Literature Review - Table of Contents

• I. Essential Guidelines and Reviews
• II. Reviews and Insulin Infusion Protocols
• III. Insulin Infusion: Surgical / Medical Intensive Care Focus
• IV. Insulin Infusion and Effects of Hyperglycemia on Cardiac Surgery and Myocardial Infarction
• V. Transitions and Perioperative Care
• VI. Hyperglycemia in Medical / Surgical Wards and Other Conditions
• VII. Iatrogenic Hypoglycemia and Sliding Scale Insulin
• VIII. Financial Aspects of Inpatient Glycemic Control

I. Essential Guidelines and Reviews

American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control
Diabetes Care. 2009 June;32(6):1119-1131. (published online May 8, 2009).Consensus: Inpatient Hyperglycemia, Endocr Pract. 2009;15(No. 4):1-17.

The 2009 ADA/AACE guidelines were published online recently. The guidelines address the following questions:

1. Does improving glycemic control improve clinical outcomes for inpatients with hyperglycemia?
2. What glycemic targets can be recommended in different patient populations?
3. What treatment options are available for achieving optimal glycemic targets safely and effectively in specific clinical situations?
4. Does inpatient management of hyperglycemia represent a safety concern?
5. What systems need to be in place to achieve these recommendations?
6. Is treatment of inpatient hyperglycemia cost- effective?
7. What are the optimal strategies for transition to outpatient care?
8. What are areas for future research?

Most clinicians want to know the new recommended BG targets:

Copied from the documented "Once IV insulin therapy has been initiated, the glucose level should be maintained between 140 and 180 mg/dL (7.8 and 10.0 mmol/L), and greater benefit may be realized at the lower end of this range. Although strong evidence is lacking, somewhat lower glucose targets may be appropriate in selected patients. Targets less than 110 mg/dL (6.1 mmol/L), however, are not recommended."

The AACE/ADA recommendations – teaching material for busy clinicians:

• A target of 140-180 mg/dl is preferable for MOST patients. 
• A target of 110-140 mg/dl may be appropriate in SELECTED patients (patients treated in sites with extensive experience and appropriate support: perhaps CABG surgical patients, sites with low rates of hypoglycemia, patients  on TPN etc). 
• A target > 180 mg/d/ or < 110 mg/dl is NOT recommended.

Future research needs to elucidate those patients who may benefit from 110-140 mg/dl, and who qualifies in the list of “SELECTED” populations.

ACE Position Statement and Consensus Conference Reviews
Garber AJ, Moghissi ES, Bransome ED Jr, et al. American College of Endocrinology Position Statement on Inpatient Diabetes and Metabolic Control. Endocr Pract. 2004;10 Suppl 2:4-9. PMID: 15251633
The American College of Endocrinology, American Association of Clinical Endocrinologists, and cosponsoring organizations (including SHM) outlined the evidence supporting inpatient glycemic control, and endorsed the need for early detection of hyperglycemia, and aggressive management to achieve glycemic targets.
The upper limits for glycemic targets:
•  in the ICU setting: 110 mg/dL
•  for non-critical care units: a preprandial glucose of 110 mg/dL, and a maximal glucose of 180 mg/dL.

ACE / ADA Inpatient Diabetes and Glycemic Control Consensus Statement
Garber A, Moghissi E, et al. American College of Endocrinology and American Diabetes Association Consensus statement on inpatient diabetes and glycemic control: a call to action.  Diabetes Care. 2006 Aug;29(8):1955-62. PMID: 16873812  also published in Endocrine Practice. 2006 July / Aug 12 (4) 458-68. PMID: 16983798
This recent conference updated an evidence review supporting inpatient glycemic control, and also outlined essential elements that institutions need to put successful glycemic control programs in place. These essential elements formed the core outline for the SHM Workbook to Optimize Glycemic Control and Reduce Hypoglycemia, which can be found here on the website.

ADA Technical Review
Clement S, Braithwaite SS, Magee MF et al; American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004;27:553-91.
An indispensable review full of practical information, as well as a well articulated review of the literature on the topic. Insulin strategies for patients in special situations and with varied forms of nutritional intake are outlined, and policy / educational issues for institutions are also addressed. PMID: 14747243

ADA Standards for Diabetes
Standards of Medical Care in Diabetes--2008
Dora JM, Kramer CK, Canani LH. Diabetes Care 31:S12-S54, 2008.
The language around glycemic targets has softened in the 2008 version of the ADA Standards.

