Glycemic Control: Hospitalized PatientsReview of Guidelines

Lukasz MaterekEndocrine RoundsSeptember 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 4.4-6.1 mmol/L

MICU

• 5 trials (fair); 1 trial (poor)• Target 4.4-6.1 mmol/L vs. 7.8-11 mmol/L• No mortality difference

SICU

• 3 trials (fair); 2 trials (poor)• Target 4.4-8.3 mmol/L vs. 10-12 mmol/L• No mortality benefits

• NICE-SUGAR– Target 4.4-6 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 4.4-6.1 mmol/L vs 10.0-11.1 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;154:268-282

©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;154:268-282

©2011 by American College of Physicians

ICU Studies

Non-ICU Studies

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;154:268-282

©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 4.0-11.0 mmol/L vs unspecified• Target 7.0-11.0 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;154:268-282

©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;154:268-282

©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=0.02

• 78 more deaths in the lower glycemic target group

Mortality from CVS cause

• 41.6% vs 35.8% • p value=0.02

• 76 more deaths in the lower glycemic target group

Hypoglycemia

• 6.8% vs 0.5% • p value < 0.001

• More hypoglycemia in the lower glycemic target group

Intensive Insulin Therapy in Critically Ill PatientsVan den Berghe et al. 2001

• 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. 2004– 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 4.5 -6 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 T1/2

The End

• Questions