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

Bohé. Intensive Care Medicine 2021. https://doi.org/10.1007/s00134-021-06526-8

Clinical Question

• In critically unwell adults does targeting individualised glycaemic control compared to glycaemia < 180 mg/dL improve 90 day mortality?

Background

• Hyperglycaemia has been shown to result in worse outcomes in the critically ill, especially in non-diabetic patients
• In 2009, NICE-SUGAR showed that intensive glucose control was harmful with  higher rates of hypoglycaemia and mortality in the intensive control group
• Some observational studies have shown that relationship between glycaemia in ICU and adverse events (hypoglycaemia and mortality) may depend on the patient’s pre-admission glycaemic control
• HbA1c or glycated haemoglobin reflects the mean plasma glucose over the life of a red blood cell (~3 months), and values at ICU admission and prior to ICU admission correlate well

Design

• Multi-centre
• Double blind randomised parallel group trial
• Conducted in mixed, medical and surgical ICUs
• Consent from patients or family obtained
• If eligible then a blood sample drawn to ascertain HbA1c
  • If deemed eligible then needed to rule out presence of exclusion criteria within 96 hours of ICU admission
• Glycaemic control was conducted in accordance with an online algorithm designed by two of the authors
  • Insulin was commenced prior to randomisation if > 180 mg/dL for all patients
• Randomisation was 1:1 and stratified by centre
  • However, if numbers in each arm differed by >4% then next patient automatically included into group with lower numbers
• Intervention maintained until patient discharged from ICU
• All clinicians blinded to HbA1c result, and glycaemic and infusion history
  • For safety, the nurse in charge could access the last glycaemic value entered and insulin infusion rate and any history of hypoglycaemic episodes
• Power calculation:
  • 2100 patients per group needed
  • 90% power to detect a 4% difference from a baseline mortality of 22% with a two-sided significance level of 5%
  • Based on NICE-SUGAR
• Modified intention to treat basis
• Trial stopped early after 49% of planned sample size recruited
  • Recommended by DSMB due to low likelihood of benefit and possibility of harm
• Conversion from mg/dL to mmol/L
  • 217 = 12.1
  • 180 = 10
  • 111 = 6.2
  • 72 = 4.0
  • 40 = 2.2

Setting

• 12 ICUs in France
• May 2015 – July 2016

Population

• Inclusion:
  • > 18 yo
  • Admitted to ICU with the expectation not to be discharged within 2 days
  • Unable to feed orally
• Exclusion:
  • Pregnancy
  • Prior enrolment
  • Limitations of therapy
  • Diabetics with a known history of transfusion > 3 red blood cell units in the last 3 months (may falsely lower HbA1c)
• 5326 patients admitted → 2075 randomised of which 158 did not receive intervention → 942 in intervention arm and 975 in conventional arm
  • Reasons for not being included:
    • 690 expected to stay in ICU for < 48 hours
    • 1300 did not have exclusion criteria assessed
    • 423 met exclusion criteria
    • 827 did not have HbA1c level within 96 hrs
• Comparing baseline characteristics of intervention (individualised control) vs. control (conventional) group
  • Age: 68 v 69
  • Female: 39 v 39%
  • BMI: 26 v 26
  • Medical admission: 82 v 82%
    • Respiratory: 37 v 36%
    • Cardiac: 14 v 16%
    • Endocrinology: 2 v 3%
  • Emergency surgery: 10 v 10%
  • Vasopressors: 31 v 31%
  • Invasive ventilation: 54 v 53%
  • Charlson score >/= 3: 44 v 46%
  • Diabetic patients: 34 v 32%
    • Insulin dependent: 8 v 8%
  • HbA1c: 5.8 v 5.8%
    • Non-diabetics: 5.6 v 5.6%
    • Diabetics: 6.9 v 6.9%
  • Insulin dose at randomisation: 0 v 0 IU/h
  • Interval from ICU admission to randomisation: 1.2 v 1.3 days
  • Days on algorithm: 4 v 4
  • No receipt of artificial nutrition: 39 v 41%
    • Calories administered similar in those receiving enteral, TPN or a mixture of both

