IMPLEMENT THE MANAGEMENT BUNDLE - WITHIN FIRST 24 HOURS OF CARE

SEVERE SEPSIS BUNDLES The changes called for on these pages mirror the individual elements of the Severe Sepsis Bundles. Taken together, we believe these changes will substantially reduce mortality due to severe sepsis. The Severe Sepsis Bundles are a distillation of the evidence-based recommendations found in the 2008 practice guidelines promulgated by the Surviving Sepsis Campaign. Ranking the Evidence Choosing therapies to treat patients with severe sepsis and septic shock requires an organized approach to evaluating the evidence. The Sepsis Resuscitation and Management Bundles were derived from the 2008 Surviving Sepsis Campaign Guidelines which incorporated the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system approach to evaluating the literature. Understanding the Bundle Concept A "bundle" is a group of therapies for a given disease that, when implemented together, may result in better outcomes than if implemented individually. In a bundle, the individual elements included are built around best evidence-based practices. The science supporting the individual treatment strategies in a bundle is sufficiently mature such that implementation of the approach should be considered either best practice or a reasonable and generally accepted practice. The purpose of creating a bundle strategy is to clearly articulate a therapeutic framework that will function as a lever for change. We anticipate thatmaking the Severe Sepsis Bundles standard practice will eliminate the piecemeal or chaotically applied of standards for sepsis care that characterize many clinical environments today. The Severe Sepsis Bundles have been designed with the hope to allow teams to follow the timing, sequence, and goals in the bundles, ito achieve a 25 percent reduction in mortality due to severe sepsis or septic shock. We hope hospitals will use the bundles to create customized protocols and pathways that will function well within their institutions. However, we encourage that each of the elements in the bundles be incorporated in those protocols. Optimally, the protocols should closely mirror the bundles, but allow flexibility for logistical and other needs specific to -each hospital. The reason to include the therapies specified in the bundles in your protocol for care is that if you use our measurement strategies and database, you will be measured as compliant (or non-compliant) with those elements. Therefore, if not all of the elements of the bundles are incorporated into your customized protocol, your performance on the quality indicators we have designed will suffer. In addition, we believe the elements to be the best strategy to improve care. There are two Severe Sepsis Bundles. Each bundle articulates objectives to be accomplished within specific timeframes. The bundles have been developed based upon the 2008 Surviving Sepsis Campaign Guidelines for the Management of Severe Sepsis and Septic Shock. The Guidelines incorporated an evidence based review of the literature and ranked the strength of each recommendation. In the following pages, the grading of the evidence supporting each element is noted and a separate page describes the evidence ranking process. Sepsis Management Bundle Evidence-based goals that must be completed within 24 hours for patients with severe sepsis, septic shock and/or lactate >4 mmol/L (36 mg/dl). For patients with severe sepsis, as many as four bundle elements must be accomplished within the first 24 hours of presentation. Some items may not be completed if the clinical conditions described in the bundle do

not prevail, but clinicians must assess for them. The goal is to perform all indicated tasks 100 percent of the time within the first 24 hours from presentation. Please note that efforts to accomplish these goals should begin immediately, but may be completed within 24 hours to qualify in the database. Changes for Improvement Bundle Element 1 Administer low-dose steroids for septic shock in accordance with a standardized ICU policy. If not administered, document why the patient did not qualify for low-dose steroids based upon the standardized protocol.

