Biomedical subjects
Publications and source records attributed to Greet Van den Berghe.
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RATIONALE: Critical illness polyneuropathy/myopathy causes limb and respiratory muscle weakness, prolongs mechanical ventilation, and extends hospitalization of intensive care patients. Besides controlling risk factors, no specific prevention or treatment exists. Recently, intensive insulin therapy prevented critical illness polyneuropathy in a surgical intensive care unit. OBJECTIVES: To investigate the impact of intensive insulin therapy on polyneuropathy/myopathy and treatment with prolonged mechanical ventilation in medical patients in the intensive care unit for at least 7 days. METHODS: This was a prospectively planned subanalysis of a randomized controlled trial evaluating the effect of intensive insulin versus conventional therapy on morbidity and mortality in critically ill medical patients. All patients who were still in intensive care on Day 7 were screened weekly by electroneuromyography. The effect of intensive insulin therapy on critical illness polyneuropathy/myopathy and the relationship with duration of mechanical ventilation were assessed. MEASUREMENTS AND MAIN RESULTS: Independent of risk factors, intensive insulin therapy reduced incidence of critical illness polyneuropathy/myopathy (107/212 [50.5%] to 81/208 [38.9%], p = 0.02). Treatment with prolonged (> or = 14 d) mechanical ventilation was reduced from 99 of 212 (46.7%) to 72 of 208 (34.6%) (p = 0.01). This was statistically only partially explained by prevention of critical illness polyneuropathy/myopathy. CONCLUSION: In a subset of medical patients in the intensive care unit for at least 7 days, enrolled in a randomized controlled trial of intensive insulin therapy, those assigned to intensive insulin therapy had a reduced incidence of critical illness polyneuropathy/myopathy and were treated with prolonged mechanical ventilation less frequently.
CONTEXT: Both excessive and insufficient activation of the hypothalamic-pituitary-adrenal axis in response to critical illness is associated with increased mortality. OBJECTIVE: The objective of the study was to study the effect of intensive insulin therapy, recently shown to reduce mortality and morbidity of critically ill patients, on the cortisol response to critical illness. DESIGN: This was a preplanned subanalysis of a large randomized, controlled study measuring serum total cortisol, cortisol-binding globulin, and albumin and calculating free cortisol levels. SETTING: The study was conducted at a university hospital surgical intensive care unit. PATIENTS: Four hundred fifty-one critically ill patients dependent on intensive care for more than 5 d and 45 control subjects matched for gender, age, height, and weight participated in this study. INTERVENTION: The intervention was strict blood glucose control to normoglycemia with insulin. RESULTS: Total and calculated free cortisol levels were equally elevated upon admission in both patient groups and thereafter were lower in intensive insulin-treated patients. Lower cortisol levels statistically related to the outcome benefit of intensive insulin therapy. Cortisol-binding globulin levels and structure were affected by critical illness but not insulin therapy, and neither were albumin levels. Administration of hydrocortisone in so-called replacement dose resulted in severalfold higher total and free cortisol levels, indicating that reevaluation of the doses used is warranted. CONCLUSIONS: Lower serum cortisol levels in critically ill patients receiving intensive insulin therapy statistically related to improved outcome with this intervention. The lower cortisol levels were not related to altered cortisol-binding capacity.
AIMS: To document the impact of intensive insulin therapy during intensive care on long-term (4 years) outcome of high-risk cardiac surgery patients. METHODS AND RESULTS: In this pre-planned sub-analysis and follow-up study of a large, randomized controlled trial on the effects of intensive insulin therapy during critical illness, we assessed long-term outcome in the 970 patients who had been admitted after high-risk cardiac surgery (mean+/-SD EuroSCORE of 6.0+/-3.7; EuroSCORE-predicted hospital mortality of 9.9%; observed hospital mortality of 7.5% in the conventional insulin group and 3.4% in the intensive insulin group). Long-term outcome was quantified as: (a) 4 years survival; (b) incidence of hospital re-admission; (c) level of activity and medical care requirements at 4 years as assessed by the Karnofsky score; and (d) perceived health-related quality-of-life at 4 years as assessed by the Nottingham Health Profile. Four years after ICU admission, the number of post-hospital discharge deaths was similar in the two study groups, reflecting maintenance of the acute survival benefit with intensive insulin therapy. Survivors who had been treated with intensive insulin during ICU stay revealed a similar risk for hospital re-admission and a comparable level of dependency on medical care. There was no effect on quality-of-life in the total group, whereas the increased survival of sicker patients with at least 3 days of insulin therapy evoked a more compromised perceived quality-of-life, in particular regarding social and family life. CONCLUSION: The short-term survival benefit obtained with insulin-titrated glycaemic control during intensive care after cardiac surgery was maintained after 4 years, without inducing increased medical care requirements but possibly at the expense of compromised perceived quality of social and family life.
