Glycemic Control: Hospitalized Patients Review of Guidelines Lukasz Materek Endocrine Rounds September 2011

Objectives: – Review available guidelines ACP ADA CDA – Discuss evidence for glycemic control inhospitalized patients – Review approach to common hospital scenarios

ACP Guidelines: February 2011 Does the use of IIT (intensive insulin therapy) to achieve tight control compared to less tight control improve outcome? Which population? Are there harms? ITT: – Intravenous insulin – Common Target mmol/L

MICU 5 trials (fair); 1 trial (poor) Target mmol/L vs mmol/L No mortality difference

SICU 3 trials (fair); 2 trials (poor) Target mmol/L vs mmol/L No mortality benefits NICE-SUGAR – Target mmol/L vs <10 mmol/L – Increased mortality (RR 1.31 CI 1.07 – 1.61) Intensive insulin therapy in the critically ill patients – Target mmol/L vs mmol/L – Decreased mortality (RR 0.58 CI 0.38 – 0.78)

Mixed ICU (MICU/SICU) 5 Trials (fair) Target 4.0 – 6.1 mmol/L vs 7.8 – 11.1 mmol/L No mortality benefit

Short-term mortality in studies of intensive insulin therapy, by the mean glucose level achieved in the intervention group. Short-term mortality includes death occurring within 28 d of or during the ICU or hospital stay; we used 28-d mortality in the meta-an... Kansagara D et al. Ann Intern Med 2011;154: ©2011 by American College of Physicians BG < 6.66 Not reported BG > 6.66

Mortality at 90 or 180 d in studies of intensive insulin therapy, by inpatient setting. Kansagara D et al. Ann Intern Med 2011;154: ©2011 by American College of Physicians ICU Studie s Non- ICU Studie s

Short-term mortality in studies of intensive insulin therapy, by inpatient setting.Short-term mortality includes death occurring within 28 d of or during the ICU or hospital stay; we used 28-d mortality in the meta-analysis when a study reported >1 outcome. Kansagara D et al. Ann Intern Med 2011;154: ©2011 by American College of Physicians ICU Studies Non-ICU Studies

General Medical Ward 0 Trials

Myocardial Infarction 3 Trials (fair); 2 Trials (poor) Target mmol/L vs unspecified Target mmol/L + insulin on discharge – Mortality reduction (RR 0.69 CI 0.49 – 0.96) Overall, no mortality reduction

Stroke / ABI 2 Trials (fair); 2 Trials (poor) Target 4.4 – 8.0 mmol/L vs <10.0 / <17.0 mmol/L Overall, no mortality reduction

Perioperative Control 1 Trial (fair); 2 Trials (poor) Target 3.9 – 10.0 mmol/L vs unspecified No difference in health outcomes – Small studies – Low event rates

Infection Risk 9 Trials (fair); 7 Trials (poor) Sepsis – Reduction of sepsis with IIT – RR 0.79 CI 0.62 – 1.00 Pooled result of wound infection, UTI, pneumonia or combination – No significance – RR 0.68 CI 0.36 – 1.30

Effects of intensive insulin therapy on rates of infection in various inpatient settings.We included inpatients in the MICU, SICU, and perioperative settings as well as patients with stroke or acute brain injury. Kansagara D et al. Ann Intern Med 2011;154: ©2011 by American College of Physicians sepsis infx

Hypoglycemia Critically ill patients and IIT – RR 5.32 CI 4.21 – 6.73 No data for general medical unit patients Is hypoglycemia a marker of severe illness or causative factor for excess mortality/morbidity?