Corresponding Bundle Element Administer Low-Dose Steriods for Septic Shock in Accordance with a Standardized ICU Policy Related Measures
Low-Dose Steroid Administration Background Intravenous corticosteroids (hydrocortisone 200 300 mg/day, for 7 days in three or four divided doses or by continuous infusion) are suggested in for adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy. We believe hospitals should strive to develop a standardized policy in their ICU for the administration of steroids in accordance with the available evidence for use. For decades, the rationale for the use of glucocorticoids in sepsis trials has been the fundamental role that they play in the stress response to infection and the anti-inflammatory effects that they exert. Randomized, controlled, high-dose glucocorticoid trials failed to improve outcomes, leading to skepticism and the avoidance of using any glucocorticoids in septic patients by most intensive care unit physicians. However, recent randomized, controlled trials with low doses of hydrocortisone in septic shock have evoked a renewed interest In the context of corticosteroid therapy for septic shock, high doses of glucocorticoids mainly refer to 30 mg/kg methylprednisolone or equivalent steroid preparations administered up to four times during a short course of 1 or 2 days. [1,2] Recent low-dose glucocorticoid trials refer to a daily dose of 200 300 mg of hydrocortisone or equivalent administered for 5 7 days or longer. [3 8] Possible Decreased Mortality Preliminary data from a 2005 Cochrane meta-analysis considering 15 randomized controlled trials of low- and high-dose corticosteroids in 2,022 patients with septic shock summarize available evidence on the use of steroids in septic shock. [9] Pooled 28-day all-cause mortality did not differ between placebo and serum (relative risk, 0.98; 95 percent CI, 0.87 1.10; p = .7). Subgroup analysis of five trials [3 7] with low-dose corticosteroids reduced 28-day all-cause mortality significantly (relative risk, 0.8; 95 percent CI, 0.67 0.95; p = .01), whereas high-dose trials did not (relative risk, 0.99; 95 percent CI, 0.83 1.17; p = .9) The number needed to treat with low-dose corticosteroids to save one additional life was nine (95 percent CI, 5 33). In addition, low-dose corticosteroids significantly reduced intensive care unit and hospital all-cause mortality and significantly increased the number of patients with shock reversal on day 7 and day 28. These data stand in contrast to results from a recently completed large European trial, CORTICUS, which failed to show a mortality benefit from administration of low-dose steroids in septic shock [12]. In this multicenter, randomized, double-blind, placebo-controlled trial, 251 patients were assigned to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test. Of the 499 patients in the study, 233 (46.7%) did not have a response to

corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). Possible interpretations and concerns about CORTICUS are detailed below. Earlier Shock Reversal: Low-dose corticosteroids promote more rapid shock reversal than when they are not administered to patients with septic shock. Numerous randomized, controlled trials with low-dose corticosteroids in patients with septic shock confirm shock reversal and reduction of vasopressor support within a few days after initiation of therapy in most patients. [3 7] The median time to cessation of vasopressors decreased in one study from 13 to 4 days [5] and, in the other study, from 7 to 3 days [8]. CORTICUS, although finding no overall decreased mortality from low-dose steroid administration, confirmed the finding of more rapid shock reversal [12]. Choice of Steroid: Hydrocortisone is preferred to other glucocorticoids in patients with septic shock in most clinical trials. Although a comparative study of different corticosteroids has not been performed in patients with septic shock, there are several reasons why hydrocortisone is preferred. First, most of the experience with low-dose corticosteroid treatment in septic shock has been with the use of hydrocortisone. [4 6,8,10,11] Second, hydrocortisone is the synthetic equivalent to the physiologic final active cortisol. Therefore, treatment with hydrocortisone directly replaces cortisol, independent of metabolic transformation. Third, hydrocortisone has intrinsic mineralocorticoid activity, whereas dexamethasone does not. No Role for Corticotropin Stimulation Testing: The use of a 250- g ACTH stimulation test to identify responders (> 9 g/dL increase in cortisol 30 60 minutes post-ACTH administration) and to discontinue therapy in these patients is no longer recommended. Clinicians should not wait for results of ACTH stimulation results to administer corticosteroids. See below for a more detailed explanation and rationale.

Grading the Evidence 1. The Surviving Sepsis Campaign suggests intravenous hydrocortisone be given only to adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy (Grade 2C). Rationale: One French multi-center, randomized, controlled trial (RCT) of patients in vasopressor-unresponsive septic shock (hypotension despite fluid resuscitation and vasopressors) showed a significant shock reversal and reduction of mortality rate in patients with relative adrenal insufficiency (defined as post-adrenocorticotropic hormone [ACTH] cortisol increase of 9 g/dL or less) (4). Two additional smaller RCTs also showed significant effects on shock reversal with steroid therapy (3,5). However, a recent large, European multicenter trial (CORTICUS) failed to show a mortality benefit with steroid therapy of septic shock (12). CORTICUS did show a faster resolution of septic shock in patients who received steroids. The use of the ACTH test (responders and nonresponders) did not predict the faster resolution of shock. Importantly, unlike the French trial, which only enrolled shock patients with blood pressure unresponsive to vasopressor therapy, the CORTICUS study included patients with septic shock, regardless of how the blood pressure responded to vasopressors. Although corticosteroids do appear to promote shock reversal, the lack of a clear improvement in mortality--coupled with known side effects of steroids such as increased risk of infection and myopathy-- generally tempered enthusiasm for their broad use. Thus, there was broad agreement that the recommendation should be downgraded from the previous guidelines (Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858-873).

