Insulin‐based regimens decrease mortality rates in critically ill patients: a systematic review
Authors: Langley Jane , Adams Gary 
Published: November 2006

AbstractObjectivesTo determine whether treatment with glucose‐insulin‐potassium (GIK), insulin and glucose, or insulin by itself is beneficial in limiting organ damage after acute myocardial infarction (AMI) and reducing mortality and morbidity among critically ill hyperglycaemic patients.MethodsSystematic review of randomized controlled trials.Main outcome measureTo assess whether tight glycaemic control reduces morbidity and mortality.Studies reviewedRandomized controlled trials of insulin‐based regimens in the treatment of critically ill patients.ResultsNine hundred and twenty‐four potentially relevant studies were identified and screened for retrieval. Of these, 16 randomized controlled trials met the inclusion criteria (Table 1). Ten studies examined the effects of GIK, and six of these studies reported a mortality reduction with GIK treatment in addition to enhanced myocardial performance. Five studies examined the administration of insulin. Among these studies, tight glycaemic control of blood glucose in one study was shown to reduce morbidity and mortality of patients in intensive care. Only one study examined insulin/glucose therapy, and it showed a post‐myocardial infarction mortality reduction of one year.

Description of Studies in Order of Treatment

(Glucose‐Insulin‐Potassium‐GIK)

Study No.
Source
Year
Study title
Study design/description
Study findings—whether tight glycaemic control improves morbidity and mortality

2
Lazar et al.
1997
GIK solutions enhance recovery after urgent coronary artery bypass grafting
Study undertaken to determine whether GIK solutions would benefit patients undergoing coronary artery bypass grafting.
Although no mortality was evident in either group. GIK therapy enhances myocardial performance and results in faster recovery from urgent coronary artery bypass grafting.

The study group consisted of 30 patients with unstableangina who required coronary artery bypass surgery: 15 patients randomized to treatment with GIK solution administered intravenously after induction of anaesthesia and continued for 12 h after aortic unclamping, the remaining 15 patients received intravenous 5% dextrose in water.

3
Diaz et al.
1998
Metabolic modulation of AMI: The ECLA GIK pilot trial
Study conducted to evaluate the impact of a GIK infusion administered during the first few hours of AMI.
A trend toward a non‐significant reduction in major and minor in‐hospital events was observed in patients allocated to GIK. However, in the patients treated with reperfusion strategies, a statistically significant reduction in mortality and a consistent trend toward fewer in‐hospital events in the GIK group was observed.

A total of 407 patients with suspected AMI were studied. In a ratio of 2 : 1 patients, 268 were randomized to receive GIK (high or low dose) and 139 to receive control.

4
Scott et al.
1999
GIK infusions in the treatment of acute stroke patients with mild to moderate hyperglycaemia. The glucose–insulin in stroke trial (GIST)
Study designed to determine whether glucose/insulin induced and maintained euglycaemia in acute stroke patients with mild to moderate hyperglycaemia can improve outcome after stroke. Fiftythree acute stroke patients with mild to moderate hyperglycaemia (7–17 mmol/L) were studied: 25 randomized to treatment with a GIK infusion (insulin concentration in the GIK was altered according to BM glucose values) and 28 to the control, which were administered as sodium chloride infusion.
Results confirm that GKI infusion in mild to moderate hyperglycaemia following acute stroke is a safe, practical, and pragmatic intervention that effectively lowers the plasma glucose levels to within normal range; however, the beneficial effects of this treatment remain to be elucidated.

5
Ceremuzynski et al.
1999
Low‐dose GIK is ineffective in AMI: results of a randomized multi‐centre Pol‐GIK trial
Study designed to assess the clinical efficacy of GIK infusion in AMI.
Low‐dose GIK treatment does not improve the survival and clinical course in AMI.

The study consisted of 954 patients: 494 randomized to treatment with low‐dose GIK infusion and 460 to the control group, which was administered sodium chloride by IV infusion.
Total mortality at 35 days was significantly higher in the GIK infusion group than in the control group.

