Use Of Intensive Insulin Therapy Research Articles

Glucose control after severe brain injury

A substantial body of evidence supports the use of intensive insulin therapy in general critical care practice, particularly in surgical intensive care unit patients. The impact of intensive insulin therapy on the outcome of critically ill neurological patients, however, is still controversial. While avoidance of hyperglycemia is recommended in neurointensive care, no recommendations exist regarding the optimal target for systemic glucose control after severe brain injury. An increase in brain metabolic demand leading to a deficiency in cerebral extracellular glucose has been observed in critically ill neurological patients and correlates with poor outcome. In this setting, a reduction of systemic glucose below 6 mmol/l with exogenous insulin has been found to exacerbate brain metabolic distress. Recent studies have confirmed these findings while showing intensive insulin therapy to have no substantial benefit on the outcome of critically ill neurological patients. Questions persist regarding the optimal target for glucose control after severe brain injury. Further studies are needed to analyze the impact of intensive insulin therapy on brain glucose metabolism and outcome of critically ill neurological patients. According to the available evidence, a less restrictive target for systemic glucose control (6-10 mmol/l) may be more appropriate.

Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis

The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate. The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

Indication and practical use of intensive insulin therapy in the critically ill

Two large randomized studies demonstrated that maintenance of normoglycemia with intensive insulin therapy for at least a few days decreases morbidity and mortality of critically ill patients. This review gives an overview of the benefits associated with this therapy and highlights the importance of achieving optimal blood glucose levels. It discusses the indications for this therapy and the fear for potential harm. A pooled analysis of the two Leuven studies (n = 2748) revealed a significantly reduced morbidity and mortality in critically ill patients for all subgroups, except those with a prior history of diabetes. An absolute reduction in risk of hospital death of 3-4% is to be expected from this therapy in an intention-to-treat analysis. When patients are treated for more than 3 days, the absolute reduction in risk of death increases to approximately 8%. The available data indicate that strict normoglycemia is required to obtain optimal clinical benefit. This increases the risk of hypoglycemia, but it remains unclear whether this is truly harmful in the setting of critical care. Maintaining strict normoglycemia by the use of intensive insulin therapy improves outcome of critically ill patients.

Effect of intensive insulin therapy on coagulation and fibrinolysis of respiratory critically ill patients

Most intensive care deaths beyond the first few days of critical illness are attributable to nonresolving multiple organ failure (MOF), either due to or coinciding with sepsis. One of the mechanisms that is thought to contribute to the pathogenesis of MOF is microvascular thrombosis. Recently, we reported improved survival and prevention of MOF of critically ill patients with the use of intensive insulin therapy to maintain normoglycemia for at least several days [1,2]. We hypothesize that intensive insulin therapy also prevents severe coagulation abnormalities, thereby contributing to less organ failure and better survival. We studied a subgroup of long-stay critically ill patients with a respiratory disease upon ICU admission, who had been enrolled in a randomized controlled trial evaluating the impact of intensive insulin therapy in medical ICU patients [2]. Plasma samples were analyzed for a panel of coagulation markers (prothrombin time, activated partial thromboplastin time, fibrinogen and D-dimer levels) that were used to assign points towards the International Society of Thrombosis and Haemostasis overt disseminate intravascular coagulation (DIC) score. Circulating plasma thrombin–antithrombin complexes and plasminogen inhibitor type 1 levels were also determined. As markers of inflammation, we measured circulating serum levels of several cytokines and CRP. Mortality of intensive insulin-treated patients was lower than of conventionally treated patients for all classes of upon-admission DIC score, except for those patients with a DIC score of 6 or higher. There was no effect of insulin therapy on any of the fibrinolytic, coagulation or inflammatory parameters tested. The accuracy of the DIC score to predict mortality in this patient sample was only moderate and comparable with that of CRP and the SOFA score. Also, circulating plasminogen inhibitor type 1 or thrombin–antithrombin complexes levels did not correlate well with mortality or DIC score. These findings indicate that the coagulation system did not play a key role in mediating the survival benefit of intensive insulin therapy.

Hyperglycemia During Critical Illness

We sought to review the literature describing the benefits of tight glycemic control in critically ill patients, comparing outcome differences in subgroup populations. We searched PubMed for relevant literature on the topic of hyperglycemia and its management in the intensive care unit. Overwhelming evidence in both surgical and medical patients conclusively demonstrates that hyperglycemia is a marker of severity of illness and is also an independent determinant of bad outcome, largely from infectious complications. Randomized trial evidence, in conjunction with historically controlled trials, supports the use of intensive insulin therapy and euglycemic control in critically ill patients, with nondiabetics possibly benefiting even more than diabetic patients. Euglycemia is best achieved, and hypoglycemia attenuated, through use of a protocolized approach. Further elaboration as to what threshold range defines euglycemia in patient subpopulations is needed and what pitfalls must be avoided in this practice. Development of continuous blood glucose monitoring has started and will someday be incorporated into routine practice in the same way that continuous electrocardiographic monitoring and pulse oximetry are standards of care in the intensive care unit. Hyperglycemia is a predictor of death and complications in critically ill patients. Early aggregated study results show that control of hyperglycemia improves outcomes. Well-designed studies involving thousands of patients have started to better elucidate the concomitant promoters of hyperglycemia and to better quantify the benefits from tight glycemic control.

