Glycemic Control in ICU

Blog Written by Dr Jose Chacko

Uncontrolled hyperglycemia may adversely impact critically ill patients through diverse mechanisms. High glucose levels may impair the innate immune response, with abnormal glycosylation of immunoglobulins.¹ Neutrophil migration is inhibited with suppression of phagocytic activity; complement fixation and bacterial opsonization are also disrupted.² Animal models have suggested that targeting normoglycemia may attenuate hyperglycemia-induced inhibition of bacterial opsonization.³ Furthermore, insulin may exert an anti-inflammatory effect that may ameliorate organ dysfunction in critical illness.⁴ However, aiming for tightly controlled blood glucose levels may lead to episodes of hypoglycemia that may adversely affect outcomes. Several landmark clinical trials have explored the impact of glycemic control in critically ill patients.

Do meticulously controlled blood glucose levels within a narrow range influence clinical outcomes in critically ill patients? 

Review of evidence 

The Leuven 1 trial – surgical ICU patients

One of the earliest studies on glycemic control in critically ill patients was from a surgical intensive care unit at the Catholic University of Leuven in Belgium. In this randomized controlled trial (RCT), patients were randomized to intensive insulin therapy to maintain a blood glucose level between 80–110 mg/dl in the intervention arm.⁹ In the conventional arm, insulin infusion was commenced if the blood glucose level was higher than 215 mg/dl, with the maintenance of levels between 180–200 mg/dl. Among the 1548 patients studied, the ICU mortality was significantly lower with intensive insulin therapy compared to conventional therapy (4.6% vs. 8.0%, p <0.04). The difference in mortality was predominantly evident in patients with a duration of ICU stay of more than 5 days, with the greatest mortality reduction observed in patients with a septic focus and multiorgan failure. Furthermore, intensive insulin therapy reduced the overall hospital mortality, incidence of bloodstream infections, acute kidney injury requiring renal replacement therapy, the number of red blood cell transfusions, and the incidence of critical illness polyneuropathy. Intensive insulin therapy also reduced the requirement for prolonged mechanical ventilation and intensive care.

The Leuven 2 trial – medical ICU patients

The Leuven 1 trial revealed evidence of benefit among surgical intensive care patients, the majority being postoperative cardiac surgical patients (62.7%). Could the beneficial effects of intensive insulin therapy be replicated in a medical intensive care unit? The Leuven 2 trial included 1200 patients admitted to the medical intensive care unit aiming for glycemic control using a similar protocol with intensive and conventional therapies.¹⁰ In this RCT, the in-hospital mortality was not significantly different between the intensive and conventional insulin therapy groups (37.3% vs. 40.0%, p = 0.33). The incidence of acute kidney injury was lower with intensive insulin therapy; besides, the time to weaning from mechanical ventilation, and the duration of stay in the ICU and hospital were lower with intensive insulin therapy. In-hospital mortality was lower in patients who stayed in the ICU for longer than 3 days, and, paradoxically, higher among patients with a duration of ICU stay of fewer than 3 days.

The NICE-SUGAR trial

Against the background of clinical trials that revealed conflicting evidence regarding possible benefits from intensive glucose control, the NICE-SUGAR study investigators conducted a multicenter RCT across 42 ICUs in Australia, New Zealand, and North America.¹¹ Patients were randomized to receive intensive insulin therapy to maintain blood glucose levels between 81–108 mg/dl or a conventional target of 180 mg/dl or lower. The study included 3054 patients in the intensive control arm and 3050 patients in the conventional arm. Death from any cause at 90 days was significantly higher in the intensive control arm compared to the conventional arm  (27.5% vs. 24.9%, OR:1.14; 95% CI, 1.02 to 1.28; P = 0.02). The treatment effect did not differ between medical and surgical patients. The incidence of severe hypoglycemia(blood glucose level <40 mg/dl) was significantly higher in the intensive compared to the conventional control group (6.8% vs. 0.5%, p <0.001). There was no difference in the duration of mechanical ventilation, hospital and ICU stay, or renal replacement therapy between groups. This large RCT conducted across a heterogeneous group of critically ill patients demonstrated possible harm from targeting normal blood glucose levels.

