EVIDENCE FROM RANDOMIZED CONTROLLED TRIALS
In the last two decades, several RCTs have investigated whether tight glucose control is beneficial or not in critically ill patients, as compared with more liberal glucose control.
Pioneer randomized controlled trials
In 2001, a pioneer RCT performed in Leuven, Belgium, found clear benefit by treating hyperglycemia, supporting a potential causal relationship between hyperglycemia and outcome. Indeed, in 1548 adult critically ill patients admitted to a predominantly surgical ICU, maintaining blood glucose concentrations in the healthy fasting range [4.4–6.1 mmol/l (80–110 mg/dl)] reduced morbidity and mortality, as compared with tolerating hyperglycemia up to the renal threshold [11.9 mmol/l (215 mg/d])] . Subsequently, the Leuven research group confirmed clinical benefit in critically ill adults admitted to the medical ICU (n = 1200) and in critically ill children (n = 700) [4,5]. Importantly, short-term benefit was maintained on the long-term and the intervention was shown to reduce healthcare costs [6–8]. Subsequent mechanistic studies attributed the benefit obtained by tight glucose control to a protection against glucose toxicity and not to glycemia-independent effects of insulin [9–11].
After the Leuven RCTs, several implementation studies and single-center RCTs have confirmed morbidity and/or mortality benefit by implementing tight glucose control [12–17]. However, multicenter RCTs in both critically ill adults and children have largely been neutral and the largest RCT, the NICE-SUGAR study (n = 6104), even found increased mortality in critically ill adults [18–25]. The increased mortality risk in NICE-SUGAR was subsequently attributed to the increased incidence of hypoglycemia . Hence, at current, tight glucose control remains highly debated, which leads to large variations in clinical practice [27▪,28▪,29].
HOW TO RECONCILE THE EVIDENCE?
Although speculative, a number of methodological differences may potentially explain the discrepant outcome effects seen across RCTs. We here review the –to our opinion– most important differences (Table 1).
Differences in blood glucose target
A first difference is the difference in blood glucose target in both control and intervention groups. In contrast to the Leuven RCTs, in which tight glucose control was compared with tolerating severe hyperglycemia, most subsequent multicenter RCTs used a lower glucose target in the control group, in general less than 10 mmol/l (180 mg/dl) [27▪]. This is explained by the shift in standard care –the implementation of some degree of glucose control– before the start of the respective multicenter RCTs. However, by comparing with a lower glucose target, the achieved difference in blood glucose concentrations between both groups was smaller, which leaves most studies underpowered to detect a difference. Yet, this does not explain the increased mortality by tight glucose control in NICE-SUGAR, as compared with an intermediate target. Aggregating evidence from Leuven and NICE-SUGAR, one could argue that the intermediate blood glucose target [<10 mmol/l (180 mg/dl)] is the optimum. However, no adequately powered RCT has compared such intermediate target with more liberal control [<11.9 mmol/l (215 mg/dl)], and other differences between Leuven and NICE-SUGAR may explain the different outcome effect [27▪]. Moreover, secondary analyses of the Leuven RCTs suggest that strict glucose control is superior to intermediate glucose control .
Apart from the blood glucose target in the control group, also the target in the intervention group differed among RCTs, especially in the pediatric RCTs [5,16,23–25]. Indeed, whereas in the Leuven pediatric RCT, the target was age-adjusted [2.8–4.4 mmol/l (50–80 mg/dl) for infants, 3.9–5.6 mmol/l (70–100 mg/dl) for children older than 1 year], subsequent multicenter RCTs did not adjust the target to the age-dependent reference value [5,23–25]. Moreover, as critically ill children also tend to develop less severe hyperglycemia than adults, there was a large overlap in achieved blood glucose concentrations in the pediatric multicenter RCTs, which led to insufficient statistical power [31,32]. Nevertheless, one of these multicenter RCTs suggested a potential benefit of tight glucose control in the high-risk subgroup of noncardiac surgery patients .
