Introduction
Uncontrolled blood glucose levels have been associated with poor clinical outcomes among critically ill patients. Stress-related release of counterregulatory hormones, including catecholamines, corticosteroids, and glucagon tend to increase blood glucose levels in critical illness (1). Hyperglycemia may lead to harm through cytokine release and generation of reactive oxygen species (2). Furthermore, it may impair the bactericidal and chemotactic effects of neutrophils. High blood glucose levels may also lead to a procoagulant state (3). These putative mechanisms behind adverse clinical outcomes led to an increasing focus on the management of hyperglycemia in hospitalized, particularly, ICU patients. It remains unclear whether adverse outcomes are directly related to hyperglycemia or if it is just a marker of such outcomes.
The Leuven trials were landmark studies that targeted control of blood glucose within a narrow range in critically ill patients. The Leuven 1 (2001) trial revealed a significantly reduced mortality among surgical patients when the blood glucose levels were maintained between 80–110 mg/dl (4). The authors could not reproduce the results in their second trial (Leuven 2, 2006) on medical ICU patients. However, they observed reduced mortality in a subgroup of patients who stayed in the ICU for longer than 3 days (5). Based on the findings of these two trials, many healthcare systems across the globe began adopting tight control of blood glucose levels as a key facet in the care of critically ill patients. However, it became abundantly clear that maintenance of blood glucose levels within a narrow, lower range may be difficult to achieve among the sickest of patients. Furthermore, aiming for tight control may also increase the likelihood of hypoglycemia and adverse outcomes.
In the meantime, the Glucontrol trial compared a target of 140–180 with 80–110 mg/dl in 21 medico-surgical ICUs. Protocol violations occurred frequently; hence the study was stopped early. The investigators observed no clinical benefit with a lower blood glucose target. Furthermore, episodes of hypoglycemia were more common in the 80–110 mg/dl group (6). In another RCT, Brunkhorst et al. also observed a significantly higher incidence of hypoglycemia with intensive compared to conventional insulin therapy (7).
Two meta-analyses were performed in the wake of the clinical conundrum related to glycemic control. Pittas et al. analyzed 35 RCTs to evaluate the effect of insulin therapy in critically ill patients (8). They observed a 15% reduction in mortality with insulin therapy compared with controls. The effect was particularly prominent when insulin therapy was titrated to pre-set glucose levels. However, a later meta-analysis by Wiener et al. including 8,432 patients from 29 RCTs came up with contrasting results. Tight control of glucose levels did not reduce mortality, regardless of target glucose levels of <110 mg/dl or <150 mg/dl. The mortality was also similar on subgroup analysis of medical, surgical, and mixed ICU patients (9).
In light of contrasting evidence, it remained unclear whether aiming for a narrow range of blood glucose levels with intensive insulin therapy would lead to improved outcomes. The two Leuven trials that appeared to support intensive control were single center trials that called for external validation in a larger RCT. The Normoglycemia in Intensive Care Evaluation– Survival Using Glucose Algorithm Regulation (NICE-SUGAR) was a randomized controlled trial (RCT) designed to test the hypothesis that intensive glucose control reduces the 90-day mortality in critically ill patients.
Population and design
The NICE-SUGAR trial was conducted between December 2004 to November 2008. The study involved 42 hospitals in Australia, New Zealand, and North America (10). The study population comprised of patients who were within 24 hours of ICU admission. Patients were expected to require continued care in the ICU for 3 or more consecutive days. Using a parallel group, randomized, controlled design, patients were allocated to intensive or conventional glucose control (Figure 1). A stratified randomization was followed based on admission type (medical or surgical) and the study region (Australia and New Zealand or North America)
Excluded
Patients who were admitted with diabetic ketoacidosis or hyperosmolar state were excluded. Also excluded were patients expected to have oral nutrition by day 3, those with a high risk of hypoglycemia, or had fulminant hepatic failure.
Intensive glucose control
In the intensive control group, intravenous insulin infusion was titrated to a target blood glucose level of 81 to 108 mg/dl (multiply by 0.0555 for conversion to mmol/l).