BACKGROUND: Intensive insulin therapy reduces morbidity and mortality in patients in surgical intensive care units (ICUs), but its role in patients in medical ICUs is unknown. METHODS: In a prospective, randomized, controlled study of adult patients admitted to our medical ICU, we studied patients who were considered to need intensive care for at least three days. On admission, patients were randomly assigned to strict normalization of blood glucose levels (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) with the use of insulin infusion or to conventional therapy (insulin administered when the blood glucose level exceeded 215 mg per deciliter [12 mmol per liter], with the infusion tapered when the level fell below 180 mg per deciliter [10 mmol per liter]). There was a history of diabetes in 16.9 percent of the patients. RESULTS: In the intention-to-treat analysis of 1200 patients, intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality (40.0 percent in the conventional-treatment group vs. 37.3 percent in the intensive-treatment group, P=0.33). However, morbidity was significantly reduced by the prevention of newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital. Although length of stay in the ICU could not be predicted on admission, among 433 patients who stayed in the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy. In contrast, among 767 patients who stayed in the ICU for three or more days, in-hospital mortality in the 386 who received intensive insulin therapy was reduced from 52.5 to 43.0 percent (P=0.009) and morbidity was also reduced. CONCLUSIONS: Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy. Further studies are needed to confirm these preliminary data. (ClinicalTrials.gov number, NCT00115479.)
Interest in the somatotropic axis, with its complex network of interactions, during critical illness started only a few decades ago. The distinguished neuroendocrine features of prolonged critically ill patients were not differentiated from those during the acute phase until the 1990s. This incomplete understanding of the somatotropic axis has contributed to some disastrous results. Aiming to stimulate the somatotropic axis without a proper preceding neuroendocrine diagnosis should be held obsolete, because recent data indicate that the patient with the best anabolic parameters may not necessarily be the most favored to survive the ICU stay. Moreover, the fascinating link between regulators of carbohydrate metabolism, such as insulin and insulin-like growth factor 1, and the somatotropic axis may lead to future therapeutic possibilities.
Striking alterations in the hypothalamic-anterior pituitary-peripheral hormone axes hallmark the state of critical illness, their severity being associated with high risk for morbidity and mortality. Early endocrine intervention strategies aimed to correct the hormone balance have been shown ineffective or even harmful because of lack of thorough pathophysiologic understanding of these neuroendocrine changes. Extensive research, however, has provided crucial insights, with the demonstration of the biphasic response of the anterior pituitary to the severe stress of critical illness.
Hyperglycemia is a common feature of the critically ill patient and has been associated with increased mortality. Maintaining normoglycemia with insulin therapy improves survival and reduces morbidity in surgical ICU patients, as shown by a large randomized controlled study. Prevention of glucose toxicity by strict glycemic control but also other metabolic and non-metabolic effects of insulin contribute to these clinical benefits.
Critically ill patients usually develop hyperglycemia, a condition referred to as "diabetes of injury." More and more evidence argues against the concept that this is an adaptive beneficial response. Indeed, the development of hyperglycemia seems to be detrimental for the outcome of critically ill patients, because maintenance of normoglycemia with intensive insulin therapy prevents morbidity and reduces mortality of critically ill patients to a large extent. The mechanisms underlying these clinical benefits are being studied further.
