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Discussion
Critical illness hyperglycemia (CIH) is probably due to endogenous counter-regulatory hormones and other diabetogenic factors, such as proinflammatory mediators and therapeutic interventions, including the administration of glucocorticoids and catecholamines, which interfere with insulin-receptor signaling and/or glucose transport and utilization within cells. On the other hand insulin therapy acts to suppress counterregulatory hormones and proinflammatory transcription factors.
Our study is the first to analyze the relationship of severe hyperglycemia in the critically ill child with the values of various hormones and with the clinical course.
Mechanisms of Production of Hyperglycemia and Relationship With Hormonal Alterations
Hyperglycemia is a state of metabolic dysregulation due to an imbalance between insulin production and insulin sensitivity in the target tissues.
C-peptide and Insulin Levels. Studies in adults suggest that CIH is primarily due to insulin resistance in spite of a situation of supranormal β-cell function, because beta cell could not secrete as much insulin as that necessary to compensate insulin resistance. However, in CIH in children, the C-peptide levels may be low or elevated. Our patients presented elevated C-peptide levels, although these levels were relatively low given the blood glucose levels at that time, which would suggest the presence both of reduced β-cell function and of increased insulin resistance.
Preissig et al., found in 41 critically ill children with hyperglycemia, that low levels of insulin were associated with a rapid onset of hyperglycemia, greater clinical severity, greater insulin requirements and increased duration of mechanical ventilation and length of PICU stay. We found higher C-peptide levels in more severely ill patients (higher PRISM, PIM2, and PELOD scores) and that higher C-peptide levels were associated with a longer PICU stay, probably because C-peptide levels were a marker of more severe ill. In contrast to the findings of Preissig et al., in our study the onset of hyperglycemia occurred later in the more seriously ill patients.
In a study of children with meningococcal sepsis and hyperglycemia 62% presented isolated insulin resistance, 17% β-cell dysfunction and 21% combined β-cell dysfunction and insulin resistance. In our patients, there was a reduction both in β-cell function and in insulin sensitivity at the time of diagnosis of the hyperglycemia. Both improved at 24 hours and β-cell function normalized at 72 hours, though a degree of insulin resistance persisted. This would suggest that the mechanism of hyperglycemia in critically ill children with severe hyperglycemia is probably multifactorial and involve both a relative reduction in insulin production due to beta cell dysfunction whose cause of the is not well known, and peripheral resistance to insulin.
It has been reported that treatment with exogenous insulin improves insulin sensitivity. In our study there was a slight improvement in insulin sensitivity at 24 hours, coinciding with insulin treatment, though sensitivity continued to be low at 72 hours.
Inotropic Index. Catecholamines may directly suppress β-cell function and insulin secretion. Some authors have reported that the inotropic index is inversely related to C-peptide levels and that hyperglycemic children have a higher inotropic index. In contrast, other authors have found no correlation between the inotropic index and blood glucose, insulin or C-peptide levels, as occurred in our study.
Corticosteroids. Corticotropin-releasing hormone and ACTH control cortisol secretion in the acute phase of critical illness, whereas non-ACTH-mediated pathways (interleukin [IL] 1, IL6, and tumor necrosis factor-α) are involved during prolonged critical illness. Protracted critical illness is associated with a fall in plasma ACTH concentrations despite the persistence of a state of hypercortisolism.
Our results, with very high initial cortisol levels, coincide with previous reports. The absence of elevated ACTH levels suggests that other factors contributed to the hypercortisolism in the majority of our patients. We found no relationship between cortisol and blood glucose levels at any time. We cannot therefore state that corticosteroids played a fundamental role in the onset of hyperglycemia in our patients.
Growth Hormone and Insulinlike Growth Factor-1. GH secretion is induced by stress and the mean serum GH level may be elevated early in the course of trauma or surgery and fall progressively during the first week. Serum IGF-1 levels are almost invariably low in critically ill patients. In acute stress situations, a low IGF-1 level in presence of enhanced GH secretion indicates GH resistance. In our study, GH and IGF-1 levels were initially low and they showed no significant modifications over the course of the study. There was no relationship of the GH and IGF-1 levels with blood glucose, insulin, or C-peptide levels, suggesting that these hormones do not play a role in the onset of hyperglycemia.
