
oxidant-dependent mechanism. Am J Physiol
Renal Physiol 2003; 284:F455–F466
28. Butler SO, Btaiche IF, Alaniz C: Relationship
between hyperglycemia and infection in critically
ill patients. Pharmacotherapy 2005; 25:963–976
29. Turina M, Fry DE, Polk HC Jr: Acute hyper-
glycemia and the innate immune system:
Clinical, cellular, and molecular aspects. Crit
Care Med 2005; 33:1624 –1633
30. Groban L, Butterworth J, Legault C, et al: In-
traoperative insulin therapy does not reduce
the need for inotropic or antiarrhythmic ther-
apy after cardiopulmonary bypass. J Cardiotho-
rac Vasc Anesth 2002; 16:405– 412
31. Van den Berghe G: Beyond diabetes: Saving
lives with insulin in the ICU. Int J Obes Relat
Metab Disord 2002; 26(Suppl 3):S3–S8
32. Van den Berghe G, Wouters PJ, Bouillon R, et al:
Outcome benefit of intensive insulin therapy in
the critically ill: Insulin dose versus glycemic
control. Crit Care Med 2003; 31:359 –366
355