The Use of Tight Glycaemic Control in Ventilated Patients - Term Paper Example

Critically explore the use of tight glycaemic control in ventilated patients in intensive care units Introduction Many medical institutions use tight glycaemic control protocols in their intensive care units. TGC refers to controlled levels of blood sugar so as to ensure medical benefits to the patients. TGC protocols became a popular standard of care after the initial, very promising, studies demonstrating that it improved patient outcomes. Several early studies demonstrated that TGC reduced mortality by one-third in surgical intensive care patients. Other early studies of TGC also demonstrated marked and significant benefits in infection rates and mortality. Typical TGC protocols consist of placing postoperative and critically ill patients on a continuous intravenous insulin infusion, checking their blood glucose concentrations on an hourly basis or other time schedule, and giving a bolus of insulin and/or changing the infusion rate of insulin based on the glucose concentration, with a goal of maintaining glucose between 4.4 and 6.7 mmol/L (80 and 120 mg/dL). Despite the numerous variations in protocols regarding timing and frequency of glucose measurements, insulin infusion rates, and target glucose values, the common target remains the same, maintaining tight glycemic control in critically ill patients. TGC studies have faced several contradictions also. Recent analysis have suggested that TGC protocols offer limited benefits in critically ill adults and revealed that TGC protocols result in an increased risk of hypoglycemia . In the background of such contradictory findings, this paper analyzes the various pros and cons of TGC in critically ill ICU patients. What is hyperglycaemia? The carbohydrates in our diet are broken down into glucose by our digestive system. This glucose then circulates to body cells through the blood stream. Insulin secreted by pancreas enables this glucose to migrate from the blood into the cells. Once inside a cell, the glucose is ‘burned’ along with oxygen to produce energy. Under normal circumstances, blood glucose is very tightly regulated by insulin according to the person’s eating habits and activity levels. Hyperglycaemia means too much glucose is circulating in the blood. A measurement of over 11mmol/L is usually considered a diagnosis of hyperglycaemia when the measurement is taken at any time, or 7mmol/L if the test is done while fasting. Some common symptoms of hyperglycaemia include excessive thirst, frequent urination, fatigue, unexplained weight loss, vision problems, such as blurring and an increased susceptibility to infections such as thrush. Hyperglycaemia in ICU patients: Post surgery stress induced hyperglycaemia is a common medical problem in critically ill patients. Patients with surgical or traumatic injury in the intensive care unit (ICU) also have significant chances of developing hyperglycaemia. Severe hyperglycaemia and high insulin resistance can enhance the risk of death in ICU patients. Though the optimal range for blood glucose in critically ill patients remains unclear, tight glycaemic control (TGC) in ventilated ICU patients has been found to reduce the mortality rate as established by different studies and research programmes. Hyperglycaemia associated with insulin resistance is common in critically ill ICU patients. Even those patients who have not had diabetes previously, develop hyperglycaemia. Patients have high chances of developing medical complications if hyperglycaemia prolongs. (Mizock BA. 1995) Early Studies: Some of the early studies in this subject have indicated that insulin infusions help in controlling glucose levels, thereby preventing deep sternal wound infections in patients. Subsequent studies have substantiated the use of intensive insulin therapy (IIT) to reduce morbidity and mortality in critically ill patients, including those medical patients who remain in the ICU for more than three days. (CA Philip J. Schneider 2007) Critically ill patients who remain in intensive care for more than a few days have a mortality of approximately 20% world-wide. These critically ill patients, in the absence of a previous diagnosis of diabetes, commonly exhibit stress hyperglycaemia and insulin resistance. (McCowen KC et al 2001) Hyperglycaemia and MOD Multiorgan dysfunction (MOD) and sepsis are a common cause of death in ICU patients irrespective of their diabetes history. Maintaining normoglycemia with IIT also improves survival in surgical ICU patients. Observational studies have also confirmed that IIT can reduce the number of deaths due to multiple-organ failure with sepsis, irrespective of previous record of diabetes or hyperglycaemia. (Capes SE et al 2000) Since stress hyperglycaemia has also been associated with impaired polymorph nuclear neutrophil function and bactericidal activity, lowering of blood glucose in critically ill patients also decreases morbidity and mortality. (Nielson CP & Hindson DA 1989) Cardiothoracic surgery patients have also shown significant