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Year : 2008  |  Volume : 52  |  Issue : 1  |  Page : 23 Table of Contents     

Intensive Insulin Therapy for Critically III Patients: Is It the Necessary Standard of Care?

1 Consultant Department of Anesthesiology, Perioperative Medicine & Pain, Apollo Gleneagles Hospitals, Kolkata., India
2 Consultant in Intensive Care, Directorate of Intensive Care, Royal Liverpool University Hospital, Liverpool., United Kingdom
3 Senior Resident, Department of Anaesthesiology, All India Institute of Medical Sciences, New Delhi., India

Date of Acceptance10-Dec-2007
Date of Web Publication19-Mar-2010

Correspondence Address:
Saikat Sengupta
Department of Anesthesiology, Perioperative Medicine & Pain, Apollo Gleneagles Hospitals, 58 Canal Circular Road Kolkata 700054
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Source of Support: None, Conflict of Interest: None

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Critically ill patients who require prolonged intensive care support are at high risk of developing multiple organ failure and death. Hyperglycaemia and resistance to insulin are closely associated with major illness or major surgery. This is true irrespective of whether patients are diabetic or not. It has been shown that tight glycaemic control using exogenous intensive insulin therapy improves outcome in critically ill patients. We review the pathophysiology of hyperglycaemia and examine the clinical and economic benefits of such therapy.

Keywords: Critically ill, Intensive insulin therapy, Tight glycaemic control

How to cite this article:
Sengupta S, Guha A, Rudra A, Maitra G, Kumar P, Roy K. Intensive Insulin Therapy for Critically III Patients: Is It the Necessary Standard of Care?. Indian J Anaesth 2008;52:23

How to cite this URL:
Sengupta S, Guha A, Rudra A, Maitra G, Kumar P, Roy K. Intensive Insulin Therapy for Critically III Patients: Is It the Necessary Standard of Care?. Indian J Anaesth [serial online] 2008 [cited 2020 Oct 25];52:23. Available from: https://www.ijaweb.org/text.asp?2008/52/1/23/60594

   Introduction Top

Morbidity and mortality in Intensive Care Units (ICU) occurring beyond the first few days of critical illness are attributable to the persistence of multiple or­gan failure and an increased susceptibility to infectious complications. The functional and structural sequelae of the systemic inflammatory response to infection and cellular injury play a role [1] . Disturbed cellular energy metabolism contributes to organ failure [2] . This was ini­tially thought to be due to inadequate tissue perfusion and cellular hypoxia. Current studies, however, also point to a disturbance in oxygen utilization along with the de­livery. This is termed as cytopathic hypoxia. [3] . Exten­sive researches during the last decade or so have fo­cused on strategies to prevent or reverse the potentially lethal effects of multiple organ failure. One of such strat­egies is tight blood glucose control (defined as the main­tenance of blood glucose levels between 80 to 110 mg.dL­1 [4.4-6 mmol.L -1 ] ) with exogenous insulin. This has been shown to reduce complications such as severe infec­tions and organ failure [4] .

   Insulin resistance and hyperglycaemia in the criti­cally ill Top

It is well known that any form of acute illness or injury results in insulin resistance, glucose intolerance and hyperglycaemia. This is what is popularly known as "diabetes of injury" [5] . Illness or trauma increases hepatic glucose production with ongoing gluconeogenesis despite hyperglycaemia and abundant release of insulin. There is hepatic insulin resistance and in the skeletal muscle as well as in the heart, insulin stimulated glucose uptake is impaired [6] . Glucose uptake in critically ill patients, how­ever, is increased but this takes place mainly in the tis­sues that are not dependent on insulin for glucose up­take such as the nervous system and red blood cells [6] . Insulin resistance in stress and critical illness is charac­terized by elevated circulating levels of IGF - binding protein-1 (IGFBP-1). It has been observed that the most severe cases of stress induced hyperglycaemia and higher levels of circulating IGFBP-1 are associated with patients with highest risks of death [7] . Counter regulatory hormonal responses, cytokine release, and signals from the nervous system, all affect glucose metabolic path­ways, bringing about the "diabetes of injury". The hor­mones involved include catecholamines, cortisol, gluca­gon, and growth hormone (GH) [Table 1]. Pro-inflam­matory cytokines affect glucose homeostasis indirectly, by stimulating counter regulatory hormone secretion and directly, by altering insulin receptor signaling. In fact, both endogenous as well as exogenously administered cat­echolamines in critical illness inhibit insulin secretion from â cells. Catecholamines also exert anti-insulin effects. [Figure 1]