2. The Surviving Sepsis Campaign suggests the ACTH stimulation test not be used to identify the subset of adults with septic shock who should receive hydrocortisone (Grade 2B). Rationale: Although one study suggested those who did not respond to ACTH with a brisk surge in cortisol (failure to achieve or > 9 g/dL increase in cortisol 30-60 mins post-ACTH administration) were more likely to benefit from steroids than those who did respond, the overall trial population appeared to benefit regardless of ACTH result, and the observation of a potential interaction between steroid use and ACTH test was not statistically significant (4). Furthermore, there was no evidence of this distinction between responders and nonresponders in a recent multicenter trial (12). Commonly used cortisol immunoassays measure total cortisol (protein-bound and free) while free cortisol is the pertinent measurement. The relationship between free and total cortisol varies with serum protein concentration. When compared to a reference method (mass spectrometry), cortisol immunoassays may over- or underestimate the actual cortisol level, affecting the assignment of patients to responders or nonresponders (13). Although the clinical significance is not clear, it is now recognized that etomidate, when used for induction for intubation, will suppress the HPA axis (14). 3. The Surviving Sepsis Campaign suggests that patients with septic shock should not receive dexamethasone if hydrocortisone is available (Grade 2B). Rationale: Although often proposed for use until an ACTH stimulation test can be administered, we no longer suggest an ACTH test in this clinical situation. Furthermore, dexamethasone can lead to immediate and prolonged suppression of the HPA axis after administration (15). 4. The Surviving Sepsis Campaign suggests the daily addition of oral fludrocortisone (50 g) if hydrocortisone is not available and the steroid that is substituted has no significant mineralocorticoid activity. Fludrocortisone is considered optional if hydrocortisone is used (Grade 2C). Rationale: One study added 50 g of fludrocortisone orally (4). Since hydrocortisone has intrinsic mineralcorticoid activity, there is controversy as to whether fludrocortisone should be added. 5. The Surviving Sepsis Campaign suggests clinicians wean the patient from steroid therapy when vasopressors are no longer required. (Grade 2D). Rationale: There has been no comparative study between a fixed duration and clinically guided regimen, or between tapering and abrupt cessation of steroids. Three RCTs used a fixed duration protocol for treatment (3,5,12), and in two RCTs, therapy was decreased after shock resolution (3,16). In four RCTs steroids were tapered over several days (3,5,12,16), and in two RCTs (4,7) steroids were withdrawn abruptly. One crossover study showed hemodynamic and immunologic rebound effects after abrupt cessation of corticosteroids (16). It remains uncertain whether outcome is affected by tapering of steroids or not. The above category 2 suggestions are weaker recommendations for care based on a number of qualitative considerations. B level evidence generally derives from randomized control trials with certain limitations or very well-done observational or cohort studies. C level evidence reflects well-done observational or cohort studies with controls. D level evidence generally reflects case series data or expert opinion. 6. The Surviving Sepsis Campaign suggests doses of corticosteroids comparable to >300 mg hydrocortisone daily not be used in severe sepsis or septic shock for the purpose of treating septic shock (Grade 1A). Rationale: Two randomized prospective clinical trials and a meta-analysis concluded that for therapy of severe sepsis or septic shock, high-dose corticosteroid therapy is ineffective or harmful (18,2,19). Reasons to maintain higher doses of corticosteroid for medical conditions other than septic shock may exist. 7. The Surviving Sepsis Campaign recommends that corticosteroids not be administered for the treatment of sepsis in the absence of shock. There is, however, no contraindication to continuing maintenance steroid therapy or to using stress-dose steroids if the patient s endocrine or corticosteroid administration history warrants (Grade 1D).

Rationale: No studies exist that specifically target severe sepsis in the absence of shock that offer support for use of stress doses of steroids in this patient population. Steroids may be indicated in the presence of a prior history of steroid therapy or adrenal dysfunction. A recent preliminary study of stress dose level steroids in community-acquired pneumonia is encouraging but needs confirmation. (20) The above category 1 recommendations are strong recommendations for care based on a number of qualitative considerations. B level evidence generally derives from randomized control trials with certain limitations or very well-done observational or cohort studies. C level evidence reflects well-done observational or cohort studies with controls. D level evidence generally reflects case series data or expert opinion. Tips 1. Use the Interim Low-Dose Glucocorticoid Policy until your institution is able to devise an appropriate policy. 2. Create a an ICU protocol that standardizes the use of low-dose steroids in septic shock to eliminate variation in care. 3. Use a sufficient dose of glucocorticoid for efficacy, for example, hydrocortisone 50 mg IV every 6 hours. 4. Resist deferring the use of low-dose steroids for fear of worsening infection in patients who remain hypotensive despite both adequate volume resuscitation and application of vasopressors. 5. An ACTH stimulation test is not recommended to ascertain whether septic shock patients should receive low-dose steroids.