Conventional group
Insulin was administered when the blood glucose level was >180 mg/dl. The dose was titrated to maintain a blood glucose level of ≤180 mg/dl. If the blood glucose level was <144 mg/dl, the insulin dose was weaned down and stopped.
Management common to both groups
Management of blood glucose level was guided by an online treatment algorithm. Control of blood glucose levels was part of the routine duties of the staff at the participating center. The intervention was discontinued at the time of ICU discharge; however, if readmission to ICU occurred, the assigned treatment was continued. The maximum duration of the intervention was up to 90 days or until death. Samples from the arterial line were used for blood glucose measurement if possible. Capillary samples were discouraged. All other care, including management of nutrition was left to clinician judgment.
Sample size
The original sample size was 4,000 patients; it was later increased to 6,100 based on the results of the second Leuven 2 trial of medical ICU patients (5). The study provided 90% power to detect an absolute mortality difference of 3.8% between groups at a baseline mortality of 30% and a two-sided alpha level of <0.05. All data were analyzed on an intention to treat basis.
Results
The investigators screened 40,171 patients; 6,104 underwent randomization – 3054 were assigned to the intensive glucose control group and 3,500 to the conventional glucose control group. Among these, 6,030 patients were included in the final analysis. Most were nonoperative admissions (intensive control vs. conventional: 63.1% vs. 62.8%). The mean APACHE II score was 21.1 ± 7.91 in the intensive control group and 21.1 ± 8.3 in the conventional group. The baseline blood glucose levels were also similar between the two groups. Patients in the intensive control group received insulin more often, and in significantly higher doses compared to the conventional group. The mean, time-weighted blood glucose level was significantly lower in the intensive control group (115 ± 18 vs. 144 ± 23 mg/dl). Patients in the intensive control group received corticosteroids more often compared to the conventional group – the most common indication was septic shock.
The primary outcome: 90-day mortality
Mortality at 90 days after randomization was significantly higher in the intensive control compared with the conventional group (27.5% vs. 24.9%; odds ratio: 1.14, 95% CI, 1.02–1.28; p = 0.02). The difference in mortality remained significant on adjusted analysis based on predefined risk factors. The proximate cause of death was similarly distributed in both groups; however, cardiovascular deaths were more common in the intensive control group. On subgroup analysis, there was no significant difference in the 90-day mortality between treatment groups among operative vs. nonoperative patients, those with diabetes, severe sepsis, and patients with APACHE II scores ≥25.
Secondary outcomes
In contrast to the 90-day mortality, the mortality at 28 days was not significantly different between the intensive control and the conventional groups (22.3% vs. 20.8%). The median length of stay in the ICU was 6 days, and the median length of stay in hospital was 17 days in both groups. The median duration of mechanical ventilation 6.6 days in both groups. The use and duration of renal replacement therapy were similar. Packed red cells were transfused in a similar number of patients in both groups; the volume of transfusion was also similar. Positive blood cultures and new-onset single or multiorgan failure occurred at similar frequencies in both groups.
Hypoglycemia
The incidence of hypoglycemia was markedly different between groups.
Severe hypoglycemia with blood glucose levels ≤40 mg/dl occurred much more often in the intensive control group (6.8% vs. 0.5%, p = 0.001). There were 272 episodes of hypoglycemia in the intensive control group compared with 16 in the conventional group. No long-term sequelae directly related to hypoglycemia were reported. The main findings of the study are summarized in Table 1.
