|Year : 2008 | Volume
| Issue : 1 | Page : 23
Intensive Insulin Therapy for Critically III Patients: Is It the Necessary Standard of Care?
Saikat Sengupta1, Arpan Guha2, Amitava Rudra1, Gaurab Maitra1, Palas Kumar1, Kajari Roy3
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 Acceptance||10-Dec-2007|
|Date of Web Publication||19-Mar-2010|
Department of Anesthesiology, Perioperative Medicine & Pain, Apollo Gleneagles Hospitals, 58 Canal Circular Road Kolkata 700054
Source of Support: None, Conflict of Interest: None
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|| |
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  . Disturbed cellular energy metabolism contributes to organ failure  . 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.  . 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  .
| Insulin resistance and hyperglycaemia in the critically ill|| |
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"  . 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  . 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  . 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  . 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 . 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 . 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 .
| Clinical benefits of intensive insulin therapy|| |
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  . 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 . 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 . The initial success of the Leuven study in reducing morbidity and mortality in surgical intensive care unit 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  .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|| |
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 . 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  . 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 . 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 . 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 and inhibits lipolysis . 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 . It suppresses nuclear factor κ-β expression and free radical generation, and enhances endothelial nitric oxide generation . 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 . 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 . 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 . Taking these factors into consideration it would appear that exogenous administration of insulin is responsible for the beneficial effects in critically ill patients .
| Cost analysis|| |
Close monitoring and intensive treatment of hyperglycaemia has become an emerging standard of care among critically ill patients. Observational studies, 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 ,, 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 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|| |
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.
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