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Hyperglycemia in Children with Meningococcal Sepsis and Septic Shock: The Relation between Plasma Levels of Insulin and Inflammatory Mediators

Department of Pediatrics (D.A.v.W., G.D.V.), Research Institute Nutrim, University Hospital Maastricht, 6202 AZ Maastricht, The Netherlands; Department of Intensive Care (T.C.J.), Erasmus MC University Medical Center, 3000 CA Rotterdam, The Netherlands; and Department of Surgery (W.A.B.), Research Institute Nutrim, Maastricht University, 6200 MD Maastricht, The Netherlands

Address all correspondence and requests for reprints to: D. A. van Waardenburg, Department of Pediatrics, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: dvwa{at}paed.azm.nl.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Hyperglycemia and insulin resistance are common findings in critically ill adult patients and are associated with increased morbidity and mortality.

Objectives: The objective of this study was to investigate the hyperglycemic response to critical illness in children.

Design: The study was designed as an observational cohort study.

Setting: The study was set in a university-affiliated pediatric intensive care unit.

Patients: Six children with meningococcal sepsis (MS) without shock and 10 children with meningococcal septic shock (MSS) were patients.

Main Outcome Measures: Differences in blood glucose levels (measured during 72 h after admission) and differences in plasma levels of glucoregulatory hormones (insulin, GH, IGF-I, cortisol, glucagons, leptin), soluble cytokine receptors (sTNF-R55, R75, sIL-1R2), and IL-6 (measured on d 3) between MS and MSS patients were assessed.

Results: Blood glucose levels on d 2 and 3 were higher in MSS patients than in MS patients [7.5 (3.9–13.0) vs. 5.1 (4.0–6.0) and 6.5 (4.0–9.9) vs. 5.5 (4.8–6.8) mmol/liter, both P < 0.05]. Maximum blood glucose values recorded in individual patients were higher in MSS patients [9.3 (6.5–13) vs. 7.2 (6.2–9.9), P < 0.05] and correlated with severity of illness (r = 0.833, P < 0.001). Insulin levels in MSS patients were significantly lower (7.2 vs. 19.0 mU/liter, P < 0.001), compatible with insufficient insulin response to hyperglycemia, whereas MS patients showed insulin resistance. Insulin levels correlated inversely with levels of sTNF-R55 and R75 (r = –0.814 and –0.878, both P < 0.001), suggesting suppression of the proinflammatory response on insulin secretion.

Conclusion: Hyperglycemia associated with hypoinsulinemia rather than insulin resistance may be the normal pathophysiological response in acute MSS in children. Our study emphasizes that application of intensive insulin therapy in critically ill children demands further investigation.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
HYPERGLYCEMIA AND INSULIN resistance are universal findings in critically ill adult patients (1, 2). In the acutely stressed state, this metabolic response can be regarded as an adaptive response, promoting cellular glucose uptake in non-insulin-dependent tissue and, as such, is important for survival. However, more prolonged hyperglycemia has been associated with increased risk of complications like infections (3), polyneuropathy, multiple organ dysfunction syndrome (4), and even death in adults (5, 6) and recently also in children (7). Prevention of hyperglycemia with intensive insulin therapy has been shown to decrease morbidity and mortality in critically ill patients in surgical intensive care units (ICU) (4) and is now widely propagated, although the mechanisms by which insulin exerts its beneficial effects are uncertain. This is underscored by the fact that high doses of insulin in the acute setting of critical illness have also been associated with adverse outcome (8). In a recent study of patients on a medical ICU, mortality was not reduced by intensive insulin therapy, and it even increased in those patients who stayed in the ICU for less than 3 d (9).

The mechanisms underlying hyperglycemia and insulin resistance are not well understood. Increased hepatic gluconeogenesis combined with hepatic and skeletal muscle insulin resistance (10, 11, 12) are considered important factors, whereas the role of plasma insulin levels is less well defined. Insulin resistance typically presents with hyperglycemia despite normal or increased insulin levels (10), although low insulin levels have been reported in the acute phase of injury (13, 14, 15). Proinflammatory cytokines play crucial roles in these mechanisms and have been shown to promote hyperglycemia either by a direct effect or via destimulation of glucoregulatory hormones. Hepatic gluconeogenesis, for instance, is promoted by increased levels of TNF-, IL-1, glucagon, and catecholamines (16, 17), whereas increased levels of TNF- and other cytokines reduce insulin-induced tyrosine phosphorylation of insulin receptor substrate-1, leading to defective glucose transporter-4 translocation and, thereby, to a diminished glucose uptake and insulin resistance in insulin-dependent tissues as skeletal and heart muscle and adipocytes. Finally, a direct inhibitory effect of TNF- and/or IL-1 on pancreatic ß-cells has been described in vitro (18).