improvement with TGC. Published observational data shows a decrease in mortality rates with improved glycemic control in cardiothoracic surgery patients. (Krinsley JS. Effect 2004) TGC is also linked to a lower risk of postoperative renal impairment and failure in patients undergoing cardiac surgery with cardiopulmonary bypass. Improved long term survival of patients has also been observed by infusing insulin-glucose followed by intensive subcutaneous insulin in diabetic patients with acute myocardial infarction. The improved survival rate seen in the first year continues for at least 3.5 years, with an absolute reduction in mortality by 11%. (Klas Malmberg, 1997) IIT Protocols and Related Trials Tight glycemic control protocols call for frequent blood glucose testing and insulin administration. Many medical institutions aim to maintain glycemic levels between 80–110 mg/dL. Tight glycemic control protocols were introduced as a result of the discovery of a direct correlation between hyperglycemia and adverse in-hospital outcomes. Moreover, increasing hyperglycemia has been independently shown to cause increased infection rates, increased mortality in ICU patients, and prolonged hospital stay. Conversely, tight glycemic control protocols have been shown to independently reduce in-hospital mortality, LOS, and infection rates. Significant reduction in surgical critical care mortality indicated by landmark trial of IIT provoked clinicians to evaluate and improve glycemic control in their practice. Many protocols have been developed and implemented in critical care units with varying degrees of effectiveness. The early protocols were paper-based and varied greatly in complexity. In recent times, computer support is being developed to make intravenous (IV) insulin, earlier considered a high-risk drug, safer and easier to use. IIT that maintains blood glucose at or below 110 mg per decilitre effectively reduces morbidity and mortality among critically ill patients in the surgical intensive care unit. (Greet Van den Berghe et al 2001) The study observed that critically ill patients who require intensive care for more than five days have a twenty percent risk of death and substantial morbidity. Critical-illness polyneuropathy and skeletal-muscle wasting in such patients prolongs the need for mechanical ventilation. Moreover, increased susceptibility to severe infections and failure of vital organs amplifies the risk of an adverse outcome. Hyperglycemia associated with insulin resistance is also common in those critically ill patients, who have no history of diabetes. It has been reported that pronounced hyperglycemia may lead to complications in such patients although data from controlled trials are lacking. In diabetic patients with acute myocardial infarction, therapy to maintain blood glucose at a level below 215 mg per decilitre improves the long-term outcome. Whereas, in non-diabetic patients with protracted critical illnesses, high serum levels of binding protein 1, an insulin-like growth factor, which reflects an impaired response of hepatocytes to insulin, increased the risk of death. This study hypothesized that hyperglycemia or relative insulin deficiency or both may directly or indirectly confer a predisposition to complications like severe infections, polyneuropathy, multiple-organ failure, and death. This hypothesis prompted a randomized, controlled trial to determine whether normalization of blood glucose levels with intensive insulin therapy reduced mortality and morbidity among critically ill patients. During the course of the trial, it was observed that IIT treatment reduced the number of deaths from multiple-organ failure with sepsis, regardless of whether there was a history of diabetes or hyperglycemia. The introduction of mechanical ventilation also supported this improved survival. Therefore, the trial established glycemic control as a preventive approach that is more broadly applicable to critically ill patients for reducing mortality during intensive care by more than 40 percent. In addition, it was observed that IIT also reduces the use of intensive care resources and the risk of complications that are common among patients requiring intensive care, including incidents of septicaemia and a corresponding need for prolonged antibiotic therapy. IIT has also been found affective in controlling acute renal failure. Besides optimization of hemodynamic status, no other strategy to prevent renal failure has proved effective. Additionally, IT also helped in reducing the risk of cholestasis, since adequate administration of glucose and insulin to hepatocytes is crucial for normal choleresis. TGC has also been found to significantly reduce the risk of micro vascular complications in both type 1 and type 2 diabetes. The DCCT/EDIC study demonstrates a significant association between tight glycaemic control and a reduction in the risk of cardiovascular events in type 1 diabetes. Tight glycaemic control is also essential to reduce the risk of developing the micro- and macro vascular complications of diabetes. ( G.U. Kuerzel