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Original Studies |
The Department of Pediatrics, Division of Pediatric Intensive Care (K.F.M.J., E.D.d.K., M.W., M.d.H., F.C.v.E., E.v.V., J.A.H.), Division of Endocrinology (A.C.S.H.-K.), Sophia Children’s Hospital, and Department of Biostatistics and Epidemiology (W.C.J.H.), Erasmus University Rotterdam, 3000 CB Rotterdam, The Netherlands
Address correspondence and requests for reprints to: Koen F. M. Joosten, Ph.D., Department of Pediatrics, Division of Pediatric Intensive Care, Sophia Children’s Hospital, Erasmus University Rotterdam, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands. E-mail: joosten{at}alkg.azr.nl
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Abstract |
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Introduction |
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In adult patients it has been shown that sepsis may lead to pronounced neuro-endocrine and metabolic alterations including increased serum cortisol concentrations; low thyroid hormones; insulin resistance; elevations of plasma glucose, lactate, and free fatty acid concentrations; and increased muscle protein breakdown (1, 2, 3, 4). During the time course of sepsis an ebb and flow phase can be detected. Main features in the ebb phase are a decrease in metabolic rate and temperature, and in the flow phase there is an increase in metabolic rate and urinary nitrogen excretion (5, 6). There are several differences between the host response of young children compared with adults during meningococcal sepsis (7). Little is known about the neuro-endocrine changes in critically ill infants and children. Previous studies in critically ill infants and children showed an altered thyroid function at the onset of acute diseases called "the euthyroid sick syndrome" (8, 9, 10, 11, 12). Dopamine infusion induces or aggravates partial hypopituitarism in newborn infants, resulting in inhibited PRL and GH secretion (8). The present study was undertaken to evaluate the time course of the endocrine and metabolic responses of children with meningococcal sepsis during the first 48 h of admission in the pediatric intensive care unit (PICU).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Children above 3 months and below 18 yr of age with septic shock and petechiae/purpura requiring intensive care treatment were enrolled in this study. The group consisted of children primary admitted or referred to the PICU of the Sophia Children’s Hospital between October 1997 and October 1998. Patients were eligible for inclusion when they met the following criteria: 1) presence of petechia/purpura; and 2) presence of shock for less than 6 h, defined as persistent hypotension (systolic blood pressure <75 mm Hg for children between 3 and 12 months, <80 mm Hg for 1–5 yr, <85 mm Hg for 6–12 yr, <100 mm Hg for children older than 12 yr), or evidence of poor end-organ perfusion, defined as at least two of the following: unexplained metabolic acidosis (pH <7.3 or base excess less than -5 mmol/L or plasma lactate levels >2.0 mmol/L); arterial hypoxia (PO2 <75 mm Hg, a PO2/FiO2 ratio <250, or transcutaneous oxygen saturation <96%) in patients without overt cardiopulmonary disease; acute renal failure (diuresis <0.5 mL/kg·h for at least 1 h despite acute volume loading or evidence of adequate intravascular volume without preexisting renal disease); or sudden deterioration of the baseline mental status. The patients participated in a randomized, double-blinded, dose-finding study of protein C concentrate (human; Immuno-Baxter, Vienna, Austria). Because protein C is assumed not to influence the endocrine and metabolic assays and did not influence mortality we did not account for it in further analysis. The Medical Ethics Committee of the Erasmus University Rotterdam approved the study protocol. Informed consent was obtained from the parents or legal representatives.
Clinical parameters
The pediatric risk of mortality (PRISM II) score was calculated based on the most abnormal values regarding 14 physiological variables during the first 6 h of admission. A higher score means a higher risk of mortality (13, 14, 15). The interval between appearance of petechiae and admission to the PICU, length of stay in the PICU, and duration of inotropic support were recorded. To distinguish nonsurvivors from survivors established parameters to monitor the severity of disease, such as PRISM, lactate, and C-reactive protein (CRP) were analyzed (14, 15).
