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Glycaemic control in Critical Care

In the ICU world we obsess and quite rightly, on physiology and correcting what is deranged.

There is a vast abundance and ever accumulating bank of research out there focussing on the gold standard…morbidity and mortality and how we can reduce it. As a result we have looked at, to name a few:

• Pretty much very facet of physiology
• Tidal volume limit strategy in ARDS
• Blood pressure target / optimisation strategy in sepsis
• Every possible biomarker to alert us to impending doom
• Technologies to keep an eye on things and alert us to problems etc etc.

So, on that note….let’s focus on blood sugar control in the critically ill patient, as this has done the round-robin too.

A highly informative review of glucose control in critical care outlines the evolution of blood sugar management in ICUs. It details how the initial enthusiasm for tight glycaemic control gave way to more modest targets, as evidence to the contrary continued to accumulate. It always amuses me when ‘the paper of the decade’, is published and we all rush off to change our practice on its findings, only to completely refute it’s mantra when another tells us to ignore it as it was pretty much killing people!!

Hyperglycaemia in the critically ill

It is common to see elevated blood sugars in critically ill patients. This is due partly to the body’s own stress response to illness resulting in stimulation of gluconeogenesis and glycogenolysis coupled with impaired glucose uptake by peripheral tissues.

Have a look at this video on the stress response (general).

See our section on diabetes here

See here for a great article on hyperglycaemia and mortality in the critically ill. This article here debates tight control. This article from Chest also debates paranoia over tight control!

Also, many of our medical interventions promote hyperglycaemia. Obvious culprits include exogenous catecholamines, corticosteroids, dextrose infusions and trespassed forms of nutrition.

When did it all start?

The original Leuven study in 2001 is attributed as being the pivotal trial that changed the practice of glycaemic control in ICUs throughout the world.

This prospective, non-blinded, randomized controlled trial was the first to investigate the effect of tight glycaemic control in critically ill adults.

It included 1548 mechanically ventilated adults admitted to a single surgical ICU in Leuven, Belgium and everyone knew the name Van Den Berghe!!

On admission to ICU, patients were randomly assigned to either intensive or conventional insulin therapy.

Patients in the intensive insulin therapy group:

• Insulin infusions were started when blood glucose exceeded 110 mg/L (6.1 mmol/L)
• Target blood glucose was 80 to 110 mg/L (4.4 to 6.1 mmol/L)
• 7% of patients required insulin infusions
• Mean blood glucose of 103 mg/dl (5.7 mmol/L)

Patients in the conventional therapy group:

• Insulin infusions were started if blood glucose exceeded 215 mg/L (11.9 mmol/L)
• Target blood glucose was 180 to 200 mg/L (10 to 11.1 mmol/L)
• 2% required insulin infusions
• Mean blood glucose was 153 mg/dl (8.5 mmol/L)

The study results favoured the intensive therapy group.

In-ICU mortality:

Intensive insulin therapy  Vs Conventional = 4.6% vs 8% (P<0.04)

This survival benefit persisted to hospital discharge, with an absolute risk reduction of in-hospital mortality of 3.7% (7.2% vs 10,9%; P=0.01).

Also, those in the intensive therapy group had reduced rates of renal replacement therapy, prolonged mechanical ventilation and extended ICU stays.

The second Leuven study in 2006 further reinforced the benefits of tight glycaemic control. Although the study showed no overall mortality benefit to intensive insulin therapy with both ICU and in-hospital mortality rates being similar among patients in the intensive and conventional insulin therapy groups. Secondary analyses of patient morbidity found lower rates of kidney injury, shorter duration of mechanical ventilation and shorter lengths of ICU and hospital stay in patients in the intensive insulin therapy group.

But….and as I always say, there’s always one! The patient subset –  “All adults receiving mechanical ventilation who were admitted to our intensive care unit (which is dedicated primarily but not exclusively to surgical patients). So not a representation of a true ICU population and a niche environment.

The tide of evidence turns…

However, after this, several subsequent studies found no mortality benefit to tight glycaemic control and reported increased risk of hypoglycaemia in intensive insulin therapy groups.

This culminated in the findings of the Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial in 2009.

NICE-SUGAR study

In this study, 6104 patients were randomly assigned to receive

• Intensive glucose control [target blood glucose range of 81 to 108 mg/dL (4.5 to 6.0 mmol/L)]
• Conventional glucose control, with a target of 180mg/L or less (10.0 mmol/L)

Results

Patient deaths:

Intensive control group = 829 patients (27.5%)

Conventional control group = 751 (24.9%)

(Odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P = 0.02).

Severe hypoglycemia (blood glucose level, ≤40 mg per deciliter [2.2 mmol per liter]):

• Intensive-control group = 206 of 3016 patients (6.8%)
• Conventional control group = 15 of 3014 (0.5%)   (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).

In the end, the study concluded that the intensive glucose control increased mortality among adults in the ICU. While a blood glucose target of ≤180 mg/dl (≤10 mmol/L) resulted in lower mortality than a target of 81 to 108 mg/dl (4.5 to 6mmol/L).

The present day

A recent meta-analysis carried out this year examined the risk of mortality and hypoglycaemia associated with different glycaemic control targets in critically ill adults.

• 36 randomised control trials consisting
• 17996 patients
• Compared insulin regimens amongst the critically ill with hyperglycaemia

Four glycaemic control groups were compared

1. Tight (Blood glucose: 4.4 to 6.1 mmol/L)
2. Moderate (6.1 to 7.8 mmol/L)
3. Mild (7.8 to 10.0 mmol/L)
4. Very mild (10.0 to 12.2 mmol/L)

The analysis found that compared to very mild control, none of the other three glycaemic control groups reduced the risk of short-term mortality.

However, severe hypoglycemia (<2.2 mmol/l) was more frequent with tight control than very mild control [RR 5.49 (3.22–9.38), p < 0.001] or mild control [RR 4.47 (2.5–8.03), p < 0.001]. Stratified analyses (cause of death, ICU type, time period, or diabetes) did not find significant between-group differences. Ranking analysis revealed the following hierarchy for avoiding death (highest to lowest rank): mild control, tight control, and very mild control.

Risk of short-term mortality:

• Very mild control vs tight control [relative risk (RR) 0.94 (95% CI 0.83–1.07, p= 0.36)]
• Very mild control vs mild control [RR 0.88 (0.73–1.06), p= 0.18]
• Very mild control vs moderate control [RR 1.1 (0.66–1.84), p= 0.72]

Unsurprisingly, tight control was more frequently associated with severe hypoglycaemia (<2.2 mmol/L)

• Tight control Vs very mild control [RR 5.49 (3.22–9.38), p< 0.001]
• Tight control vs mild control [RR 4.47 (2.5–8.03), p < 0.001]

Ultimately, there was no mortality benefit for tight glycaemic control in critically ill adults.

Conclusion

With all of this in mind, we were concerned about our patients and this spurred us to undertake an audit to see if wee were actually doing our cohort any harm. Findings can be seen here.

It seems something like glucose can be so harmful, yet it is the fundamental source of fuel we all need to survive and produce the vital ATP that keeps our cellular processes going! It is quite interesting that this, along with even oxygen, are now considered so harmful in excess. They certainly are in shortage!

The message here is….go easy on glucose, but make sure you check it and make it a priority on your ward rounds. You don’t want to be a ‘diabetic’ for too long, but you don’t want to seem stingy equally!!

Written by Dr Richard Pertwee – ICU Research and Social Media Fellow

Edited by JW

December 21st 2016