Stress Of Critical Illness Research Articles

CRRT-associated ketoacidosis: Aseriesof5cases.

Continuous renal replacement therapy (CRRT) is a dialysis modality used in critically ill patients with acute kidney injury (AKI). Although most dialysate and replacement fluids are dextrose-containing, CRRT-associated hypophosphatemia sometimes warrants the use of phosphorus-containing solutions which are dextrose free. The other less commonly used dextrose-free dialysate solutions are certain formulations of Prismasol and Prismasate. As glucose is a small molecule, which is readily cleared with dialysis, use of these solutions can result in increased caloric loss, net glucose deficit, and shifting of the metabolic pathway towards gluconeogenesis and ketogenesis. Starvation ketosis is usually a benign entity, however when combined with factors such as stress of critical illness, can produce metabolic acidosis which at times can be severe. We describe five patients who developed worsening metabolic acidosis despite adequate clearance from CRRT and were diagnosed with CRRT-associated ketoacidosis. Administration of dextrose-containing fluids or tube feeds promptly resulted in resolution of ketonemia and acidosis. Recognition of this entity is of great importance as the reflexive reaction to increase the prescribed dose of CRRT to improve the acidosis, in fact worsens the problem.

Micronutrient deficiencies in critical illness

Low micronutrient levels in critical illness have been reported in multiple studies. Because of the antioxidant properties of various micronutrients, micronutrient deficiency may augment oxidative stress in critical illness. However, it remains unclear whether micronutrient concentrations in ICU patients are different from those in healthy age-matched controls. It is also unclear whether micronutrient deficiency develops, worsens, or resolves during ICU admission without supplementation. We prospectively studied a cohort of adult critically ill patients. Micronutrient levels, including selenium, β-carotene, vitamin C, E, B1 and B6 were measured repeatedly during the first week of ICU admission. We compared the micronutrient concentrations at ICU admission to those of healthy age-matched controls. In addition, associations between micronutrient concentrations with severity of illness, inflammation and micronutrient intake were investigated. Micronutrient blood concentrations were obtained from 24 critically ill adults and 21 age-matched healthy controls. The mean micronutrient levels at admission in the ICU patients were: selenium 0.52μmol/l, β-carotene 0.17μmol/l, vitamin C 21.5μmol/l, vitamin E 20.3μmol/l, vitamin B1 129.5nmol/l and vitamin B6 41.0nmol/l. In the healthy controls micronutrient levels of selenium (0.90μmol/l), β-carotene (0.50μmol/l), vitamin C (45μmol/l) and vitamin E (35.5μmol/l) were significantly higher, while vitamin B1 (122nmol/l) and B6 (44nmol/l) were not significantly different between patients and controls. Selenium, vitamin B1 and vitamin B6 levels remained stable during ICU admission. Vitamin C levels dropped significantly until day 5 (p<0.01). Vitamin E and β-carotene levels increased significantly on days 5-7 and day 7, respectively (p<0.01). Micronutrient levels were not associated with severity of illness, CRP or micronutrient intake during the admission. At admission, ICU patients already had lower plasma levels of selenium, β-carotene, vitamin C and vitamin E than healthy controls. Vitamin C levels dropped significantly during the first days of ICU admission, while β-carotene and vitamin E levels increased after 5-7 days. No association between micronutrient levels and severity of illness, C-reactive protein (CRP) or micronutrient intake was found. Progressive enteral tube feeding containing vitamins and trace elements does not normalize plasma levels in the first week of ICU stay. This was a hypothesis generating study and more investigation in a larger more diverse sample is needed.

Clinical Study of Hyperglycemia and SARS-CoV-2 Infection in Intensive Care Unit Patients.