Collection of blood
Arterial blood samples were collected within 2 h after admission (T = 0), after 24 h (T = 24), and 48 h (T = 48) for determination of thyroid hormones, insulin, glucose, pre-albumin, CRP, nonesterified free fatty acids (NEFAs), and lactate. Blood samples for cortisol and ACTH were taken at T = 0 and 12 h (T = 12) after admission. An ACTH test was not performed because all children had severe stress due to the life-threatening disease on admission. A diurnal rhythm for cortisol and ACTH was estimated by sampling blood on the second day of admission at 0800 h and subsequently at 1400 and 2000 h.
Hormonal assays
Cortisol/ACTH.The plasma concentrations of cortisol were measured by competitive luminescence immunoassay. The detection limits were 0.03–1.38 µmol/L. The plasma concentrations of ACTH were measured by immunoradiometric assay (ELSA-ACTH; CIS-Bio International, Gifsuryvette, France), using two monoclonal antibodies. The within-run coefficients of variation were 6.1% at 22 pg/mL, 2.9% at 59 pg/mL, and 2.1% at 778 pg/mL. The between-run coefficients of variation were 5.3% at 40 pg/mL, 4.8% at 203 pg/mL and 1.3% at 1055 pg/mL. The reference values for cortisol were: 0800 h, 0.2–0.6 µmol/L; 1400 h, 0.1–0.5 µmol/L; and 2000 h, 0.05–0.3 µmol/L. The reference value for ACTH was 20–100 ng/L. From the values of cortisol and ACTH the cortisol/ACTH ratio was calculated.
Thyroid hormones.Plasma T4, T3, and reverse T3 (rT3) were measured by established RIA procedures, as described previously (16, 17). The reference values of the laboratory were: T4, 64–132 nmol/L; T3, 1.1–2.6 nmol/; and rT3, 0.15–0.43 nmol/L. From the values of T3 and rT3 the T3/rT3 ratio was calculated. The plasma concentrations of free T4 (fT4) were measured by a direct, labeled antibody, competitive immunoassay technique (Amerlite MAB fT4 Assay; Ortho-Clinical Diagnostics, Strassbourg, France). The within-assay coefficients of variation were 7.6% at 5.43 pmol/L, 4.3% at 16.1 pmol/L, and 3.5% at 52.8 pmol/L. The between-assay coefficients of variation were 9.0% at 5.67 pmol/L, 5.6% at 17.4 pmol/L, and 4.2% at 49.2 pmol/L. The reference value for fT4 was 11–25 pmol/L.
The plasma concentrations of TSH were measured by an ultrasensitive immunometric assay (Amerlite TSH-30; Ortho-Clinical Diagnostics), using one monoclonal antibody. The within-assay coefficients of variation were 8.0% at 0.087 mIU/L, 4.2% at 4.22 mIU/L, and 4.1% at 21.5 mIU/L. The between-assay coefficients of variation were 11.7% at 0.077 mIU/L, 6.6% at 4.25 mIU/L, and 5.1% at 21.4 mIU/L. The reference value for TSH was less than 4.5 mE/L.
Insulin/glucose.Insulin was measured in serum with an immunoradiometric assay. The detection limit was 5–400 mU/L. Glucose measurements were determined on the routine clinical chemistry analyzers (Dimension ES; Dupont Medical Products, Wilmington, DE) (reference values: hypoglycemia, <2.6 mmol/L; hyperglycemia, >11 mmol/L). From the values of insulin and glucose the insulin to glucose ratio was calculated.
Metabolic assays
Lactate was measured by enzymatic end point determination (Hitachi 911; Roche Molecular Biochemicals, Mannheim, Germany) (normal, <2.0 mmol/L). CRP was determined by an immunonephelometric assay (normal, <5 mg/L) (18). Plasma NEFA concentrations were determined by the enzymatic method (Nefac-kit; Wako, Instruchemie BV, Neuss, Germany). The reference values for NEFAs were: children between 4 months and 10 yr, 0.3–1.1 mmol/L; children more than 10 yr, 0.2–0.8 mmol/L.
