Hyperglycaemia is a common element of the early phase of the neuroendocrine response to stress which is observed following the onset of illness or injury in both adults and children, and is sometimes referred to as the diabetes of critical illness,1–4 as a result of accelerated glucose production and acute development of relative insulin resistance.
Stress has long been recognised as a programmed, co-ordinated and adaptive process conferring survival advantage which may, if prolonged, lead to secondary harm.5 Stress hyperglycaemia was therefore usually explained as being an adaptive response whose purpose could potentially be beneficial by maintaining intravascular volume or increasing energy substrate delivery to vital organs, and it was not usually treated unless glucose levels were grossly and persistently elevated. These assumptions around the lack of harm from or benefits of stress hyperglycaemia have increasingly been questioned in the light of reports from a wide range of illnesses and populations which have shown hyperglycaemia to be related to worse clinical outcomes.
Myocardial infarction
In a meta-analysis,6 patients with acute myocardial infarction, and without diabetes mellitus, who had glucose concentrations in the range 6.1–8.0 mmol/l or higher had a 3.9-fold [95% confidence interval (CI) 2.9- to 5.4-fold] higher risk of death than patients who had lower glucose concentrations. Glucose concentrations higher than values in the range of 8.0–10.0 mmol/l on admission were associated with increased risk of congestive heart failure or cardiogenic shock.
Stroke
Capes et al.7 conducted a systematic review and meta-analysis of the literature relating glucose levels in the interval immediately post stroke to the subsequent course. A comprehensive literature search was carried out to identify cohort studies reporting mortality and/or functional recovery after stroke in relation to admission glucose level. In total, 32 studies were identified, and predefined outcomes could be analysed for 26 of these. After stroke, the unadjusted relative risk (RR) of in-hospital or 30-day mortality associated with an admission glucose level above the range of 6–8 mmol/l was 3.07 (95% CI 2.50 to 3.79) in non-diabetic patients and 1.30 (95% CI 0.49 to 3.43) in diabetic patients. Non-diabetic stroke survivors whose admission glucose level was above the range of 6.7–8 mmol/l also had a greater risk of poor functional recovery (RR 1.41; 95% CI 1.16 to 1.73).
Head injury and multisystem trauma
Hyperglycaemia has been shown to be an independent predictor of poor outcomes in adults with head injury8 and in cases of multiple trauma.9
Pulmonary function
Hyperglycaemia has been shown to be associated with diminished pulmonary function in adults, even in the absence of diabetes mellitus,10 and a range of risk factors for lung injury.11
Gastrointestinal effects
Hyperglycaemia has been shown to be associated with delayed gastric emptying,12 decreased small bowel motility and increased sensation and cerebral-evoked potentials in response to a range of gastrointestinal stimuli in adult volunteers.13–16
Infections
The in vitro responsiveness of leucocytes stimulated by inflammatory mediators is inversely correlated with glycaemic control.17 This reduction in polymorphonuclear leucocyte responsiveness may contribute to the compromised host defence associated with sustained hyperglycaemia,17 and, indeed, hyperglycaemia has been shown to be associated with an increased rate of serious infections after adult cardiac18 and vascular surgery.19
These studies, which associate poorer outcomes with patients with the highest levels of stress glycaemia, raise the question of whether high blood glucose levels simply identify the more severely ill patients, in whom worse outcomes are inevitable, or whether specific homeostatic or allostatic glycaemic dysfunction influences outcomes independently. If the latter were true, then perhaps measures to prevent or limit stress-induced hyperglycaemia would improve clinical outcomes.
Does hyperglycaemia matter for adults in the critically ill setting?
Although the importance of good glycaemic control has long been established in minimising complications of chronic hyperglycaemia in patients with diabetes mellitus,20,21 and a number of mechanisms for glucotoxicity identified,22 in the era up to the year 2000, a permissive approach was typically adopted when managing non-diabetic patients in intensive care settings. A very reasonable question, however, is Could shorter-term hyperglycaemia in non-diabetic populations be associated with clinically important adverse outcomes? Early reports from adult populations started to explore the possible association between acute stress-induced hyperglycaemia and outcome in both diabetic and non-diabetic patients.