Reports indicate that coronaviridae may inhibit insulin secretion. In this report we aimed to describe the course of glycemia in critically ill patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We studied 36 SARS-CoV-2 patients (with no history of diabetes) in one intensive care unit (ICU). All the patients were admitted for hypoxemic respiratory failure; all but four required mechanical ventilation. The mean (±SD) age of the patients was 64.7 (9.7) years; 27 were men; the mean (±SD) duration of ICU stay was 12.9 (8.3 days). Twenty of 36 patients presented with hyperglycemia; brief intravenous infusions of short-acting insulin were administered in six patients. As of May 29 2020, 11 patients had died (seven with hyperglycemia). In 17 patients the Hyperglycemia Index [HGI; defined as the area under the curve of (hyper)glycemia level*time (h) divided by the total time in the ICU] was <16.21 mg/dl (0.90 mmol/l), whereas in three patients the HGI was ≥16.21 mg/dl (0.90 mol/l) and <32.25 mg/dl (1.79 mmol/l). In our series of ICU patients with SARS-CoV-2 infection, and no history of diabetes, a substantial number of patients had hyperglycemia, to a higher degree than would be expected by the stress of critical illness, lending credence to reports that speculated a tentative association between SARS-CoV-2 and hyperglycemia. This finding is important, since hyperglycemia can lead to further infectious complications.

Mitochondrial Dysfunction in Critical Illness: Implications for Nutritional Therapy.

This paper will review the evidence for mitochondrial dysfunction in critical illness, describe the mechanisms which lead to multiple organ failure, and detail the implications of this pathophysiologic process on nutritional therapy. Mitochondria are particularly sensitive to increased oxidative stress in critical illness. The functional and structural abnormalities which occur in this organelle contribute further to the excessive production of reactive oxygen species and the reduction in generation of adenosine triphosphate (ATP). To reduce metabolic demand, mitochondrial dysfunction develops (a process likened to hibernation), which helps sustain the life of the cell at a cost of organ system failure. Aggressive feeding in the early phases of critical illness might inappropriately increase demand at a time when ATP production is limited, further jeopardizing cell survival and potentiating the processes leading to multiple organ failure. Several potential therapies exist which would promote mitochondrial function in the intensive care setting through support of autophagy, antioxidant defense systems, and the biogenesis and recovery of the organelle itself. Nutritional therapy should supplement micronutrients required in the mitochondrial metabolic pathways and provide reduced delivery of macronutrients through slower advancement of feeding in the early phases of critical illness. A better understanding of mitochondrial dysfunction in the critically ill patient should lead to more innovative therapies in the future.

The microbiome: implications for perioperative and critical care.

The host-microbiota relationship is integral in human health and can be rapidly disrupted in ways that may contribute to poor recovery from surgery or acute illness. We review key studies by organ system to understand the effect of perioperative and critical illness stress on the microbiota. Throughout the review, our focus is on potential interventions that may be mediated by the microbiome. Although any perioperative intervention can have a profound impact on the gut microbiota, it is less clear how such changes translate into altered health outcomes. Preoperative stress (anxiety, lack of sleep, fasting), intraoperative stress (surgery itself, volatile anesthetics, perioperative antibiotics, blood transfusions), and postoperative stress (sepsis, surgical site infections, acute respiratory distress syndrome, catecholamines, antibiotics, opioids, proton pump inhibitors) have all been associated with alterations of the commensal microflora. These factors (e.g. administration of antibiotics or opioids) can create a favorable environment for emergence of pathogen virulence and development of serious infections and multiorgan failure. Data to recommend therapies aimed at restoring a disrupted microbiota, such as probiotics/prebiotics and fecal microbiota transplants is currently scarce. The microbiome is likely to play an important role in the perioperative and ICU setting but existing data is largely descriptive. There is an expanding number of mechanistic studies that attempt to disentangle the complicated bi-directional relationship between the host and the resident microbiota. When these results are combined with ongoing clinical studies, we should be able to offer better therapies aimed at restoring the microbiota in the future.

Whole Blood Redox Potential Correlates With Progressive Accumulation of Oxygen Debt and Acts as A Marker of Resuscitation in A Swine Hemorrhagic Shock Model.