et al 2003) Adequate replacement of basal insulin levels is important for effective glycaemic control in patients with type 1 and often type 2 diabetes. To achieve this, insulin analogues incorporating structural modifications to regular human insulin have been produced. However, currently available insulin preparations such as NPH insulin have significant shortcomings, like the duration of action and variability of absorption. ( G.U. Kuerzel et al 2003) However, it is essentially important to standardise the protocols for IIT, in order to address differences in glycaemic targets, nutritional and glucose supplementation, and insulin dosing strategy. Various experience suggest that many of the hyperglycaemic events take place during the first 36 hours of IIT, which coincides with the establishment of enteral feed while intravenous glucose is concomitantly administered. This glucose infusion is solely part of the IIT protocol and was not administered to other ICU patients prescribed insulin. The clinical value of this initial glucose infusion is not yet known and its future would depend on whether IIT works by reducing hyperglycaemia or through another action of insulin, which may be anti-inflammatory, anti-coagulant, or anabolic. TGC Contradictions The benefits of good glycaemic control in ICU patients have been substantiated by various researchers. Most medical bodies recommend glycaemic targets between 6.5 and 7.5%. However, it is also well known that even in clinical trials, a majority of patients fail to achieve optimal glycaemic control. The reasons for this failure are complex and multifactorial. Medical practitioners often delay the initiation and intensification of insulin unnecessarily. The reason for this could be the fear of causing hypoglycaemia or weight gain in patients, or doubts about patients' self-care abilities and inadequate resources to provide the necessary structured education to support patient self-management. Also, patients may not be willing to follow the treatment advice. This can be attributed specifically to behavioural aspects such as self-monitoring, diet and exercise. Further, there is a limit to the medical benefits of existing exogenous insulin therapies due to their imperfect pharmacokinetic and pharmacodynamic profiles. The problem of variability of effect from injection to injection with basal insulin formulations is a major problem with IIT. Improvements in this area are essential to achieve the intended benefits of TGC. On a practical note, recommendations for the implementation of tight glucose control using intensive insulin therapy cannot be discontinued until questions relating to optimal blood glucose level and the corresponding categories of patients have been resolved. The issues of glucose variability and the most efficient method of preventing hypoglycaemia will most likely represent important parameters for comparing the safety and quality of protocols used for tight glucose control. In this section, we will look at some prominent controversies surrounding TGC. Though several studies have established TGC, yet controversy surrounds several areas of TGC. First, the precise blood glucose targets are unclear. Data from one observational study also suggested that a less strict target blood glucose range of 4 to 8 mmol/l may achieve similar mortality benefits. Also, several complex protocols are required to achieve TGC in clinical practice. Frequent blood glucose measurements and changes to insulin infusion rates depending on the rate of change of blood glucose levels need to be conducted. (Rob Shulman et al 2007) Another major concern about stringent glycaemic targets is that patients may be at increased risk for hypoglycaemia. This has also led, at least in part, to the premature cancellation of the multi-centre German Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study. In another incident it was found that attempting to achieve TGC, using a complex protocol assisted by computerized decision support, was extremely difficult. The introduction of a computerized decision supported IIT protocol did not assure high quality glycaemic control. Hyperglycaemia was particularly prevalent during the early stages of IIT, when enteral feed was being established while exogenous glucose was being administered. Whether the use of exogenous glucose should be included at the onset of IIT call for further investigations. Furthermore, poorer glycaemic control occurred in those patients with a higher BMI and APACHE II score. It is essential to develop more flexible protocols for patients with a higher BMI and APACHE II score. Finally, the existing literature demonstrates that non-computerized TGC protocols may not achieve prolonged target glycaemia. The degree of glucose control achieved is also not comprehensively described in the Leuven study. In several other trials, relatively short durations of achievement of target glycaemia were reported after introducing a nurse implemented IIT protocol. In this case, ideal glycaemic range sustained for 11.5 hours/day. In a recent