| |
Intensive versus Conventional Glucose Control in Critically Ill Patients
The NICE-SUGAR Study Investigators
|
| |
| |
NEJM March 26, 2009
"In this large, international, randomized trial involving adults in the ICU, we found that intensive glucose control, as compared with conventional glucose control, increased the absolute risk of death at 90 days by 2.6 percentage points; this represents a number needed to harm of 38. The difference in mortality remained significant after adjustment for potential confounders.....In conclusion, our trial showed that a blood glucose target of less than 180 mg per deciliter resulted in lower mortality than a target of 81 to 108 mg per deciliter. On the basis of our results, we do not recommend use of the lower target in critically ill adults....
.......Overall, the distributions of proximate causes of death were similar in the two groups (P=0.12) (Table 3). However, deaths from cardiovascular causes were more common in the intensive-control group (345 of 829 patients [41.6%]) than in the conventional-control group (269 of 751 patients [35.8%]) (absolute difference, 5.8 percentage points; P=0.02)......Severe hypoglycemia (defined as a blood glucose level 40 mg per deciliter [2..2 mmol per liter]) was recorded in 206 of 3016 patients (6.8%) undergoing intensive glucose control, as compared with 15 of 3014 patients (0.5%) undergoing conventional control (odds ratio, 14.7; 95% CI, 9.0 to 25.9; P<0.001). The recorded number of episodes of severe hypoglycemia was 272 in the intensive-control group, as compared with 16 in the conventional-control group...... No long-term sequelae of severe hypoglycemia were reported.....[authors concluded] Severe hypoglycemia was significantly more common with intensive glucose control.....In our trial, more patients in the intensive-control group than in the conventional-control group were treated with corticosteroids, and the excess deaths in the intensive-control group were predominantly from cardiovascular causes. These differences might suggest that reducing blood glucose levels by the administration of insulin has adverse effects on the cardiovascular system.35,36 However, our trial was not designed to examine such mechanisms; further research is needed to understand the increased mortality in our trial.....Our findings suggest that a goal of normoglycemia for glucose control does not necessarily benefit critically ill patients and may be harmful. Whether the harm we observed resulted from the reduced blood glucose level, increased administration of insulin, occurrence of hypoglycemia, methodologic factors specific to our trial, or other factors is unclear."
ABSTRACT
Background- The optimal target range for blood glucose in critically ill patients remains unclear.
Methods- Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). We defined the primary end point as death from any cause within 90 days after randomization.
Results- Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0..84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39).
Conclusions- In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987 [ClinicalTrials.gov] .)
Hyperglycemia is common in acutely ill patients, including those treated in intensive care units (ICUs).1 The occurrence of hyperglycemia, in particular severe hyperglycemia, is associated with increased morbidity and mortality in a variety of groups of patients,2,3,4,5 but trials examining the effects of tighter glucose control have had conflicting results.6,7,8,9,10,11,12,13 Systematic reviews and meta-analyses have also led to differing conclusions.14,15 Nevertheless, many professional organizations recommend tight glucose control for patients treated in ICUs.16,17
Barriers to widespread adoption of tight glucose control include the increased risk of severe hypoglycemia,14 concerns about the external validity of some studies,18,19 the difficulty in achieving normoglycemia in critically ill patients,20,21 and the increased resources that would be required.22 Because of these issues and uncertainty about the balance of risks and benefits, tight glucose control is used infrequently by some clinicians.23,24 We designed the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial to test the hypothesis that intensive glucose control reduces mortality at 90 days.
Results
Study Participants
Participants were recruited and had follow-up during the period from December 2004 through November 2008; 6104 were randomly assigned to one of the two treatment groups: 3054 to intensive glucose control and 3050 to conventional glucose control (Figure 1). Where delayed consent was permitted, every patient or a legal surrogate was approached for consent. Delayed consent to the use of study-related data was withheld, or previously obtained consent was withdrawn, for 38 of the 3054 patients (1.2%) assigned to intensive control and 36 of the 3050 patients (1.2%) assigned to conventional control; thus, study data were available for 3016 and 3014 patients, respectively. At 90 days, an additional six patients (0.2%) in the intensive-control group and two (0.1%) in the conventional-control group were lost to follow-up. Of the 6030 patients for whom study data were available, 5275 (87.5%) were recruited in Australia or New Zealand.