Oxidation-reduction reactions involve electron exchanges that require optimal balance for proper cell function. This balance is measured via redox potential and reflects oxidative stress. Despite the critical role of oxidative stress in critical illness and injury, little is known regarding redox potential. We hypothesize redox potential measurements will correlate with accumulation of O2 debt produced by hemorrhage over time. Ten swine were studied using a polytrauma hemorrhagic shock model. Whole blood and plasma redox potential measures were obtained at defined stages of O2 debt (20 mL/kg, 40 mL/kg, 60 mL/kg, 80 mL/kg), and through resuscitation. Redox potential was determined by measuring open circuit potential using novel gold nanoporous electrodes with Ag/AgCl reference. Whole blood redox potential showed negative change as O2 debt accumulated, exhibiting positive response during resuscitation, and correlated with O2 debt across all animals (P < 0.001). Redox potential changes throughout O2 debt accrual were significant compared with baseline (P≤0.05), and at end resuscitation compared with O2 debt 60 mL/kg (P = 0.05) and 80 mL/kg (P = 0.02). Whole blood redox potential measures also correlated with oxygen extraction ratio, ScvO2, and lactic acid, appearing very sensitive to acute changes. Plasma redox potential showed no correlation with O2 debt. Whole blood redox potential demonstrates significant correlation to O2 debt at all stages in this model. These results set the stage for further study of redox potential as a direct measure of oxidative stress and potential clinical tool. Given redox potential plasma performance, these measures should be made in whole blood versus plasma.

Increased Dicarbonyl Stress as a Novel Mechanism of Multi-Organ Failure in Critical Illness

Molecular pathological pathways leading to multi-organ failure in critical illness are progressively being unravelled. However, attempts to modulate these pathways have not yet improved the clinical outcome. Therefore, new targetable mechanisms should be investigated. We hypothesize that increased dicarbonyl stress is such a mechanism. Dicarbonyl stress is the accumulation of dicarbonyl metabolites (i.e., methylglyoxal, glyoxal, and 3-deoxyglucosone) that damages intracellular proteins, modifies extracellular matrix proteins, and alters plasma proteins. Increased dicarbonyl stress has been shown to impair the renal, cardiovascular, and central nervous system function, and possibly also the hepatic and respiratory function. In addition to hyperglycaemia, hypoxia and inflammation can cause increased dicarbonyl stress, and these conditions are prevalent in critical illness. Hypoxia and inflammation have been shown to drive the rapid intracellular accumulation of reactive dicarbonyls, i.e., through reduced glyoxalase-1 activity, which is the key enzyme in the dicarbonyl detoxification enzyme system. In critical illness, hypoxia and inflammation, with or without hyperglycaemia, could thus increase dicarbonyl stress in a way that might contribute to multi-organ failure. Thus, we hypothesize that increased dicarbonyl stress in critical illness, such as sepsis and major trauma, contributes to the development of multi-organ failure. This mechanism has the potential for new therapeutic intervention in critical care.

Pilot Mechanistic Study of Insulin Modulation of Somatotrophic Hormones, Inflammation, and Lipid Metabolism During Critical Illness in Children.

To evaluate the mechanism of insulin modulation on somatotrophic response, inflammation, and lipid metabolism in critically ill children. Open-label randomized mechanistic study. Two-center, tertiary PICU study. Thirty critically ill children between 1 month and 14 years old, requiring mechanical ventilation and with evidence of two or more organ system failures. Randomized physiologic design of hyperinsulinemic-euglycemic clamp using continuous insulin infusion at 0.1 U/kg/hr versus conventional management. Thirteen children underwent hyperinsulinemic-euglycemic clamp. Blood samples for somatotrophic, inflammatory, and metabolic evaluation were obtained before randomization, and 24 and 72 hours later. A growth hormone oscillation profile was obtained during the first night. There was no difference between groups at baseline. Growth hormone resistance, increased proinflammatory cytokines, and increased lipolysis with low lipoprotein levels were present in all patients. Hyperinsulinemic-euglycemic clamp did not affect growth hormone, insulin-like growth factor-1 or insulin-like growth factor binding protein-3 levels. By day 2, insulin reduced insulin-like growth factor binding protein-1 levels. Tumor necrosis factor-α and interleukin-1β were similar in both groups, whereas interleukin-6 levels reduced over time only in children receiving hyperinsulinemic-euglycemic clamp. Hyperinsulinemic-euglycemic clamp also decreased free fatty acid levels, which was accompanied by increased low-density lipoprotein cholesterol and relative increase in high-density lipoprotein levels. Total cholesterol and triglycerides were unchanged. Insulin does not reverse most of the somatotrophic changes induced by the stress of critical illness. Rather, it may improve lipid metabolism and down-regulate some markers of the inflammatory response.