Furnary et al.18 noted that hyperglycaemia is associated with higher sternal wound infection rates following adult cardiac surgery and questioned whether more aggressive control of glycaemia might lead to lower infection rates. In a prospective study of 2467 consecutive diabetic patients who underwent open-heart surgical procedures, patients were classified into two sequential groups. The control group included 968 patients treated with sliding-scale-guided intermittent subcutaneous insulin injections. The study group included 1499 patients treated with a continuous intravenous insulin infusion in an attempt to maintain a blood glucose level of < 11.1 mmol/l. Compared with subcutaneous insulin injections, continuous intravenous insulin infusion induced a significant reduction in perioperative blood glucose levels, which was associated with a significant reduction in the incidence of deep-sternal wound infection in the continuous intravenous insulin infusion group [0.8% (12 of 1499) vs. 2.0% (19 of 968) in the intermittent subcutaneous insulin injection group; p = 0.01]. The use of perioperative, continuous intravenous insulin infusion in diabetic patients undergoing open-heart surgical procedures appeared to significantly reduce the incidence of major infections.
Malmberg et al.23 randomly allocated patients with diabetes mellitus and acute myocardial infarction to intensive insulin therapy (n = 306) or standard treatment (controls, n = 314). The mean (range) follow-up was 3.4 (1.6–5.6) years. There were 102 (33%) deaths in the treatment group compared with 138 (44%) deaths in the control group (RR 0.72; 95% CI 0.55 to 0.92; p = 0.011). The effect was most pronounced among a predefined group that included 272 patients who had not received insulin treatment previously and who were at a low cardiovascular risk (0.49; 0.30 to 0.80; p = 0.004). Intensive insulin therapy improved survival in diabetic patients with acute myocardial infarction. The effect seen at 1 year continued for at least 3.5 years, with an absolute reduction in mortality of 11%.
In 2001, Van den Berghe and colleagues from Leuven, Belgium,24 extended this approach to non-diabetic hyperglycaemic populations. They performed a single-centre randomised trial in adults undergoing intensive care following surgical procedures which showed that the use of insulin to tightly control blood glucose led to a reduction in mortality from 10.9% to 7.2%, and a significantly lower incidence of a range of important complications of critical illness including renal failure, infection, inflammation, anaemia and polyneuropathy and need for prolonged ventilatory support.
The same group undertook a similar trial in non-surgical, adult, critically ill patients25 and again found benefits from the control of blood glucose with intensive insulin therapy. Patients were randomly assigned to a regimen of strict normalisation of blood glucose (4.4–6.1 mmol/l) with use of insulin or conventional therapy whereby insulin was administered only when blood glucose levels exceeded 12 mmol/l, with the infusion tapered when the level fell below 10 mmol/l. In the intention-to-treat analysis of the 1200 patients, intensive care unit (ICU) and in-hospital mortality were not significantly altered by intensive insulin therapy; however, for those patients who stayed > 3 days in intensive care (an a priori subgroup), mortality was significantly reduced from 52.5% to 43% (p = 0.009). Morbidity was significantly reduced by intensive insulin therapy, with a lower incidence of renal injury and shorter length of mechanical ventilation and duration of hospital stay noted. For patients who stayed > 5 days in intensive care after trial entry, all morbidity end points were significantly improved in the intensive insulin therapy group.
Although the precise mechanisms by which different glucose control strategies might influence clinical outcomes had not been fully elucidated, the clinical effects of ‘tight glycaemic control’ (TGC) for adults in critical care appeared promising. As a result, TGC was widely adopted in adult critical care standards in the years following the publication of Van den Berghe et al. 2001 paper.24
Stress hyperglycaemia in the critically ill child
Over 12,000 children are admitted to ICUs in England and Wales each year.26 Hyperglycaemia occurs frequently during critical illness or after major surgery in children, with a reported incidence of up to 86%,3 but children in critical care may not respond to interventions in the same way as adults.