The baseline characteristics of the treatment groups were similar (Table 1). The mean (±SD) age was 60.4±17.2 and 59.9±17.1 years in the intensive-control group and the conventional-control group, respectively; the percentage of male patients, 62.6% and 64.2%; the mean APACHE II score, 21.1±7.9 and 21.1±8.3; and the percentage of operative admissions, 36.9% and 37.2%.
The assigned study treatment, intensive or conventional blood glucose management according to the study-treatment algorithm, was administered to 5997 of 6030 patients (99.5%): 2998 of 3016 (99.4%) in the intensive-control group and 2999 of 3014 (99.5%) in the conventional-control group. The median duration of study treatment was 4.2 days (interquartile range, 1.9 to 8.7) in the intensive-control group and 4.3 days (interquartile range, 2.0 to 9.0) in the conventional-control group (P=0.69).
Study treatment was discontinued prematurely in 304 of 3054 patients (10.0%) in the intensive-control group and 225 of 3050 patients (7.4%) in the conventional-control group. Reasons for discontinuation were withdrawal because of a request by the patient or surrogate (26 patients [0.9%] assigned to intensive control and 22 patients [0.7%] assigned to conventional control) or by the treating physician (115 patients [3.8%] and 48 patients [1.6%], respectively), because of serious adverse events (13 patients [0.4%] and 1 patient [<0.1%], respectively), because of a change in the focus of treatment to palliative care (116 patients [3.8%] and 115 patients [3.8%], respectively), and miscellaneous reasons (34 patients [1.1%] and 39 patients [1.3%], respectively).
At the completion of the trial, data on vital status 90 days after randomization were unavailable for 82 of 6014 patients (1.4%), 44 in the intensive-control group and 38 in the conventional-control group. For 74 of these patients, the vital-status data were missing because consent had been withheld or withdrawn (Figure 1).
Insulin Administration and Treatment Effects
Patients undergoing intensive glucose control were more likely than those undergoing conventional control to have received insulin (2931 of 3014 patients [97.2%] vs. 2080 of 3014 [69.0%], P<0.001), and they received a larger mean insulin dose (50.2±38.1 units per day, vs. 16.9±29.0 with conventional control; P<0.001) (Table 2). The mean time-weighted blood glucose level was significantly lower in the intensive-control group than in the conventional-control group (115±18 vs. 144±23 mg per deciliter [6.4±1.0 vs. 8.0±1.3 mmol per liter], P<0.001). Additional measures of glycemic control are shown in Table 2 and Figure 2A and 2B.
Nutrition and Concomitant Treatment
During the first 14 days after randomization, the mean daily amount of nonprotein calories administered was 891±490 kcal in the intensive-control group and 872±500 kcal in the conventional-control group (P=0.14). Of this amount, 624±496 kcal (70.0%) and 623±496 kcal (71.4%), respectively, were given as enteral nutrition; 173±359 kcal (19.4%) and 162±345 kcal (18.6%) as parenteral nutrition; and 93.4±88.8 kcal (10.5%) and 87.2±93.5 kcal (10.0%) as intravenous glucose (Table 2, and Appendix B in the Supplementary Appendix).
After randomization, more patients in the intensive-control group than in the conventional-control group were treated with corticosteroids (1042 of 3010 [34.6%] vs. 955 of 3009 [31.7%], P=0.02). The median time from randomization to commencement of corticosteroid treatment was 0 days (interquartile range, 0 to 1) in both groups (P=0.34). The most common indication for corticosteroid administration in both groups was the treatment of septic shock, occurring in 376 of the 1042 patients in the intensive-control group (36.1%) who received corticosteroids, as compared with 328 of the 955 patients in the conventional-control group (34.3%) (absolute difference, 1.7 percentage points; 95% confidence interval [CI], -2.5 to 5.9; P=0.42) (Table 2).