An unusual case of central diabetes insipidus &amp; hyperglycemic hyperosmolar state following cardiorespiratory arrest

BackgroundWe are describing an unusual case of severe hyperglycemia and hypernatremia, resistant to treatment.Case presentationA thirty year old female with adenocarcinoma of rectum was admitted with increasing lethargy, headache and drowsiness. She deteriorated rapidly and had cardiac arrest, following which she remained comatose. Her initial serum glucose and sodium were normal, but after receiving dexamethasone and mannitol, the serum glucose progressively increased to 54.7 mmol/L and sodium to 175 mmol/L, despite receiving very high dose of intravenous (IV) insulin infusion. She was evaluated for diabetes insipidus because of continued polyuria even after correction of hyperglycemia. Her serum osmolality was 337 mmol/kg, and urine osmolality was 141 mmol/kg which rose to 382 mmol/kg, after receiving 4 mcg of IV Desmopressin.ConclusionOur patient developed central diabetes insipidus post cardiac arrest and severe dehydration because of diabetes insipidus. Stress of critical illness, dehydration, dexamethasone and IV dextrose infusion were likely responsible for this degree of severe and resistant to treatment hyperglycemia.

Managing stress in critical illness

Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD *See also p. 3283. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. The author is employed by the National Institutes of Health (NIH).

59 Effect of Insulin on the Metabolic and Neuroendocrine Stress Responses to Critical Illness in Children

Background/aims: Neuroimmunoendocrine and metabolic dysfunctions are present in critical illness. We investigated whether insulin could reverse or limit these changes.Methods: Open-label randomized controlled physiology study of the effects of insulin during critical illness. 31 children with multiple organ dysfunction syndrome were recruited: 13children received continuous insulin infusion (0.1Unit/Kg/hr) and glucose was added if required to maintain glucose levels between 4.5 and 7.0mmol/L. Blood samples for neuroimmunoendocrine and metabolic evaluation were obtained before randomization, and 24 and 72hours later. A growth hormone(GH) oscillation profile was obtained during the first night.Results: At baseline both groups were similar. There was also no absolute difference in between the groups, at any time, in GH, IGF-1 and IGFBP-3. GH had higher relative increase in children receiving insulin, which suggests worsened GH resistance. By day 2, insulin decreased IGFBP-1 levels. At the same time insulin decreased free fatty acid levels, which was accompanied by increased LDL cholesterol and relative increase in HDL levels. Total cholesterol and triglycerides were unchanged. TNF-alpha and interleukin(IL)-1beta decreased in both groups, whereas IL-6 levels were significantly reduced significantly in children receiving insulin.Conclusions: Insulin does not reverse most of the neuroendocrine changes induced by stress of critical illness. However, it does appear to improve lipid metabolism (preserved LDL and HDL cholesterol) and down-regulate inflammation (decreased IL-6). These findings suggest that insulin in critical illness acts as a modulator of lipid dysfunction, which suggests new targets for future investigations. Figure 1 Insulin effect on neuroendocrine, metabolic and inflammatory stress responses. There was no absolute difference in GH, IGF-1 and IFGBP-3 levels between groups at any time (A, B, C), but insulin decreased IGFBP-1 levels on day 2 (D). Insulin also decreased FFA (E) levels, which was accompanied by an increase in LDL cholesterol (F) and a percentage increase in HDL levels on day 2 (G). TNF-alpha decreased in both groups, byt Il-6 levels reduced significantly only in children receiving.

