Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock Dellinger RP, Levy MM, Rhodes A, Annane D, Carcillo JA, Gerlach H, Opal S, Sevransky J, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally M, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld G, Webb S, Beale RJ, Vincent JL, Moreno R, and the SSC Management Guidelines Committee Crit Care Med. 2013;41:580–637 Intensive Care Med. 2013;39:165-228 The Surviving Sepsis Campaign (SSC) has recently published recommendations and guidelines for the management of severe sepsis and septic shock. Each of the authors who wrote a section of the publication have prepared a slide presentation for that section, which ESICM and SCCM are making available to physicians around the world. This should help to disseminate the latest guidelines and the up-to-date supporting literature, and advance the care of septic patients.

Surviving Sepsis Campaign (SSC) 2012 Guidelines Glucose Control Crit Care Med. 2013;41:580–637 Intensive Care Med. 2013;39:165-228 This section relates to glucose control. For many years, physicians were not very aggressive about the treatment of hyperglycemia within the ICU, and it was not unusual to see patients with serum glucose levels above 200 mg/dL. In a 2001 landmark paper in the New England Journal of Medicine, van den Berghe and colleagues showed that intensive insulin therapy could improve survival in ICU patients. This changed the way intensivists approached the problem of glucose control in the ICU.

Surviving Sepsis Campaign 2012 Guidelines – Glucose Control We recommend protocolized approach to blood glucose management, commencing insulin dosing when 2 consecutive blood glucose levels are >180 mg/dL. This protocolized approach should target upper blood glucose <180 mg/dL rather than upper target blood glucose <110 mg/dL. Grade 1A NICE-SUGAR. N Engl J Med. 2009;360:1283–1297 van den Berghe G. N Engl J Med. 2001;345:1359–1367 Dellinger P. Crit Care Med. 2013;41:580–637 Dellinger P. Intensive Care Med 2013;39:165-228 The 2008 Surviving Sepsis Campaign guidelines recommended intravenous insulin therapy to reduce blood glucose levels, targeting glucose levels to a range <150 mg/dL. The present recommendations have changed, recommending to commence insulin dosing with a trigger of blood glucose levels >180 mg/dL and targeting blood glucose <180 mg/dL (based on the NICS-SUGAR study) rather than an upper target blood glucose <110 mg/dL (based on the van den Berghe studies).

Surviving Sepsis Campaign 2012 Guidelines – Glucose Control Large randomized single-center trial (predominantly cardiac surgical ICU) demonstrated reduced ICU mortality with intensive intravenous insulin targeting blood glucose to 80–110 mg/dL. van den Berghe G. N Engl J Med. 2001;345:1359–1367 Second randomized trial of intensive insulin therapy using this protocol enrolled medical ICU patients with anticipated ICU LOS of >3 days; overall mortality was not reduced. van den Berghe G. N Engl J Med 2006;354:449–461 Dellinger P. Crit Care Med 2013; 41:580–637 Dellinger P. Intensive Care Med 2013;39:165-228 The results of the 2 van den Berghe studies.

Intensive Insulin Therapy in Critically Ill Patients Kaplan-Meier curves showing cumulative survival of patients who received intensive insulin treatment or conventional treatment in the ICU (predominantly cardiac surgical ICU patients) in the first van den Berghe study. Patients discharged alive from the ICU (panel A) and from the hospital (panel B) were considered to have survived. In both cases, the differences between the treatment groups were significant (survival in ICU, nominal P=0.005 and adjusted P<0.04; in-hospital survival, nominal P=0.01). Tight glycemic control= 80-110 mg/dL vs. 215 mg/dL + maintenance 180 and 200 mg/dL. van den Berghe et al. N Engl J Med. 2001;345:1359

Intensive Insulin Therapy in Critically Ill Patients The effect of intensive insulin treatment on the time from ICU admission until death is shown for the intention-to-treat group (panel A) and the subgroup of patients staying in the ICU for 3 or more days (panel B) in the second van den Berghe study in medical ICU patients. P values for the intention-to-treat group were not significant, whereas they were for the subgroup staying in the ICU for 3 or more days. Tight glycemic control= 80-110 mg/dL vs. 215 mg/dL + maintenance 180 and 200 mg/dL. van den Berghe et al. N Engl J Med. 2006;354:449

But…

Surviving Sepsis Campaign 2012 Guidelines – Glucose Control Subsequent RCTs studied mixed populations of surgical and medical ICU patients and found that intensive insulin therapy did not significantly decrease mortality, whereas the NICE-SUGAR trial demonstrated an increased mortality. Brunkhorst FM. VISEP. N Engl J Med. 2008;358:125–139 Preiser JC. Glucontrol. Intensive Care Med. 2009;35:1738 Annane D. COIITSS. JAMA .2010;303:341–348 NICE-SUGAR. N Engl J Med. 2009;360:1283–1297 Dellinger P. Crit Care Med. 2013;41:580–637 Dellinger P. Intensive Care Med. 2013;39:165-228 Subsequent randomized controlled trials (RCTs), referenced here, studied mixed populations of surgical and medical ICU patients, and found that intensive insulin therapy did not significantly decrease mortality. In fact, the NICE-SUGAR trial demonstrated an increased mortality.

