Clinical challenges of glycemic control in the intensive care unit: A narrative review

Table 1 Landmark studies comparing intensive insulin therapy and conventional management

Study	Journal and year of publication	Study, location	Patient population	Glycemic target	Glucose measurement	Nutrition	Results	Conclusion	Comments
Intensive insulin therapy in critically ill patients[16]	N Engl J Med, 2001	Single institution	1548 patients, mainly surgical patients	IIT 80-110 mg/dL (4.4-6.1 mmol/L)	Arterial blood glucose using glucose analyzer	On admission- IV glucose 200-300 g/24 h	ICU mortality	IIT reduces mortality and morbidity in critically ill patients in the surgical ICU
		Leuven, Belgium		Conventional 180-200 mg/dL (10-11.1 mmol/L)		Day 2- TPN, total enteral or combined enteral parenteral feeding started	IIT 4.6%
							Conventional 8% (P < 0.04)
							Risk reduction in IIT
							ICU mortality 42% (22%-62%)
							In hospital mortality 34%
							Blood stream infections 46% (25%-67%)
							Acute renal failure requiring RRT 41%
							RBC transfusion 50%
							Critical illness polyneuropathy 44%
Intensive insulin therapy in the medical ICU[17]	N Engl J Med, 2006	Single institution	1200 patients, medical ICU patients	IIT 80-110 mg/dL (4.4-6.1 mmol/L)	Arterial or capillary using POC glucometer	Routine guidelines	In hospital mortality	IIT significantly reduced morbidity but not mortality among all patients in the medical ICU	Risk of death and disease seems to be reduced in patients treated for three or more days in the ICU with IIT
		Leuven, Belgium		Conventional 180-200 mg/dL (10-11.1 mmol/L)			IIT 37.3%
							Conventional 40% (P = 0.33)
							Reduction in new kidney injury in IIT (8.9% to 5.9%, P = 0.04)
							Early weaning from mechanical ventilation in IIT group [HR 1.21 (1.02-1.44), P = 0.03]
							Early discharge from ICU in IIT [HR 1.15 (1.01-1.32), P = 0.04]
							Early hospital discharge in IIT [hazard ratio 1.16 (1-1.35) P = 0.05]
Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients[11]	Critical Care Med, 2008	Single center	523, mixed medical and surgical	IIT 80-110 mg/dL (4.4-6.1 mmol/L)	Arterial or capillary using POC glucose analyzer	Routine institutional guideline	ICU mortality	No difference in mortality between IIT and conventional insulin therapy
				Conventional 180-200 mg/dL (10-11.1 mmol/L)			IIT 13.5%	Increased hypoglycemia in the IIT group
							Conventional 17.1% P = 0.3
							IIT and mortality
							Adjusted hazard ratio 1.09 (0.7-1.72)
							Hypoglycemia
							IIT 28.6%
							Conventional 3.1% P < 0.0001
Strict glycemic control in patients hospitalized in a mixed medical and surgical intensive care unit: a randomized clinical trial[13]	Crit Care, 2008	Single center	504 mixed medical and surgical patients	IIT 80-110 mg/dL (4.4-6.1 mmol/L)	Arterial or capillary using POC glucose analyzer	Combination of enteral and parenteral nutrition	28-d mortality	No difference in mortality between IIT and conventional insulin therapy
				Conventional 180-200 mg/dL (10-11.1 mmol/L)		Nutrition was similar in both groups	IIT 36.6%	Increased hypoglycemia in the IIT group
							Conventional 32.4%
							Relative risk 1.1 (0.85-1.42)
							ICU mortality
							IIT 33.1%
							Conventional 31.2%
							Relative risk 1.06 (0.82-1.36)
							Hypoglycemia
							IIT 8.5%
							Conventional 1.7%
							Relative risk 5.04 (1.2 -21.12)
							Conventional 26% (P = 0.74)
							Mean difference in SOFA score
							IIT 7.8
							Conventional 7.7 (P = 0.88)
							Severe hypoglycemia (glucose < 40 mg/dL)
							IIT vs conventional group (17% vs 4.1% P < 0.001)
							Serious adverse events
							IIT group vs conventional group (10.9% vs 5.2%, P = 0.01)
Intensive insulin and pentastarch resuscitation in severe sepsis, VISEP study[12]	N Engl J Med, 2008	Multicenter, multidisciplinary ICU, 18 academic tertiary hospitals in Germany	537 patients with severe sepsis/septic shock	IIT 80-110 mg/dL (4.4-6.1 mmol/L)	Arterial or capillary using POC glucometer	Routine guidelines	28-d mortality	The use of IIT placed critically ill patients with sepsis at increased risk of serious adverse events related to hypoglycemia	Trial stopped early due to safety reasons
				Conventional 180-200 mg/dL (10-11.1 mmol/L)			IIT 24.7%
A prospective randomized multicenter controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: The Glucontrol study[14]	Intensive Care Med, 2009	Multi Center	1101 patients	Group 1 7.8-10 mmol/L	Arterial, central venous or capillary using blood gas analyzer or glucometer	Routine guidelines	ICU mortality	Underpowered but showed a lack of clinical benefit of intensive insulin therapy (target 4.4-6.1 mmol/L) associated with a n increased incidence of hypoglycemia as compared to a 7.8-10 mmol/L target	Trial stopped early due to high rate of unintended protocol violations
		21 medical surgical ICU’s		Group 2 4.4-6.1 mmol/L			Group 1 15.3%
							Group 2 17.2%
							P = 0.4
							28-d mortality
							Group 1 15.3%
							Group 2 18.7%
							P = 0.1438
							Hypoglycemia (blood glucose < 2.2 mmol/L)
							Group 1 2.7%
							Group 2 8.7%
							P < 0.0001
Intensive versus conventional glucose control in critically ill patients	N Engl J Med, 2009	International	6104 patients, Both medical and surgical	IIT 81-108 mg/dL (4.5-6 mmol/L)	Arterial or capillary using POC, blood gas or laboratory analyzer	Discretion of treating physician	Mortality (90 d)	IIT increased mortality among adults in the ICU
The NICE-SUGAR investigation[18]		42 hospitals (38 academic tertiary care hospitals, 4 community hospitals)		Conventional less than 180 mg/dL (10 mmol/L)			IIT 27.5%	A blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81-108 mg/dL
							Conventional 24.9% [odds ratio for intensive control 1.14 (1.02-1.18)]
							Median survival time lower in IIT than in conventional group [hazard ration 1.11 (1.01-1.23) P = 0.03]
							Severe hypoglycemia < 40 mg/dL
							IIT 6.8%
							Conventional 0.5% (P < 0.001)
Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial, COIITS trial[15]	JAMA, 2010	Multicenter	509 patients with septic shock and SOFA of 8 or more and received hydrocortisone	IIT 80-110 mg/dL (4.4-6.1 mmol/L)	Arterial blood using blood gas analyzer or laboratory analyzers.		Mortality	IIT did not improve in hospital mortality among patients treated with hydrocortisone for septic shock as compared to conventional insulin therapy
		11 ICUs, France		Conventional Physician discretion			IIT 45.9%
							Conventional therapy 42.9% (RR 1.07, P = 0.5)
							Severe hypoglycemia (blood glucose < 40 mg/dL)
							IIT 16.4%
							Conventional 7.8% (P = 0.003)

ICU: Intensive care unit; POC: Point of care; IIT: Intensive insulin therapy.