Differences in glucose measurement and insulin protocol
A second difference between RCTs on tight glucose control in the ICU is the used protocol to measure and control blood glucose. In the pioneer RCTs showing benefit, blood glucose was measured on arterial blood using an accurate blood gas analyzer, and insulin was only administered through continuous intravenous infusion, without boluses. Insulin was titrated by the nurses, using a standard protocol that allowed intuitive decision-making . This approach led to a relatively high time in target range. Several subsequent studies, including NICE-SUGAR, had a less standardized protocol, allowing a variety of –at that time– inaccurate glucometers. Moreover, venous and capillary blood glucose measurements often were allowed, which can be inaccurate in case of simultaneous intravenous glucose infusion and in patients with shock, respectively. Finally, the insulin protocol of NICE-SUGAR allowed insulin boluses and did not necessarily correct for changes in feeding intake . The combination of potentially inaccurate glucose measurements and an unvalidated insulin protocol that allows boluses may substantially increase glucose variability – also associated with poor outcome– and may lead to episodes of undetected and prolonged hypoglycemia . Although speculative, this may explain why NICE-SUGAR found excess mortality by tight glucose control. Hence, if tight glucose control is applied, blood glucose should be measured frequently with an accurate device, preferably on arterial blood, and insulin should probably only be titrated through continuous intravenous infusion using a protocol that corrects for trends in blood glucose and feeding intake [34,35▪].
Differences in nutritional management
Third, feeding intake largely differed between the RCTs on tight glucose control, explained by a long-lasting controversy about the optimal feeding regimen for critically ill patients. In the pioneer Leuven RCTs, patients received early parenteral nutrition as part of standard care at that time [3–5]. However, this feeding strategy increases the degree of hyperglycemia and was afterwards shown to be harmful in two large multicenter RCTs, also when iatrogenic hyperglycemia is treated [36,37]. In several other RCTs on tight glucose control, including NICE-SUGAR, parenteral feeding intake was lower in the acute phase . Withholding parenteral nutrition in the acute phase – the current feeding standard for critically ill patients – increases the risk of hypoglycemia when tight glucose control is applied [36,37]. It currently remains unknown whether tight glucose control is protective or not in the absence of early parenteral nutrition, when provided with adequate tools.
In view of the divergent results between subsequent RCTs, several open questions remain.
Iatrogenic hypoglycemia: harmful or not?
Tight glucose control inevitably increases the risk of hypoglycemia. Multiple observational studies have associated the occurrence of hypoglycemia with poor outcome [1,2]. The central nervous system has been presumed to be particularly vulnerable. Evidently, long-lasting hypoglycemia is known to be harmful. It remains unclear, however, whether a short-lasting iatrogenic episode of hypoglycemia is by itself harmful or not . Indeed, the association between hypoglycemia and outcome is confounded by severity of illness, with sicker patients being more prone to hypoglycemia. Several lines of evidence suggest that a short-lasting episode of iatrogenic hypoglycemia may be innocent. Indeed, several nested case–control studies could not identify harm by an iatrogenic episode of hypoglycemia when corrected for baseline risk factors and duration of ICU stay [7,38,39]. In addition, a long-term follow-up study of the pediatric Leuven RCT found an improved neurocognitive outcome of critically ill children 4 years after randomization to tight glucose control, despite a high incidence of hypoglycemia, suggesting that hyperglycemia is more deleterious to the brain than hypoglycemia . In this regard, an animal study found that not profound hypoglycemia, but rebound hyperglycemia during glucose reperfusion induced neuronal death . Also in NICE-SUGAR, long-term follow-up of the subgroup of patients with traumatic brain injury did not find long-term harm by tight glucose control, despite a significant increase in severe hypoglycemia . However, proof of innocence of short-lasting iatrogenic hypoglycemia would require a RCT, which is obviously not justifiable. Moreover, NICE-SUGAR statistically attributed harm by tight glucose control in the total study population to the increased incidence of hypoglycemia . Therefore, it seems prudent to prevent hypoglycemia as much as possible by frequent and accurate glucose measurements and by use of a validated insulin protocol.
Which patient subgroups benefit more or less from tight glucose control?
Observational studies and experts have suggested that certain patient subgroups may respond differently to the impact of tight glucose control, including patients after cardiac surgery, patients in the neuro-ICU and patients with preexisting diabetes [1,42▪▪]. Subgroup analyses of RCTs largely refute this, however. Indeed, subgroup analyses from Leuven and NICE-SUGAR did not find a different effect among subgroups, with the potential exception of patients with preadmission diabetes [20,30]. Indeed, in a secondary analysis of the Leuven studies, benefit of tight glucose control was present in all studied subgroups, except in the patients with preexisting diabetes .
An individualized blood glucose target?
