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Effective Glycemic Control Outside of the Critical Care Unit Christopher A. Newton, MD, FACE [email protected] Division of Endocrinology Grady Memorial Hospital Emory University November 3, 2012 Dallas, TX • November 2–4, 2012 Objectives • Describe acute care populations that are at high risk for hyperglycemia • Identify essential components to achieving glycemic control in the acute care setting Dallas, TX • November 2–4, 2012 DEFINITIONS Dallas, TX • November 2–4, 2012 Accepted Glycemic Ranges Dallas, TX • November 2–4, 2012 Glycemic Thresholds • In-hospital hyperglycemia is defined as an admission or in-hospital blood glucose >140 mg/dL • Hypoglycemia is defined as any blood glucose <70 mg/dL • A patient with an HbA1c >6.5% can be identified as having diabetes Dallas, TX • November 2–4, 2012 • Comparison of sensitivity and specificity achieved for the diagnosis of diabetes based on fasting plasma glucose at various levels of HbA1c from data in NHANES III and 19992004 NHANES Dallas, TX • November 2–4, 2012 J Clin Endocrinol Metab, July 2008, 93(7):2447–2453 INCIDENCE OF HYPERGLYCEMIA Dallas, TX • November 2–4, 2012 Distribution of Patient-DayWeighted Mean POC BG Values ICU Non-ICU DATA from ~49 million POC-BG testing (12 M ICU; 37 M non-ICU) from 3.5 million patients (653,359 ICU; 2,831,436 nonICU). The mean POC-BG was 167 mg/dL for ICU patients and 166 mg/dL for non-ICU patients. Dallas, TX • November 2–4, 2012 Swanson et al. Endocrine Practice, October 2011 Distribution of Patient-DayWeighted Mean POC BG Values • Data from ~37 million BG readings from 2,831,436 non-ICU patients - mean POC-BG: 166 mg/dL Dallas, TX • November 2–4, 2012 Swanson et al. Endocrine Practice, October 2011 Hyperglycemia Is Common 50 Patients, % 40 Diabetes No Diabetes 50 40 78% 30 30 20 20 10 10 0 0 <110 110-140 140-170 170-200 >200 26% <110 110-140 140-170 170-200 >200 Mean BG, mg/dL Dallas, TX • November 2–4, 2012 Kosiborod M, et al. J Am Coll Cardiol. 2007;49(9):1018-183:283A-284A. IGT and Undiagnosed T2DM Are Common in Acute MI and Stroke 2-hour OGTT Norhammar A, et al. Lancet 2002;359:2140−4. Matz K, et al. Diabetes Care 2006;792−7. Dallas, TX • November 2–4, 2012 CLINICAL OUTCOMES ASSOCIATED WITH HYPERGLYCEMIA Dallas, TX • November 2–4, 2012 Hyperglycemia: Independent Marker of In-Hospital Mortality * * P < 0.01 Dallas, TX • November 2–4, 2012 Umpierrez GE et al, J Clin Endocrinol Metabol 87:978, 2002 Hyperglycemia and Pneumonia Outcomes * * * * * P<0.05 vs BG<198 mg/dL N=2471 patients with community acquired pneumonia Dallas, TX • November 2–4, 2012 McAllister et al, Diabetes Crae 28:810-815, 2005 30 Day Mortality and In-hospital Complications among Non-cardiac Surgery Patients * * † * * * # † p = 0.1 * p = 0.001 # p =0.017 Dallas, TX • November 2–4, 2012 A Frisch et al. Diabetes Care, May 2010 INSULIN PROTOCOL DEVELOPMENT Dallas, TX • November 2–4, 2012 Key Elements – BG Targets • Glucose Target in non-ICU setting: – Premeal glucose targets <140 mg/dL – Random glucose <180 mg/dL – To avoid hypoglycemia, reassess insulin regimen if glucose levels fall below 100 mg/dL – Occasional patients may be maintained with a glucose range below and/or above these cutpoints Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Dallas, TX • November 2–4, 2012 Consensus Panel. Endocr Pract. 2009;15(4). http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf Key Elements - Monitoring • Glucose monitoring is an obvious, but crucial, element of success • Monitoring glucoses: – Provides assessment of current glucose – Are interpreted for adjusting medications based upon the trends in the glucoses • Frequency depends upon treatment regimen utilized – Quicker interventions need more frequent Dallas, TX • November 2–4, 2012 assessments Key Elements - Personnel • Physician / Physician Assistant / Nurse Practitioner • Nurses • Pharmacy Staff • Laboratory Staff • Administration • Many other people – Patients? Dallas, TX • November 2–4, 2012 Key Elements - Medication Antihyperglycemic Therapy SC Insulin