Bundle Element 2 Administer recombinant human activated protein C (rhAPC) in accordance with a standardized ICU policy. If not administered, document why the patient did not qualify for rhAPC.

ADMINISTER RECOMBINANT HUMAN ACTIVATED PROTEIN C (RHAPC) BY A STANDARD POLICY

Disclosure
The Surviving Sepsis Campaign has been underwritten in part by an unrestricted educational grant by Eli Lilly, Inc., the manufacturer of Recombinant Human Activated Protein C (rhAPC). During the deliberations of the 2004 and 2008 Surviving Sepsis Campaign Guidelines Committees, there was no industry input into guidelines development and no industry presence at any of the meetings. In 2008, the Guidelines Committee meetings were made possible by a grant from the Society of Critical Care Medicine. In both 2004 and 2008, the industry sponsors of educational grants to the Surviving Sepsis Campaign did not see the guidelines until the manuscript was peer reviewed and accepted for publication in final form. Corresponding Bundle Element Recombinant Activated Protein C administered in accordance with a standardized ICU policy. Related Measures Background The Surviving Sepsis Campaign suggests that adult patients with sepsis-induced organ dysfunction associated with a clinical assessment of high risk of death, most of whom will have APACHE II 25 or multiple organ

failure, receive drotrecogin alfa (activated), a.k.a, recombinant activated protein C (rhAPC), if there are no contraindications. The Surviving Sepsis Campaign recommends that adult patients with severe sepsis and low risk of death, most of whom will have APACHE II <20 or one organ failure, do not receive rhAPC. Mortality Benefit The first trial to assess the efficacy of rhAPC was the PROWESS trial. PROWESS was a phase 3, multinational, double-blind, placebo-controlled trial of rhAPC (24 g kg-1 hr-1 during 96 hrs) in patients with severe sepsis. The trial was powered to document a 15 percent reduction in the relative risk of 28-day all-cause mortality. [1] The trial was stopped early due to a statistically significant difference observed between the treatment and the placebo groups after the second interim analysis of 1,520 patients. The trial demonstrated a significant reduction in the 28-day all-cause mortality: absolute reduction of mortality, -6.1 percent (30.8 percent to 24.7 percent); relative risk reduction of mortality, 19.4 percent (95 percent confidence interval, 6.630.5; p = .005); and range of number needed to treat, 16 54. Nevertheless, subsequent trials made interpretation of these results less straightforward. Please see Grading the Evidence below. APACHE II Score In the PROWESS trial, patients were prospectively stratified, in part, by their baseline Acute Physiology and Chronic Health Evaluation (APACHE) II score. There are practical and methodologic limitations of the APACHE II score, which is not typically used to clinically manage individual patients. Nevertheless, the US Food and Drug Administration approved rhAPC for sepsis-induced organ dysfunction associated with high risk of death, such as APACHE II > 25. In the European community, the European Agency for the Evaluation of Medicinal Products approved rhAPC for the treatment of adult patients with two or more organ dysfunctions. The APACHE II score may be calculated courtesy of the French Society of Anesthesia and Intensive Care (see http://www.sfar.org/scores2/apache22.html). Risk Assessment At present, risk assessment is best determined by bedside clinical evaluation and judgment. The use of a standardized policy in intensive care units for the administration of rhAPC may help to clarify decision-making about when to apply rhAPC. See Interim Drotrecogin Alfa (Activated) Administration Policy for a policy that may be used until your intensive care unit or hospital creates one. Cost-Effectiveness Cost-effectiveness appears to be related to the severity of illness as calculated by APACHE II score. The costeffectiveness analysis of the PROWESS trial could document a $27,400 cost per quality-adjusted life-year when limited to patients with an APACHE II score of 24, whereas rhAPC was considered cost ineffective in patients with a lower risk of death. [2,3] Exclusion Criteria Many patients were not included in trials establishing the efficacy of rhAPC in severe sepsis. Therefore, the effect of rhAPC is not documented in morbidly obese patients, those patients admitted to an intensive care unit in moribund state with an almost certain likelihood to die, in children, and in pregnant women. Patients with acute pancreatitis were not included in the PROWESS trial, nor were patients who required anticoagulation for a documented or suspected deep-vein thrombosis or pulmonary embolism. In addition, hematologic diseases that could interfere with the anticoagulant effects of rhAPC (resistance to activated PC [Leyden mutation], hereditary deficiency of Protein C, Protein S, or antithrombin, known anticardiolipin antibody, lupus anticoagulant, and homocystinemia) were considered as exclusion criteria.