References to hyperglycaemia and its management in critically ill children were identified through searches in MEDLINE27 from 1990 to December 2006. Articles were also identified through searches of the authors’ own files. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the genesis of this research proposal. The search terms used were ‘glycaemia’, ‘control’, ‘insulin’, ‘critical illness’ and ‘intensive care’; the limits applied were ‘clinical trials’, ‘meta-analysis’, ‘randomised controlled trial’ and ‘humans’ and ‘age 0–18 years’. No randomised trials or meta-analyses of glycaemic control in childhood critical illness were identified.
The non-randomised studies identified included a number of reports of critically ill children receiving care in general,3,28,29 cardiac surgical,30,31 trauma9,32,33 and burns34 ICUs, all showing that high blood glucose levels occur frequently and that levels are significantly higher in children who die than in children who survive. As in adults, the occurrence of hyperglycaemia was associated with poorer outcomes including death, sepsis and longer length of intensive care stay for critically ill children.
Srinivasan et al.3 studied the association of timing, duration and intensity of hyperglycaemia with mortality in critically ill children. The study had a retrospective, cohort design and included 152 critically ill children receiving vasoactive infusions or mechanical ventilation. A peak blood glucose of > 7 mmol/l occurred in 86% of patients. Non-survivors had a higher peak blood glucose [mean ± standard deviation (SD)] than survivors (17.3 ± 6.4 mmol/l vs. 11.4 ± 4.4 mmol/l, p < 0.001). Non-survivors had more intense hyperglycaemia during the first 48 hours in the paediatric intensive care unit (PICU) (7 ± 2.1 mmol/l) than survivors (6.4 ± 1.9 mmol/l, p < 0.05). Median blood glucose levels > 8.3 mmol/l were associated with a threefold increased risk of mortality compared with median levels of < 8.3 mmol/l. Univariate logistic regression analysis showed that peak blood glucose and the duration and intensity of hyperglycaemia were each associated with PICU mortality (p < 0.05). Multivariate modelling controlling for age and paediatric risk of mortality scores showed an independent association of peak blood glucose and duration of hyperglycaemia with PICU mortality (p < 0.05). This study demonstrated that hyperglycaemia is common among critically ill children. Peak blood glucose and duration of hyperglycaemia appear to be independently associated with mortality. The study was limited by its retrospective design, its single-centre location and the absence of cardiac surgical cases, a group which make up approximately 40% of paediatric intensive care (PIC) admissions in the UK.
Yates et al.30 conducted a retrospective review of data from 184 children < 1 year of age who underwent major cardiac surgery over a 22-month period ending in August 2004. Factors analysed included peak glucose levels and duration of hyperglycaemia. The duration of hyperglycaemia was significantly longer in children who developed renal insufficiency, liver insufficiency and infection and those who required mechanical circulatory support or who died, and was associated with longer PICU and hospital lengths of stay (LOS).
Hall et al.35 investigated the incidence of hyperglycaemia in infants with necrotising enterocolitis (NEC) and the relationship between glucose levels and outcome in these infants. Glucose measurements (n = 6508) in 95 neonates with confirmed NEC admitted to the surgical ICU were reviewed. Glucose levels ranged from 0.5 to 35.0 mmol/l; 69% of infants became hyperglycaemic (> 8 mmol/l) during their admission; and 32 infants died. The mortality rate tended to be higher in infants whose peak glucose concentration exceeded 11.9 mmol/l than in those with peak glucose concentrations of < 11.9 mmol/l, and the late (> 10 days after admission) mortality rate was significantly higher in the former infants (29% vs. 2%; p = 0.0009). Linear regression analysis indicated that peak glucose concentration was significantly related to LOS (p < 0.0001).
Branco et al.29 showed an association between hyperglycaemia and increased mortality in children with septic shock. They prospectively studied children admitted to a regional PICU with septic shock refractory to fluid therapy over a period of 32 months. The peak glucose level in those with septic shock was 11.9 ± 5.4 mmol/l (mean ± SD), and the mortality rate was 49.1% (28/57). In non-survivors, the peak glucose level was 14.5 ± 6.1 mmol/l, which was higher (p < 0.01) than that found in survivors (9.3 ± 3.0 mmol/l). The RR of death in patients with peak glucose levels of ≥ 9.9 mmol/l was 2.59 (p = 0.012).