The diabetes of injury used to be interpreted as an adaptive stress response and as such important for sur­vival. The overall increase in glucose turnover and the realisation that hyperglycaemia persisted despite a state of hyperinsulinemia were considered arguments in fa­vor of tolerating moderately elevated blood glucose lev­els during critical illness. If hyperglycaemia of critical illness is considered to be beneficial in promoting cellu­lar glucose uptake in non-insulin dependent tissues, tol­erating modest degrees of hyperglycaemia is beneficial. Consequently, blood glucose concentrations of 160­200mg.dL -1 (11 mmol.L -1 )were recommended to maxi­mize cellular glucose uptake while avoiding hyperosmolarity[6] . It was generally considered that mod­erate hyperglycaemia was a buffer against hypoglycaemia induced brain damage. In 2001, however the critical care community was forced to reconsider this dogma[8] . A large, randomized, controlled, clinical study conducted by Greet Van den Berghe and her colleagues, often referred to as the "Leuven study" showed that preventing even moderate hyperglycaemia during criti­cal illness substantially improved outcome[4] .

   Clinical benefits of intensive insulin therapy Top

The study done by Van den Berghe of critically ill patients, of which the majority was non-diabetic, showed that titrating insulin infusion during intensive care to strict normoglycaemia (below 110mg.dL -1 [6 mmol.L -1 ]) re­duced mortality when compared to conventional insulin treatment. In the conventional insuline treatment, arm insulin infusion was started when blood glucose exceeded 200mg.dL -1 (11 mmol.L -1 ) and blood glucose levels were targeted to be between 150-160mg.dL -1 (8-9 mmol.L -1 ) 4.6% of patients in the Intensive Insulin Therapy group died during intensive care, compared with 8.0% in the conventional treatment group, representing an apparent risk reduction of 42%. Intensive insulin therapy also re­duced in-hospital mortality: the greatest reductions in­volved deaths due to multiple organ failure with a septic focus [4] . Prior to this, the DIGAMI study had shown that patients with diabetes mellitus who had an acute myo­cardial infarction, benefited from a glucose-insulin infu­sion therapy and the avoidance of excessive hyperglycaemia (blood glucose > 200mg.dL -1 [11 mmol.L­1 ]) improved both the short term as well as long term outcome[9] . Current studies have aimed at much lower level of blood glucose. The benefit of intensive insulin therapy has been particularly observed in patients with prolonged critical illness, requiring intensive care stay for more than five days, with reduction in mortality rates from 20% to 10%. Besides reducing mortality rates in­tensive insulin therapy and tight glycaemic control have had several beneficial effects in reducing the incidence of severe nosocomial infections, acute renal failure, liver dysfunction, critical illness polyneuropathy, muscle weak­ness and anaemia. It reduced the times that patients were dependent in intensive care. Intensive insulin therapy induced a slightly higher incidence of hypoglycaemia as compared with the conventional therapy, but these epi­sodes were never associated with clinically relevant se­quelae. The use of insulin titration algorithms prevented the occurrence of hypoglycaemia.