Risk for hypoglycemia in studies of intensive insulin therapy in various inpatient settings.We included inpatients in the MICU, SICU, and perioperative settings as well as patients with traumatic brain injury. Kansagara D et al. Ann Intern Med 2011;154: ©2011 by American College of Physicians

ACP Recommendations: – ACP recommends not using intensive insulin therapy to strictly control blood glucose in non- SICU/MICU patients – Strong recommendation – Moderate quality of evidence Avoid targets <7.8 Targets not precisely defined

ACP Recommendations: – ACP recommends not using ITT to normalize blood glucose in SICU/MICU patients – Strong recommendation – High quality of evidence No benefit of ITT (target 4.4 – 6.1 mmol/L) Excess hypoglycemia

ACP Recommendations: – ACP recommends a target blood glucose level of 7.8 – 11.1 mmol/L if insulin therapy is used in SICU/MICU patients – Weak recommendation – Moderate quality of evidence – Limited data for 10.0 – 11.1 mmol/L range

ADA: Diabetes Care January 2011 Summary of recommendations

Critically Ill Patients Initiate insulin therapy for treatment of persistent hyperglycemia: – threshold 10 mmol/L – Target 7.8 – 10.0 mmol/L – More stringent goals may be appropriate in selected patients if hypoglycemia is avoided Traget 6.1 – 7.8 mmol/L – Target of <6.1 mmol/L not recommended

NICE-SUGAR Largest RCT (6104 subjects) Compared targets 4.5 – 6 mmol/L; mean achieved 6.4 mmol/L 8 – 10 mmol/L; mean achieved 8 mmol/L Bottom line 6.4 vs 8.0 mmol/L in critically ill

90-day mortality 27.5% vs 24.9% p value= more deaths in the lower glycemic target group

Mortality from CVS cause 41.6% vs 35.8% p value= more deaths in the lower glycemic target group

Hypoglycemia 6.8% vs 0.5% p value < More hypoglycemia in the lower glycemic target group

Intensive Insulin Therapy in Critically Ill Patients Van den Berghe et al intensive insulin therapy – maintenance of blood glucose at a level between 4.4 and 6.1 mmol/L conventional treatment – infusion of insulin only if the blood glucose level exceeded 11.9 mmol/L and maintenance of glucose at a level between 10 and 11 mmol/L

Achieved AM BG levels in the study 5.7±1.1 mmol/L vs. 8.5±1.8 mmol/L Only 39 percent of the patients treated with the conventional approach received insulin; 9.6±1.8 mmol/L, as compared with 7.8±1.4 mmol/L in the patients who did not receive insulin.

Thirty-five patients in the intensive-treatment group (4.6 percent) died during intensive care, as compared with 63 patients (8.0 percent) in the conventional-treatment group apparent risk reduction of 42% – confidence interval 22-62%

after adjustment for repeated interim analyses the median unbiased estimate of the reduction in mortality was 32 % – Adjusted confidence interval, 2 to 55 %; P<0.04

26 Trial Meta-Analysis IIT vs Conventional Therapy Relative Risk of Death – 0.93 (CI 0.83 – 1.04)

ICU Subgroup Analysis Benefit of IIT in the surgical ICU – RR 0.63 (CI 0.44 – 0.91) Benefit of IIT in the medical ICU – RR 1.0 (CI 0.78 – 1.28) Benefit if IIT in the mixed ICU – RR 0.99 (VI 0.86 – 1.12)

Non-critically Ill No clear evidence for specific blood glucose goals If eating, premeal target <7.8 mmol/L and random levels of < 10 mmol/L Less stringent goals if multiple comorbidities Scheduled insulin with correction scale should be utilized (not Sliding Scale)

Non-critically Ill Reassess regimen if BG < 5.6 mmol/L Modify regimen if BG < 3.9 mmol/L Scheduled insulin which delivers basal, nutritional and correction insulin is preferred

CDA: 2008 Critically ill patients: – Van den Berghe et al 2001 Critically ill patients (large surgical group) – Meta-analysis Lau et al – Van den Berghe et al 2006 Medical ICU Patients No difference in primery end point of in-hospital mortality

Recommendation IV Insulin strategy should be used to achieve targets of mmol/L in post-op ventilated ICU patients Medical ICU patients when BG is >6.1 mmom/L

Stroke 1 small study n=25 – BG > 7, increased infarct size GIST-UK; 2007: RTC n=933 – GIK vs NS infusions – No mortality or morbidity difference Subgroup of Van den Berghe et al 2006 Medical ICU Patients with neurological conditions No benefit