Sepsis in adults often has a gradual and not well-defined onset and occurs in patients with coexisting disorders such as chronic or acute nutrient depletion, cancer, or recent surgery. In contrast, meningococcal septic shock (MSS) in children is a fulminant form of sepsis with an acute and well-defined onset, occurring in previously healthy children. Still it features most of the secondary outcome parameters used in the Van de Berghe study, such as a high incidence of multiple organ dysfunction syndrome, renal insufficiency, and red blood cell transfusion (4). In MSS in children it is, therefore, interesting to study mechanisms of hyperglycemia in the acute phase of sepsis. Such insight into the pathophysiology of this response in this age group is necessary before exogenous insulin therapy can be safely applied to children. The objective of the present study was to investigate the hyperglycemic response in children with MSS with the emphasis on plasma levels of insulin and inflammatory mediators.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Study protocol

Children between 3 months and 16 yr of age admitted to the pediatric ICU (PICU) of the University Hospital Maastricht between December 1998 and December 2000 were enrolled in the study if they fulfilled the diagnosis of severe meningococcal disease. Patients were retrospectively classified as having either MS or MSS. MS was defined according to the sepsis criteria of the Society of Critical Care Medicine and the American College of Chest Physicians, adapted to infants and children (19), in combination with petecchiae and/or purpura and a positive blood or spinal fluid culture with neisseria meningitidis. MSS was defined as MS in combination with the presence of systolic hypotension occurring within the first 12 h after admission refractory to one or more fluid bolus and requiring inotropic medication or vasopressors. In children younger than 4 yr, systolic blood pressure had to be less than 75 mm Hg, and in children between 4 and 12 yr, less than 85 mm Hg. Exclusion criteria were: death within 24 h, acute renal failure (manifested by urine production less than 0.25 ml/kg·h), and extensive skin and/or limb necrosis. By definition, all MSS patients received inotropic medication or vasopressor therapy (dopamine and/or norepinephrine) and were mechanically ventilated. All patients were treated with iv antibiotics and did not receive corticosteroids or insulin. The study was approved by the local Medical Ethical Committee, and informed consent was obtained from the parents.

Enteral and parenteral intake

All patients received iv dextrose solution at a rate of approximately 4 mg/kg·min as part of the standard care. Continuous enteral feeding was started at low rates within the first 24 h after admission (Nutrison Pediatric, Nutricia, Zoetermeer, The Netherlands) and slowly increased during the next days. The rates of administration of both enteral feeding and iv dextrose were not changed in the 6 h before blood sampling. Patients did not receive either amino acids or lipids parenterally.

Clinical parameters

The physiologic stability index (PSI) (20) was calculated over the first 24 h after admission. Other clinical parameters that were recorded included use of mechanical ventilation, maximum doses of inotropic medication and vasopressors given, and total carbohydrate and nutritional intake.

Blood analysis

Blood sampling. Serial determinations of blood glucose levels were performed in both patient groups starting at admission and continuing at 8-h intervals during the subsequent 3 d of their stay in the PICU. Arterial blood samples for the determination of plasma levels of insulin, glucagon, GH, IGF-I, cortisol, leptin, and plasma levels of soluble TNF receptor 55 and 75 (sTNF-R55 and R75), soluble IL-1 receptor 2 (sIL-1R2), and IL-6 were collected on the third day after admission (61.7 ± 3.3 h after admission; mean ± SEM), between 0900 and 1000 h from an indwelling arterial catheter. At this time, all patients were in a circulatory and respiratory stable condition. To calculate insulin to glucose ratios, a blood glucose level was determined from the same blood sample. Blood for cytokine analysis was collected in EDTA-containing tubes and immediately centrifuged for 15 min at 4000 rpm at 4 C. Plasma was then frozen at –70 C until analysis.