6
Besogul et al.
1999
Chemical, biochemical and histochemical assessment of pre‐treatment with GIK for patients undergoing mitral valve replacement in the third and forth functional groups of the New York Heart Association.
A study designed to investigate the potentially beneficial effects of pre‐operative treatment with GIK for patients undergoing mitral valve replacement.
No significant reduction in mortality was evident throughout the period of the trial; however, the patients receiving GIK required less inotropic support, had fewer ventricular arrhythmias, and exhibited improved haemodynamic indices: cardiac output increased & systemic vascular resistance decreased.

A total of 30 patients were studied: 15 randomly assigned to treatment with GIK infusion and 15 to the control group, which was administered an equivalent volume of sodium chloride.

7
Lazar et al.
2000
GIK solutions improve outcomes in diabetic patients who have coronary artery operations.
Study undertaken to determine whether GIK would improve myocardial performance and limit morbidity after coronary artery bypass grafting in diabetic patients.
Although no mortality was evident in either group. GIK therapy enhances myocardial performance and results in faster recovery from urgent coronary artery bypass grafting.

A total of 40 patients were studied: 20 randomized to receive a GIK infusion and 20 to the control group, which received 5% dextrose in water.

9
Ulgen et al.
2001
The effect of GIK solution on ventricular late potentials and heart rate variability in AMI.
Study designed to investigate the effects of GIK solution on ventricular late potentials (VLP) and high rate variability (HRV) during the early period of AMI.
Although treatment with GIK solution did not find a statistically significant reduction in mortality, the results suggest that GIK therapy in the early periods of AMI shows beneficial effects: decreased post‐myocardial infarction angina and ischaemia.

(High rate variability and presence of VLP are known to correlate with an increased risk of ventricular tachycardia and sudden death in AMI.)

A total of 72 patients were studied: 34 randomized to treatment with GIK and 38 to the placebo.

10
Szabo et al.
2001
Effects of high‐dose GIK on myocardial metabolism after coronary surgery in patients with type 2 diabetes.
Study designed to investigate the effects of high‐dose GIK on myocardial substrate utilization after coronary surgery in patients with type 2 diabetes.
Although no mortality was evident in either group, it can be concluded that high‐dose GIK significantly enhances myocardial performance.

A total of 20 patients were randomly allocated: 10 received high‐dose GIK infusion post‐operatively and the remaining 10 in the control group received standard post‐operative care, including insulin infusion if required, to maintain blood glucose below 10 mmol/L.

11
Smith et al.
2002
Coronary revascularisation: a procedure in transition from on‐pump to off‐pump? The role of GIK revisited in a randomized, placebo‐controlled study
A study designed to investigate an optimized GIK solution regimen as an alternative myocardial protective strategy in off‐pump coronary artery bypass graft surgery and as a supplement to conventional coronary artery bypass surgery using cardiopulmonary bypass (CPB). The study consisted of 44 patients scheduled for elective multi vessel surgery using either conventional CPB (n = 22) or off‐pump coronary artery bypass techniques (n = 22). Pre‐ischaemic, ischaemic, and post‐ischaemic administration of GIK solution was carried out, (optimally dosed to ensure non‐esterfied fatty acid suppression (NEFA), and supplemented with magnesium (a glycolytic cofactor).
GIK solution did not achieve any clinical benefit. However, compared with CPB, off‐pump coronary artery bypass surgery significantly reduced ischaemic injury and post‐operative infections.

13
Lell et al.
2002
GIK infusion for myocardial protection during off‐pump coronary artery surgery.
Study undertaken to evaluate the clinical effectiveness of GIK infusion in preventing myocardial damage and maintaining cardiac performance in patients undergoing off‐pump myocardial revascularization.
A GIK infusion used as an adjunct to reperfusion therapy for AMI causes insulin‐resistant hyperglycaemia in elective off‐pump coronary artery bypass patients, with no demonstrable benefit.

A total of 46 patients undergoing off‐pump coronary artery bypass were studied: 21 were randomly assigned to treatment with GIK infusion and 20 to the control group, which was administered sodium chloride (five patients were excluded due to cardiovascular instability).