Outcomes
Ninety days after randomization, 829 of 3010 patients (27.5%) in the intensive-control group had died, as compared with 751 of 3012 patients (24.9%) in the conventional-control group (Table 3). The absolute difference in mortality was 2.6 percentage points (95% CI, 0.4 to 4.8), and the odds ratio for death with intensive control was 1.14 (95% CI, 1.02 to 1.28; P=0.02). The difference in mortality between the two treatment groups was still significant after adjustment for the predefined baseline risk factors (adjusted odds ratio, 1.14; 95% CI, 1.01 to 1.29; P=0.04). The median survival time was lower in the intensive-control group than in the conventional-control group (hazard ratio, 1.11; 95% CI, 1.01 to 1.23; P=0.03) (Figure 3A).
Overall, the distributions of proximate causes of death were similar in the two groups (P=0.12) (Table 3). However, deaths from cardiovascular causes were more common in the intensive-control group (345 of 829 patients [41.6%]) than in the conventional-control group (269 of 751 patients [35.8%]) (absolute difference, 5.8 percentage points; P=0.02). In the intensive-control group and the conventional-control group, the majority of deaths occurred in the ICU (546 of 829 patients [65.9%] and 498 of 751 patients [66.3%], respectively) or in the hospital after discharge from the ICU (220 of 829 patients [26.5%] and 197 of 751 patients [26.2%], respectively). The remaining deaths (63 of 829 patients [7.6%] undergoing intensive control and 56 of 751 patients [7.5%] undergoing conventional control) occurred after hospital discharge. In both groups, potentially life-sustaining treatments were withheld or withdrawn in more than 90% of the patients who died (see Appendix D in the Supplementary Appendix).
During the 90-day study period, there was no significant difference between the two groups in the median length of stay in the ICU or hospital (Table 3). At 90 days, 7 of the 3016 patients (0.2%) in the intensive-control group and 6 of the 3014 patients (0.2%) in the conventional-control group were still in the ICU (P=0.78), and 174 patients (5.8%) and 166 patients (5.5%), respectively, were still in the hospital (P=0.66).
The number of patients in whom new single or multiple organ failures developed were similar with intensive and conventional glucose control (P=0.11) (Table 3). There was no significant difference between the two groups in the numbers of days of mechanical ventilation and renal-replacement therapy or in the rates of positive blood cultures and red-cell transfusion (Table 3).
With respect to 90-day mortality, subgroup analyses suggested no significant difference in the treatment effect for the comparisons of operative and nonoperative patients (P=0.10), patients with and those without diabetes (P=0.60), patients with and those without severe sepsis (P=0.93), and patients with an APACHE II score of 25 or more and those with a score of less than 25 (P=0.84) (Figure 3B). Tests for interaction indicated a possible trend toward subgroup-specific treatment effects for patients with trauma as compared with those without trauma (P=0.07) and for patients receiving corticosteroids at baseline as compared with those not receiving corticosteroids (P=0.06).
Severe hypoglycemia (defined as a blood glucose level 40 mg per deciliter [2.2 mmol per liter]) was recorded in 206 of 3016 patients (6.8%) undergoing intensive glucose control, as compared with 15 of 3014 patients (0.5%) undergoing conventional control (odds ratio, 14.7; 95% CI, 9.0 to 25.9; P<0.001). The recorded number of episodes of severe hypoglycemia was 272 in the intensive-control group, as compared with 16 in the conventional-control group; 173 of all 288 episodes (60.1%) were confirmed by a laboratory measurement, 112 (38.9%) were unconfirmed bedside readings, and 3 (1.0%) were of unknown confirmation status. No long-term sequelae of severe hypoglycemia were reported.
Discussion
In this large, international, randomized trial involving adults in the ICU, we found that intensive glucose control, as compared with conventional glucose control, increased the absolute risk of death at 90 days by 2.6 percentage points; this represents a number needed to harm of 38. The difference in mortality remained significant after adjustment for potential confounders. Severe hypoglycemia was significantly more common with intensive glucose control.