Urinary nitrogen excretion
Urine was collected daily for 24 h and analyzed for urinary nitrogen. Total urinary nitrogen excretion was defined as 1.25x urinary urea nitrogen, to adjust for the urinary nitrogen loss as ammonia, creatinine, and uric and amino acids (19). No correction was made for nitrogen losses through stools, skin, wounds, nasogastric suction, or blood sampling.
Caloric intake
The patients were fed enteral and/or parenteral according to a
standard feeding protocol. During the stay in the PICU glucose was
administered at a rate of 
4–6 mg/kg·min. If enteral feeding could
not be started on the second day, parenteral feeding was started. The
initial dose of proteins was 1.0 g/kg·day (Aminovenös N-paed
10%; Fresenius, ’s-Hertogenbosch, Holland) and of lipids (in
case the body temperature was <38.5 C) was 1.0 g/kg·day (Intralipid
20%; Pharmacia & Upjohn, Inc., Woerden, Holland).
If clinically possible, enteral and/or parenteral nutrition was
adjusted on days 3 and 4 to normal needs for healthy children. The
total caloric intake was recorded and calculated daily. The amount of
caloric intake was corrected for extra protein calories such as plasma
and/or albumin infusions. To estimate the adequacy of caloric intake,
the amount of energy intake was compared with calculated values for
resting energy expenditure for healthy children according to the
formula of Schofield (20) for age, sex, and weight.
Statistics
Statistical analysis was performed with a statistical analysis software program (SPSS 7.0 for Windows 95; SPSS, Inc., Chicago, IL). The results are expressed as medians (interquartiles), unless specified otherwise. The Mann-Whitney U test was used for comparison of clinical and laboratory tests between survivors and nonsurvivors. For survivors, the Wilcoxon signed rank test was used for comparison on different time points of different laboratory tests. Spearman’s correlation coefficient (r) was used to evaluate the relationship between different parameters. Two-tailed P values of 0.05 or less were considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Twenty-six patients admitted to the PICU fulfilled the inclusion
criteria and were included in the study; there were 16 males and 10
females (Table 1
). The median age was 23
months (range, 4–185). Cultures of blood revealed Neisseria
meningitidis in all 26 patients.
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Eight children died after a median stay in the PICU for 10 h
(range, 2–40); eighteen children survived, and they stayed in the PICU
for a median of 86 h (range, 30–312). There was a significant
difference in age between nonsurvivors and survivors (10 vs.
29 months, P < 0.05). The interval between appearance
of petechiae and admission to the PICU was 5.8 h (range,
2.5–18.). There was a significant difference between nonsurvivors and
survivors for the interval between appearance of petechiae and
admission to the PICU (3.5 vs. 7.0 h, P
< 0.05). Concomitant therapy during the study period included
antibiotics, administration of plasma, and inotropics for all patients
[10 patients received dopamine, 22 received noradrenaline, and 25
received dobutamine (24 patients received a combination of
inotropics)]. Nonsurvivors received significantly higher doses of
inotropics (dobutamine and noradrenaline, P < 0.01).
The 18 survivors received inotropic therapy for a median of 49 h
(range, 9–170). Administration of corticosteroids is not a routine
procedure in The Netherlands. For that reason, none of the children
received corticosteroid therapy on admission. Seventeen patients
required mechanical ventilatory support and sedation with
benzodiazepines. The parameters to monitor severity of disease were
significantly different between nonsurvivors and survivors [PRISM
score (31 vs. 17, P < 0.01); arterial
lactate levels (7.3 vs. 3.2 mmol/L, P <
0.01; Fig. 1); and CRP levels (34 vs. 78 mg/L,
P < 0.01)] (Table 2).
In survivors, compared with levels on
admission, lactate levels decreased significantly after 24 and
normalized after 48 h, and CRP levels were significantly increased
after 24 and 48 h.