Recommended for most medical-surgical patients ACE/ADA Task Force on Inpatient Diabetes. Diabetes Care. 2006 & 2009 Diabetes Care. 2009;31(suppl 1):S1-S110.. OADs Not Generally Recommended Dallas, TX • November 2–4, 2012 Key Elements - Medication • AACE/ADA Consensus Statement: Noninsulin therapies in the hospital? – Sulfonylureas are a major cause of hypoglycemia – Metformin contraindicated in setting of decreased renal blood flow and with use of iodinated contrast dye – Tyiazolidinediones associated with edema and CHF – Alpha-glucosidase inhibitors are weak glucose lowering agents – GLP1-directed therapies can cause nausea and have a greater effect on postprandial glucose Dallas, TX • November 2–4, 2012 Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009 Key Elements - Insulin • Sliding scale short-acting insulin (SubQ) • Subcutaneous basal/bolus therapy – NPH and Regular – Long-acting and Rapid-acting analogs • Subcutaneous continuous infusion • Intravenous insulin Dallas, TX • November 2–4, 2012 Key Elements - Insulin • Study Type: Prospective, multicenter RCT • Population: 130 subjects insulin naïve T2DM • Basal-Bolus Protocol: – Starting total daily dose (TDD): • 0.4 unit/kg/day for BG between 140-200 mg/dL • 0.5 unit/kg/day for BG between 201-400 mg/dL – ½ TDD as insulin glargine and ½ as glulisine • Glargine – once daily at same time each day • Glulisine – three equally divided doses with meals Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 30:2181–2186, 2007 Sliding Scale Insulin • Before meal: Supplemental Sliding Scale Insulin (# of units) • Bedtime: Give ½ of Supplemental Sliding Scale Insulin Blood Glucose (mg/dL) Insulin Sensitive Usual Insulin Resistant >141-180 2 4 6 181-220 4 6 8 221-260 6 8 10 261-300 8 10 12 301-350 10 12 14 351-400 12 14 16 >400 14 16 18 Dallas, TX • November 2–4, 2012 Umpierrez GE et al. Diabetes Care. 2007;30:2181-2186. BG, mg/dL Rabbit 2 Trial: Changes in Glucose Levels With Basal-Bolus vs. Sliding Scale Insulin aP<.05. 240 220 200 180 160 140 120 100 Admit 1 a a a b b b b Sliding-scale Basal-bolus 2 3 4 5 6 7 8 9 10 Days of Therapy bP<.05. • Sliding scale regular insulin (SSRI) was given 4 times daily • Basal-bolus regimen: glargine was given once daily; glulisine was given before meals. 0.4 U/kg/d x BG between 140-200 mg/dL 0.5 U/kg/d x BG between 201-400 mg/dL Dallas, TX • November 2–4, 2012 Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186. BG, mg/dL Rabbit 2 Trial: Treatment Success With Basal-Bolus vs. Sliding Scale Insulin 300 280 260 240 220 200 180 160 140 120 100 Slidingscale Basalbolus Hypoglycemia rate: Basal Bolus Group: BG < 60 mg/dL: 3% BG < 40 mg/dL: none Admit1 2 3 4 1 2 3 4 5 6 7 Days of Therapy Sliding Scale Group: BG < 60 mg/dL: 3% BG < 40 mg/dL: none Persistent hyperglycemia (BG>240 mg/dl) is common (15%) during SSI therapy Dallas, TX • November 2–4, 2012 Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186. Basal-Bolus vs Sliding Scale Insulin in Hospitalized Patients with T2DM • The mean insulin daily dose was significantly higher in the basal-bolus group than in the sliding scale group Insulin Type Mean Insulin Dose, units / day Basal-Bolus Group SSI Group Basal insulin 22 ± 2 - Rapid-acting insulin 20 ± 1 - - 12.5 ± 2 Regular insulin Dallas, TX • November 2–4, 2012 Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186. • Study Type: Prospective, multicenter, randomized, open-label trial in general surgery (non-ICU) • Population: 211 subjects with T2DM on diet and/or oral hypoglycemic agents or low dose insulin (<0.4 units/kg/day) • Primary Outcomes: Differences between groups in mean daily blood glucose and composite of hospital complications (wound infection, pneumonia, respiratory failure, acute renal failure, bacteremia Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 RABBIT 2 Surgery Treatment on Admission All SSI Glar+Glu P-value Diet alone, n 17 11 6 NS Oral antidiabetic agents, n 153 80 73 NS Insulin + oral antidiabetic agents, n 20 11 9 NS Type of surgery All SSI Glar+Glu P-value Cancer 76 40 36 NS GI-GU benign 59 