Individualised versus conventional glucose control in critically-ill patients: the CONTROLING study-a randomized clinical trial

Abstract

Purpose: Hyperglycaemia is an adaptive response to stress commonly observed in critical illness. Its management remains debated in the intensive care unit (ICU). Individualising hyperglycaemia management, by targeting the patient's pre-admission usual glycaemia, could improve outcome.

Methods: In a multicentre, randomized, double-blind, parallel-group study, critically-ill adults were considered for inclusion. Patients underwent until ICU discharge either individualised glucose control by targeting the pre-admission usual glycaemia using the glycated haemoglobin A1c level at ICU admission (IC group), or conventional glucose control by maintaining glycaemia below 180 mg/dL (CC group). A non-commercial web application of a dynamic sliding-scale insulin protocol gave to nurses all instructions for glucose control in both groups. The primary outcome was death within 90 days.

Results: Owing to a low likelihood of benefit and evidence of the possibility of harm related to hypoglycaemia, the study was stopped early. 2075 patients were randomized; 1917 received the intervention, 942 in the IC group and 975 in the CC group. Although both groups showed significant differences in terms of glycaemic control, survival probability at 90-day was not significantly different (IC group: 67.2%, 95% CI [64.2%; 70.3%]; CC group: 69.6%, 95% CI [66.7%; 72.5%]). Severe hypoglycaemia (below 40 mg/dL) occurred in 3.9% of patients in the IC group and in 2.5% of patients in the CC group (p = 0.09). A post hoc analysis showed for non-diabetic patients a higher risk of 90-day mortality in the IC group compared to the CC group (HR 1.3, 95% CI [1.05; 1.59], p = 0.018).

Conclusion: Targeting an ICU patient's pre-admission usual glycaemia using a dynamic sliding-scale insulin protocol did not demonstrate a survival benefit compared to maintaining glycaemia below 180 mg/dL.

Trial registration: ClinicalTrials.gov NCT02244073.

Keywords: Glucose control; Glycated haemoglobin A1c; Hyperglycaemia; Individualised glucose control; Insulin.

Fig. 1

Assessment, randomization, and follow-up of the study patients. During the stay in the intensive care unit (ICU), a family member of one patient from both groups withdrew consent to continue the study intervention. At this time, the intervention and the recalling of the data were stopped for these two patients

Fig. 2

Probability of survival and hazard ratios for death, according to treatment group. Panel a shows Kaplan–Meier estimates for the probability of survival, which at 90 days was similar in both the conventional glucose control (CC) group and the individualised glucose control (IC) group (log rank test, p = 0.23). Each “+” represents a censoring. Panel b shows the hazard ratios (and 95% confidence intervals) for death from any cause in the individualised glucose control group compared to the conventional glucose control group, among all patients and in different subgroups (post hoc analysis). The hazard ratios were estimated from the Cox model adjusted on the age, sex, body mass index, Charlson score, diabetes status, ICU admission type, SAPS II score, and invasive ventilation. If the subgroup was defined from one of the adjusted variables, this variable was removed from the model. Surgery includes emergency and scheduled surgeries

Fig. 3

Glycaemic level and insulin administration during intervention according to treatment group and A1C level. Patients are separated into five subgroups according to A1C levels (≤ 5%, > 5 and ≤ 6%, > 6 and ≤ 7%, > 7 and ≤ 8% and > 8%). Panel a shows the relationship between time-weighted average glycaemic level and A1C level. Panel b shows the relationship between time-weighted average insulin infusion rate and A1C level. Conventional glucose control group and individualised glucose control group are displayed in red and blue, respectively. Horizontal line indicates the median value. Box height indicates IQR with the lower and upper edges of the box representing the 25th and 75th percentiles, respectively. The lower whisker represents the 10th percentile and the upper whisker the 90th percentile. If no horizontal line is present within the box, the median value is the same as the 25th percentile. The coloured horizontal lines indicate the glycaemic target for each group. Only the patients who had at least two glycaemia measurements are represented (897 patients in the individualised glucose control group and 931 in the conventional glucose control group). The number of patients in each group and in each A1C level subgroup is provided below the figure. P values for the comparison between groups in each A1C level subgroup were calculated using the Wilcoxon–Mann–Whitney test: *< 0.05, **< 0.01, ***< 0.001, ****< 0.0001. To convert glycaemic level to mmol/L, multiply values by 0.0556