• Critically ill patients: blood glucose levels should be kept as close to 110 mg/dl (6.1 mmol/l) as possible and generally <140 mg/dl (7.8 mmol/l). (A) These patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose range without increasing risk for severe hypoglycemia. (E)
• Non–critically ill patients: there is no clear evidence for specific blood glucose goals. Because cohort data suggest that outcomes are better in hospitalized patients with fasting glucose <126 mg/dl and all random glucoses <180–200 mg/dl, these goals are reasonable if they can be safely achieved. Insulin is the preferred drug to treat hyperglycemia in most cases.(E)
  

ASHP Recommendations for Safe Use of Insulin in Hospitals
American Society of Health-System Pharmacists and the Hospital and Health-System Association of Pennsylvania: Recommendations for Safe Use of Insulin in Hospitals.
Accessed as a pdf at: http://www.ashp.org/s_ashp/docs/files/Safe_Use_of_Insulin.pdf  (April 23, 2009).

The case for supporting inpatient glycemic control programs now: The evidence and beyond 
Braithwaite SS, Magee M, Sharretts JM, Schnipper JL, Amin A, Maynard G; Society of Hospital Medicine Glycemic Control Task Force.  J Hosp Med. 2008 Sep;3(5 Suppl):6-16. PMID: 18951385

Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism.
Deedwania P, Kosiborod M, Barrett E, Ceriello A, Isley W, Mazzone T, Raskin P; American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism.Circulation. 2008 Mar 25;117(12):1610-9. Epub 2008 Feb 25. PMID: 18299505

Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline.
Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ; Endocrine Society. J Clin Endocrinol Metab. 2009 Mar;94(3):709-28. Epub 2008 Dec 16. PMID: 19088155

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II. Reviews and Insulin Infusion Protocols

Reviews

Designing and implementing insulin infusion protocols and order sets 
Ahmann AJ, Maynard G. J Hosp Med. 2008 Sep;3(5 Suppl):42-54. PMID: 18951382

No patient left behind: Evaluation and design of intravenous insulin algorithms
Braithwaite, SSB Godara, H, Song, HJ et all. Endocrine Practice 2006:12 Supp 3:72-78. PMID: 16905521

Intravenous insulin infusion therapy: Indications, methods, and transition to subcutaneous insulin therapy
Bode BW, Braithwaite SS, Steed RD, Davidson PC. Endocrine Practice. 2004;10 Suppl 2:71-80. PMID: 15251644

Protocols

Note: see the review article above by Ahmann and Maynard to gain perspective on these protocols

Description and evaluation of a glycemic management protocol for patients with diabetes undergoing heart surgery
Markovitz LJ, Wiechmann RJ, Harris N, et al. Endocr Pract. 2002; 8:10-18. PMID: 11939754
Used in cardiac surgery patients. The first published paper form of the “column method,” it used a higher goal than typically proposed today. It has been modified by many parties with adjustment of goals. Offers a specific infusion rate and directed sensitivity adjustments for nursing personnel.

The rationale and management of hyperglycemia for in-patients with cardiovascular disease: Time for a Change
Trence DL, Kelly JL, Hirsch, IB. J Clin Endocrninol Metab 2003: 88: 2430-2437. PMID: 12788838
This protocol was adapted from the Markovitz protocol above, using four columns representing algorithms of increasing insulin resistance. Although the article reports success with this method, specific results are not reported.

Glucommander: a computer-directed intravenous insulin system shown to be safe, simple, and effective in 120,618 h of operation
Davidson PC, Steed RD, Bode BW. Diabetes Care. 2005; 28:2418-23. PMID: 16186273
The same concepts have been used to develop a computer assisted insulin infusion protocol. One such method has been published using the Glucommander but a number of institutions are using similar computer-assisted methods. This method has been at least as good as paper methods using a continuously updated insulin sensitivity algorithm. It should nearly eliminate nursing errors.
Other methods use the present glucose and change from last glucose to constantly adjust to any situations. They generally require more calculations by the nurse. These methods have been proposed to be more agile or flexible but there have been no direct comparisons with the column methods looking at effectiveness, nursing errors, or hypoglycemic risk.

Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project
Furnary AP, Wu Y, Bookin SO. Endocr Pract. 204; 10 (suppl 2):21-33. PMID: 15251637
Protocol used in cardiac surgery patients. It has been intensified at least four times since its original version in 1992. This particular version was used from 2001-2003 with a stated glucose goal of 100-150 mg/dl. It uses a combination of fixed adjustments (e.g. 0.5 units/hour) and relative adjustments (e.g. 50%). Goal glucose is reportedly attained in 3 hours. A more intensive protocol with a goal below 110 mg/dl is now used but this protocol has not been published. Although publications propose the updated protocols are found at www.portlandprotocol.org , the website does not have any protocol included at this time. The published material is quite detailed in terms of morbidity and mortality benefits but has much less detail about complications and nursing ease of use.