Adverse Effects of Treatment with rhAPC

Bleeding is the most frequent and serious adverse event that may be induced by rhAPC treatment, and patients at high risk of serious bleeding events should not be treated with rhAPC. [1] The risk of bleeding events should be carefully weighed at the initial clinical evaluation of severely septic patients. Clinicians should consider needed surgeries and/or invasive procedures. Intracranial bleeding is the most severe bleeding event observed in clinical studies or rhAPC. The main risk factors for intracranial bleeding were severe thrombocytopenia and meningeal infection. Patients with a baseline platelet count of < 30,000/mm3 should not receive rhAPC; previous platelet transfusion should likely not be used to allow rhAPC treatment; platelet count should be carefully monitored by short-time sequential measurements during treatment to anticipate the platelets decrease; platelet transfusion should be used to maintain platelet count at > 30,000/mm3. Grading the Evidence 1. The Surviving Sepsis Campaign suggests that adult patients with sepsis-induced organ dysfunction associated with a clinical assessment of high risk of death, most of whom will have APACHE II 25 or multiple organ failure, receive rhAPC if there are no contraindications (Grade 2B except for patients within 30 days of surgery where it is Grade 2C). Relative contraindications should also be considered in decision making. 2. The Surviving Sepsis Campaign recommends that adult patients with severe sepsis and low risk of death, most of whom will have APACHE II <20 or one organ failure, do not receive rhAPC (Grade 1A). Category 1 recommendations are strong recommendations for care based on a number of qualitative considerations, while Category 2 designations are weaker recommendations for care or suggestions. B level evidence generally derives from randomized controlled trials with certain limitations or very well-done observational or cohort studies. C level evidence reflects well-done observational or cohort studies with controls. D level evidence generally reflects case series data or expert opinion. Rationale: The evidence concerning use of rhAPC in adults is primarily based on two randomized controlled trials (RCTs): PROWESS (1,690 adult patients, stopped early for efficacy) (1) and ADDRESS (stopped early for futility) (4). Additional safety information comes from the open-label observational study ENHANCE (5). The ENHANCE trial also suggested early administration of rhAPC was associated with better outcomes. PROWESS involved 1,690 patients and documented 6.1% in absolute total mortality reduction with a relative risk reduction (RRR) of 19.4%, 95% CI 6.6-30.5%, number needed to treat (NNT): 16 (1). Controversy associated with the results focused on a number of subgroup analyses. Subgroup analyses have the potential to mislead due to the absence of an intent to treat, sampling bias, and selection error (6). The analyses suggested increasing absolute and relative risk reduction with greater risk of death using both higher APACHE II scores and greater number of organ failures (7). This led to drug approval for patients with high risk of death (such as APACHE II 25) and more than one organ failure in Europe. The ADDRESS trial involved 2,613 patients judged to have a low risk of death at enrollment. Twenty-eight-day mortality from all causes was 17% on placebo vs. 18.5% on APC, relative risk (RR) 1.08, 95% CI 0.92-1.28 (4). Again, debate focused on subgroup analyses; analyses restricted to small subgroups of patients with APACHE II score > 25 or more than one organ failure which failed to show benefit; however, these patient groups also had a lower mortality than in PROWESS. Relative risk reduction of death was numerically lower in the subgroup of patients with recent surgery (n=502) in the PROWESS trial (30.7% placebo vs. 27.8% APC) (7) when compared to the overall study population (30.8% placebo vs. 24.7% APC) (1). In the ADDRESS trial, patients with recent surgery and single organ dysfunction who received APC had significantly higher 28-day mortality rates (20.7% vs. 14.1%, p=0.03, n=635). (4) Serious adverse events did not differ in the studies (1,4,5) with the exception of serious bleeding, which occurred more often in the patients treated with APC: 2% vs. 3.5% (PROWESS; p=0.06) (1); 2.2% vs. 3.9% (ADDRESS; p<0.01) (4); 6.5% (ENHANCE, open label) (5).