Potential effects of stress in critical illness through the role of stress neuropeptides

To critically review evidence on the hypothesis that the multitude of cognitive and psychological stressors perceived by critically ill individuals may contribute to the development of pathophysiologic sequlae through modulation of the levels of stress neuropeptides. Critically ill individuals experience high levels of stress and intense adverse emotions. Although psychological stress has long been recognized as a factor in disease, and despite the nursing tenet on the importance of patients' psychological responses, in critical care, the potential physiologic effects of stress have received little attention. DESIGN, METHODS: Narrative critical review. Databases searched included Medline, CINAHL, PubMed and the Cochrane Library. Evidence on the role of stress neuropeptides and pertinent findings in critically ill individuals are reviewed. Limbic and extra-limbic brain structures along with specific stress neuropeptides [corticotrophin releasing hormone (CRH), adrenocorticotropin hormone (ACTH), neuropeptide Y , vasopressin, prolactin, oxytocin, substance P, cholecystokinin, endorphins, enkephalins, somatostatin, noradrenaline, melatonin] are involved in emotional and stress responses. Research evidence indicates that stress neuropeptide levels may be altered in critical illness. Moreover, they mediate processes such as immunity, endothelial response and oxidative stress. A framework for future research and practice is presented. It is probable that, in critical illness, psychological stress accentuates pathophysiological sequlae, through release of neuropeptides. The role of neuropeptides is suggested as an important field of investigation for critical care nursing. However, currently available data are insufficient to draw firm conclusions. Focussed studies on the physiologic correlates of psychological stress in the critically ill are needed. If this hypothesis is corroborated, bedside quantification of selected neuropeptides may contribute to the assessment of stress and of the effectiveness of psychological support interventions in the future. Moreover, psychosocial and, probably, pharmacological support interventions may be effective adjuncts to the care of the critically ill.

Implementation of an Inpatient Diabetes Management Team in the University Hospital Setting

A long history of clinical evidence points out the untoward effects of hyperglycemia in humans. Hyperglycemia acutely impairs leukocyte function, immunoglobulin action, wound healing, cardiac metabolism, glomerular filtration, and endothelial function.1 In addition, the stress of critical illness causes an increase in counterregulatory hormones. This leads to alterations in carbohydrate metabolism by increasing peripheral glucose demand and enhancing hepatic glucose production and insulin resistance, which results in a relative insulin deficiency and hyperglycemia.2 Moreover, clinical interventions also predispose patients to hyperglycemia, particularly the use of corticosteroids, vasopressors, and enteral or parenteral nutrition.3 In a study by Umpierrez et al.,4 hyperglycemia (defined as a fasting blood glucose level > 126 mg/dl or a random blood glucose level > 200 mg/dl on two separate occasions) occurred in 38% of hospitalized patients. Twenty-six percent of these patients with hyperglycemia had a known history of diabetes, but 12% had no history of diabetes. Newly discovered hyperglycemia was associated with longer hospital stays, higher admission rates to the intensive care unit, and a greater chance of being discharged to a rehabilitation facility than of being discharged home. The take-home message is that hyperglycemia is common in patients during hospitalization, and this hyperglycemia is associated with adverse outcomes. A variety of approaches, most involving development and use of intensive insulin therapy protocols to improve glucose management in the hospital setting, seem to improve metabolic outcomes. Whether these approaches improve actual outcomes of morbidity and mortality is not yet known outside of the critical care setting. Several early clinical trials suggest a benefit of intensive glucose control in the critical care setting on morbidity (especially infection), length of stay, hospital costs, and mortality in selected groups of patients.5,6 More recently, clinical trials involving intensive insulin therapy in critical care units …

Sympathetic Overstimulation During Critical Illness: Adverse Effects of Adrenergic Stress