Key aspects of Glycemic Control – 

Time in the target range 

Could wide variations in blood glucose levels lead to adverse outcomes? Is the duration of time within the target range important? In an observational study, the maintenance of a blood glucose target between 72–136 mg/dl for more than 70% of the time was independently associated with improved survival.¹² Reduced organ dysfunction was observed when the duration of time within the target range of blood glucose was more than 50%. More than 80% of the time within a target blood glucose range of 70–140 mg/dl was associated with survival among non-diabetic, critically ill patients in another observational trial.¹³ It is also noteworthy that the time in the target range was a low 31% in the NICE-SUGAR trial compared to 53.1% in the Leuven 1 trial of surgical patients that showed improved survival with intensive insulin therapy.¹⁴ The duration of time with maintenance of blood glucose in the target range may be an important determinant of clinical outcomes.

Should blood glucose targets be based on hemoglobin A1c levels?

The recently published CONTROLING study compared a target of 180 vs. blood glucose target range based on “usual glycemia” in a multi-centric RCT. Usual glycemia was calculated based on the hemoglobin A1c (HbA1c) level using the formula:

Usual glycemia = (28.7×A1C) – 46.7

In the individualized control group, the blood glucose target was set to the usual glycemia level +15 mg/dl or less, with a range of 111–217 mg/ dl. In the conventional control group, the blood glucose level was maintained at 180 mg/dl or less. The blood glucose targets were maintained throughout the ICU stay. The all-cause mortality at 90 days was not significantly different between groups (individualized vs. conventional groups: 32.8% vs. 30.5%). No difference was observed in other clinical endpoints including the 28-day mortality, ICU length of stay, duration of vasoactive drug support, mechanical ventilation, and renal replacement therapy. On post-hoc analysis, the 90-day mortality was higher among non-diabetic patients in the individualized control group, surgical patients, and patients with HbA1c levels between 5–6%.

Diabetics vs. non-diabetics

A more liberal target range among diabetic patients has been shown to be associated with reduced mortality in a before-and-after study.¹⁵ On the other hand,  in critically ill patients without pre-existing diabetes, a retrospective cohort study has demonstrated the association of hyperglycemia with mortality.¹⁶

In a retrospective cohort study, Kwan et al. evaluated frequency and outcomes associated with relative hypoglycemia in 1592 critically ill diabetic patients. Relative hypoglycemia was defined as a decrease in blood glucose levels below 30% of baseline levels, as estimated by HbA1c levels. The 28-day mortality was significantly higher among patients who developed relative hypoglycemia. Besides, the incidence of absolute hypoglycemia (blood glucose <70 mg/dl) was significantly higher among patients who experienced relative hypoglycemia.

Thus, the optimal target range may vary between patients with and without diabetes mellitus and need to be tailored to the clinical situation.

Continuous measurement of glucose levels

Intermittent measurement at set time intervals may result in wide fluctuation in blood glucose levels and unidentified episodes of hypoglycemia, leading to adverse clinical outcomes.¹⁷ Continuous subcutaneous glucose monitoring systems measure glucose levels every few minutes, might enable more efficient control, and reduce the risk of hypoglycemia.¹⁸Meizhu et al. compared glucose control using a continuous subcutaneous glucose monitoring system with conventional, intermittent point-of-care measurements.¹⁹ Time in the target range of blood glucose between 144–180 mg/dl was significantly longer with continuous monitoring (51.5% vs. 29.0%, p <0.001). The mean glucose level and incidence of hypoglycemia (<72 mg/dl) did not differ between groups. However, the duration of hypoglycemia was significantly lower with continuous monitoring. This study suggests that continuous subcutaneous monitoring may enable better maintenance of blood glucose within the target range with fewer episodes of hypoglycemia.