Thyrotropin and Thyroxine. In critically ill patients, T3 is typically low on admission, with normal or slightly elevated TSH and T4 levels. TSH levels subsequently normalize while T3 levels remain low and, in serious diseases such as meningococcal sepsis, T4 levels fall. In our study, a large proportion of the children had low TSH levels at the time of diagnosis of hyperglycemia, with normal T4 values. However, T4 levels fell progressively, probably reflecting the severity of the illness. We are therefore unable to state that there is a clear link between thyroid hormone alterations and the onset of hyperglycemia.
Relationship of BLood Glucose Levels and Treatment With Prognosis
Most studies have reported that hyperglycemia occurs early in critical illness and is independently associated with death. However, it is unclear whether this association is indicative of the severity of the underlying illness or that hyperglycemia is itself a risk factor. Other studies in critically ill children have found no association between the blood glucose levels and mortality or length PICU stay.
Our study showed that children with persistent severe hyperglycemia had a high mortality (13%)—the overall mortality in our PICU over the study period was 3%. This fact suggest that hyperglycemia is a marker of severity and an indicator of risk of death. However, although the number of patients was low, we did not find a relationship between the absolute blood glucose, C-peptide, or insulin values and mortality. The presence of hyperglycemia would therefore appear to be a marker of severity in the critically ill patient but not itself worsen the prognosis.
On the other hand, we found that the onset of hyperglycemia occurred later in patients that died than in survivors and nonsurvivors presented greater insulin resistance at 72 hours after diagnosis. This could indicate the existence of two types of hyperglycemia in the critically ill patient. An initial, frequently transitory hyperglycemia caused by the stress of admission to the PICU and that is not associated with a poor prognosis, and another of later onset that could reflect more serious metabolic dysregulation with persistent insulin resistance and that is an indicator of mortality.
In our study, the main factors associated with mortality and the length of PICU stay were the clinical severity scores and the presence of severe multiorgan failure with the need for CRRT and ECMO.
Initial studies in critically ill patients found short-term benefits to maintaining normoglycemia. However recent studies have found that intensive treatment with insulin does not decrease mortality and may even be associated with a higher mortality and hypoglycemia. A large proportion of our patients received insulin treatment despite our use of more restrictive indications for insulin treatment and less strict glycemic control objectives. None of our patients developed hypoglycemia, which confirms that insulin treatment with moderate objectives reduces the risk of hypoglycemia.
Corticosteroids and Prognosis. The higher corticosteroids levels in the patients who died support the hypothesis that these patients had more serious illness and therefore had a more marked adrenal response. Many studies have analyzed the relationship of corticosteroid levels and the adrenal response with the prognosis of septic patients, reporting contradictory results. The data from our study only allow us to state that critically ill children with hyperglycemia very often present elevated corticosteroid levels and that patients who die have higher levels than survivors. In critically ill children, both low and elevated corticosteroid levels may be indicators of severity and of risk of death. However, the number of patients who died in our study was small and further studies are necessary to confirm these results.
Limitations
Our study has certain limitations. The number of patients was low and most of them were in the postoperative period of cardiac surgery. The number of patients could not permit to perform a multiple logistic regression analysis and it is a small sample size to detect a difference in mortality. There was no control group without hyperglycemia to compare hormonal changes. However it is very difficult to achieve a control group with the same characteristics and severity as the study group but without hyperglycemia. To use HOMA in critically ill patients in those glucose and insulin concentrations are not in a steady state and/or are receiving exogenous insulin has limitations because this method has not been verified in these situations and for this reason the interpretation of the results has to be made with caution. The duration of the study was limited, as patients were only studied for 72 hours and we therefore do not know the changes in the hormone levels over the subsequent days, although the majority of the patients achieved adequate glycemic control at 72 hours. PRISM and PIM was measured to evaluate the severity of illness at different times although these scores only have been validated in the first 24 hours of admission. Analytical measures were made at fixed times, independently of the hour of the day and this fact could influence in some hormone values as ACTH or cortisol. Finally, we did not measure other factors that could mediate in the onset of hyperglycemia in the critically ill patient, such as catecholamines, cytokines, glucagonlike peptide-1 or nonesterified fatty acids.
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