Intracranial hemorrhage (ICH) occurred in the PROWESS trial in 0.1% (placebo) and 0.2% (APC) (n.s.) (1), in the ADDRESS trial 0.4% (placebo) vs. 0.5 % (APC) (n.s.) (4); in ENHANCE 1.5% (5). Registry studies of rhAPC report higher bleeding rates than randomized controlled trials, suggesting that the risk of bleeding in actual practice may be greater than reported in PROWESS and ADDRESS (8,9). The two RCTs in adult patients were methodologically strong, precise, and provide direct evidence regarding death rates. The conclusions are limited, however, by inconsistency that is not adequately resolved by subgroup analyses (thus the designation of moderate quality evidence). Results, however, consistently fail to show benefit for the subgroup of patients at lower risk of death, and consistently show increases in serious bleeding. The RCT in pediatric severe sepsis failed to show benefit and has no important limitations. Thus, for low risk and pediatric patients, the Surviving Sepsis Campaign rates the evidence as high quality. For adult use there is probable mortality reduction in patients with clinical assessment of high risk of death, most of whom will have APACHE II >25 or multiple organ failure. There is likely no benefit in patients with low risk of death, most of whom will have APACHE II <20 or single organ dysfunction. The effects in patients with more than one organ failure but APACHE II <25 are unclear and in that circumstance one may use clinical assessment of the risk of death and number of organ failures to support a decision. There is a certain increased risk of bleeding with administration of rhAPC which may be higher in surgical patients and in the context of invasive procedures. Decision on utilization depends upon assessing likelihood of mortality reduction versus increases in bleeding and cost. A European Regulatory-mandated randomized controlled trial of rhAPC vs placebo in patients with septic shock is now ongoing (10). Tips 1. Investigate whether the pharmacy has established indications for use of drotrecogin alfa in the institution. 2. Create a standardized ICU policy for the use drotrecogin alfa (activated). 3. Use the Interim Drotrecogin Alfa (Activated) Administration Policy until finalized. 4. Provide in-service training to ICU personnel on administration, side effects, and expected laboratory alterations when using drotrecogin alfa.

Bundle Element 3 Maintain adequate glycemic control. Click here to see SSC Statement on Glucose Control in Severe Sepsis (2009)

MAINTAIN ADEQUATE GLYCEMIC CONTROL

Corresponding Bundle Element Glucose control maintained > lower limit of normal, but < 180 mg/dL (10 mmol/L). Related Measures Introduction Effective glucose control in the intensive care unit (ICU) has been shown to decrease morbidity across a large range of conditions and also to decrease mortality. Hyperglycemia, caused by insulin resistance in the liver and muscle, is a common finding in ICU patients. Some have considered it to be an adaptive response, providing glucose for the brain, red blood cells, and wound healing. Traditionally, hyperglycemia has only been treated when blood glucose increases to >215

mg/dL (>12 mmol/L). Conventional wisdom in the ICU has been that some degree of hyperglycemia is beneficial and that hypoglycemia is dangerous and should be avoided. The extent of appropriate glucose control has been evaluated in recent years. Initial Investigations Intensive Insulin Therapy

An initial investigation by Van den Berghe and colleagues [2] suggested that controlling blood glucose levels by intensive insulin therapy decreased mortality and morbidity in surgical critically ill patients. The trial was a large single-center study of postoperative surgical patients. The design employed a continuous infusion of insulin to maintain glucose between 80 and 110 mg/dL (4.4 6.1 mmol/L). Exogenous glucose was begun simultaneously with insulin, with frequent monitoring of glucose (every 1 hour) and intensity of monitoring was greatest at the time of initiation of insulin. This protocol called for implementing a strategy to maintain normoglycemia with an insulin infusion while providing for normal intake of glucose (9 g/hr) and calories (19 kcal kg-1 day-1). A total of 35 of 765 patients (4.6 percent) in the intensive insulin group died in the ICU in study by Van den Berghe et al., compared with 63 patients (8.0 percent) in the conventional therapy group. Intensive insulin therapy halved the prevalence of: Bloodstream infections Prolonged inflammation ARF requiring dialysis or hemofiltration Critical illness polyneuropathy Transfusion requirements Patients receiving intensive insulin therapy were also less likely to require prolonged mechanical ventilation and intensive care. Rigorous insulin treatment reduced the number of deaths from multiple-organ failure with sepsis, regardless of whether there was a history of diabetes or hyperglycemia. Surgical vs. Medical Patients The same protocol used in the first Van den Berghe trial for surgical patients was subsequently tested in medical patients. [3] Patients who were considered to need intensive care for at least three days were enrolled in a prospective, randomized, single-center, controlled study. On admission, patients were randomly assigned to strict normalization of blood glucose levels (80 to 110 mg/dL [4.4 to 6.1 mmol/L]) with the use of insulin infusion or conventional therapy (i.e., insulin administered when the blood glucose level exceeded 215 mg/dL [12 mmol/L], with the infusion tapered when the level fell below 180 mg/dL [10 mmol/L]). 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. The authors concluded that 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. Meta-analyses and Severe Sepsis Specific Inquires