Krinsley et al confirmed the survival benefit of implementing tight blood glucose control with insulin in a mixed medical-surgical care population[10] . The initial suc­cess of the Leuven study in reducing morbidity and mor­tality in surgical intensive care unit[4] prompted the same workers to see whether intensive insulin therapy also improves prognosis of patients in medical ICU. In 2006, Van den Berghe and her colleagues found that intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. They also found that the risk of subsequent death and disease was reduced in patients treated for three or more days [11] .The substantial improvement of outcome with such a simple measure is a major progress in the current prac­tice of intensive care.

   Mechanisms explaining the beneficial effects of intensive insulin therapy Top

How does a simple intervention - preventing hyperglycaemia with insulin - during a relatively short time a patient is in intensive care unit prevent the feared complications such as sepsis, multiple organ failure and even death? Normal cells are relatively protected against the deleterious effects of brief exposure to moderate hyperglycaemia by down regulation of glucose transport­ers[12] . In diabetes mellitus, prolonged untreated hyperglycaemia contributes to the development of chronic debilitating complications. Except in embryonic devel­opment, where hyperglycaemia causes acute toxicity, the time required for hyperglycaemia to cause disorders in patients with diabetes is several orders of magnitude longer than the time it took to prevent life threatening complications with intensive insulin therapy in the ICU [13] . In order to understand how metabolic control with insu­lin proved to be so acutely protective in the critically ill; a few key questions need to be answered. Is glycaemic control crucial in bringing the clinical benefits of inten­sive insulin therapy, or is blood glucose control epiphenomenal to the other metabolic and non-metabolic effects of insulin? Are there factors predisposing the critically ill to hyperglycaemia - induced toxicity? What are the common pathways mediating the plethora of clini­cal benefits of intensive insulin therapy?

Hyperglycaemia is associated with a number of pathophysiological changes such as increased leucocyte rolling and adhesion, activation of monocytes, and in­creased expression of cytokines and chemokines[14] . The function of granulocytes is impaired. Thus hyperglycaemia enhances the inflammatory response and decreases the specific immune response. It also has an effect in ischaemia- reperfusion injury. Blood flow is decreased during reperfusion, an effect that can be coun­teracted by L-arginine[15] . An interaction between glu­cose metabolism and nitric oxide metabolism appears to exist. In this context it seems that control of hyperglycaemia per se can be correlated to improved outcomes in critically ill patients.

In addition to its hypoglycaemic action, insulin pro­motes muscle protein synthesis[16] and inhibits lipolysis[17] . insulin also produces a variety of anti-inflammatory re­sponses. Intensive Insulin therapy significantly reduces C-reactive protein levels and increases mannose bind­ing lectin from baseline in patients requiring ICU care for more than 5 days[18] . It suppresses nuclear factor κ-­β expression and free radical generation, and enhances endothelial nitric oxide generation[19] . Insulin also has a cardio protective function as it reduces thromboxane A 2 production and plasma plasminogen activator inhibitor-1 activity, thereby reducing platelet aggregation and in­creasing fibrinolysis[20] . TNF causes endothelial dysfunc­tion and apoptosis, triggers procoagulant activity and fibrin deposition, and enhances nitric oxide synthesis in a variety of cells. Administration of exogenous insulin sup­presses TNF production in a dose dependent manner[21] . Insulin has been shown to stimulate the activity of en­zymes essential in the formation of prostaglandin E 2 and I 2 precursors which are potent vasodilators and inhibi­tors of platelet aggregation[22] . Taking these factors into consideration it would appear that exogenous adminis­tration of insulin is responsible for the beneficial effects in critically ill patients[23] .