Relationship Between Hyperglycemia and Infection in Critically Ill Patients

Hyperglycemia is a common problem encountered in hospitalized patients, especially in critically ill patients and those with diabetes mellitus. Uncontrolled hyperglycemia may be associated with complications such as fluid and electrolyte disturbances and increased infection risk. Studies have demonstrated impairment of host defenses, including decreased polymorphonuclear leukocyte mobilization, chemotaxis, and phagocytic activity related to hyperglycemia. Until 2001, hyperglycemia (blood glucose concentrations up to 220 mg/dl) had been tolerated in critically ill patients not only because high blood glucose concentrations were believed to be a normal physiologic reaction in stressed patients and excess glucose is necessary to support the energy needs of glucose-dependent organs, but also because the true significance of short-term hyperglycemia was not known. Recent clinical data show that the use of intensive insulin therapy to maintain tight blood glucose concentrations between 80 and 110 mg/dl decreases morbidity and mortality in critically ill surgical patients. Intensive insulin therapy minimizes derangements in normal host defense mechanisms and modulates release of inflammatory mediators. The principal benefit of intensive insulin therapy is a decrease in infection-related complications and mortality. Further research will define which patient populations will benefit most from intensive insulin therapy and firmly establish the blood glucose concentration at which benefits will be realized.

Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients

Maintenance of normoglycaemia by use of insulin reduces morbidity and mortality of patients in surgical intensive care. Studies on mitochondrial function in critical illness or diabetes suggest that effects of intensive insulin therapy on mitochondrial integrity contribute to the clinical benefits. Enzyme activities of the respiratory-chain complexes and oxidative-stress-sensitive glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were measured by spectrophotometry in 36 snap-frozen samples of liver and skeletal muscle obtained after death from patients who had been randomly assigned intensive (normoglycaemia) or conventional (hyperglycaemia) insulin therapy and who were similar in terms of admission diagnoses and causes of death. Mitochondrial ultrastructure was examined by electron microscopy in a random subgroup (n=20). In the liver, hypertrophic mitochondria with an increased number of abnormal and irregular cristae and reduced matrix electron density were observed in seven of nine conventionally treated patients. Only one of 11 patients given intensive insulin treatment had these morphological abnormalities (p=0.005). The effect on ultrastructure was associated with higher activities of respiratory-chain complex I (median 1.53 [IQR 1.14-3.01] vs 0.81 [0.54-1.43] U/g liver; p=0.008) and complex IV (1.69 [1.40-1.97] vs 1.16 [0.97-1.40] U/g; p=0.008) in the intensive group than in the conventional group. There was no detectable difference in GAPDH activity. In skeletal muscle, mitochondrial ultrastructure and function were not affected by intensive insulin therapy. Strict glycaemic control with intensive insulin therapy prevented or reversed ultrastructural and functional abnormalities of hepatocyte mitochondria. The lack of effect on skeletal-muscle mitochondria suggests a direct effect of glucose toxicity and glucose control, rather than of insulin, as the likely explanation. Maintenance or restoration of mitochondrial function and cellular energetics is another therapeutic target, in addition to optimisation of cardiac output, systemic oxygen delivery, and regional blood flow, that might improve outcome for critically ill patients. Our findings could help to explain the mechanism underlying the reduction in mortality found when normoglycaemia was maintained with insulin, and further support use of intensive insulin therapy in this setting.

Nocturnal hypoglycemia in patients with insulin-treated diabetes

While use of intensive insulin therapy has proven effective for reducing risk of long-term complications of hyperglycemia in people with diabetes, overnight hypoglycemia remains a significant barrier to intensive therapy. Findings from numerous studies indicate that nocturnal hypoglycemia is a frequent event among patients with type 1 diabetes, while severe hypoglycemic episodes are approximately three times more likely in patients on intensive insulin therapy than in those on conventional therapy. Nocturnal hypoglycemia remains frequent, even when specific approaches—use of short-acting insulin analogues to manage postprandial glucose surges, peakless long-acting insulin analogues as basal therapy, and strategically selected bedtime snacks—aim to avert this problem. Thus, nocturnal hypoglycemia continues to threaten the well-being of patients with diabetes and cause concerns for their family members and caregivers. Continuing research is required to improve methods for detection and prompt correction of hypoglycemia in order to achieve a safe level of euglycemia in people with diabetes.

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Reducing injection pain in children and adolescents with diabetes: a review of indwelling catheters.