A meta-analysis of 35 trials on insulin therapy in critically ill patients, including 12 randomized trials, demonstrated a 15 percent reduction in short-term mortality (RR 0.85, 95% confidence interval 0.75-0.97) but did not include any studies of insulin therapy in medical ICUs [4]. A multi-center randomized controlled trial focusing on patients with severe sepsis (VISEP) failed to demonstrate improvement in mortality [5]. In VISEP, the investigators randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy. Of the 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensivetherapy group (112 mg/dL [6.2 mmol/L]) than in the conventional-therapy group (151 mg/dL [8.4 mmol/L], 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. Further, the VISEP investigators found that the rate of severe hypoglycemia (glucose level, < 40 mg/dL [2.2 mmol/L]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0 percent vs. 4.1 percent, P<0.001), as was the rate of serious adverse events (10.9 percent vs. 5.2 percent, P=0.01). The trial was stopped earlier than planned for these reasons. NICE-SUGAR Study Based on the foregoing studies, most clinicians believed that there was a benefit to glucose control in terms of mortality and morbidity. However, the optimal target range for blood glucose in critically ill patients remained unclear. The NICE-SUGAR study investigators [1] chose to evaluate whether there was a difference in mortality between subjects randomly assigned to either intensive glucose control, with a target blood glucose range of 81 to 108 mg/dL (4.5 to 6.0 mmol/L), or conventional glucose control, with a target of < 180 mg/dL (< 10.0 mmol/L). To be considered, patients were expected to require treatment in the ICU on three or more consecutive days. Of the 6,104 patients who underwent randomization, 3,054 were assigned to undergo intensive control and 3,050 to undergo conventional control. A total of 829 patients (27.5 percent) in the intensive-control group and 751 (24.9 percent) in the conventional-control group died. Thus, the odds of dying with intensive control were 1.14 times greater than with conventional control (P=0.02). In addition, severe hypoglycemia (blood glucose level of 40 mg/dL [2.2 mmol/L]) was reported in 206 of 3,016 patients (6.8 percent) in the intensivecontrol group and in 15 of 3,014 patients (0.5 percent) in the conventional-control group (P<0.001). Thus, the incidence of hypoglycemia was lower in the conventional group. With regard to morbidity and length of stay, NICE-SUGAR demonstrated that there was no significant difference between the two treatment groups in the median number of days in the ICU or hospital, or the median number of days of mechanical ventilation or renal-replacement therapy. The NICE-SUGAR investigators concluded that that intensive glucose control increased mortality among adults in the ICU and that a blood glucose target of < 180 mg/dL resulted in lower mortality than did a target of 81 to 108 mg/dL.

Grading the Evidence The Surviving Sepsis Campaign recommends that, following initial stabilization, patients with severe sepsis and hyperglycemia who are admitted to the ICU receive IV insulin therapy to reduce blood glucose levels (Grade 1B). Rationale: The Surviving Sepsis Campaign is reviewing specific recommendations and ranges for glucose control shortly. Presently, IHI also advocates for a target threshold less than <180 mg/dL for criticially ill patients based on the NICE-SUGAR trial data. Category 1 recommendations are strong recommendations for care basd on qualitative considerations. "B" level evidence generally derives from randomized control trails with certain limitations or very well-done

observational or cohort studlies. C level evidence reflects well-done observational or cohort studies with controls. D level evidence generally reflects case series data or expert opinion.