The potentially different effect of tight glucose control in patients with preexisting diabetes may point to adaptations to chronic hyperglycemia, whereby acute lowering of blood glucose may be unwanted. In this regard, the degree of chronic hyperglycemia may play a role. Observational studies in diabetes patients have found a flattening and rightward displacement of the U-shaped association between blood glucose concentrations and short-term mortality, especially in patients with poorly controlled diabetes [1,43,44]. Patients with poorly controlled diabetes, as expressed by a high HbA1c level upon ICU admission, also appear more vulnerable to hypoglycemia . However, whether the optimal blood glucose target depends on the preexisting level of blood glucose control, remains unclear. A multicenter RCT aiming to compare individualized – based on the upon admission HbA1c level – versus standard glucose control was recently terminated by the data safety monitoring board (https://clinicaltrials.gov/ct2/show/NCT02244073). The results of this RCT have not been published yet.
Impact of tight glucose control in the absence of early parenteral nutrition
As mentioned above, the nutritional standard differed between RCTs. A meta-analysis suggested that the benefit of tight glucose control related to the amount of parenteral calories administered. Benefit was only present in RCTs in which a high amount of (early) parenteral feeding was administered, however, without adjustment for confounders . In contrast, a secondary analysis of the Leuven RCTs suggested that the benefit of tight glucose control was also present in patients receiving the lowest amount of parenteral glucose . In the absence of an adequately powered RCT, the impact of tight glucose control in the absence of early parenteral nutrition, when provided with adequate tools, remains unknown. This is currently being investigated by a multicenter RCT (https://www.clinicaltrials.gov/ct2/show/NCT03665207).
STRATEGIES TO IMPROVE THE QUALITY AND SAFETY OF BLOOD GLUCOSE CONTROL
In view of the open questions, the ideal blood glucose target remains unclear and may depend on the context. Nevertheless, the divergent effect between RCTs illustrates that tight glucose control is a complex intervention, which requires frequent and accurate monitoring of blood glucose and a reliable algorithm, especially when strict glucose control is aimed for. Several strategies may further improve the quality and safety of blood glucose control, including the use of validated computerized algorithms, (near-)continuous glucose monitoring (CGM) and closed-loop glucose control [35▪,42▪▪]. Several software algorithms have been developed, with high performance confirmed outside expert centers [35▪,47,48▪]. Use of these validated algorithms may decrease the incidence of hypoglycemia and prevent large glucose fluctuations [47,48▪].
Theoretically, (near-)CGM and closed-loop blood glucose control could virtually prevent episodes of severe hypoglycemia, which may further improve the quality and safety of tight glucose control. Several CGM devices have been developed, either with an intravascular or interstitial sensor. However, accuracy of several devices does not meet the strict standards for CGM put forward by experts [42▪▪,49]. Hence, a substantial number of CGM devices currently have no regulatory approval for use in critically ill patients [42▪▪]. In addition, the discussion about the ideal blood glucose target for critically ill patients, the substantial cost and limited durability of a CGM device, as well as the absence of studies demonstrating cost-effectiveness preclude widespread use, and have withheld companies to invest in CGM [42▪▪,50]. Nevertheless, some CGM devices have shown improved blood glucose control as add-on to standard monitoring [51,52]. Likewise, closed-loop glycemic control has the potential to significantly improve the quality and safety of the intervention [17,53,54]. However, largely the same limitations as for CGM devices preclude its widespread use at current.
The optimal blood glucose target for critically ill patients remains unclear. Tight glucose control is safe and effective in patients receiving early parenteral nutrition when provided with accurate monitoring and a reliable insulin protocol. The efficacy and safety of the treatment in the absence of early parenteral nutrition remains unclear. In the absence of new evidence, it seems prudent to at least prevent severe hyperglycemia, hypoglycemia and large glucose fluctuations in all ICU patients. There is no evidence for a different response across patient subgroups, with the possible exception of patients with diabetes, who may benefit from a higher glucose target.
Financial support and sponsorship
J.G. and G.V.d.B. receive a research grant from the Research Foundation – Flanders (FWO; T003617N). J.G. receives a research grant from the University of Leuven (C24/17/070) and a postdoctoral research fellowship supported by the Clinical Research and Education Council of the University Hospitals Leuven. G.V.d.B. receives structural research financing via the Methusalem program funded by the Flemish government through the university of Leuven (METH14/06) and a European Research Council Advanced Grant (ERC-2017-ADG-785809).
Conflicts of interest
There are no conflicts of interest.
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Keywords:Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.
critical illness; hyperglycemia; hypoglycemia; insulin; intensive care