The term ''adrenergic'' originates from ''adrenaline'' and describes hormones or drugs whose effects are similar to those of epinephrine. Adrenergic stress is mediated by stimulation of adrenergic receptors and activation of post-receptor pathways. Critical illness is a potent stimulus of the sympathetic nervous system. It is undisputable that the adrenergic-driven ''fight-flight response'' is a physiologically meaningful reaction allowing humans to survive during evolution. However, in critical illness an overshooting stimulation of the sympathetic nervous system may well exceed in time and scope its beneficial effects. Comparable to the overwhelming immune response during sepsis, adrenergic stress in critical illness may get out of control and cause adverse effects. Several organ systems may be affected. The heart seems to be most susceptible to sympathetic overstimulation. Detrimental effects include impaired diastolic function, tachycardia and tachyarrhythmia, myocardial ischemia, stunning, apoptosis and necrosis. Adverse catecholamine effects have been observed in other organs such as the lungs (pulmonary edema, elevated pulmonary arterial pressures), the coagulation (hypercoagulability, thrombus formation), gastrointestinal (hypoperfusion, inhibition of peristalsis), endocrinologic (decreased prolactin, thyroid and growth hormone secretion) and immune systems (immunomodulation, stimulation of bacterial growth), and metabolism (increase in cell energy expenditure, hyperglycemia, catabolism, lipolysis, hyperlactatemia, electrolyte changes), bone marrow (anemia), and skeletal muscles (apoptosis). Potential therapeutic options to reduce excessive adrenergic stress comprise temperature and heart rate control, adequate use of sedative/analgesic drugs, and aiming for reasonable cardiovascular targets, adequate fluid therapy, use of levosimendan, hydrocortisone or supplementary arginine vasopressin.

Chapter 1: pathophysiology of hypopituitarism in the setting of brain injury

The complex pathophysiology of traumatic brain injury (TBI) involves not only the primary mechanical event but also secondary insults such as hypotension, hypoxia, raised intracranial pressure and changes in cerebral blood flow and metabolism. It is increasingly evident that these initial insults as well as transient events and treatments during the early injury phase can impact hypothalamic-pituitary function both acutely and chronically after injury. In turn, untreated pituitary hormonal dysfunction itself can further hinder recovery from brain injury. Secondary adrenal insufficiency, although typically reversible, occurs in up to 50% of intubated TBI victims and is associated with lower systemic blood pressure. Chronic anterior hypopituitarism, although reversible in some patients, persists in 25-40% of moderate and severe TBI survivors and likely contributes to long-term neurobehavioral and quality of life impairment. While the rates and risk factors of acute and chronic pituitary dysfunction have been documented for moderate and severe TBI victims in numerous recent studies, the pathophysiology remains ill-defined. Herein we discuss the hypotheses and available data concerning hypothalamic-pituitary vulnerability in the setting of head injury. Four possible pathophysiological mechanisms are considered: (1) the primary brain injury event, (2) secondary brain insults, (3) the stress of critical illness and (4) medication effects. Although each of these factors appears to be important in determining which hormonal axes are affected, the severity of dysfunction, their time course and possible reversibility, this process remains incompletely understood.

A review of the use of insulin protocols to maintain normoglycaemia in high dependency patients