Intensive insulin therapy in critically ill patients
Van Den Berghe G, Wouters P, Weekers F, et al. N Engl J Med. 2001;345:1359-1367. PMID:11794168
Protocol used in surgical ICU patients whenever glucose rose over 110 mg/dl. The same protocol was later used in a study of medical ICU patients with slightly different results (see more info about this protocol and paper in next section. Glucose goal is 80-110 mg/dl. Frequent adjustments using rate of change to calculate relative rate adjustments by the nurse. Reported ‹5% incidence of hypoglycemia but this was defined as glucose < 40mg/dl, suggesting a more significant issue, and the followup MICU paper had significantly high rates of hypoglycemia also. Best outcomes prospective outcomes study reported.

Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit
Goldberg PA, Siegel MD, Sherwin RS, et al. Diabetes Care. 2004; 27:461-467

Memoirs of a Root Canal Salesman: The Successful Implementation of a Hospital-Wide Intravenous Insulin Infusion Protocol
Goldberg PA. Endocrine Practice 2006; 12(suppl 3): 79-85. PMID: 16905522
Originally reported in Diabetes Care, with a goal of 100-139 mg/dl for medical ICU patients, this protocol has been republished with a goal range of 90-119 mg/dl. It utilizes two tables. The first helps the nurse identify the infusion rate “delta” according to the present BG and rate of glucose change. The second table converts the Δ to an insulin infusion rate change, dependent on the current infusion rate. Hypoglycemia (designated as < 60 mg/dl) is reported as 5.4% “of patient days” in the MICU and slightly lower in the cardiothoracic ICU.  It uses 3 tables to adjust rates. Reached goal of 80-110 in 10.6 hours. Hypoglycemia is 1.6% < 60 mg/dl.

Design and Implementation of GRIP, a computerized glucose control system at a surgical intensive care unit
Vogelzang M, Zijlstra F. and Nijsten, MWM. BMC: Medical Informatics and Decision Making. 2005; 5:38. PMID: 16359559
Use of a computer program receiving information directly from the POC testing and selects an ongoing infusion rate and interval for the next glucose test. It looks at rate of change over a period of hours in making calculations and recommendations. Glucose levels < 60 mg/dl occurred in about 11% of patients. The authors propose this will be free online in the future.

Performance of a dose-defining insulin infusion protocol among trauma service intensive care unit admissions
Braithwaite SS, Edkins R, MacGregor KL, et al. Diabetes Technol Ther. 2006;8:476–488. PMID: 16939372
Dr. Braithwaite is an author of the original Markovitz protocol, above, and has continued to evolve this protocol as have others. In this article, the authors publish their 6-column protocol, designed to attain glucose levels < 110 mg/dL in trauma patients. The hypoglycemic rate (< 70 mg/dL) was 11% of patients.

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III. Insulin Infusion: Surgical / Medical Intensive Care Focus

Intensive insulin therapy in critically ill patients
Van Den Berghe G, Wouters P, Weekers F, et al. N Engl J Med. 2001;345:1359-1367. PMID: 11794168
This classic paper served as a catalyst for improving inpatient glycemic control. 1548 critically ill adult patients from surgical intensive care units were randomized to intensive insulin infusion to keep blood glucose levels < 110 mg/dL vs usual care. The intensive insulin infusion group enjoyed reduced mortality by 34%, and reduced important morbidities by 41-50%.

Intensive insulin therapy in the Medical ICU
Van den Berghe G, Wilmer A, Hermans G, et al. N Engl J Med. 2006;354:449-61
The long awaited followup study in MICU patients, using methodology very similar to the landmark “Van Den Berghe I” study of SICU patients, had mixed results. Several ICU morbidities, such as renal dysfunction and prolonged mechanical ventilation, were improved in the intensive infusion group, but overall mortality differences were not significantly different. Mortality was lower in the subpopulation in the MICU > 3 days, identified as an a priori population of interest. Concerns over excessive hypoglycemia and a non-significant increase in mortality in the subgroup in the MICU < 3 days have given some fuel for debate about what the ICU glycemic target should be and about the best methods to achieve it.

Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K; German Competence Network Sepsis (SepNet). N Engl J Med 2008;358:125-39. PMID: 18184958

Note: After the remarkable benefits demonstrated in the 2001 van den Berghe article and the more mixed results in the medically critically ill in van den Berghe II in 2006, others tried to use the same protocol with lesser results. Brunkhorst used the van den Berghe protocol in sepsis patients. The study was stopped early due to high rates of hypoglycemia, as was the Glucontrol study referred to in the article below (Glucontrol only published in abstract form). The van den Berghe protocol, while well studied and famous, is widely maligned for causing 3-4 times the hypoglycemia rate of well done protocols cited in other literature. See Designing and implementing insulin infusion protocols and order sets , Ahmann AJ, Maynard G. J Hosp Med. 2008 Sep;3(5 Suppl):42-54.for more details.