Laboratory determinations. Blood glucose levels (Uni Kit III; Roche, Basel, Switzerland) were analyzed with the COBAS FARA semiautomatic analyzer (Roche). Plasma insulin (Insulin RIA 100 kit; Pharmacia, Uppsala, Sweden), glucagon (DPS, Los Angeles, CA), and IGF-I (DSL-5600 ACTIVE; DSL Deutschland, Sinsheim, Germany) concentrations were analyzed by RIA. Immunometric assays were used to determine plasma GH (Nichols Institute Diagnostics, San Juan Capistrano, CA) and cortisol (Chiron Diagnostics, East Walpole, MA) concentrations. Urinary dopamine and epinephrine excretion was measured in an 8-h urinary collection.

sTNF-R55 and R75, sIL-1R2, and IL-6 were determined in EDTA plasma using available double-sandwich ELISA kits (Hycult Biotechnology, Uden, The Netherlands). Assays were carried out according to the manufacturer’s instructions. For detection of plasma leptin levels by ELISA, reagents, kindly provided by Dr. R. Devos (Hoffmann La-Roche, Welwyn Garden City, UK), were used. The detection limit of this leptin assay is 0.04 ng/ml. C-reactive protein (CRP) was measured on a routine clinical chemistry analyzer, Synchron LX 20, by immunoturbidimetry, with a detection limit of 5.0 mg/liter and a measuring range of 5.0–488 mg/liter (Beckman Coulter, Inc., Fullerton, CA).

Statistical analysis

The Mann-Whitney U test was used to compare differences between two groups, and Spearman’s rank correlation coefficients were used to identify possible correlations between plasma levels of soluble TNF receptors, plasma glucose, and hormone concentrations and PSI. Statistical analysis was defined as a two-tailed P < 0.05. Analysis was performed with the SPSS statistical software package for Windows (version 11.5; SPSS Inc., Chicago, IL). Data are presented as either mean ± SEM or median (range).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patient characteristics

Sixteen patients admitted to the PICU were included in the study. Ten patients were classified as MSS patients and six patients were classified as MS/meningitis without shock (MS patients). Patient characteristics are shown in Table 1. Median age and body weight were similar in both groups. MSS patients had significantly higher disease severity scores as expressed by PSI. The amount of enteral intake was still low at the moment of blood sampling (<25% of estimated requirements) but similar in both groups. Total carbohydrate intake (both iv and enteral) did not differ between both groups (MSS vs. MS patients: 3.67 ± 0.76 vs. 3.86 ± 0.28 mg/kg·min; data not shown). No significant difference in renal function as expressed by plasma creatinine levels was found (MS vs. MSS patients: 48.5 ± 10.1 and 42.7 ± 5.2 µg/liter, respectively).

Differences in severity of the hyperglycemic response between MSS and MS patients were analyzed by comparing median blood glucose levels at admission and in the subsequent three 24-h intervals. Furthermore, the percentage of elevated blood glucose values and the maximum blood glucose value (peak blood glucose level) recorded in individual patients in the 3-d study period were analyzed. To this end, blood glucose levels were measured serially in all patients starting at admission and subsequently at 8-h intervals (2.8 ± 0.1 measurements per patient per day). Hyperglycemia was defined using three cutoff values (6.1, 7.8, and 11.1 mmol/liter), based on earlier studies reporting adverse outcome of high blood glucose values in adult critically ill patients (4), pediatric burn patients (21), or diabetic patients (22). Median blood glucose levels in MSS and MS patients at admission and in the three subsequent 24-h intervals are shown in Table 2. No differences were found at admission and in the first 24-h period, but blood glucose levels were significantly higher in MSS patients on d 2 and 3. In MSS patients, 57.0% of all measured blood glucose levels were higher than 6.1 mmol/liter, whereas 23.3 and 3.1% exceeded 7.8 mmol/liter and 11.1 mmol/liter, respectively. In MS patients, these percentages were 42.2, 13.6, and 0% (², not significant). In MSS patients, the peak blood glucose levels were higher than in MS patients [9.3 (6.5–13) vs. 7.2 (6.2–9.9), P < 0.05]. Furthermore, the relationship between hyperglycemia and severity of illness was assessed by correlating the peak blood glucose levels with the PSI, resulting in a strong correlation (r = 0.833, P < 0.001).

To obtain better insight into the pathophysiology of hyperglycemia in sepsis, the association between glucose levels and metabolic and inflammatory parameters was assessed.