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On admission, nonsurvivors had significantly lower serum cortisol
levels than survivors (0.62 vs. 0.89 µmol/L,
P < 0.05), whereas the ACTH levels were extremely high
in those who did not survive (1234 vs. 231 ng/L,
P < 0.01) (Table 2
and Fig. 2). The
cortisol/ACTH ratio was significantly different between nonsurvivors
and survivors (P < 0.01). ACTH and the cortisol/ACTH
ratio correlated well with parameters to monitor the severity of
disease (PRISM, lactate, and CRP) (Table 3). In those who survived 12 h after
admission levels of cortisol (0.73 µmol/L) and ACTH (31 ng/L)
decreased significantly in comparison with levels on admission; on the
second day after admission there was a further significant decrease of
levels of cortisol (0.54 µmol/L) and ACTH (18 ng/L) in comparison
with levels on admission and the levels of 12 h after admission
(Table 2). In 14 survivors, on day 2, a cortisol/ACTH profile was
performed; in none of them could a circadian rhythm be detected in the
three samples taken at 0800, 1400, and 2000 h.
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On admission, data of nonsurvivors and survivors showed
significant differences in levels of rT3 (0.75
vs. 1.44 nmol/L, P < 0.01), the
T3/rT3 ratio (0.76
vs. 0.43, P < 0.01), TSH (0.97
vs. 0.29 nmol/L, P < 0.01), and
T3 (0.53 vs. 0.38 nmol/L,
P < 0.05), whereas the levels of
T4 and fT4 were not
significantly different between the two groups (Table 2 and Fig. 3). In comparison with normal reference values,
the levels of T4 and T3
were decreased in both nonsurvivors and survivors, and those of
rT3 were increased. The median
fT4 and TSH levels were within the normal
reference range. On admission, there were, except for
fT4, significant correlations between levels of
TSH, T3, rT3, and the
T3/rT3 ratio with the
parameters to monitor the severity of disease (Table 3). After 48
h survivors showed significantly increased levels of TSH,
T3, and the
T3/rT3 ratio and
significantly decreased levels of rT3 and
fT4 in comparison with levels on admission,
whereas the level of T4 did not change
significantly. For survivors 48 h after admission median levels of
T3, T4, and
rT3 remained below normal reference values,
whereas median fT4 and TSH levels remained within
the normal reference values (Fig. 2).
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On admission, nonsurvivors showed significantly different levels
of insulin (5 vs. 13 mU/L, P < 0.05) and
glucose (3.9 vs. 6.3 mmol/L, P < 0.05)
compared with survivors (Table 2 and Fig. 4). The
insulin to glucose ratio did not show statistical significance between
survivors and nonsurvivors (Table 2). On admission, two of the children
had a hypoglycemia (2.4 and 1.6 mmol/L) and two children had a
hyperglycemia (11.6 and 14.3 mmol/L). After 48 h survivors showed
significantly increased levels for insulin and the insulin to glucose
ratio in comparison with levels on admission, whereas the levels of
glucose showed no changes (Fig. 4). There were no significant
correlations between insulin, glucose and the insulin to glucose ratio
vs. the levels of cortisol and the parameters to monitor the
severity of disease (Table 3).
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On admission, nonsurvivors had significantly lower NEFA levels
than survivors (0.32 vs. 0.95 mmol/L, P <
0.01) (Table 2 and Fig. 1). Median NEFA levels for both nonsurvivors
and survivors remained within normal reference values on admission.
NEFA levels decreased significantly after 48 h in comparison with
the levels of admission and after 24 h. Levels of NEFA correlated
negatively with lactate and PRISM score (P < 0.01)
(Table 3).
Nitrogen excretion
Nitrogen excretion was assessed in 16 survivors. The median nitrogen excretion was not significantly different between the first 24 h and the second 24 h after admission 271 mg/kg·day (range, 64–940) vs. 251 mg/kg·day (range, 152–737).
Caloric intake
For survivors, the median difference between actual energy intake and calculated resting energy expenditure was -45% (range, -83% to 24%) during the first 24 h after admission and -42% (range, -83% to 27%) during the second 24 h after admission.