Current controversies around tight glucose control in critically ill patients.
Devoa P, Preiser JC. Curr Opin Clin Nutr Metab Care 2007;10(2):206-9. PMID: 17285011
Includes reference to the Glucontrol study.

Benefits and risks of tight glucose control in critically ill adults: a meta-analysis.
Wiener RS, Wiener DC, Larson R JAMA. 2008 Aug 27;300(8):933-44. PMID: 18728267

Intensive insulin therapy in the ICU: benefit versus harm?
Brunkhorst FM, Reinhart K. Intensive Care Med. 2007 Jul;33(7):1302. Epub 2007 Apr 26. PMID: 17458537

Intensive Insulin Therapy in Mixed Medical/Surgical Intensive Care Units: Benefit Versus Harm.
Van den Berghe G, Wilmer A, Milants I, et al. Diabetes 2006;55(11):3151-9. PMID: 17065355

Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial.
De La Rosa Gdel C, Donado JH, Restrepo AH, Quintero AM, González LG, Saldarriaga NE, Bedoya M, Toro JM, Velásquez JB, Valencia JC, Arango CM, Aleman PH, Vasquez EM, Chavarriaga JC, Yepes A, Pulido W, Cadavid CA; Grupo de Investigacion en Cuidado intensivo: GICI-HPTU.Crit Care. 2008;12(5):R120. Epub 2008 Sep 17. PMID: 18799004

Tight Blood Glucose Control With Insulin in the ICU: Facts and Controversies.
Vanhorebeek I, Langouche L, Van den Berghe G. Chest 2007;132(1):268-78. PMID: 17625087

Effect of intensive glucose management protocol on the mortality of critically ill adult patients
Krinsley JS. Mayo Clin Proc. 2004;79:992-1000. PMID: 15301325
A protocol in a “real world” mixed MICU / SICU setting achieved glycemic control and related improvements in morbidity and mortality outcomes in a heterogenous population of critically ill inpatients. While not a RCT, this paper revealed that tight glycemic control was achievable, and was associated with improved outcomes similar to those found in the original Van Den Berghe study.

Insulin therapy for critically ill hospitalized patients: a meta-analysis of randomized, control trials
Pittas AG, Siegel RD, Lau J. Arch Inter Med. 2004;164:2005-2011. Meta-analysis of 35 clinical trials evaluating the effect of intensive insulin infusion therapy on mortality in critically ill inpatients found a 15% reduction in short-term mortality. PMID: 15477435

Survival benefits of intensive insulin therapy in critical illness: impact of maintaining normoglycemia versus glycemia-independent actions of insulin
Ellger B. Debaveye Y. Vanhorebeek I. Langouche L. Giulietti A. Van Etten E. Herijgers P. Mathieu C. Van den Berghe G. Diabetes. 2006; 55(4):1096-105. PMID: 16567534

Multicentric, Randomized, Controlled Trial to Evaluate Blood Glucose Control by the Model Predictive Control Algorithm vs Routine Glucose Management Protocols in Intensive Care Unit Patients
Plank J et al. Diabetes Care: 2006 29 271-276. PMID: 16443872

A practical approach to hyperglycemia management in the intensive care unit: evaluation of an intensive insulin infusion protocol
Quinn JA, Snyder SL, Berghoff JL et al. Pharmacotherapy. 2006; 26:1410-20. PMID: 16999651

Intensive versus conventional glucose control in critically ill patients.
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. N Engl J Med. 2009 Mar 26;360(13):1283-97. Epub 2009 Mar 24. PMID: 19318384 

Glucose control in the ICU--how tight is too tight?
Inzucchi SE, Siegel MD. N Engl J Med. 2009 Mar 26;360(13):1346-9. Epub 2009 Mar 24. PMID: 19318385     

The NICE-SUGAR study was a multinational, open label trial randomizing 6,104 ICU patients to the use of intravenous insulin infusion to achieve a blood glucose (BG) of 81-108 mg/dL in the intervention arm, compared less stringent control with BG levels of 144-180 mg/dL.  The results showed a small increase in death at 90 days in the tight control patients (27.5% vs 24.9% mortality), a distinctly different outcome than the influential van den Berghe 1 study.  Severe hypoglycemia was also more common in the tight control group (6.8% vs 0.5%).  The thoughtful editorial by Inzucchi and Siegel provides excellent perspective on the implications of the results. This study will likely lead to a revision of guideline glycemic targets in the ICU, but should not be viewed as a reason to abandon insulin infusion and reasonable glycemic control in the ICU.  The following reference is the first meta-analysis to incorporate NICE-SUGAR results, and concludes that very tight control of glucose in the critical care setting may still benefit some perioperative patients.

Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data
Griesdale DE, de Souza RJ, van Dam RM, Heyland DK, Cook DJ, Malhotra A, Dhaliwal R, Henderson WR, Chittock DR, Finfer S, Talmor D. CMAJ. 2009 Apr 14;180(8):821-7; discussion 799-800. Epub 2009 Mar 24. PMID: 19318387

Joint Statement from ADA and AACE on the NICE-SUGAR Study on Intensive Versus Conventional Glucose Control In Critically Ill Patients
American Diabetes Association and American Association of Clinical Endocrinologists. Response to March 24 article in the New England Journal of Medicine. http://professional.diabetes.org/News_Display.aspx?TYP=9&CID=71082 Accessed April 21, 2009.

Impact of the NICE Sugar Study Flyer
Submitted and prepared by Cheryl O’Malley, MD this flyer was developed for use within her system to post around for physicians and staff to better understand some of the important details in the NICE study and how it applies to them.
View the Flyer

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IV. Insulin Infusion and Effects of Hyperglycemia on Cardiac Surgery and Myocardial Infarction

Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism.
Deedwania P, Kosiborod M, Barrett E, Ceriello A, Isley W, Mazzone T, Raskin P; American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism.Circulation. 2008 Mar 25;117(12):1610-9. Epub 2008 Feb 25. PMID: 18299505

Value of postoperative blood glucose in predicting complications and length of say after coronary artery bypass grafting
Fish LH, Weaver TW, Moore AL, Steel LG. Am J Card 2003;92:74-76. PMID: 12842253

Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac Surgery.
Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, et al. Ann Intern Med. 2007:146:233-243. PMID: 17310047
This single center study that already had an intensive insulin infusion protocol in place in their SICU randomized 400 patients undergoing on-pump cardiac surgery to tight (target 80-100 mg/dL, mean glucose 114 mg/dL) vs usual (infusion started if glucose > 200 mg/dL, mean 157 mg/dL) glycemic control introperatively. All patients received tight glycemic control in the cardiac ICU. The composite outcomes showed no difference between the two groups. More patients suffered from stroke in the intervention arm (8 patients vs 1 patient, p = .02). Death occurred in 4 intervention patients and no control patients, p =  .06. All other outcomes showed no difference. The thoughtful accompanying editorial by van den Berghe offers perspective.

Does Tight Blood Glucose Control during Cardiac Surgery Improve Patient Outcome?
Van den Berghe G. Ann Intern Med 2007;146;307-308. PMID: 17310055

Cardiac Surgery - Portland Experience

Clinical Effects of Hyperglycemia in the Cardiac Surgery Population: The Portland Diabetic Project
Furnary AP, Wu Y. Endocr Pract. 2006:12 (Suppl 3): 22-26. PMID: 16905513
The paper is the latest update of the Portland Diabetic Project, a prospective, non-randomized, observational study of 5,510 consecutive diabetic cardiac surgery patients spanning 1987-2005. The three day blood glucose average (3-BG) has been progressively reduced for the population through the use of continuous insulin infusion (CII). Both CII for three days duration and a favorable 3-BG were independently associated with improved mortality, deep sternal wound infection rates, and length of stay. Diabetes itself is not an independent risk factor for adverse outcomes, while hyperglycemia is. More Portland experience is recounted in the four reports that follow.

Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project
Furnary AP, Wu Y, Bookin SO. Endocr Pract. 2004; Suppl 2:21-33. PMID: 15251637

Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting
Furnary AP, Gao G, Grunkemeier GL, et al. J Thorac Cardiovasc Surg. 2003;125:1007-21. PMID: 12771873

Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures
Furnary AP, Zerr KJ, Grunkemeier GL, et al. Ann Thorac Surg. 1999;67:352-60; discussion 360-2. PMID: 10197653

Glucose control lowers the risk of wound infection in diabetics after open heart operations
Zerr KJ, Furnary AP, Grunkemeier GL, et al. Ann Thorac Surg. 1997;63:356-361. PMID: 9033300

Cardiac Surgery - Other Experience

Outcomes and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting
Estrada CA, Young JA, Nifong LW, et al. Ann Thorac Surg 2003;75:1392-9.
For patients undergoing CABG, each 50 mg/dL increase in BG level added 0.76 days to LOS and increased inpatient costs by $2,824.
Each 50 mg/dL lowering of the 3 day average post op blood glucose reduced LOS by 1 day.