28 31 NS Vascular 31 15 16 NS Trauma 38 20 18 NS Others 7 5 2 NS Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 RABBIT 2 Surgery: Basal-Bolus Regimen • D/C oral anti-diabetic drugs on admission • Starting total daily dose (TDD): 0.5 unit/kg/day • TDD reduced to 0.3 unit/kg/day in patients >70 years old or with creatinine >2 mg/dL • ½ TDD as glargine and ½ TDD as glulisine – Glargine – once daily at same time of day – Glulisine – three equally divided doses with meals • Goal glucoses: 100-140 mg/dL Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 Basal-Bolus Dose Adjustment Blood glucose levels Change in Daily Insulin Dose* Fasting and pre-meal BG between 100-140 mg/dl in the absence of hypoglycemia no change Fasting and pre-meal BG between 141-180 mg/dl in the absence of hypoglycemia Increase by 10% Fasting and pre-meal BG between >181 mg/dl in the absence of hypoglycemia Increase by 20% Fasting and pre-meal BG between 70-99 mg/dl in the absence of hypoglycemia Decrease by 10% Fasting and pre-meal BG between <70 mg/dl Decrease by 20% * Daily insulin adjustment was primarily focused on glargine dose. * The treating physicians were allowed to adjust prandial (glulisine) insulin dose, and to use the total supplemental dose, patient’s nutritional intake, and results of BG testing to adjust insulin regimen. Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 RABBIT 2 Surgery: Glucoses During Therapy * * † R = Randomization ‡ † † * p<0.001 † p=0.01 ‡ p=0.02 Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 RABBIT 2 Surgery: Mean Glucose During Day * * * * *p<0.001 Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 RABBIT 2 Surgery: Postoperative Complications P=0.003 P=0.05 P=NS P=0.10 P=0.24 * Composite of hospital complications: wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 RABBIT 2 Surgery: Impact on Need for ICU Post-surgical ICU Admission ICU Length of Stay P=0.003 P=0.16 Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 RABBIT 2 Surgery: Hypoglycemia p<0.001 p<0.001 There were no differences in hypoglycemia between patients treated with insulin prior to admission compared to insulin-naïve patients. p=0.057 Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 RABBIT 2 Surgery: Insulin Doses Insulin Type Mean Insulin Dose, units / day Basal-Bolus Group SSI Group 33.4 12.3 Basal insulin 21.8 ± 8.6 - Rapid-acting insulin 14.8 ± 7.6 - - 12.3 ± 6.5 Total daily dose Regular insulin SSI: range of daily regular insulin= 9.7 to 14.4 units after 24hr treatment 88.5% of patients received <20 units and 39.4% <10 units per day. Dallas, TX • November 2–4, 2012 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011 • Study Type: Prospective, randomized, open-label trial • Population: 130 subjects with T2DM on oral hypoglycemic agents or insulin therapy • Study Sites: – Grady Memorial Hospital, Atlanta, GA – Rush University Medical Center, Chicago, IL Dallas, TX • November 2–4, 2012 Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009 DEAN Trial: Changes in Mean Daily Blood Glucose Concentration 240 Detemir + aspart NPH + regular BG, mg/dL 220 200 P=NS 180 160 140 120 100 Pre-Rx BG 0 1 2 3 4 5 6-10 Duration of Therapy, d Data are means SEM. Basal-bolus regimen: detemir was given once daily; aspart was given before meals. NPH/regular regimen: NPH and regular insulin were given twice daily, 2/3 in AM, 1/3 in PM. Dallas, TX • November 2–4, 2012 Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564-569. DEAN Trial Blood glucose (mg/dL) Detemir + Novolog NPH + Regular Dallas, TX • November 2–4, 2012 Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564-569. DEAN Trial: Insulin Doses • The mean total daily insulin dose was not significantly different between treatment groups Insulin Type Total Units/day Basal insulin/day Rapid-acting insulin Mean Insulin Dose, units / day Detemir-Novolog NPH-Regular 56 ± 45 45 ± 32 Detemir: 30 ± 28 NPH: 27 ± 20 Novolog: 27 ± 20* Regular: 18 ± 14 * P < 0.05 Dallas, TX • November 2–4, 2012 Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564-569. DEAN Trial: Hypogylcemia • NPH/Regular – BG <40 mg/dL: 1.6% – BG <60 mg/dL: 25.4% • Detemir/Aspart – BG <40 mg/dL: 4.5% – BG <60 mg/dL: 32.8% To determine risk factors for hypoglycemic events during SC insulin therapy Dallas, TX • November 2–4, 2012 Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564-569. Interim Summary • Treatment with basal bolus improved glycemic control and reduced hospital complications compared to SSI in medicine and surgery patients with T2DM • Basal-bolus insulin regimen is preferred insulin regimen over Sliding Scale Insulin in the hospital management of non-ICU patients with T2DM Dallas, TX • November 2–4, 2012 Hypoglycemia Risk Factors p-value Variable (univariate) BG <60 mg/dL BG <70 mg/dL Age 0.036 0.001 Weight 0.027 0.001 HbA1c 0.521 0.658 Creatinine 0.011 0.002 Enrollment BG 0.166 0.319 Previous treatment 0.005 <0.001 Previous insulin treatment <0.001 <0.001 Treatment group <0.001 <0.001 *p-values are from Wilcoxon Two-Sample Test Dallas, TX • November 2–4, 2012 Umpierrez et al, ADA Scientific Meeting, Poster #516, 2009 CAN HYPOGLYCEMIA FROM INSULIN BE AVOIDED? Dallas, TX • November 2–4, 2012 Hypoglycemia: Triggering Events • Transportation off ward, causing meal delay • Failure to measure blood glucose before insulin doses • New NPO status • Interruption of – – – – IV dextrose therapy TPN Enteral feedings Continuous venovenous hemodialysis Dallas, TX • November 2–4, 2012 SubQ Basal Insulin Action sc insulin n=20 T1DM Mean ± SEM 4.0 24 3.0 16 2.0 12 8 1.0 Glargine 0 4 8 12 16 Time (hours) Adapted from Lepore M. et al., Diabetes 49:2142-8, 2000 20 4 0 NPH 0 µ mol/Kg/min mg/Kg/min 20 24 Dallas, TX • November 2–4, 2012 Intravenous Insulin • By-passes the delay associated with subcutaneous insulin administration • Insulin from an IV infusion or IV bolus will disappear from bloodstream in 7 minutes – With sufficiently frequent monitoring, can decrease the insulin dose prior to onset of hypoglycemia • Majority of medical centers limit this option to intensive/critical care settings Dallas, TX • November 2–4, 2012 IV versus SubQ Insulin • Long-acting subcutaneous insulin – Slow steady release of insulin into blood stream – Can be mimicked by continuous infusion • Rapid-acting subcutaneous insulin – Faster absorption of insulin from subcutaneous space (doesn’t last) – Similar to a temporary increased infusion rate (not the same as IV bolus) Dallas, TX • November 2–4, 2012 Successful Insulin Infusion Protocols • Reaches and maintains BG successfully within a prespecified target range • Includes a clear algorithm for making temporary corrective changes in the IV insulin rate as patient requirements change • Incorporates the “rate of change” in BG, not just the absolute values • Incorporates the current IV insulin rate • Minimizes hypoglycemia; provides specific directions for its treatment when it occurs • Provides specific guidelines for timing and selection of Dallas, TX • November 2–4, 2012 doses for the transition to SC insulin IV Insulin in Non-ICU • Retrospective review in 200 patients – 90 General Medicine /110 General Surgery – Mean glucose 322 mg/dL • Targeted glucose <150 mg/dL for 85% – 67% achieved glucose <150 by day 2 – Mean glucose during infusion: 170 mg/dL Dallas, TX • November 2–4, 2012 Smiley D, et al. J Hosp Med. 2010;5:212-217. Hypoglycemia on IV Insulin Dallas, TX • November 2–4, 2012 Smiley D, et al. J Hosp Med. 2010;5:212-217. Transition from IV Continuous Insulin Infusion to SC Insulin Therapy We recommend that all patients with type 1 and type 2 diabetes be transitioned to scheduled sc insulin therapy at least 1–2 h before discontinuation of CII. We recommend that sc insulin be administered before discontinuation of CII for patients without a history of diabetes who have hyperglycemia requiring more than 2 unit/h. We recommend POC testing with daily adjustment of the insulin regimen after discontinuation of CII. Dallas, TX • November 2–4, 2012 Transition From Intravenous to Subcutaneous Insulin Known Diabetics: Calculate total daily insulin requirement: based on insulin rate