Table 3 shows the results of the metabolic evaluation in MSS and MS patients. Interestingly, plasma insulin levels were low in most MSS patients although they were normal to elevated in MS patients, resulting in a highly significant difference in median insulin levels between both groups. Insulin to glucose ratios were also significantly lower in MSS patients compared with MS patients. Although plasma insulin levels were low in MSS patients (Table 3), blood glucose levels correlated positively with plasma insulin levels (r = 0.782, P < 0.01) (Fig. 1). This indicates that the pancreatic ß-cells in these patients still respond to glucose levels, but at a lower overall level. These findings are supportive for normal or enhanced insulin sensitivity in these patients. However, MS patients were insulin resistant as shown by their high insulin to glucose ratios (>2.5). Median plasma levels of the glucoregulatory hormones showed no significant differences between both groups (Table 3). Interestingly plasma levels of leptin, a hormone that participates in the regulation of insulin sensitivity, were low in both groups of patients. Plasma triglyceride levels were elevated in both groups of patients compatible with increased lipolysis or increased hepatic lipogenesis, although levels of nonesterified fatty acids were within normal limits. Sympathico-adrenal activity, expressed as urinary excretion of epinephrine, was similar in both patient groups.

View larger version (16K): [in this window] [in a new window]   FIG. 1. Relationship between plasma insulin levels and blood glucose levels in MSS patients.

Taken together, these data show that plasma levels of both insulin and inflammatory mediators differ significantly between MSS and MS patients. This led us to further analyze the correlation between parameters of glucose metabolism and inflammation. A highly significant inverse correlation was found between plasma levels of insulin on the one hand and levels of sTNF-R55 and R75 on the other hand, both for the whole patient population (Table 4) as for the MSS group (r = –0.754 and r = –0.850, both P < 0.01) (Fig. 2, insulin vs. sTNF-R75). Blood glucose levels correlated with severity of illness as mentioned before, but not with inflammatory mediators besides a weak association with sIL-1R2 (Table 4). Also, a correlation was found between blood glucose and plasma leptin levels, suggesting a role for this hormone in the regulation of glucose metabolism in our septic patients. Other glucoregulatory hormones were not significantly correlated with either inflammatory parameters or disease severity.

View larger version (15K): [in this window] [in a new window]   FIG. 2. Relationship between plasma insulin levels and plasma levels of soluble TNF receptor 75 in MSS patients (filled circles) and MS patients (open circles). The solid line indicates correlation of the whole patient population (r = –0.878, P < 0.001); the dashed line indicates the correlation of the MSS population (r = –0.850, P < 0.01).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

In our prospective study with standardized blood sampling during 72 h after admission, we demonstrate that hyperglycemia is strongly correlated with severity of illness as expressed by the PSI, which is supported by Faustino and Apkon (7). Although a causal relationship cannot be conferred from our data, it shows that children with the highest risk of dying have the highest blood glucose values and may benefit most from treatment aimed at reducing hyperglycemia. Furthermore, our study shows significant differences in plasma insulin levels and insulin to glucose ratios between MS and MSS patients. MSS patients showed signs of insufficient insulin response to hyperglycemia, whereas MS patients were insulin resistant. The relationship between insulin levels and severity of illness was further illustrated by the strong inverse correlation between insulin and PSI. Similarly, Joosten et al. (23) reported low insulin levels and low insulin to glucose ratios in surviving children with MSS with even lower values in nonsurviving children. In surviving patients, both parameters increased gradually in the first 48 h. However, we demonstrate that insulin levels and insulin to glucose ratios remained lower in MSS than in MS patients up to 72 h. This contrasts with findings in adult critically ill patients in which low insulin levels are only reported during hypovolemic shock (13) or in early stages of sepsis (14, 24), whereas, in later stages, hyperinsulinemia is a constant feature. Low insulin levels in early sepsis have been attributed to suppressed insulin secretion due to strong -adrenergic inhibition of pancreatic ß-cells. However, our patients were in a stabilized circulatory state, although receiving inotropic support. However, we cannot exclude the role of (endogenous or exogenous) catecholamines on either the systemic or splanchnic circulation in our septic patients. Neural influences may also have contributed to the differences in insulin levels in our patients because the autonomic nervous system has the potential to play a major role in control of insulin secretion in response to glucose (25), whereas insulin secretion is also under the influence of gastrointestinal hormones as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (26).

In contrast to the differences in plasma insulin levels between MS and MSS patients, levels of cortisol, GH, IGF-I, and glucagon did not discriminate between the MS and MSS patients, which is supported by earlier studies in children with meningococcal disease (23, 27). Leptin levels were low in both groups of patients as reported by Blanco-Quiros et al. (28), whereas, in adults with sepsis, both high and unchanged leptin data were reported (29, 30, 31). Leptin is a pleiotrope adipocyte-derived hormone that regulates feeding behavior, substrate use, and energy balance, but also the inflammatory response. Leptin levels are increased related to body fat stores and decline early in starvation due to a down-regulation of human adipose tissue leptin production resulting from changes in free fatty acid levels as well as changes in glycemia/insulinemia (32). Prolonged fasting may explain the low leptin levels in our patients because, both before and during admission, nutritional intake was well below estimated requirements.