Time course in nonsurvivors
Six of the eight nonsurvivors died within 14 h because shock
persisted in all; in two of these six children it was combined with
pulmonary edema, in one child with convulsions, in one child with
pulmonary hypertension, and in one child with cerebral death. Two
children died after 24 h (25 and 40 h). For these children,
the interval between appearance of petechiae and admission to the PICU
was significantly longer (7 and 8 h) compared with the other six
children [median, 3.5 h (range, 0.5–4. h; P <
0.05)]. These two children also showed higher cortisol levels on
admission (0.73 and 1.05 µmol/L; Fig. 2, 
) than the other six
children. After 24 h both children showed decreased levels of
ACTH, but these levels still remained above normal reference values
(163 and 805 ng/L). In one of these two children a cortisol measurement
was done after 24 h, showing only a slight improvement of the
level of cortisol (from 0.73 to 0.80 µmol/L) in view of the ultimate
state of stress. Furthermore, both children showed after 24 h an
increase in rT3 levels (from 0.95 to 1.65 nmol/L)
and CRP (from 34 to 111 mg/L). The level of lactate, however, increased
in both children. In the child who lived for 40 h shock persisted,
recurrent convulsions developed, and severe bradycardias occurred a few
hours before death. In the child who lived for 25 h shock
persisted, and a combination with severe pulmonary hypertension lead to
death.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One of the most striking alterations in our study concerned a
significant difference in cortisol/ACTH response between nonsurvivors
and survivors on admission. Nonsurvivors showed an inadequate cortisol
response in combination with very high ACTH levels, whereas survivors
showed a normal stress response with significantly higher cortisol
levels in combination with moderately increased ACTH levels. ACTH and
the cortisol/ACTH ratio were strongly correlated with survival and
parameters to monitor the severity of disease. Low cortisol levels in
nonsurvivors and high cortisol levels in survivors have been reported
in the past in children with meningococcal sepsis (21, 22). More recently, only one other study in children with
meningococcal sepsis reported the levels of ACTH in relation with the
levels of cortisol. Significantly higher ACTH levels were found in
those who died (23). The decreased production of cortisol
in relation with high levels of ACTH might be caused by various
mechanisms. First, the low production of cortisol might be the result
of bilateral adrenal hemorrhages [described previously as the
Waterhouse-Friderichsen syndrome (21, 22)], due to severe
coagulation disorders found in meningococcal sepsis (15).
Second, alternatively, an inadequate perfusion of the adrenal cortex
due to hypotension might have lead to impaired adrenal function with
diminished cortisol production. Our study seems to support this
mechanism because we found a strong negative correlation between levels
of cortisol and lactate. Third, in the presence of higher levels
of endotoxin and tumor necrosis factor 
(as seen in nonsurvivors),
there might be a decreased adrenal ACTH receptor binding and a
suppressed synthesis of cortisol (24, 25). Salem et
al. (26) reported a family of peptides (called
corticostatins) that might impair the sensitivity of the adrenals to
ACTH during sepsis. It remains a question whether treatment with
supplemental steroids, which is not a routine treatment in The
Netherlands, will be beneficial (27). In our study, there
was a very rapid and aggressive course of the disease in four of the
five nonsurvivors who died within 12 h after admission. In
nonsurvivors the interval between appearance of petechiae and admission
to the PICU was significantly shorter compared with survivors,
indicating the importance of the time course of disease. We believe
that if corticosteroid treatment is started after referral and
admission on the intensive care unit therapy might only benefit a very
small group of children. In that case, the time delay before initial
corticosteroid treatment the infection process might have gone beyond
any currently available therapeutic approach. Based on our data,
however, we feel that a large randomized, double-blind, controlled
study has to be designed to treat children with steroids as soon as
possible after the first signs of disease. The results of this study
might give an answer on the role of administration of steroids with in
respect the time course of the disease.
During critical illness, cortisol has an important role on the metabolism of fatty acids, glucose, and protein (28). There is evidence to suggest that NEFAs may be the preferred fuel for oxidation in critical illness (29). In our study, we found on admission a positive correlation between levels of cortisol and NEFAs. Nonsurvivors had significant lower levels of NEFAs than survivors, indicating a lack of an adequate metabolic stress response in those who died. Nonsurvivors also showed significant lower levels of glucose, but there was no correlation with the levels of cortisol, indicating other mechanisms causing hypoglycemia (30).