Table 1. Main findings of the study
| Outcome | Intensive control (81–108 mg/dl) | Conventional (≤180 mg/dl) | OR (95% CI) | P-value |
| Primary outcome, 90-d mortality | 27.5% | 24.9% | 1.14 (1.02–1.28) | 0.02 |
| 28-d mortality | 22.3% | 20.8% | 1.09 (0.96–1.23) | 0.17 |
| Severe hypoglycemia (<40 mg/dl) | 6.8% | 0.5% | 14.7 (9.0–25.9) | <0.001 |
| Median ICU LOS | 6 (2–11) | 6 (2–11) | 0 | 0.84 |
| Mean ventilation days | 6.6 ± 6.6 | 6.6 ± 6.5 | 0 | 0.56 |
| Median hospital LOS | 17 (8–35) | 17 (8–35) | 0 | 0.86 |
| New-onset organ failure | 41.4% | 42.7% | ||
| RRT | 15.4% | 14.5% | 0.9 (-0.9–2.7) | 0.34 |
Study conclusions
The NICE-SUGAR trial revealed increased 90-day mortality with the intensive control strategy of blood glucose management (81 to 108 mg/dl) mg/dl compared with conventional control (equal to or less than 180 mg/dl). The increase in the absolute risk of death was 2.6 percentage points. The number needed to cause harm was 38 – one additional death when 38 patients are treated with an intensive control strategy. Besides, severe hypoglycemia with blood glucose level of ≤40 mg/dl was more common when the intensive control strategy was employed.
Strengths
The NICE-SUGAR trial was a large, pragmatic RCT that evaluated clinical outcomes in a heterogenous group of ICU patients with an intensive glucose control compared with a conventional strategy. A uniform protocol of insulin dosing was applied across centers. The multicentric design offered generalizability of the results. The study explored the most relevant clinical outcomes in critically ill patients. There was robust adherence to the treatment algorithm and minimal loss to follow-up. The mean blood glucose levels differed substantially between groups during the 90-day study period, as envisaged by the investigators. The incidence of hypoglycemia was low compared with those reported in contemporaneous studies.
Limitations
The mean, time-weighted blood glucose level was slightly higher (115±18 mg/dl) than the target range of 81–108 mg/dl in the intensive control group. This finding exemplifies the practical difficulty in maintaining the blood glucose level within a narrow range for extended periods. Blinding was not feasible and could have led to bias. It is unclear if the higher use of corticosteroids in the intensive control group may have influenced the outcomes. Most patients received early enteral feeds; the outcomes may be different among patients who receive early or supplemental parenteral nutrition in the first few days of ICU admission. In the intensive control group, the treatment protocol was discontinued prematurely, based on clinician judgment or switch to palliative care. These patients were analyzed on an intention-to-treat basis, as belonging to the intensive control group. It is unclear whether this aspect of the study would have impacted outcomes. The 90-day mortality was significantly lower with conventional glucose control. Yet, the absence of a significant difference in the 28-day mortality and the similar incidence of new-onset organ dysfunction between the two groups were difficult to explain.
Post-hoc analysis
The NICE-SUGAR investigators evaluated the association between the degree of hypoglycemia, and the risk of death in a subsequent post-hoc analysis (11). A blood glucose level between 41–70 mg/dl was considered to represent moderate hypoglycemia and a level <40 mg/dl, severe hypoglycemia. Intensive glucose control resulted in a higher incidence of moderate and severe hypoglycemia compared to conventional control; both were associated with a higher risk of death. There was a dose-response relationship; increase in mortality was related to the severity of hypoglycemia. However, the study does not establish a cause-effect relationship between hypoglycemia and the risk of death.
Summary
In one of the largest RCTs in the history of critical care, the NICE-SUGAR trial demonstrated increased mortality with an intensive glucose control strategy with target levels between 81 to 108 mg/dl compared with conventional control between 144–180 mg/dl. Severe hypoglycemia was more common in the intensive control group. There was a strong association between hypoglycemia and mortality, with lower glucose levels resulting in a higher risk of death. The NICE-SUGAR trial provided robust evidence that lowering the blood glucose level below a threshold level of 144 mg/dl does not offer any additional benefit; on the contrary, it carries a higher risk of poor outcomes related to hypoglycemia. This well-conducted, multicentric trial, with robust statistical analysis, dampened the unfettered enthusiasm aroused by earlier RCTs with a tight glucose control strategy.
References
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6. Preiser JC, Devos P, Ruiz-Santana S, Mélot C, Annane D, Groeneveld J, et al. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009 Oct;35(10):1738–48.
7. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008 Jan 10;358(2):125–39.
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