Medical in-patients No recommendations for targets Use proactive approach, not Sliding Scale Availability of glucose especially when NPO Avoid hypoglycemia Glucagon should be available

Perioperative control CABG – Intraoperative target 5.5 – 10.0 mmol/L – Reduced mortality and infection risk – Use of IIT for target 4.4 – 5.6 mmol/L showed no benefit of IIT

Perioperative control Minor or Moderate OR Small studies Limited ecidence Target 5 – 11 mmol/L – Note: monocular phacoemulsification cataract surgery with mod-severe nonproliferative diabetic neuropathy in patients with hyperglycemia could worsen retinopathy and maculopathy with rapid glycemic correction

Summary ACP supports the most “less tight control” ADA based on recent evidence but support a a lower target in the ICU setting CDA limited as guidelines established before the recent trials published

Approach to Hospitalized Patient with severe insulin resistance J Clin Endocrinol Metab Sept 2011

Causes of insulin resistance in hospitalized patients Stress response Obesity Electrolyte disturbance: low K/Ca/Mg or high Ca Feeds Fatty emulsion eg. Propofol Steroids/Tacrolimus/Sirolimus Anesthetic Agents: volatile agents Hormonal agents: octreotide, leuprolide, bicalutamide Hormonal disorders: Cushing’s Syndrome, Acromegaly, Hyperaldosteronism, Pheochromocytoma

Approach to Patient Rule-out pseudo-resistance – Check IV bag, tubing, IV site Review medications Assess for concurrent diseases Check electrolytes Check if dextrose is used Assess feeds, Intralipid

If patient receiving SC – Change to IV insulin infusion – SC insulin may be poorly absorbed due to edema poor perfusion etc

Feeds/TPN May consider adding regular insulin to TPN bag – Will decrease risk of hypoglycemia if TPN held – Max dose 50% of daily requirement of insulin Change feed to enteral feeds Decrease or hold TPN with consultation Decrease Intralipid – Changing from FFA infusion to soybean fat

Transition form IV to SC Suggestions by authors – Larsen and Goldner (2011)

Patient on and staying on continuous feeds Requirement for Basal and Supplemental Insulin – Estimates 24hr insulin requirements from the IV infusion (eg. units/hr x 24 hrs) – Options: 1/3 dose as NPH q8h ½ dose as glargine or detemir q12h Full dose as glargine or detemir q24h

Overlap IV with SC for 3 hrs; sorter if glucose falls < 5.5 mmol/L Change BG checks to q4h once IV is off Add fast acting analog or regular insulin q4h Reassess and adjust

Currently on continuous feeds with plans to stop and advance diet Requirement for Basal, Bolus and Supplemental insulin – Stop feeds while continuing with the IV infusion – After 4-5 hrs estimate basal requirements New rate while off feeds eg. 2 units/hr ~24hr req 48 units – Options Give entire basal dose as once daily glargine or detemir or use split dosing half in the morning, half at HS Use NPH: 2/3 ACB and 1/3 evening or 50:50 split

Estimate requirement for meals – Give fast acting analog or regular using a CHO ratio with meals, if previous ratio unknown start with 1:15; if resistant use 1:7  1:5 – Use fixed dose approx 50% of basal insulin dose divided for each meal (units of basal/3 = units for each meal) – If limited intake may need small doses with adjustment as intake improves Overlap IV insulin Blood glucose checks AC meals and HS, consider 3 AM checks

Currently on continuous feeds with plan for intermittent or overnight feeds Scheduled overnight feeds – Calculate 24hr requirements as previously – At initiation of feeds: administer NPH in the evening with additional 5-10 units of fast acting analog or regular insulin – Check BG at 3AM and at the end of the feeds – Adjust as required – If patient eating during the day assess BG levels and treat if required

If bolus feeds – Add fast acting insulin at the time of planned feeds – Base dose on CHO count and use a ratio or fixed dose insulin

Steroids May need additional insulin NPH may be used in the AM when steroids are given and adjusted as the dose of steroids is tapered Meal time insulin may also need to be increased for 4 – 8 hrs after the steroid is given Multiple doses of dex have a long T 1/2

The End Questions