MS and MSS in our patients were characterized by high levels of the soluble cytokine receptors (sTNF-R55 and 75, sIL-1R2), IL-6, and CRP with significantly higher levels in the MSS patients. Soluble cytokine receptors are shed by macrophages and endothelial cells upon activation. Although expression of TNF- and IL-1 is rapidly down-regulated and only detectable in the most acute stage of the disease, levels of sTNF-R55, R75, and sIL-1R2 are more stable (33). Our data are supported by van Deuren et al. (34, 35), who found similar levels of soluble cytokine receptors in a group of pediatric patients with meningococcal disease. In their studies, sTNF-R55, R75, and sIL-1R2 levels differentiated between shock and nonshock patients and correlated with admission TNF- and IL-1 levels. In the present study, levels of soluble cytokine receptors strongly correlated with the admission PSI, supporting the relationship between soluble cytokine receptor levels and clinical disease severity in meningococcal disease.

Analysis of the relationship between parameters of glucose metabolism and inflammatory state in MS and MSS patients resulted in highly significant but inverse correlations between plasma insulin levels and levels of sTNF-R55 and R75. Although a causal relationship cannot be conferred from the data, our findings are compatible with an inhibitory effect of the inflammatory response on insulin secretion. This is supported by several in vitro studies showing IL-1 and TNF- mediated inhibition of insulin secretion by pancreatic ß-cells (18, 36).

The metabolic response to critical illness involves multiple neuroendocrine alterations with different features in the acute and chronic stages. The acute hyperglycemic response is an adaptive process to ensure provision of essential metabolic substrates for survival. Proinflammatory cytokines (TNF-, IL-1) play a crucial role by promoting hepatic gluconeogenesis and diminishing glucose uptake in insulin-dependent nonimmune tissues via inhibition of insulin secretion. However, insulin resistance does not play an important role as evidenced by the normal or even enhanced insulin sensitivity in our MSS patients.

The differences between adults and children may be explained by the important differences between adult and pediatric sepsis. Sepsis in adults often develops gradually after major surgery or injury and is superposed on an underlying illness, whereas MSS occurs abruptly in otherwise healthy children. Next, although most deaths in adult sepsis are caused by progressive organ failure after several days of intensive care treatment, most deaths in children with MSS occur in the first 24 h after admission from refractory circulatory shock.

Our findings of prolonged hypoinsulinemic hyperglycemia in children with MSS may have important consequences for the management of hyperglycemia in MSS in children. Because tight glycemic control with exogenous insulin therapy has beneficial effects in adult sepsis, pediatric intensivists consider applying this treatment in pediatric septic patients. However, our study shows that the acute phase of sepsis in children is quite different from the hyperinsulinemic hyperglycemia associated with insulin resistance in adult sepsis. Our data suggest that suppression of the hyperglycemic and proinflammatory responses in sepsis with exogenous insulin when these responses are still crucial in the phase of overwhelming bacterial infection may not be supportive and may even be potentially detrimental. However, further investigations are warranted to unravel the role of insulin and insulin therapy in septic children. Such studies should include a greater number of patients and a more intensive follow-up of plasma levels of glucose, insulin, catecholamines, and inflammatory mediators in combination with markers of splanchnic circulation (gastric tonometry). This will necessitate a multicenter design given the relatively low incidence of MS and MSS. It would also be of particular interest to compare the hyperglycemic response between children with meningococcal and postoperative sepsis to look for possible explanations for the differences in clinical response to intensive insulin therapy found in adults (4, 9).

In conclusion, MSS in children is characterized by significant hyperglycemia associated with low plasma insulin levels. Plasma insulin levels are inversely correlated with levels of soluble cytokine receptors, suggesting a suppressive effect of proinflammatory mediators on insulin secretion. Our findings emphasize that the use of intensive insulin therapy in children with MSS demands further investigation.

	Footnotes

 
Disclosure Statement: D.A.v.W., T.C.J., and G.D.V. have nothing to declare. W.A.B. has equity interests in Hycult Biotechnology (Uden, The Netherlands).

First Published Online May 30, 2006

Abbreviations: CRP, C-reactive protein; ICU, intensive care unit; MS, meningococcal sepsis; MSS, meningococcal septic shock; PICU, pediatric intensive care unit; PSI, physiologic stability index.

Received March 8, 2006.

Accepted May 23, 2006.

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