The association of diabetes and glucose control with surgical site infection among cardiothoracic surgery patients
Latham R, Lancaster AD, Covington JF, et al. Infec Control Hosp Epidemiol. 2001;22:605-212. PMID: 11776345

Myocardial Infraction

Hyperglycemia, diabetes and glucose intolerance are common conditions in patients with acute MI with hyperglycemia is strongly and consistently associated with poor outcomes in these patients.

Inpatient Diabetes: Review of Data from the Cardiac Care Unit
Hirsch, I. Endocrine Practice 2006: 12 Supp 3 27-34. PMID: 16905514
A nice recent review of prospective and retrospective studies exploring the relationship between inpatient hyperglycemia / diabetes and the acute MI patient.

Myocardial Infraction - DIGAMI 1

Prospective randomized study of intensive insulin treatment on long-term survival after acute myocardial infarction in patients with diabetes mellitus
Malmberg K. BMJ. 1997;314:1512-1515. PMID: 9169397

Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study
Malmberg K, Norhammar A, Wedel H, et al. Circulation. 1999;99:2626-32. PMID: 10338454

DIGAMI I treatment arm patients were randomized to glucose insulin infusion for 24 hours followed by multiple daily injections of insulin for 3 or more months. They experienced a 29% reduction in mortality at one year that held up on follow-up at an average of 3.4 years.

Myocardial Infraction - DIGAMI 2 and CREATE-ECLA

In both DIGAMI 2 and CREATE-ECLA, insulin-glucose infusion patients failed to reach glycemic targets, and showed that insulin infusion, in the absence of improved glycemic control, has no effect on outcomes.

Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity
Malmberg K, Ryden L, Wedel H; DIGAMI 2 Investigators. Eur Heart J. 2005;26:650-61. PMID: 15728645

Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial
Mehta SR, Yusuf S, Diaz R; CREATE-ECLA Trial Group Investigators. JAMA. 2005;293:437-46. PMID: 15671428

Other Studies in Acute Myocardial Infarction

Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes : a systematic overview
Capes SE, Hunt D, Malmberg K, Gerstein HC. Lancet. 2000;355:773-778. This meta-anlaysis of 15 studies of hospitalized acute MI patients reported that blood glucose levels > 110 mg/dL were associated with more mortality and CHF. PMID: 10711923

Short-term mortality of myocardial infarction patients with diabetes or hyperglycaemia during admission
Sala J, Masia R, Gonzalez de Molina FJ; REGICOR Investigators. J Epidemiol Community Health. 2002;56:707-12. PMID: 12177090

Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes
Kasiborod M, Rathore SS, Inzucchi S et al. Circulation 2005;111:3078. PMID: 15939812

Acute hyperglycemia is associated with adverse outcomes after acute myocardial infarction in the coronary intervention era
Ishihara M, Kojima S, Sakamoto T, et al. Am Heart J. 2005;150:814-20. PMID: 16209987
Acute hyperglycemia, but not the pre-existing label of diabetes, was a predictor of inpatient mortality after acute MI, in this study of 1,253 patients.

Prognostic value of admission glucose in non-diabetic patients with myocardial infarction
Timmer JR, van der Horst IC, Ottervanger JP, et al. Am Heart J. 2004; 148:399-404. PMID: 15389225
Elevated glucose levels were associated with larger infarct size and reduced residual LV function in 356 patients without a diagnosis of diabetes, who were being treated with reperfusion therapy for ST-segment elevation MI.

The association between hyperglycaemia on admission and 180-day mortality in acute myocardial infarction patients with and without diabetes
Ainla T, Baburin A, Teesalu R, et al. Diabet Med. 2005;22:1321-5. PMID: 16176190

Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study
Norhammar A, Tenerz A, Nilsson G, et al. Lancet. 2002;359:2140-4. PMID: 12090978
Undiagnosed diabetes and impaired glucose tolerance were found to be common in acute MI patients without a prior diagnosis of diabetes.