   Cost analysis Top

Close monitoring and intensive treatment of hyperglycaemia has become an emerging standard of care among critically ill patients. Observational studies[24],[25] among a large cohort of cardiovascular surgery pa­tients have demonstrated substantial decreases in wound infection rates and hospital mortality when patients are treated with continuous iv infusion of insulin with the aim of achieving euglycaemia. The overall mortality in the continuous insulin infusion (CII) group of 2.5% was significantly lower than that in the subcutaneous injec­tion (SQI) group - 5.3%. Furthermore, cardiac-related mortality was significantly greater in the SQI group (4.2%) than in the CII group (1.6%). Findings from other studies [4],[10],[11] have shown decreases in blood stream infections, prolonged antibiotic use, renal replacement therapy, prolonged mechanical ventilation and prolonged ICU stay in patients who had tight glycaemic control, which translated into substantial cost savings. The 2006 Leuven study showed that morbidity was reduced in the intensive insulin treatment group, as reflected by a newly acquired kidney injury (8.9 to 5.9%, P= 0.04) and in ear­lier weaning from mechanical ventilation, as compared with the conventional treatment group (hazard ratio, 1.21; 95% CI - 1.02 to 1.44, p= 0.03), along with earlier dis­charge from ICU (hazard ratio 1.15; 95% CI - 1.01 to 1.32, p= 0.04) and from the hospital (hazard ratio 1.16, 95% CI - 1.00 to 1.35, p= 0.05)

Krinsley and Jones[26] did an economic analysis of a 1600 -patients "before - and - after" study of intensive glycaemia management. There was a non significant decrease in resource costs among non ventilated patients in the treatment period and a large decrease in resource costs among the ventilated patients driven by significant decreases in imaging and laboratory costs. The adjusted cost savings over a period of one year was USD 348,400 (267,896 Euros) for ICU days, USD 328,600 (252,672 Euros) for ventilator days, USD 66,400 (51,057.2 Eu­ros) for post ICU days, USD 259,700 (199,692 Euros) for imaging, USD 43,900 (33,756.2 Euros) for pharmacy and USD 243,800 (187,466 Euros) for laboratory usage. The net annualized decrease in costs during the treatment period was USD 1580 (1,214.91 Euros) per pa­tient.

   The future Top

It is clear that several mechanisms are involved and interrelated in explaining the clinical benefits of in­tensive insulin therapy in the critically ill. Accelerated toxicity of hyperglycaemia and lack of insulin effect during critical illness explain why the consequences are so rap­idly deleterious in critical illness. The direct effects of preventing hyperglycaemia as well as the distinct meta­bolic and non-metabolic effects of insulin that occur con­comitantly with tight glycaemic control are likely to play a role. The relative contribution of these different mecha­nisms is yet unknown. Several questions await an an­swer. The exact molecular basis for the increased sus­ceptibility for these toxic effects in the critically ill re­mains to be explored. Exploring the molecular link be­tween improved glycaemic and lipid control and insulin, endothelial function, inflammation, and clinical outcome will be required. Manipulation of these pathways that are linked with outcome but are unresponsive to intensive insulin therapy may point to the potential for other therapeutic strategies to further improve survival in the ICU.

A simple metabolic intervention i.e. maintaining normoglycaemia with insulin has improved survival and reduced morbidity of critically ill patients. This reflects a major clinical progress in modern intensive care. The potential for improvement in ICU patient outcomes, com­bined with the economics of implementing therapy with a low cost drug, make intensive insulin therapy an at­tractive option.

