Should strict normoglycaemia be maintained in critically ill children?
Authors: Dick G. Markhorst, Marc van Heerde, Frans B. Plötz, Martin C. J. Kneyber
Journal: Intensive Care Medicine (2008)

Sir: Several recent studies clearly identify the development of hyperglycaemia as an important risk factor in terms of mortality and morbidity of critically ill patients. In patients undergoing cardiac surgery, hyperglycaemia has been associated with a substantial mortality risk and delayed extubation [1, 2]. Strong evidence favouring a strategy targeting strict glucose control (4.5–6.0 mmol/l) came from the landmark prospective, randomized, controlled study on intensive insulin therapy in adult surgical critically ill patients [3]. Recently, the clinical benefits of this therapy in adults were largely confirmed in a large, randomized, controlled trial in a strictly medical adult ICU patient population [4]; however, whether the maintenance of normoglycaemia in critically ill children is also beneficial on patient outcome is undetermined. In an effort to analyse the presently available evidence related to paediatric critically ill patients, we performed a structured critical appraisal of the literature.

In critically ill children (patient) does insulin therapy in order to maintain strict normoglycaemia (intervention) improve survival, or reduce morbidity (outcome)? We have performed the following search strategy: Secondary (Cochrane library) and primary (PubMed) sources were included in the search. These databases were searched for: (“Insulin”[Mesh] or “Hyperglycemia”[Mesh] or “Glucose Metabolism Disorders”[Mesh] or “Glucose”[Mesh]) and (“Critical Illness”[Mesh] or (“Intensive Care”[Mesh] or “Intensive Care Units, Pediatric”[Mesh])) and systematic [sb] not (“Diabetic Ketoacidosis”[Mesh] or “Diabetes Mellitus”[Mesh]). Our search yielded 37 results, five relevant to the question, two related to children. One of the publications used a pooled database [4] partly described in a previous study. [3] One study was non-observational only. The three remaining studies are given in Table 1. 



Table 1

Overview of relevant papers



In critically ill adults, it has been shown that maintenance of strict normoglycaemia (4.5–6.0 mmol/l) with intensive insulin therapy substantially prevents morbidity and reduces mortality [4]. The risk of hypoglycaemia increases with this therapy, but it is unclear whether this is truly harmful in the setting of adult intensive care. In paediatric critically ill patients, hyperglycaemia is prevalent and is associated with a worse outcome [5, 6]. This association in itself, however, does not imply a causal relation. Whereas in adult studies maintenance of blood glucose levels between 80 and 110 mg/dl (4.5–6.0 mmol/l) has shown to reduce both mortality and morbidity [4], in the described paediatric studies higher glucose levels above 150 mg/dl (8.3 mmol/l) or above 178 mg/dl (10 mmol/l) have been found to be predict mortality [5, 6]. Uniform criteria to define hyperglycaemia in critically ill children have yet to be established and may differ between age groups. Moreover, the acute phase of sepsis    in children may differ significantly from the hyperinsulinaemic hyperglycaemia associated with insulin resistance in adult sepsis. In a recent study it has been shown that children in shock due to meningococcal sepsis showed signs of insufficient insulin response to hyperglycaemia, whereas patients without signs of shock were insulin resistant [7]. In paediatric critically ill patients, hypoglycaemia is also prevalent and is related to increased mortality [8]. Hypoglycaemia was significantly more common in patients receiving intensive insulin therapy [4]. Insulin therapy in sick children with high blood glucose levels, exceeding 178 mg/dl (10 mmol/l), can be advocated, but based on current evidence, there is insufficient data to extrapolate to critically ill children that strict glucose control is beneficial. Currently, two large registered and ongoing European randomised controlled trials on the subject of tight glucose control in critically ill paediatric patients are being performed: Control of Hyperglycaemia in Paediatric Intensive Care (ISRCTN 61735247, London, http://www.chip-trial.org.uk) and Tight Glycemic Control With Intensive Insulin Treatment in PICU (NCT00214916, Leuven).

In conclusion, no randomised controlled studies focusing on strict glucose control in paediatric patients were found. In critically ill adults maintenance of strict normoglycaemia with intensive insulin therapy reduces morbidity and mortality (evidence grade A). In paediatric ill patients, hyperglycaemia is prevalent and levels above 178 mg/dl (10 mmol/l) are associated with increased mortality (grade B).Ill children, however, are also susceptible to hypoglycaemia. Based on current evidence, insulin therapy aimed at strict glucose control [blood glucose levels between 80 and 110 mg/dl (4.5–6 mmol/l)] cannot be recommended in paediatric critically ill patients. Any future change in practice should be based on evidence from current randomised clinical trials.