during the last 4-hours of infusion, (e.g., 2 units/hour = 48 U/day) Start SC insulin as follow: ½ dose as basal (Glargine, Detemir) ½ dose as prandial (Lispro, Aspart, Glulisine) If patient not able to eat: give basal but hold prandial insulin Dallas, TX • November 2–4, 2012 Smiley et al. Ann. N.Y. Acad. Sci 1212:1-11, 2010 Transition From Intravenous to Subcutaneous Insulin No History of Diabetes (stress hyperglycemia): If HbA1c >7%, treat as diabetes If HbA1c <6.4% If insulin requirements during CII is <2 U/hr, stop infusion and use correction doses for BG >140 mg/dl If requirements >2 U/hr during CII, start SC insulin: ½ dose as basal (Glargine, Detemir) ½ dose as prandial (Lispro, Aspart, Glulisine) Dallas, TX • November 2–4, 2012 Smiley et al. Ann. N.Y. Acad. Sci 1212:1-11, 2010 CONTINUOUS SUBCUTANEOUS INSULIN INFUSION Dallas, TX • November 2–4, 2012 Keys to CSII Use in the Hospital • AACE/ADA Inpatient Hyperglycemia – Candidates for inpatient CSII use are those using CSII as outpatients • Must have mental and physical capacity to do so – Nursing personnel must document basal rates and bolus doses on regular basis – Hospital personnel with expertise in CSII therapy is essential Dallas, TX • November 2–4, 2012 Potential Issues with CSII Use • Many nurses (and physicians) are unfamiliar with the technology and thus uncomfortable with allowing its continued use – Knowledge scores 67% for those with prior experience with CSII user vs 17% (p<0.01) – Agreed CSII effective strategy for managing diabetes in the hospital – Only 27% thought they could safely care for a patient using CSII Dallas, TX • November 2–4, 2012 Noschese et al. Diabetes. 2006;55:846-P. Policy for Continued CSII Use • List of suggested contraindications – Altered state of consciousness – Critically ill – Risk of suicide – “other reason” deemed appropriate by MD • Set of rules to guide medical staff • Requirement of signed informed consent detailing conditions for CSII use Dallas, TX • November 2–4, 2012 Bailon et al. Endocr Pract. 2009;15:24-29. Procedures for Patients Admitted to Hospital on CSII • • • • • • • • Presence of insulin pump, brand of pump and insulin type are identified Blood or capillary glucose level is determined Contraindications for continued use of insulin pump are assessed Physician order for alternate insulin therapy is obtained if CSII must be discontinued Patient’s consent for CSII is obtained Admitting physician writes initial order for insulin pump therapy using the preprinted order form Endocrinology, diabetes education, and nutrition consultations are ordered by admitting physician Insulin pump basal-bolus blood glucose record flow sheet is placed at the patient’s bedside Dallas, TX • November 2–4, 2012 Bailon et al. Endocr Pract. 2009;15:24-29. Insulin Pump Therapy: One Institution’s Experience • Frequency of hypoglycemic and hyperglycemic events among hospitalized patients receiving continuous subcutaneous insulin infusion (insulin pump) therapy Dallas, TX • November 2–4, 2012 Leonhardi BJ, et al. J Diabetes Sci Technol. 2008;2(6):948-962 Pump “On” vs Pump “Off” BG > 200 mg/dL BG < 70 mg/dL Dallas, TX • November 2–4, 2012 Bailon et al. Endocr Pract. 2009;15:24-29. Hypo and Hyperglycemia With and Without CSII Dallas, TX • November 2–4, 2012 Bailon et al. Endocr Pract. 2009;15:24-29. Pitfalls to Continued CSII Use • Limited experience – Published reports suggest 1-2 patients/mo • Supplies – Tubing needs to be changed at most Q3days – Different pumps need different reservoirs • Determining who is “in charge” and tracking the insulin dosing • Pumps and MRI’s don’t mix • Note, this is “continued” not “initiating”… Dallas, TX • November 2–4, 2012 CONCLUSIONS Dallas, TX • November 2–4, 2012 Summary • Hyperglycemia is common in hospitals • Evidence on the management of hyperglycemia in non-ICU settings is increasing – Vast majority of studies utilize subQ insulin • Intravenous insulin can be implemented in non-ICU’s – Has been most often studied in ICU’s • SubQ insulin infusion can be continued Dallas, TX • November 2–4, 2012