VISEP Intensive Insulin Trial The VISEP study showed no significant difference in mortality at 28 days between patients in the tight glycemic control group (24.7%; glucose 80-110 mg/dL) versus those in the control group (26.0%; glucose 180-200 mg/dL). Brunkhorst FM. N Engl J Med. 2008;358:125

Intensive vs. Conventional Glucose Control in Critically Ill Patients 10 20 30 40 50 60 70 80 90 Time, days 100 Hospital survival probability (%) P = 0.386 Intensive Glucose Control Control In the Glucontrol study, 30-day mortality also was not different between the intensive insulin group (17.0%) [target blood glucose treatment group, 4.4–6.1 mmol/L (81-108 mg/dL)] and the control group (18.8%) [7.8–10.0 mmol/L (140-180 mg/dL)]. 28-day mortality - treatment group 100/536 (18.7%); control group 83/542 (15.3%); P = 0.14 Hospital mortality - treatment group 125/536 (23.3%); control group 105/542 (19.4%); P = 0.11 Preiser JC. Glucontrol. Intensive Care Med .2009;35:1738

Intensive Insulin Therapy for Septic Shock - COIITSS Study There were also no in-hospital mortality differences in the COIITSS study, with a 45.9% mortality in patients treated with intensive insulin (80-110 mg/dL) and 42.9% mortality in patients treated with conventional insulin therapy (physician discretion). Annane D. JAMA. 2010;303:341-348

Intensive vs. Conventional Glucose Control in Critically Ill Patients Tight glycemic control= 81-108 mg/dL vs. <180 mg/dL In the NICE-SUGAR study, Kaplan–Meier estimates for the probability of survival at 90 days were greater in the conventional-control group (target blood glucose range, <180 mg/dL) than in the intensive-control group (target blood glucose range, 81-108 mg/dL) [hazard ratio, 1.11; 95% confidence interval, 1.01 to 1.23; P = 0.03]. Mortality rates were 27.5% in the intensive-control group and 24.9% in the conventional-control group. NICE-SUGAR. N Engl J Med. 2009;360:1283

Surviving Sepsis Campaign 2012 Guidelines - Glucose Control As there is no evidence that targets between 140 and 180 mg/dL are different from targets of 110 to 140 mg/dL, the recommendations use an upper target blood glucose ≤180 mg/dL without a lower target other than hypoglycemia. Treatment should avoid hyperglycemia (>180 mg/dL), hypoglycemia, and wide swings in glucose levels. Dellinger P. Crit Care Med. 2013;41:580–637 Dellinger P. Intensive Care Med. 2013;39:165-228 Self-explanatory

Tight Glycemic Control in the ICU: Systematic Review and Meta-analysis In a meta-analysis of 7 tight glycemic control trials, Marik showed that tight glycemic control did not reduce the 28-day mortality (odds ratio 0.95; 95% confidence interval, 0.87-1.05). Marik PE. Chest. 2010;137:544

Severe Hypoglycemia ≤40mg/dL (2.2 mmol/L) 5.1% 0.8% 18.7% 3.1% 17% 4.1% 8.7% 2.7% 16.4% 7.8% 6.8% 0.5% As seen in this slide, multiple studies have demonstrated a much higher incidence of hypoglycemia in patients randomized to tight glycemic control. Treatment vs control P<0.001

Surviving Sepsis Campaign 2012 Guidelines - Glucose Control Mortality in clinical trials of intensive insulin therapy by high or moderate control groups The randomized controlled trials that reported benefit compared intensive insulin therapy to high controls (180–200 mg/dL) [odds ratio, 0.89 (0.73–1.09)], whereas those that did not demonstrate benefit compared intensive therapy to moderate controls (108–180 mg/dL) [odds ratio, 1.14 (1.02 to -1.26)].

Surviving Sepsis Campaign 2012 Guidelines - Glucose Control We recommend blood glucose values be monitored every 1-2 hours until values and insulin infusion rates are stable, then every 4 hours thereafter. Grade 1C Dellinger P. Crit Care Med. 2013;41:580–637 Dellinger P. Intensive Care Med. 2013;39:165-228 Recommendations for frequency of glucose monitoring

Surviving Sepsis Campaign 2012 Guidelines - Glucose Control We recommend that glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may not accurately estimate arterial blood or plasma glucose values. No Grade Dellinger P. Crit Care Med. 2013;41:580–637 Dellinger P. Intensive Care Med. 2013;39:165-228 Self-explanatory

Surviving Sepsis Campaign 2012 Guidelines - Glucose Control Capillary point-of-care testing found to be inaccurate with frequent false glucose elevations over range of glucose levels, but especially in hypoglycemic and hyperglycemic glucose ranges and in hypotensive patients or patients receiving catecholamines.. Hoedemaekers CW. Crit Care Med. 2008;36:3062–3066 Khan AI. Arch Pathol Lab Med. 2006;130:1527–1532 Desachy A. Mayo Clin Proc. 2008;83:400–405 Fekih Hassen M. Diabetes Res Clin Pract. 2010;87:87–91 Dellinger P. Crit Care Med. 2013;41:580–637 Dellinger P. Intensive Care Med. 2013;39:165-228 Patient populations with inaccuracies for capillary blood point-of-care testing