Summary 

• Tight glycemic control has failed to live up to the initial promise in real-world studies
• Failure to maintain blood glucose levels consistently within the target range and episodes of hypoglycemia may have contributed to adverse clinical outcomes
• Time in the target range may be important to ensure efficient control
• There is observational data that suggests hyperglycemia-associated mortality in non-diabetics; however, in diabetic patients, higher glycemic targets may be more appropriate
• Diabetic patients may be particularly vulnerable to the adverse effects associated with relative hypoglycemia; future research should focus on optimal blood glucose range in critically ill diabetic patients
• Continuous subcutaneous measurement of blood glucose levels may enable maintenance of blood glucose levels in the target range and lower the risk of hypoglycemia

References 

1.         Turina M, Fry DE, Polk HC. Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med. 2005;33(7):1624-1633. doi:10.1097/01.ccm.0000170106.61978.d8

2.         Jafar N, Edriss H, Nugent K. The Effect of Short-Term Hyperglycemia on the Innate Immune System. The American Journal of the Medical Sciences. 2016;351(2):201-211. doi:10.1016/j.amjms.2015.11.011

3.         Weekers F, Giulietti AP, Michalaki M, et al. Metabolic, endocrine, and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness. Endocrinology. 2003;144(12):5329-5338. doi:10.1210/en.2003-0697

4.         Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab. 2003;88(3):1082-1088. doi:10.1210/jc.2002-021478

5.         Sodi-Pallares D, Testelli MR, Fishleder BL, et al. Effects of an intravenous infusion of a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction. A preliminary clinical report. Am J Cardiol. 1962;9:166-181. doi:10.1016/0002-9149(62)90035-8

6.         Rogers WJ, Stanley AW, Breinig JB, et al. Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion. Am Heart J. 1976;92(4):441-454. doi:10.1016/s0002-8703(76)80043-9

7.         Apstein CS, Opie LH. Glucose-insulin-potassium (GIK) for acute myocardial infarction: a negative study with a positive value. Cardiovasc Drugs Ther. 1999;13(3):185-189. doi:10.1023/a:1007757407246

8.         Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2003;125(5):1007-1021. doi:10.1067/mtc.2003.181

9.         Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367. doi:10.1056/NEJMoa011300

10.       Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-461. doi:10.1056/NEJMoa052521

11.       NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. doi:10.1056/NEJMoa0810625

12.       Chase JG, Shaw G, Le Compte A, et al. Implementation and evaluation of the SPRINT protocol for tight glycaemic control in critically ill patients: a clinical practice change. Crit Care. 2008;12(2):R49. doi:10.1186/cc6868

13.       Krinsley JS, Preiser JC. Time in blood glucose range 70 to 140 mg/dl >80% is strongly associated with increased survival in non-diabetic critically ill adults. Crit Care. 2015;19:179. doi:10.1186/s13054-015-0908-7

14.       Krinsley JS, Preiser JC. Is it time to abandon glucose control in critically ill adult patients? Curr Opin Crit Care. 2019;25(4):299-306. doi:10.1097/MCC.0000000000000621

15.       Krinsley JS, Preiser JC, Hirsch IB. Safety and efficacy of personalised glycemic control in critically ill patients: A 2-year before and after international trial. Endocr Pract. 2017;23(3):318-330. doi:10.4158/EP161532.OR

16.       Falciglia M, Freyberg RW, Almenoff PL, D’Alessio DA, Render ML. Hyperglycemia-Related Mortality in Critically Ill Patients Varies with Admission Diagnosis. Crit Care Med. 2009;37(12):3001-3009. doi:10.1097/CCM.0b013e3181b083f7

17.       Hermanides J, Vriesendorp TM, Bosman RJ, Zandstra DF, Hoekstra JB, Devries JH. Glucose variability is associated with intensive care unit mortality. Crit Care Med. 2010;38(3):838-842. doi:10.1097/CCM.0b013e3181cc4be9

18.       De Block C, Manuel-y-Keenoy B, Rogiers P, Jorens P, Van Gaal L. Glucose control and use of continuous glucose monitoring in the intensive care unit: a critical review. Curr Diabetes Rev. 2008;4(3):234-244. doi:10.2174/157339908785294460.