Most children and adolescents find the pain when injecting insulin quite minimal but still significantly more painful than a placebo injection. However, injection pain and needle phobia are major problems for a small number of patients, even after many years of diabetes. Needle diameter is of less importance for the experienced pain. The use of indwelling catheters (Insuflon, Unomedical, Lynge, Denmark) for introducing insulin injections at the onset of diabetes results in an evident relief of preinjection anxiety, injection problems, and the procedural pain of repeated injections. The average indwelling time is 3-5 d. Fixation problems and local redness at the insertion site are the most frequent side effects. However, the frequency is low and they can be dealt with effectively. Needles of 8-10 mm should be used for injecting to avoid penetration of the tubing of the catheter. Using indwelling catheters for up to 4-5 d does not affect the absorption of insulin, when the catheter is inserted in an area free from lipohypertrophies. The long-term (measured by hemoglobin A1c) and short-term metabolic control (measured by blood glucose profiles and serum-free insulin) is not altered. Using this type of injection aid may decrease the risk of future injection problems, such as needle phobia, in very select patients. In conclusion, indwelling catheters can safely be used from the onset of diabetes to lessen injection pain in children and adolescents, and may facilitate the use of intensive insulin therapy in this age group.

Incorporation of beta cell redifferentiation therapy into a lipoprivic strategy for reversing type 2 diabetes

Type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM), at least in the majority of patients characterized by insulin resistance and increased visceral fat, appears to be precipitated by the exposure of tissues to excessive levels of free fatty acids; this can contribute to the muscle insulin resistance, excessive hepatic gluconeogenesis, and beta cell dysfunction that collaborate to impair glycemic control. The resultant hyperglycemia, in turn, exacerbates the insulin resistance and beta cells dysfunction. The failure of glucose-stimulated insulin secretion (GSIS) in beta cells helps to sustain the elevations of serum glucose and free fatty acids, which in turn reinforce the failure of GSIS, possibly by inhibiting expression of the transcription factor IDX-1; NIDDM thus represents a vicious cycle that is not easily broken. A new strategy for achieving rapid loss of body fat – hepatothermic therapy (HT), an integrated approach involving exercise training, low-fat, low-glycemic-index food choices, and a supplementation program that promotes hepatic fatty acid oxidation – shows promise for alleviating the excessive fat exposure at the root of the diabetic syndrome, as well as the underlying insulin resistance syndrome responsible for increased macrovascular risk. However, when HT proves incapable of breaking the vicious cycle sustaining beta cell dysfunction, a supplementary strategy, beta cell redifferentiation therapy (BRT), may be required. BRT consists of a protocol in which near-normoglycemia is maintained for several weeks through use of intensive insulin therapy (e.g. artificial pancreas) or other effective measures, during which time beta cell GSIS can be expected to substantially recover owing to relief from glucolipotoxicity. Clinical experience demonstrates that this improved beta cell function, in certain cases, can persist for months or years after temporary BRT. A portion of the improved glycemic control achieved with very low calorie diets in NIDDM is reflective of improved GSIS, presumably consequent to a sustained reduction in diurnal glycemia. Long-lived analogs of glucagon-like peptide-1 (GLP-1) may find a key role in BRT; this incretin hormone not only potentiates GSIS, but also appears to increase the expression and activity of IDX-1 in beta cells, thus promoting beta cell redifferentiation. If HT is instituted prior to and following BRT to alleviate the FFA overexposure that initially precipitated the diabetic syndrome, it seems likely that the benefits of BRT will be conserved in the long term, thus enabling a reversal of NIDDM – in other words, maintenance of normoglycemia without medication. Since NIDDM is inherently preventable, its reversal should be the fundamental goal of diabetes therapy.

Insulin therapy in Europe.

The prevalence of type 1 diabetes is rising in all European countries, particularly in Scandinavia and the UK. Insulin therapy in Europe is strongly influenced by the results of the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), both of which showed the importance of tight metabolic control in patients with diabetes. The importance of tight glycemic control is also emphasized in the Saint Vincent Declaration, which established 5-year goals for antidiabetic therapy in Europe. Insulin therapy in Europe has been significantly improved over the past 10 years, owing to a number of developments. These include increased use of intensive insulin therapy in patients with type 1 diabetes; the development of new insulin analogs, including insulin glargine for injection therapy and short-acting agents that are particularly suitable for use in pumps and the establishment of comprehensive and standardized treatment goals and guidelines. Nevertheless, important obstacles must still be overcome to optimize therapy for patients with diabetes and reduce the long-term complications of this disease. These obstacles include low public awareness of diabetes and its symptoms, training of physicians as well as patients that is often insufficient to ensure adherence to professional guidelines for diabetes care, and limitations in communication among professional care providers.

Pancreas Transplantation for the Prevention of Diabetic Nephropathy

Diabetic nephropathy is the leading cause of kidney failure in the United States. Poor glycemic control, hypertension, and smoking have been implicated as risk factors for the development and progression of diabetic nephropathy in patients with type 1 diabetes mellitus. Improved medical therapy including angiotensin-converting enzyme inhibitors and tight glycemic control with use of intensive insulin therapy have been shown to reduce the progression of diabetic nephropathy substantially based on albumin excretion rates. Despite these improvements in medical management, many patients still experience progression from early diabetic nephropathy to end-stage renal disease. Successful pancreas transplantation leads to normal glycemic control in patients with type 1 diabetes, but historically it has generally been limited to patients with both kidney failure and diabetes. In this review of the current treatment of diabetic nephropathy, we examine the potential role of preemptive pancreas transplantation in patients with diabetic nephropathy.