In conducting our trial, we sought to ensure a high degree of internal and external validity by concealing treatment assignments before randomization, selecting a long-term outcome that is not subject to biased ascertainment, evaluating a number of clinically important outcomes, achieving nearly complete follow-up, and following a predefined statistical-analysis plan.30 The management of blood glucose levels was standardized - nearly all patients received their assigned treatment, the mean blood glucose levels differed significantly between the two treatment groups during the 90-day study period, and the rate of severe hypoglycemia was low in comparison with the rates in other trials.
Limitations of our trial include the use of a subjective criterion - expected length of stay in the ICU - for inclusion, the inability to make treating staff and study personnel unaware of the treatment-group assignments, and achievement of a glucose level modestly above the target range in a substantial proportion of patients in the intensive-control group.. We did not collect specific data to address potential biologic mechanisms of the trial interventions or their costs. On the basis of the results in the predefined pairs of subgroups, we cannot exclude the possibility that intensive glucose control may benefit some patients.
Our findings differ from those of a recent meta-analysis showing that intensive glucose control did not significantly alter mortality among critically ill adults.14 In keeping with the trials included in the meta-analysis, patients in our trial who were assigned to intensive glucose control, as compared with those assigned to conventional control, had lower blood glucose levels, received more insulin, and had more episodes of severe hypoglycemia.14 A unique feature of our trial was the standardized, complex management of blood glucose made possible at multiple centers through a computerized treatment algorithm accessible on centralized servers.. In addition, our patients received predominantly enteral nutrition, consonant with current evidence-based feeding guidelines,33 whereas a substantial proportion of the patients included in the meta-analysis received predominantly parenteral nutrition.14,34
Our trial had greater statistical power than previous trials, as well as a longer follow-up period than all but two trials in the meta-analysis. Thus, our results may be due to a specific effect of our treatment algorithm, may be most generalizable to patients receiving predominantly enteral nutrition, or may reflect harm not apparent in trials with shorter follow-up and lower statistical power.
In our trial, more patients in the intensive-control group than in the conventional-control group were treated with corticosteroids, and the excess deaths in the intensive-control group were predominantly from cardiovascular causes. These differences might suggest that reducing blood glucose levels by the administration of insulin has adverse effects on the cardiovascular system.35,36 However, our trial was not designed to examine such mechanisms; further research is needed to understand the increased mortality in our trial.
Since the original study by Van den Berghe et al.,12 intensive glucose control has been widely recommended16,17 on the assumption that treatment aimed at normoglycemia will benefit patients. As noted in other fields of medicine,37 a clinical trial targeting a perceived risk factor (in this case, hyperglycemia) is a test of a complex strategy that may have profound effects beyond its effect on the risk factor (here, the blood glucose level). Our findings suggest that a goal of normoglycemia for glucose control does not necessarily benefit critically ill patients and may be harmful. Whether the harm we observed resulted from the reduced blood glucose level, increased administration of insulin, occurrence of hypoglycemia, methodologic factors specific to our trial, or other factors is unclear.
In conclusion, our trial showed that a blood glucose target of less than 180 mg per deciliter resulted in lower mortality than a target of 81 to 108 mg per deciliter. On the basis of our results, we do not recommend use of the lower target in critically ill adults.
Supported by grants from the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, and the Canadian Institutes for Health Research.
Dr. Finfer reports receiving reimbursement for travel to present research results at scientific meetings from Eli Lilly, Cardinal Health, and CSL Bioplasma and for serving on steering committees for studies sponsored by Eli Lilly and Eisai (paid to the George Institute for International Health); he also reports that the George Institute for International Health, an independent, not-for-profit institute affiliated with the University of Sydney, has received research funding from Servier, Novartis, Eisai, Merck Sharp & Dohme, Pfizer Australia, Fresenius Kabi Deutschland, and Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.
|
|
| |
| |
|
|
|
