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

Blog written by Dr Jose Chacko

Background – 

Hyperglycaemia is an adaptive response to stress and is commonly seen in critically ill patients. Individualising hyperglycaemia management similar to blood pressure management, by targeting the patient’s pre-admission usual glycaemic, is a novel concept and has not been explored before in large RCT.

Setting and design

The CONROLING study is a multicentric, double-blind, RCT conducted in 12 centres in France. The study included patients from medical, surgical, and mixed ICUs and was conducted between May 2015 to July 2016.

Study population 

Critically ill adult patients

Exclusion

Severe hypoglycemia, pregnancy, limitation of therapy. Diabetic patients who underwent transfusion of more than 3 red blood cell units over the past 3 months (this may affect HbA1c levels)

Glucose control

Usual glycemia was calculated as (28.7×A1C) – 46.7

Individualized glucose control

Target: The glycemic target was set to the usual glycaemia level +15 mg/dL or less. A minimum glucose level of 111 mg/ dL (corresponding to an A1C level of 4.96%); maximum of 217 mg/dl (corresponding to an A1C level of 8.67%)

Conventional control

Target: 180 mg/dL or less (used prior to randomization) was maintained.

Management common to both groups

Insulin infusion when blood glucose was above 180 mg/dl and titrated to target levels. The rate of infusion was unchanged if the blood glucose level was between the target level and not lower than 29 mg/dl below the target level. The dose was reduced if the blood glucose level was between 63 mg/dl and lower than 29 mg/dl below the target level. The infusion was ceased if the blood glucose level was less than 63 mg/dl, and 30% dextrose administered. The insulin dose was titrated using an app-based dynamic sliding scale protocol

The targets were maintained until ICU discharge. The intervention could be altered if circumstances demanded, based on clinician judgment. Nurses were trained in the use of the CPG application that was used to titrate the rate of insulin. All other care was left to physician judgment.

Sample size

2100 patients per group would achieve for 90% power to detect a 4%-decrease of absolute 90-day mortality, assuming a baseline mortality of 22% in the conventional control group, for 5% level of significance.

The trial was stopped after the first interim analysis by the data and safety monitoring board after analysis of the first 1860 randomized patients. A low likelihood of benefit and evidence of the possibile of harm related to hypoglycemia was noted. At the time of stopping, 2075/4200 patients (49%) had been included.

4636 patients were screened;

Primary outcome

All-cause mortality at 90 days

Mortality occurred in 308/938 (32.8%) patients in the IC group and 295/968 (30.5%) in the CC group. Survival at 90 days was not significantly different between the two groups (67.2%, 95% CI [64.2%; 70.3%] for the IC group, and 69.6%, 95% CI [66.7%; 72.5%] for the CC group, p = 0.23

No difference was observed after adjustment for age, sex, body mass index, Charlson score, diabetes status, ICU admission type, SAPS II score, and the use of invasive ventilation.

Secondary outcomes

IC vs. CC groups

28-d mortality: (74.3%, 95% CI [71.6%; 77.2%]) vs. (78%, 95% CI [75.4%; 80.6%] p=0.07

ICU length of stay: (4.10 days [1.80–9.99] vs. 4.32 [1.85– 10.02] p=0.23

Not significantly different:

• Duration of vasoactive drug support
• Duration of antimicrobial treatment
• Duration of mechanical ventilation
• Duration of renal replacement therapy

Hypoglycemic events

No significant difference was found in the frequency of severe hypoglycemia (less than 40 mg/dl) between the two groups (3.9% for IC group vs. 2.5% for CC group, p=0.09). However, hypoglycemia below 72 mg/dL was significantly more common in the IC group (31.2% vs. 15.8%, p < 0.0001).

Post-hoc analysis

90-d mortality significantly higher in

• Non-diabetic patients in the IC group (HR 1.3, 95% CI [1.05; 1.59], p=0.018).
• Surgical patients (HR 1.83, 95% CI [1.12; 3.02], p=0.017)
• Patients with A1C between 5–6%

Probability of 90-d survival lower in both groups among patients with blood sugar level of less than 72 mg/dl

Summary

• The first study on individualized glycemic target based on A1C level
• Glycemic control based on an app (CPG)
• Individualized control based on A1C did not improve 90-day survival compared to maintaining glycaemia below a fixed level of 180 mg/dL
• Target blood sugar levels at a set level higher than the usual glycaemia (not aim for usual glycemia) needs to be investigated
• The trial was stopped after the first interim analysis, the study may have been underpowered
• Patients in the IC group were managed according to the conventional target of >180 mg/dl for varying periods before randomization
• Question of precision of glucometric blood sugar assessments