Faustino and Apkon28 demonstrated that hyperglycaemia occurs frequently among critically ill non-diabetic children and is associated with higher mortality and longer LOSs in PICUs. They performed a retrospective cohort study of 942 non-diabetic patients admitted to a PICU over a 3-year period. The prevalence of hyperglycaemia was based on initial PICU glucose measurement, peak value within 24 hours and peak value measured during PICU stay up to 10 days after the first measurement. Using three cut-off values (6.7, 8.3 and 11.1 mmol/l), the prevalence of hyperglycaemia was 16.7–75.0%. The RR for death increased for peak glucose within 24 hours of > 8.3 mmol/l (RR, 2.50; 95% CI 1.26 to 4.93) and peak glucose within 10 days of > 6.7 mmol/l (RR, 5.68; 95% CI 1.38 to 23.47).
Pham et al.34 reviewed the records of children with ≥ 30% total body surface area burn injury admitted to a regional paediatric burn centre during two consecutive periods, during the first of which patients received ‘conventional insulin therapy’ (n = 31), and during the second of which they were managed with TGC (n = 33). Intensive insulin therapy was positively associated with survival and a reduced incidence of infections. The authors concluded that intensive insulin therapy to maintain normoglycaemia in severely burned children could be safely and effectively implemented in a paediatric burns unit and that this therapy seemed to lower infection rates and improve survival.
There was, therefore, mounting evidence to suggest that stress hyperglycaemia occurred in both neonates and children (as in adults). From adult studies, TGC appeared to offer the possibility of clinical benefits, particularly following surgery, but there was no convincing randomised controlled trial (RCT) evidence for children, whether or not admitted to PICUs following surgery. This was of particular importance as approximately one-third of admissions of children to UK PICUs are associated with surgery, in particular cardiac surgery.
Evidence on the cost-effectiveness of tight glycaemic control
The existing evidence on the clinical effectiveness of TGC is derived from studies in both critically ill adults and critically ill children. However, to inform whether or not the NHS should provide TGC rather than conventional management (CM) for critically ill children, it is important to consider whether or not the additional costs associated with implementing a TGC protocol are offset by subsequent reductions in resource use and improved health outcomes. Limited evidence suggests that any additional costs associated with implementing a TGC protocol may be relatively small.36 A post-hoc analysis of the Van den Berge 2001 RCT24,37 for critically ill adults admitted for surgery reported that TGC can reduce ICU LOS, and hence hospital costs.37 However, this study had several limitations. The study was not designed to measure costs; resource use after the initial hospital episode was not recorded; the study was undertaken in a single centre and lacked generalisability; and it is unclear whether the results apply to other patient groups (e.g. critically ill children, patients not admitted for surgery).
For critically ill children, any assessment of the effect of a TGC protocol compared with CM on resource use and costs is hindered by the lack of evidence from RCTs. The costs of each PICU bed-day are substantial (ranging from £1000 to £5000 per bed-day),38 so if TGC reduces PICU LOS then it would be anticipated to also reduce short-term costs (i.e. those incurred within 30 days of admission to the PICU). It is also plausible that TGC may have an effect on longer-term costs. A previous study reported that around 10% of PICU survivors had residual long-term disability (median follow-up of 3.5 years from initial admission).39 Therefore, the long-term costs following PICU survival may be substantial, and may be increased if TGC increases PICU survival, or reduced if improved blood glucose control reduces morbidity. There is little available evidence on the net effect of TGC compared with CM on longer-term morbidity and hence costs, either in general or specifically for critically ill children.
The previous evidence, therefore, raises the hypotheses that TGC may have an impact on costs, both in the short term (e.g. 30 days post PICU admission) and in the longer term (e.g. 12 months post PICU admission). It would, therefore, seem important to consider the net effect of TGC on costs alongside any change in clinical outcomes. No previous study has considered the effect of TGC on health service costs for paediatric patients.
The Control of Hyperglycaemia in Paediatric intensive care (CHiP) trial, therefore, sought to address the question of whether or not a policy of strictly controlling blood glucose using insulin in children admitted to PIC reduces mortality and morbidity and is cost-effective.