In this study, we examined the ACTH/cortisol axis as an important modulator of cardiovascular and metabolic homeostasis during critical illness. We did not examine the serum concentrations of the catecholamines and glucagon that might have influenced the anabolic effects of insulin and GH. Preliminary data of a comparable group of children with meningococcal sepsis showed that nonsurvivors had significantly increased levels of GH and low levels of insulin-like growth factor I compared with survivors (manuscript in preparation). Research is in progress to assess the etiology and consequences of the alterations of the GH/insulin-like growth factor I axis.
Alterations in the thyroid axis in critically ill children are called "the euthyroid sick syndrome" (8, 9, 10, 11, 12). In our study, both survivors and nonsurvivors showed the features of "the euthyroid sick syndrome," decreased levels of T3 and T4, increased levels of rT3, normal levels of fT4, and no compensatory increased levels for TSH. Nonsurvivors, however, showed significantly higher T3 levels and lower rT3 levels compared with survivors. Low levels of T3 and increased levels of rT3 are explained by an adaptive mechanism aimed at preventing protein catabolism and lowering energy requirements in severely ill patients. It might, thus, be postulated that nonsurvivors are not able to adapt in the same way as survivors (31, 32, 33, 34). The euthyroid sick syndrome may be mediated by cytokines and can be induced or aggravated by dopamine and glucocorticoids, whereas somatostatin may play a suppressive role (9, 28, 35, 36, 37). In our study, 10 of the survivors received dopamine. Our study was not designed to study the immediate relation of thyroid function after dopamine withdrawal as done previously in children after cardiac surgery (28).
To get a better insight in the resolution of the hormonal and metabolic changes in children who survived, we evaluated the time course. Cortisol and ACTH levels in those who survived were on day 2 already significantly lower compared with the levels on admission and after 12 h. The cortisol and ACTH levels were within normal reference values, however, the circadian rhythm of cortisol was not seen. These findings suggest a persisting hyperactivity of the adrenal gland despite normalization of cortisol and ACTH levels. Furthermore, 2 days after admission levels of total T4 remained unaltered, whereas levels of fT4 and TSH increased but remained within normal reference values. Levels of rT3 decreased and levels of T3 and the T3/rT3 ratio increased, but all these levels still remained below normal reference values. These data indicate a slightly restoration but not a normalization of the thyroid function at day 2. Levels of NEFAs had decreased significantly at 2 days after admission, indicating that lipolysis had diminished. Levels of insulin and glucose showed a variable pattern within the normal range during the first 2 days after admission, which is in contrast to studies in critically ill adults where hyperglycemia and glucose intolerance with elevated insulin levels are hallmarks of stressed metabolism (38). Whether children with septic shock have a different insulin/glucose response compared with adults is not known. Although several hormonal axes and levels of NEFAs and lactate indicated the restoration of anabolism at the second day after admission, the urea nitrogen excretion did not change significantly and remained high. This is in accordance with studies in critically ill adult patients in which protein breakdown remained increased after the return to baseline values of the stress hormones and cytokines (39). In some studies of critically ill adult patients and critically ill children an improvement in protein synthetic rate or an improvement of nitrogen retention could be achieved by provision of exogenous nutrition (40, 41, 42). In our study, the provision of calories was far below the estimated need for calories during the first 2 days after admission (respectively, 45% and 42% too low). The low caloric supply might, therefore, be responsible for the high and unaltered excretion of nitrogen during these days in our patients.
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Acknowledgments |
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Received July 9, 1999.
Revised January 31, 2000.
Revised June 1, 2000.
Accepted June 15, 2000.
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F. de Groof, K. F. M. Joosten, J. A. M. J. L. Janssen, E. D. de Kleijn, J. A. Hazelzet, W. C. J. Hop, P. Uitterlinden, J. van Doorn, and A. C. S. Hokken-Koelega Acute Stress Response in Children with Meningococcal Sepsis: Important Differences in the Growth Hormone/Insulin-Like Growth Factor I Axis between Nonsurvivors and Survivors J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3118 - 3124. [Abstract] [Full Text] [PDF]
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