Impaired glucose metabolism predicts mortality after a myocardial infarction
Bolk J, van der Ploeg T, Cornel JH et al. Int J Cardiol. 2001; 79:207-14. PMID: 11461743

Mechanism by which hyperglycemia plays a role in the setting of acute cardiovascular illness.
Zarich S. Rev Cardiovasc Med. 2006;Suppl 2:S35-S43. PMID: 17224876

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V. Transitions and Perioperative Care

Bridge over troubled waters: Safe and effective transitions of the inpatient with hyperglycemia 
O'Malley CW, Emanuele M, Halasyamani L, Amin AN; Society of Hospital Medicine Glycemic Control Task Force.  J Hosp Med. 2008 Sep;3(5 Suppl):55-65. PMID: 18951384

Conversion of intravenous insulin infusions to subcutaneously administered insulin glargine in patients with hyperglycemia.
Schmeltz LR, DeSantis AJ, Schmidt K, O'Shea-Mahler E, Rhee C, Brandt S, Peterson S, Molitch ME:Endocr Pract 12:641–650, 2006.
PMID: 17229660

Evaluation of glycemic control following discontinuation of an intensive insulin protocol
Czosnowski QA, Swanson JM, Lobo BL, Broyles JE, Deaton PR, Finch CK. J Hosp Med. 2009 Jan;4(1):28-34. PMID: 19140192

Inpatient Management of Hyperglycemia: the Northwestern Experience
DeSantis AJ, Schmeltz LR, Schmidt K, O'Shea-Mahler E, Rhee C, Wells A, Brandt S, Peterson S, Molitch M. Endocrine Practice. 2006;12: 491-505. Recently published. PMID: 17002924  

Intravenous insulin infusion therapy: Indications, methods, and transition to subcutaneous insulin therapy. 
Bode B, Braithwaite S, Steed R, et al.  Endocr Pract. 2004; 10(Suppl2): 71-80. PMID: 15251644

Effects of outcome on in-hospital transition from intravenous insulin infusion to subcutaneous therapy.
 Furnary A and Braithwaite S.  Am J Cardiol 2006;98:557-564. PMID: 16893717

Perioperative Glucose Control in the Diabetic or Nondiabetic Patient.
Smiley D, Umpierrez G. Southern Med J. 2006;99:580-589. PMID: 16800413

Management of Hyperglycemia in Type 2 Diabetes: a Consensus Algorithm for the Initiation and Adjustment of Therapy: a Consensus Statement from the American Diabetes Association and the European Association for the Study of Diabetes.
Nathan, D.M., Buse, J.B., Davidson, M.B., et al:  Diabetes Care 2006; 29: 1963-1972. PMID: 16873813

Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Diabetes Care. 2008 Jan;31(1):173-5. PMID: 18165348

A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Update regarding thiazoladinediones.
D, Buse J, Davidson M et al. Diabetes Care. 2008;29:1963-1972.

American Association of Clinical Endocrinologists Inpatient Glycemic Control Resource Center.
Final Transition-Inpatient to outpatient/Effective Discharge Planning Sample Discharge Plans/Inpatient diabetes discharge prescription. http://resources.aace.com/pages.asp?id=27&did=p Accessed April 1, 2009.

The Transition from insulin infusions to long-term diabetes therapy: the argument for insulin analogs.
Braithwaite S. Semin Thorac Cardiovasc. 2006;18:366-378. PMID: 17395034

Perioperative Care of the Geriatric Patient with Diabetes or Hyperglycemia.
Maynard G, O’Malley CW, Kirsh SR. Clin Geriatr Med 24 (2008) 649 – 665. PMID: 18984379

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VI. Hyperglycemia in Medical / Surgical Wards and Other Conditions

Current state of affairs, reviews, and editorials

The case for supporting inpatient glycemic control programs now: The evidence and beyond 
Braithwaite SS, Magee M, Sharretts JM, Schnipper JL, Amin A, Maynard G; Society of Hospital Medicine Glycemic Control Task Force.  J Hosp Med. 2008 Sep;3(5 Suppl):6-16.

Key article to persuade colleagues of the importance of glycemic control incorporating the latest evidence. PMID: 18951385

Evaluation of hospital glycemic control at US Academic Medical Centers
Boord J.B, Greevy R.A., Braithwaite S.S., Arnold P.C., Selig P.M., Brake,H. Cuny J. Baldwin D. J Hosp Med. 2009 Jan;4(1):35-44.
PMID: 19140174

Inpatient management of diabetes and hyperglycemia among general medicine patients at a large teaching hospital.
Schnipper JL, Barsky EE, Shaykevich S, Fitzmaurice G, Pendergrass ML.  J Hosp Med. 2006 May;1(3):145-50. PMID: 17219488

Diabetes care in the hospital: is there clinical inertia?
Knecht LA, Gauthier SM, Castro JC, Schmidt RE, Whitaker MD, Zimmerman RS, Mishark KJ, Cook CB. J Hosp Med. 2006 May;1(3):151-60. PMID: 17219489

Diabetes care in hospitalized noncritically ill patients: More evidence for clinical inertia and negative therapeutic momentum.
Cook CB, Castro JC, Schmidt RE, Gauthier SM, Whitaker MD, Roust LR, Argueta R, Hull BP, Zimmerman RS.  J Hosp Med. 2007 Jul;2(4):203-11. PMID: 17683100

