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Leanna R. Miller, RN, MN, CCRN-CSC, PCCN-CMC, CEN, CNRN, NP Education Specialist LRM Consulting Nashville, TN Behavioral Objectives Describe the etiology of hyperglycemia in critical illness. Discuss the most common complications associated with glucose abnormalities in the ICU. Identify an algorithm for monitoring glucose levels and managing insulin therapy in the ICU. Case Study 42 – year old man acute exacerbation of asthma associated with community – acquired pneumonia he has no history of diabetes or other chronic diseases Case Study Medications Cefotaxime Azithromycin Nebulized albuterol IV hydrocortisone Case Study His blood glucose on admission is 105 mg/dL On the next day his blood glucose is 195 mg/dL and HA1C of 5.3% Should his glucose be treated? Incidence Hyperglycemia is exceedingly common in critical illness and may be seen in virtually all adult medical ICU patients when the threshold blood glucose (BG) value is set at >110 mg/dL Overview van den Berghe and coworkers in 2001 directly addressed this question and demonstrated that targeting strict euglycemia (80 to 110 mg/dL) can lead to meaningful morbidity and mortality reductions among surgical ICU patients supported by mechanical ventilation Pathophysiology stress hyperglycemia was considered adaptive, providing vital fuel to organs that rely largely on glucose for energy only excessive glucose excursions, generally above the renal threshold of 220 mg/dL (known to induce osmotic diuresis and infectious complications), were treated with insulin. Overview recent research has highlighted the association between hyperglycemia and increased morbidity and mortality in a number of disease states, including critical illness Overview hyperglycemia has been shown to correlate with development of congestive heart failure, cardiogenic shock, and hospital mortality among patients admitted for acute myocardial infarction Overview after an ischemic stroke, the degree of hyperglycemia appears to independently predict infarct expansion and neurologic outcome Hyperglycemia & Critical Illness Hyperglycemia during critical illness can be best characterized as a state of insulin resistance that develops in the context of: increased hepatic gluconeogenesis and glycogenolysis impaired peripheral glucose uptake and higher circulating levels of insulin Hyperglycemia & Critical Illness Counterregulatory hormones, such as glucagon, cortisol, growth hormone, and catecholamines, as well as elevated levels of cytokines play an important role in up-regulating hepatic glucose production Hyperglycemia & Critical Illness Some of these hormones and cytokines have also been shown to directly oppose insulin, resulting in increased lipolysis and proteolysis, which serve to provide substrates for further gluconeogenesis Hyperglycemia & Critical Illness As patients become bed-bound in the ICU, exercise-stimulated uptake in skeletal muscle disappears Hyperglycemia & Critical Illness the increased counterregulatory environment of critical illness and the impairments in glycogen synthase activity compromise glucose uptake in the heart, skeletal muscle, and adipose tissue Hyperglycemia & Critical Illness insulin-stimulated uptake by carriers such as GLUT-4 (solute carrier family 2, facilitated glucose transporter member 4) is decreased Hyperglycemia and Its Biologic Effects number of important biologic effects that may explain the apparent association between glucose excursions and poor outcomes in the ICU Hyperglycemia and Its Biologic Effects the higher risk of organ failure seen in patients with hyperglycemia, likely in part arises from alterations in microcirculation that lead to inadequate oxygen delivery as a result of endothelial dysfunction Hyperglycemia and Its Biologic Effects even when oxygen delivery is adequate, certain types of tissue appear to be at risk for bioenergetic failure and cellular death resulting from mitochondrial dysfunction when faced with persistent hyperglycemia Hyperglycemia and Its Biologic Effects hyperglycemia has a number of immunomodulatory effects can compromise innate immunity by: impairing polymorphonuclear neutrophil function intracellular bactericidal activity, & opsonic activity Hyperglycemia and Its Biologic Effects high glucose levels can promote excessive inflammation as evidenced by increasing proinflammatory cytokines (such as tumor necrosis factor-α and interleukins 1β, 6, 8, and 18), inducing nuclear factor-κB, and upregulating leukocyte adhesion molecules Hyperglycemia and Its Biologic Effects Hyperglycemia additionally induces formation of advanced glycation end products, which is now recognized to promote inflammation and endothelial dysfunction. high BG levels lead to oxidative stress and promote a procoagulant state Clement S et al. Dia Care 2004;27:553-591 Insulin Administration normalizes blood sugar levels prevents endothelial dysfunction preserves mitochondrial structure improves innate immunity modulates excessive inflammation regulates apoptosis Insulin Administration reverses the state of dyslipidemia in critical illness normalizes the procoagulant state regulates oxidative stress attenuates the catabolic state of