Insulin‐only Infusion

16
Ingels et al.
2006
Strict blood glucose control with insulin during intensive care after cardiac surgery: impact on 4 years survival, dependency on medical care, and quality of life
Sub‐analysis and follow‐up study of a large, randomized controlled trial on the effects of intensive insulin therapy during critical illness
Short‐term survival benefit was obtained after 4 years, without inducing increased medical care requirements, with insulin‐titrated glycaemic control maintained during intensive care after cardiac surgery.

15
Van den Berghe et al.
2006
Intensive insulin therapy in the medical ICU
A prospective, randomized, controlled study of adult patients admitted to our medical ICU. On admission, patients were randomly assigned to strict normalization of blood glucose levels (80–110 mg/dL, 4.4–6.1 mmol/L) with the use of insulin infusion or to conventional therapy (insulin administered when the blood glucose level exceeded 215 mg per/dL (12 mmol/L), with the infusion tapered when the level fell below 180 mg/dL (10 mmol/L)). There was a history of diabetes in 16.9% of the patients.
Intensive insulin therapy significantly reduced morbidity, but not mortality, among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy.

8
Van den Berghe et al.
2001
Intensive insulin therapy in critically ill patients
Study designed to assess whether normalization of blood glucose levels with intensive insulin therapy reduces mortality and morbidity among critically ill patients.
Intensive insulin therapy to maintain blood glucose at or below 6.1 mmol/L reduces morbidity and mortality among critically ill patients in the surgical ICU.

A total of 1548 were studied: 783 randomly assigned to the intensive treatment group with the aim of maintaining normoglycaemia (4.4–6.1 mmol/L) and 765 to the conventional group in which an insulin infusion was titrated to maintain blood glucose levels between 10 & 11.1 mmol/L.

12
Groban et al.
2002
Intra‐operative insulin therapy does not reduce the need for inotropic or anti‐arrhythmic therapy after cardiopulmonary bypass
Study designed to determine whether attempted glucose control through intra‐operative insulin therapy reduces the need for inotropic or anti‐arrhythmic therapy after cardiopulmonary bypass.
Intra‐operative insulin therapy did not reduce mortality or the use of inotropic or anti‐arrhythmic support after cardiac surgery with CPB.

A total of 381 patients were studied: 188 randomized to treatment with insulin infusion in an attempt to maintain blood glucose within set parameters and 193 to the control group, which was administered sodium chloride.

14
Rao et al.
2002
The insulin cardioplegia trial: myocardial protection for urgent coronary artery bypass grafting
Study undertaken to evaluate the clinical impact of insulin‐enhanced cardioplegia on patients at high risk and undergoing coronary artery bypass surgery for unstable angina.
Despite encouraging results from smaller studies, the trial failed to demonstrate any clinical benefit of insulin‐enhanced cardioplegia solution for patients undergoing high‐risk isolated coronary artery bypass grafting.

A total of 1127 patients were studied: 557 were randomly assigned at operation to receive cardioplegic solution supplemented with insulin and 570 were assigned to a placebo.

Insulin‐Glucose Method of Administration

1
Malmberg et al.
1995
Randomized trial of insulin‐glucose infusion followed by subcutaneous insulin treatment in diabetic patients with AMI : effects on mortality at one year.
Study investigating how insulin–glucose infusion followed by multi‐dose insulin treatment in diabetic patients with AMI affected mortality during the subsequent 12 months of follow‐up.
Insulin–glucose infusion followed by multi‐dose insulin regime statistically improved long‐term prognosis in diabetic patients with AMI.

A total of 620 patients were studied: 306 were randomized to treatment with insulin‐glucose infusion followed by multi‐dose subcutaneous insulin for more that 3 months, and 314 to conventional therapy (insulin administered only if deemed clinically necessary).

ConclusionsThere is increasing evidence that maintaining normoglycaemia and treatment with insulin‐based regimens is beneficial in limiting organ damage and significantly reduces both morbidity and mortality in critically ill patients who require intensive care therapy. Copyright © 2007 John Wiley & Sons, Ltd.