The severity of striking alterations in the hypothalamic-anterior pituitary-peripheral hormone axes, which are the hallmark of severity of critical illness, is associated with a high risk for morbidity and mortality. Most attempts to correct the hormone balance are ineffective or harmful because of lack of pathophysiologic understanding. Extensive research has provided more insight in the biphasic neuroendocrine response to critical illness: the acute phase is characterized by an actively secreting pituitary but low peripheral effector hormone levels. In contrast, in prolonged critical illness, uniform suppression of the neuroendocrine axes, predominantly of hypothalamic origin, contributes to low serum levels of the respective target-organ hormones.
This article reviews the mechanisms behind the observed changes in plasma thyroid hormone levels in the acute phase and the prolonged phase of critical illness. It focuses on the neuroendocrinology of the low triiodothyronine syndrome and on thyroid hormone metabolism by deiodination and transport.
Interest in the somatotropic axis,with its complex network of interactions, during critical illness arose only a few decades ago. Te distinguishing neuroendocrine features of prolonged critical illness were not differentiated from those during the acute phase until the early 1990s. This incomplete understanding of the somatotropic axis contributed to some disastrous results, such as the multicenter growth hormone trial. The goal of stimulating the somatotropic axis without a proper preceding neuroendocrine diagnosis should be held obsolete. Moreover, the fascinating link between regulators of carbohydrate metabolism, such as insulin and insulin-like growth factor I, and the somatotropic axis may lead to future therapeutic possibilities.
Critical illness is characterized by striking alterations in the hypothalamic-anterior-pituitary-peripheral-hormone axes, the severity of which is associated with a high risk of morbidity and mortality. Most attempts to correct hormone balance have been shown ineffective or even harmful because of a lack of pathophysiologic insight. There is a biphasic (neuro)endocrine response to critical illness. The acute phase is characterized by an actively secreting pituitary, but the concentrations of most peripheral effector hormones are low, partly due to the development of target-organ resistance. In contrast, in prolonged critical illness, uniform (predominantly hypothalamic) suppression of the (neuro)endocrine axes contributes to the low serum levels of the respective target-organ hormones. The adaptations in the acute phase are considered to be beneficial for short-term survival. In the chronic phase, however, the observed (neuro)endocrine alterations appear to contribute to the general wasting syndrome. With the exception of intensive insulin therapy, and perhaps hydrocortisone administration for a subgroup of patients, no hormonal intervention has proven to beneficially affect outcome. The combined administration of hypothalamic releasing factors does, however, hold promise as a safe therapy to reverse the (neuro)endocrine and metabolic abnormalities of prolonged critical illness by concomitant reactivation of the different anterior-pituitary axes.
OBJECTIVE: To perform an analysis of healthcare resource utilization with intensive insulin therapy, which has recently been shown to reduce morbidity and mortality rates of mechanically ventilated critically ill patients in a surgical intensive care unit. DESIGN: A post hoc cost analysis. SETTING: Surgical intensive care unit. PATIENTS: Patients were 1548 mechanically ventilated patients admitted to a surgical intensive care unit. INTERVENTIONS: A post hoc cost analysis was conducted based on data collected prospectively as part of a large randomized controlled trial. The analysis performed was a healthcare resource utilization analysis in which the cost of hospitalization in the intensive care unit was determined based on length of stay and the frequency of crucial cost-generating morbid events occurring in the intensive and conventional insulin treatment groups. Sensitivity analyses were performed to evaluate the robustness of the findings. Discounting of costs was not performed as treatment was limited to the intensive care stay and follow-up was not continued beyond hospitalization. MEASUREMENTS AND MAIN RESULTS: In the intensive treatment group, total treatment cost was 109,838 Euros (144 Euros per patient). In the conventional treatment group, total treatment cost was 56,359 Euros (72 Euros per patient). The excess cost of intensive insulin therapy was 72 Euros per patient. The total hospitalization cost in the intensive treatment group was 6,067,237 Euros (7931 Euros per patient) compared with 8,275,394 Euros (10,569 Euros per patient) in the conventional treatment group. The excess cost of intensive care unit hospitalization in the conventional vs. intensive treatment group was 2638 Euros per patient. These intensive care unit benefits were not offset by additional costs for care on regular wards. CONCLUSIONS: Intensive insulin therapy, which reduces morbidity and mortality rates of mechanically ventilated patients admitted to a surgical intensive care unit, is associated with substantial cost savings compared with conventional insulin therapy.