critical illness Review of Available RCTs In the original single-center surgical ICU study from Belgium(2001) a BG target of 80 to 110 mg/dL absolute risk reduction in ICU mortality of 3.4% relative risk reduction of 42% Review of Available RCTs meaningful morbidity benefits – reductions in: ventilator days development of infection acute kidney injury Review of Available RCTs mortality improvements were further amplified (to an ARR of 9.6%) among the subset of patients who required ICU-level care for more than 5 days Review of Available RCTs VISEP (2008)targeted patients with severe sepsis or septic shock designed as a four-arm study to assess two concurrent interventions glycemic control (BG targets 80 – 110 mg/dl) fluid resuscitation Review of Available RCTs insulin arm of the study was prematurely terminated due to excessive hypoglycemia (defined as BG <40 mg/dL) in 12.1% of patients Review of Available RCTs later, the fluid resuscitation arms of the study were also stopped early owing to concerns about increased organ failure in the 10% pentastarch arm Review of Available RCTs Glucontrol enrolled a mixed ICU population investigated whether IIT (defined as BG of 80 to 110 mg/dL) led to better outcomes compared with a control group with moderate hyperglycemia ranging between 140 and 180 mg/dL Review of Available RCTs Glucontrol study also terminated early, this time because of excessive protocol violations and hypoglycemia No difference in hospital or 28-day mortality was observed Review of Available RCTs NICE-SUGAR, enrolled 6,100 patients and confirmed that the tightest glucose control was not necessary—and that it may even lead to potential harm NICE-SUGAR assumed a 3% to 4% absolute risk reduction in death Safe Glycemic Management in ICU Sampling Blood (vascular catheter) – danger of contamination with IV fluids Fingerstick – inaccurate in patients with edema or anemia Safe Glycemic Management in ICU Measurements Glucometer – fastest, least accurate Blood gas machine – fast, accurate Laboratory analysis – slowest, most accurate Safe Glycemic Management in ICU Interpretation < 140 mg/dL – consider context - monitoring less frequent 140 – 180 mg/dL - HA1C – frequent monitoring > 180 mg/dL - HA1C , consider insulin – monitor per algorithm Safe Glycemic Management in ICU Insulin Use Choose an insulin algorithm Validate algorithm Develop criteria for insulin use (upper & lower limits) Develop safety procedure Develop quality – assurance process Glycemic Variability wide fluctuations in glucose levels induce apoptosis, endothelial activation, and oxidative stress more than sustained hyperglycemia glycemic variability has been shown to be a more powerful predictor of mortality than mean BG values among a heterogenous group of ICU patients Glycemic Variability In one study, for the same degree of glucose control (mean BG ranging between 80 and 110 mg/dL), mortality ranged from 4.2% to 27.5% depending on the degree of glucose variability Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008;36(11):3008-3013 Hypoglycemia All insulin infusion protocols, no matter how well executed, almost always lead to some increase in hypoglycemic events Hypoglycemia hypoglycemia rates in study settings, where significant hypoglycemia is defined as a BG level <40 mg/dL may range from approximately 5% to nearly 19% Hypoglycemia some conditions commonly encountered in the ICU are associated with an increased risk of hypoglycemia knowledge of these conditions may help identify subgroups that require closer monitoring Hypoglycemia – High Risk patients receiving bicarbonate-based fluid during CVVHD hemodynamically unstable patients in need of inotropic support women patients with known diabetes Hypoglycemia – High Risk septic patients patients taking octreotide patients with interruptions in or intolerance to nutritional support Hypoglycemia no studies to date that have definitively demonstrated the dangers of hypoglycemia it is well established that prolonged and severe hypoglycemia can deplete astrocyte glycogen stores and lead to cell death and brain injury Hypoglycemia Those already brain injured, such as neurosurgical patients, or who have prolonged hypoxemia from refractory respiratory failure may be at higher risk for accelerated astrocyte store depletion may constitute a particularly vulnerable subset that requires special attention. Recommentations enthusiasm for rigid glycemic control has waned accepting markedly elevated BG values should remain a relic of the past Recommentations Based on the best available evidence, an approach targeting a moderate BG value between 140 and 180 mg/dL, as endorsed by the American Association of Clinical Endocrinologists and the American Diabetes Association, seems most prudent Recommentations Wide fluctuations in glucose values should also be avoided, given increasing data pointing to the detrimental effects of glycemic variability Case Study 42 – year old man acute exacerbation of asthma associated with community – acquired pneumonia he has no history of diabetes or other chronic diseases Case Study His blood glucose on admission is 105 mg/dL On the next day his blood glucose is 195 mg/dL and HA1c of 5.3% Should his glucose be treated?