advance, researchers from New Zealand developed and piloted a model-based approach that manages TGC on the basis of controlling nutritional intake in addition to insulin. A pilot study of 19 patients reported that 62% of measurements taken every one to two hours were in the glycaemic range from 4.1 to 6.1 mmol/l in a general ICU population. (Kanji S et al 2004) Observational studies have also suggested that strict glucose control is able to reduce hospital mortality in mixed medical/surgical ICUs but other non-experimental studies in similar settings have not confirmed that the mean glucose level is an independent risk factor for ICU mortality. It remains unclear if intensive insulin therapy is equally efficacious in both medical and surgical patients. (Whitcomb BW et al 2005) Also, in this study, it was found that intensive glucose control did not reduce the morbidity or the mortality of patients admitted to a mixed medical/surgical ICU with medical problems, non-cardiovascular surgeries or trauma. These results differ from two previous studies which demonstrated decrease in mortality and morbidity in cardiovascular-surgical ICU patients and a decrease in mortality in a subgroup of patients with an ICU stay longer than two days. A possible explanation for these differences could be the different type of patients in each study. The first study was conducted in a surgical ICU where 63% of the patients had cardiovascular problems. In these patients, the decrease in mortality recorded for the intensive insulin group was associated with a decrease in both the frequency of infections and in the number of deaths due to multiple organ failure of known sepsis origin. (Whitcomb BW et al 2005) It was also observed that strict glucose control did not decrease morbidity or mortality in patients hospitalised in a mixed medical/surgical ICU. Instead, the intervention produced an important increase in severe hypoglycaemia. Therefore, the combination of an insufficient difference between the treatment groups in blood glucose values and lack of power makes it impossible to draw any conclusion on the efficacy of tight glycaemic control. A recent prospective study in a medical ICU population also found that reduced blood glucose levels did not significantly reduce in-hospital mortality for the whole group of target patients. Mortality rates reduced only for the subgroup of patients with an ICU stay of 3 days or more. Therefore, the available evidence is inconsistent in regard to the beneficial effects of normoglycaemia. Further progress in establishing the role of glycaemic control in critically ill patients certainly requires an excellent glucose measuring and reporting system. The system should be able to give fast and reliable results that can be used in a nurse-driven insulin infusion algorithm that reduces hyperglycemia without inducing hypoglycaemia. According to a Meta analysis conducted by American Diabetes Association, TGC in critically ill adult patients is not associated with significantly reduced hospital mortality. However, it is associated with an increased risk of hypoglycaemia. (Renda Soylemez Wiener et al 2008) Patients in ICU commonly have hyperglycemia, which is associated with increased morbidity and mortality. Several subsequent studies question the findings of the study by Van den Berghe et al which reported that intensive glucose control reduced mortality. However, the three subsequent studies in medical- and general-ICU patients did not demonstrate a mortality benefit with tight glucose control. Though intensive glucose control has been recommended various medical associations, it has been found that lowering blood glucose levels below about 140 to 180 mg/dL for patients in a general ICU did not provide added benefit, and levels below this can conversely harm the patients. (Marlene Busko 2009) Conclusion Further progress in establishing the role of glycaemic control in critically ill patients certainly requires an excellent glucose measuring and reporting system. The system should be able to give fast and reliable results that can be used in a nurse-driven insulin infusion algorithm that reduces hyperglycemia without inducing hypoglycaemia. Medicine experts assert that until further evidence becomes available, it would be reasonable to continue attempts to optimize the management of blood glucose rather than abandoning them. References: Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345:1359-1367. Biotransformation of Insulin Glargine After Subcutaneous Injection in Healthy Subjects from Current Medical Research and Opinion Posted 03/25/2003. G.U. Kuerzel, U. Shukla, H.E. Scholtz, S.G. Pretorius, D.H. 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Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaarden E, Bobbaers H, Bouillon R: Intensive insulin therapy in the medical ICU. N Engl J Med 2006, 354:449-461. Whitcomb BW, Pradhan EK, Pittas AG, Roghmann MC, Perencevich EN: Impact of admission hyperglycemia on hospital mortality in various intensive care unit populations. Crit Care Med 2005, 33:2772-2777. Read More