   References Top

1.Fink MP and Evans TW. Mechanisms of organ dysfunction in critical illness: report from a round table conference held in Brussels. Intensive Care Medicine 2002; 28: 369-375.  Back to cited text no. 1      
2.Brealey D, Brand M, Hargreaves I, Heales S, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360: 219-223.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Singer M and Brealey D. Mitochondrial dysfunction in Sepsis. Biochem Soc Symp 1999; 66: 149-166.  Back to cited text no. 3      
4.Van den Berghe G, Wouters P, Weekers F, et al. Intensive Insu­lin Therapy in critically ill patients. N Engl J Med 2001; 345: 1359-1367  Back to cited text no. 4      
5.McCowen KC, Malhotra A and Bistrian BR. Stress induced hyperglycaemia. Crit Care Clin 2001; 17: 107-124.  Back to cited text no. 5      
6.Mizock BA. Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med 1995; 98: 75-84  Back to cited text no. 6      
7.Van den Berghe G, Baxter RC, Weekers F, et al. A paradoxical gender dissociation within the growth hormone/ insulin-like growth factor I axis during protracted critical illness. J Clin Endocrinol Metab 2000; 85: 183-192.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]  
8.Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycemia. Best Pract Res Clin Endocrinol Metab 2001; 15: 533-551  Back to cited text no. 8      
9.Malmberg K,et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic pa­tients with acute myocardial infarction (DIGAMI study): ef­fects on mortality at 1 year. J Am Coll Cardiol 1995;26: 57-65.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.Krinsley JS. Effect of an intensive glucose management proto­col on the mortality of critically ill adult patients. Mayo Clin Proc 2004 ;79: 992-1000.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Van den Berghe G, Wilmer A, Hermans G, et al. Intensive Insu­lin Therapy in the Medical ICU. N Eng J Med 2006 ;354: 449­-461.  Back to cited text no. 11      
12.Klip A, Tsakaridis T, Marrette A,et al. Regulation of expression of glucose transporters by glucose: a review of studies in vivoand in cell cultures. FASEB J 1994;8: 43-53.  Back to cited text no. 12      
13.Van den Berghe G. How does blood glucose control with insu­lin save lives in intensive care? J Clin Invest 2004 ; 114: 1187-­1195.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Marfella R, Siniscalchi M, Esposito K, et al. Effects of stress hyperglycemia on acute myocardial infarction: role of inflam­matory immune response in functional cardiac outcome. Dia­betes Care 2004 ; 26: 3129-3135.  Back to cited text no. 14      
15.Guigliano D, Marfella R, Coppola L, et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperg­lycemia. Circulation 1997; 95: 1783-1790.  Back to cited text no. 15      
16.Sakurai Y, Aarsland A, Herndon DN,et al. Stimulation of muscle protein synthesis by long term insulin infusion in severely burned patients. Ann Surg 1995, 222: 283-97.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]  
17.Aarsland A, Chinkers D, Wolfe R R et al. Rate of hepatic very low density lipoprotein triglyceride secretion remains un­changed. Ann Surg 1996, 223; 777-789.  Back to cited text no. 17      
18.Hansen TK, Thiel S, Wouters,et al. Intensive insulin therapy exerts anti-inflammatory effects in critically ill patients and counteracts the low mannose binding lectin levels. J Clin Endocrinol Metab 2003; 88:1082-8.  Back to cited text no. 18      
19.Das UN. Current advances in sepsis and septic shock with particu­lar emphasis on the role of insulin. Med Sci Monit 2003; 9; 181-92  Back to cited text no. 19      
20.Davi G, Catalano I, Averna M et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Eng J Med 1990; 322: 1769-94.  Back to cited text no. 20      
21.Satomi N, Sakurai A, Haranaka K. The relationship of hy­poglycemia to TNF production and antitumor activity : the role of glucose, insulin and macrophages. J Natl Cancer Inst 1985; 74: 1255-60.  Back to cited text no. 21  [PUBMED]    
22.Das UN. Is Insulin an anti-inflammatory molecule? Nutrition 2001; 17: 409-13.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]  
23.Hiesmayr MJ. Hyperglycemia and outcome after myocardial infarction and cardiac surgery: so what. Seminars in Cardiothor. And Vasc Anaesth 2006; 3: 220-23.  Back to cited text no. 23      
24.Furnary AP, Zerr KJ, Grumkemier GL,et al. Continuous intra­venous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical pro­cedures. Ann Thor Surg1999; 67: 352-360.  Back to cited text no. 24      
25.Furnary AP, Gao G, Grumkemier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergo­ing coronary artery bypass grafting. J Thor Cardiovasc Surg 2003 125: 1007-1021.  Back to cited text no. 25      
26.Krinsley JS and Jones RL. Cost analysis of intensive glycaemic control in critically ill patients. Chest 2006; 129: 644-650.  Back to cited text no. 26      


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