Intervention

• Individualised glycaemic control
  • Glycaemic target calculated using HbA1c +15 mg/dL
  • Limits set at minimum of 111mg/dL and a maximum 217 mg/dL for safety reasons
  • The median HbA1c of 5.8% results in a calculated target of 120 mg/dL (+ 15 mg/dL)

Control

• Standard glycaemic control
  • Glycaemic target < 180mg/dL
  • Insulin infusion initiated when greater than this

Management common to both groups

• Algorithm gave nurse instructions for insulin administration, sampling for glycaemia and correction for hypoglycaemia.
• Sampling time between 1 – 6 hours depending on levels and previous stability
• Following randomisation insulin commenced if above set target, it was reduced if 29mg/dL less than target
• If levels reached 63 mg/dL then insulin stopped and 30% dextrose administered
• All other care at the discretion of treating teams

Outcome

• Primary outcome: 90-day survival (intervention v control)
  • 67.2% [95% CI 64.2 – 70.3] v 69.6% [95% CI 66.7 – 72.5], p = 0.23
  • No difference when adjusted for multiple parameters including age, diabetic status, BMI and receipt of invasive ventilation
  • Post hoc subgroup analysis:
    • Significantly higher risk of 90 day mortality in intervention group for non-diabetics, surgical group and those with an HbA1c between 5 – 6%
• Secondary outcomes:
  • No significant difference in 28d mortality, ICU length of stay, duration of vasoactive support, RRT requirement, mechanical ventilation and non-prophylactic anti-microbial use
• Adverse Events:
  • Severe hypoglycaemia (<40mg/dL)
    • 3.9% v 2.5% (p = 0.09)
  • Any hypoglycaemia (<72 mg/dL)
    • 31.2% v 15.8% (p < 0.0001)
  • This was significantly higher in non diabetic patients, but not for diabetic patients

Authors’ Conclusions

• Targeting a patient’s usual glycaemic level did not show a survival benefit compared to conventional control and targeting a glycaemic level of 180 mg/dL

Strengths

• Double blinded trial in an area of critical care with few randomised trials despite the frequency with which parameters for blood glucose control are set for ICU patients
• Balanced baseline characteristics between groups
• Minimal protocol violations (<1%)
• Blinding methods minimise performance and detection bias
• Minimal loss to follow up (n=9)

Weaknesses

• Trial ended early prior to enrolment of calculated sample size
• Time lag bias as data collected in 2016 but not published until 2021
• Large numbers not assessed for exclusion criteria may result in selection bias
• The allowance of 96 hours following ICU admission for enrolment is a long time in the critically unwell
  • The intervention group received the same target as the conventional group until randomisation (<180mg/dL) results in contamination bias
  • Patients in the intervention group spent 26% of their ICU stay without an individualised target (and exposed to a target of 180 mg/dL)
• The authors postulate that insulin resistance may change over critical illness
  • If this is true, does the use a value that reflects glycaemic control over the three months prior to critical illness provide the best method for targeting personalised glycaemic control whilst critically unwell?
• The algorithm used was not validated prior to it’s use
• The mean difference in time-weighted blood glucose was only 13 mg/dL between groups (0.7mmol/L) (eTable 3). It is unlikely this is clinically relevant
  • However if stratified by HbA1c there was statistical separation in time-weighted blood glucose for all HbA1c levels except between 7 and 8% (which was expected as an HbA1c of 7.4% = a target of 180mg/dL)

The Bottom Line

• Until better evidence becomes available surrounding personalised glycaemic targets in ICU, I will continue to adopt a conventional target for all patients

External Links

• [editorial] The goal of personalized glucose control in the critically ill remains elusive
• [article] CONTROLING Study
• [IBCC] Stress Hyperglycaemia in the ICU

Metadata

Summary author: George Walker @hgmwalker89
Summary date: 7th December 2021
Peer-review editor: @davidslessor

Picture by: Pixabay