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PURPOSE OF REVIEW: The importance of glucose metabolism and insulin therapy during myocardial ischaemia is increasingly being investigated. Insulin is used to achieve a tight glucose control or as part of glucose-insulin-potassium therapy. We have reviewed (1) the physiological and physiopathological consequences of hyperglycaemia focusing on potential machanisms of myocardial ischaemia, (2) the effects of insulin on vascular tone, on the release of free fatty acids, on inflammatory pathways, on the switch of energy source and on apoptosis, and (3) clinical data reporting the effects of intensive insulin therapy and glucose-insulin-potassium solutions during myocardial ischaemia and ischaemic heart failure. RECENT FINDINGS: In addition to its known toxic cellular effects, hyperglycaemia increases the activity of inducible nitric oxide synthase and promotes inflammation. Conversely insulin exerts anti-inflammatory and anti-apoptotic effects. Glucose-insulin-potassium solutions could improve survival after acute myocardial infarction or after surgery, according to recent meta-analyses, but confirmation of these data is eagerly awaited. SUMMARY: Hyperglycaemia is toxic, while insulin is beneficial during acute myocardial ischaemia. Some recent evidence confirms a substantial benefit of insulin administered either alone to achieve a tight glucose control or as a component of glucose-insulin-potassium therapy. Further research is needed to confirm that tendency and to define the threshold of tight glucose control.
Critically ill patients who depend on intensive care for more than a few days reveal profound erosion of lean body mass, which is thought to contribute to high morbidity and mortality. Despite a shortfall of evidence that supplemental feeding actually alters clinical outcome of these life-threatening disease states, this observation evoked an almost universal, albeit often inappropriate, use of nutritional support (NS) in the critically ill, administered via the parenteral or the enteral route. Lack of knowledge and overenthusiasm subsequently resulted in complications associated with both parenteral nutrition (PN) and enteral nutrition (EN), which led to the standing controversy over which should be preferred. With time, however, it became clear that EN and PN are not mutually exclusive and that critically ill patients requiring NS should be fed according to the functional status of the gastrointestinal tract. In addition, tight blood glucose control with insulin is advised in fed critically ill patients because overall metabolic control appears to surpass any outcome benefit attributed to the route of feeding. Recently, various special nutritional formulas have been suggested to prevent or treat multiorgan failure in the critically ill, among other pathways via modulation of immune function. Although special nutritional formulas may be promising in a variety of clinical settings, based on currently available data, these cannot be recommended for routine use in critically ill patients.
Intensive insulin therapy (IIT) improves the outcome of prolonged critically ill patients, but concerns remain regarding potential harm and the optimal blood glucose level. These questions were addressed using the pooled dataset of two randomized controlled trials. Independent of parenteral glucose load, IIT reduced mortality from 23.6 to 20.4% in the intention-to-treat group (n = 2,748; P = 0.04) and from 37.9 to 30.1% among long stayers (n = 1,389; P = 0.002), with no difference among short stayers (8.9 vs. 10.4%; n = 1,359; P = 0.4). Compared with blood glucose of 110-150 mg/dl, mortality was higher with blood glucose >150 mg/dl (odds ratio 1.38 [95% CI 1.10-1.75]; P = 0.007) and lower with <110 mg/dl (0.77 [0.61-0.96]; P = 0.02). Only patients with diabetes (n = 407) showed no survival benefit of IIT. Prevention of kidney injury and critical illness polyneuropathy required blood glucose strictly <110 mg/day, but this level carried the highest risk of hypoglycemia. Within 24 h of hypoglycemia, three patients in the conventional and one in the IIT group died (P = 0.0004) without difference in hospital mortality. No new neurological problems occurred in survivors who experienced hypoglycemia in intensive care units (ICUs). We conclude that IIT reduces mortality of all medical/surgical ICU patients, except those with a prior history of diabetes, and does not cause harm. A blood glucose target <110 mg/day was most effective but also carried the highest risk of hypoglycemia.