This paper critically examines the evidence base for and issues involved in the introduction of an insulin protocol to maintain normoglycaemia in patients within a medical/surgical high dependency ward. A growing body of evidence has linked hyperglycaemia to worsened clinical outcomes. This has led to intravenous insulin protocols becoming a new standard of care in intensive care units. However, the use and benefits of insulin protocols within high dependency units have not yet been addressed in the literature. The literature was examined for the 10-year period up to January 2005. The databases searched were MEDLINE, OVID, CINHAL, the British Nursing Index, the EBSCO collection, the COCHRANE library, the Department of Health, and guidelines within the Scottish Intercollegiate Guidelines Network and National Institute for Clinical Excellence using the key words insulin, protocol, hyperglycaemia, critical care, intensive care and high dependency. The literature reports that both medical and surgical intensive care patients treated with intravenous insulin protocols to maintain normoglycaemia experienced significantly reduced mortality and morbidity. Resulting hypoglycaemic episodes were limited with no incidence of patient deterioration. A review of published intravenous insulin protocols used in intensive care settings revealed their safe and effective use in nurse to patient ratios similar to those present in high dependency units. In the light of this evidence, it would seem safe and ethically correct to enable high dependency patients to benefit from this cheap intervention. An insulin protocol tailored for the glycaemic control of high dependency patients has been suggested, although it may have to be commenced in conjunction with other fluid and nutrition protocols to safeguard the risk of hypoglycaemic events. Further research into the safety and benefit of insulin protocols in high dependency populations is required. The stress of critical illness often leads to hyperglycaemia, which is linked to worsened clinical outcomes. Both medical and surgical intensive care patients treated with intravenous insulin protocols to maintain normoglycaemia experienced significantly reduced mortality and morbidity. This paper identifies that, to date, no research into the benefits of glycaemic control in high dependency populations has been published. The case for the introduction of insulin protocols into high dependency units is therefore examined and an insulin protocol suggested.

Glycemic control and nutrition in the intensive care unit

Hospital clinicians frequently encounter hyperglycemia due to diabetes or the stress of critical illness in patients who are receiving nutrition support. A growing body of evidence suggests that hyperglycemia in the hospital is associated with adverse outcomes (e.g. disability after acute cardiovascular events, infection and death) and that improvement in outcomes can be achieved with improved glycemic control or insulin. Therefore, familiarity with the implications of hyperglycemia and with its treatment are essential for clinicians practicing in hospital settings. Questions persist regarding the optimal glucose goal range in differing patient groups. In addition, while the technology to deliver glycemic control in intensive care unit settings is widely available, data are limited about effective and safe insulin infusions. Research should focus on the risks and benefits of providing nutrition support in this group of patients, optimal glucose goal ranges, and on methods of achieving desired glucose goal ranges.

Clinical potential of insulin therapy in critically ill patients.

Stress of critical illness is often accompanied by hyperglycaemia, whether or not the patient has a history of diabetes mellitus. This has been considered to be part of the adaptive metabolic response to stress. The level of hyperglycaemia in patients with acute myocardial infarction (MI) or stroke upon admission to the hospital has been related to the risk of adverse outcome. However, until recently, there was no evidence of a causal relationship and thus stress-induced hyperglycaemia was only treated with exogenous insulin when it exceeded 12 mmol/L (220 mg/dL). In patients with known diabetes, even higher levels were often tolerated. Recently, new data became available in support of another approach. In this review, we focus on the new evidence and the clinical aspects of managing hyperglycaemia with insulin in critically ill patients, drawing a parallel with diabetes management. Particularly, the 'Diabetes and Insulin-Glucose infusion in Acute Myocardial Infarction (DIGAMI) study' and the 'insulin in intensive care study' have provided novel insights. The DIGAMI study showed that in patients with diabetes, controlling blood glucose levels below 12 mmol/L for 3 months after acute MI improves long-term outcome. In the recent study of predominantly surgical intensive care patients, the majority of whom did not previously have diabetes, it was shown that an even tighter control of blood glucose with exogenous insulin, aiming for normoglycaemia, dramatically improved outcome. Indeed, in this large prospective, randomised, controlled study, 1548 intensive care patients had been randomly allocated to either the conventional approach, with insulin infusion started only when blood glucose levels exceeded 12 mmol/L, or intensive insulin therapy, with insulin infused to maintain blood glucose at a level of 4.5-6.1 mmol/L (80-110 mg/dL). Intensive insulin therapy reduced intensive care mortality by more than 40% and also decreased a number of morbidity factors including acute renal failure, polyneuropathy, ventilator-dependency and septicaemia. Future studies will be needed to further unravel the mechanisms that explain the beneficial effects of this simple and cost-saving intervention. Although available evidence supports implementation of intensive insulin therapy in surgical intensive care, the benefit for other patient populations, such as patients on medical intensive care units or hospitalised patients who do not require intensive care but who do present with stress-induced hyperglycaemia, remains to be investigated.