Bundle Element 4 Prevent excessive inspiratory pleateau pressures on mechanically ventilated patients.

PREVENT EXCESSIVE INSPIRATORY PLATEAU PRESSURES

Corresponding Bundle Element Inspiratory plateau pressures maintained < 30 cm H2O for mechanically ventilated patients. Related Measures Background

Patients with sepsis are at increased risk for developing acute respiratory failure, and most patients with severe sepsis and septic shock will require endotracheal intubation and mechanical ventilation. Nearly 50 percent of patients with severe sepsis will develop acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Patients with lung injury will have bilateral patchy infiltrates on chest x-ray, low paO2:FIO2 ratios (less than 300 for ALI or less than 200 for ARDS), and pulmonary capillary wedge pressure less than 18 cm H20, although this last measure is often clinically not available. High tidal volumes that are coupled with high plateau pressures should be avoided in ALI/ARDS. Clinicians should use as a starting point a reduction in tidal volumes over 1 to 2 hours to a low tidal volume (6 mLkg1lean body weight-1) as a goal in conjunction with the goal of maintaining end-inspiratory plateau pressures of < 30 cm H2O. Mortality Reduction The largest trial of a volume- and pressure-limited strategy showed a 9 percent decrease of all-cause mortality in patients ventilated with tidal volumes of 6 mL/kg of estimated lean body weight (as opposed to 12 mL/kg) while aiming for a plateau pressure of < 30 cm H2O. (1) The formal ARDSnet protocol for mechanical ventilation is available at http://www.ardsnet.org/lowvtrefcard.pdf and is encouraged for use in septic patients. Permissive Hypercapnea Hypercapnia (allowing PaCO2 to increase above normal, so-called permissive hypercapnia) can be tolerated in patients with ALI/ARDS if required to minimize plateau pressures and tidal volumes. Although an acutely elevated PCO2 may have physiologic consequences that include vasodilatation and increased heart rate, blood pressure, and cardiac output, allowing modest hypercapnia in conjunction with limiting tidal volume and minute ventilation has been demonstrated to be safe in small, nonrandomized series. (2,3) No upper limit for PCO2 has been established. Some authorities recommend maintaining pH at > 7.20 to 7.25, but this has not been prospectively established. The use of hypercarbia is limited in patients with preexisting metabolic acidosis and is contraindicated in patients with increased intracranial pressure. (4) Sodium bicarbonate infusion may be considered in select patients to facilitate use of permissive hypercarbia. (5) Experimental models suggest that respiratory acidosis may confer protection against various forms of inflammatory injury. (6)

Positive End-Expiratory Pressure (PEEP) Provide adequate supplemental oxygen to maintain a pulse oximetric saturation of > 90 percent. A minimum amount of PEEP should be set to prevent lung collapse at end expiration. Setting PEEP based on severity of oxygenation deficit and guided by the FIO2 required to maintain adequate oxygenation is one acceptable approach. For patients supported by mechanical ventilation or who are appropriate candidates for a pressurized face mask, PEEP or continuous positive airway pressure may be used to increase mean and end-expiratory airway pressures, allowing the reduction of the oxygen concentrations below potentially toxic levels (FIO2 < 0.60). Tips

Create a standardized protocol that prompts users to use tidal volumes no greater than 6 mL/kg IBW and to maintain plateau pressures less than 30 cm H20.

Make execution of an ARDSnet-like protocol the primary responsibility of the respiratory therapists, if possible. Have stakeholders work in concert with the respiratory therapy department to create and deploy a clinical protocol for ALI/ARDS ventilation. Avoid synchronized intermittent mandatory ventilation (SIMV) during the acute phase of illness. Instead, use mandatory modes of ventilation such as assist control (ACV) or pressure control (PCV) to prevent spontaneously large tidal volumes. Do not allow peak pressures to govern ventilator management. The key value is the plateau pressure. The weight for determining the Vt should be the ideal body weight, not the fat or over-hydrated weight. The ideal body weight is calculated from the patient s height. Do not worry about the pCO2 unless the pH is less than a threshold the clinical team cannot accept. Some intensivists are comfortable with pH as low as 7.10. Most clinicians like to see pH greater than 7.21. Timid clinicians use pH in the range of 7.25 or 7.30. Where renal dysfunction prevents compensation, bicarbonate can be used to help maintain the pH. However, constant bicarbonate infusions can also contribute to CO2 production. THAM does not have this side effect.