Introduction: Overview of efforts and lessons learned
Maynard G., Umpierrez G.J Hosp Med. 2008 Sep;3(5 Suppl):1-5. PMID: 18951383

Newly diagnosed diabetes/hyperglycemia in hospitals: what should we do?
Fonseca V.Endocr Pract. 2006 Jul-Aug;12 Suppl 3:108-111. PMID: 16905526 

Hyperglycemia associated with poor outcomes in a broad variety of conditions and populations

Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes
Umpierrez GE, Isaacs SD, Bazargan N, et al. J Clin Endocrinol Metab. 2002;87:978-982. PMID: 11889147
Retrospective review of 1,886 hospitalized patients revealed that in hospital hyperglycemia was very common and patients with hyperglycemia frequently did not have a pre-existing diagnosis of diabetes. Hyperglycemia in those without prior diagnosis of diabetes carried an 18-fold increased risk of mortality, while those with hyperglycemia and a prior history of diabetes had a 2.5 fold increase in mortality compared to a control group.

Admission hyperglycemia as a prognostic indicator in trauma
Yendamuri S, Fulda GJ, Tinkoff GH. J Trauma. 2003;55:33-8. PMID: 12855878

Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview
Capes SE, Hunt D , Malmberg K Pathak P, et al. Stroke 2001;32:2426-2432. PMID: 11588337

IV insulin during acute cerebral infarction in diabetic patients
Bruno A, Saha C, Williams et al. Neurology. 2004; 62:1441-2. PMID: 15111697

How important is hyperglycemia during acute brain infarction?
Bruno A, Williams LS, Kent TA. Neurologist. 2004; 10:195-200. Review. PMID: 15245585

Perioperative glycemic control and risk of infectious complications in a cohort of adult with diabetes
Golden S, Peart -Vigilance C Kao W, et al. Diabetes Care 1999;22:1408-1414. PMID: 10480501

Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk).
Khaw KT, Wareham N, Luben R, et al. BMJ. 2001;322:1-6.

Unrecognized diabetes among hospitalized patients.
Levetan CS, Passaro M, Jablonski K, Ratner RE. Diabetes Care.1998;21:246-249. PMID: 9539990

Early postoperative glucose control predicts nosocomial infection rate in diabetic patients
Pomposelli JJ, Baxter JK, Babineau TJ, et al. J Parenter Enteral Nutr. 1998;22:77-81. PMID: 9527963

Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen
Weiser MA, Cabanillas ME, Konopleva M,et al. Cancer. 2004; 100 (6):1179-85. PMID: 15022284

Early peri-operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study
Thomas MC, Mathew TH, Russ GR et al. Transplantation. 2001; 72 (7):1321-4. PMID: 11602863

The relation between hyperglycemia and outcomes in 2,471 patients admitted to the hospital with community-acquired pneumonia
McAlister FA. Majumdar SR. Blitz S. Rowe BH. Romney J. Marrie TJ. Diabetes Care 2005: 28: 810-815. PMID: 15793178

Resources with tips on subcutaneous insulin regimens, measurement, and implementation strategies (and often infusion regimens as well)

Glycemic Control Implementation Guide: Workbook for Improvement: Improving Glycemic Control, Preventing Hypoglycemia, and Optimizing Care of the Inpatient with Hyperglycemia and Diabetes.
SHM Glycemic Control Task Force. Society of Hospital Medicine website, Glycemic Control Quality Improvement Resource Room http://www.hospitalmedicine.org/gc  accessed 2/10/09.

Society of hospital medicine glycemic control task force summary: Practical recommendations for assessing the impact of glycemic control efforts 
Schnipper J.L., Magee M, Larsen K, Inzucchi S.E., Maynard G. J Hosp Med. 2008 Sept;3(5 Suppl): 66-75. PMID: 18951387

Management of diabetes and hyperglycemia in the hospital: A practical guide to subcutaneous insulin use in the non-critically ill, adult patient.  Wesorick D, O’Malley C, Rushakoff R, Larsen K, Magee M. J Hosp Med. 2008 Sept;3(5 Suppl): 17-28. PMID: 18951381

Subcutaneous insulin order sets and protocols: Effective design and implementation strategies 
Maynard G, Wesorick D.H,, O’Malley C, Inzucchi S.E. . J Hosp Med. 2008 Sept;3(5 Suppl):29-41. PMID: 18951386

American Diabetes Association Diabetes in Hospitals Writing Committee
Clement S, Braithwaite SS, Magee MF et al. Diabetes Care. 2004;27:553-91. PMID: 14747243

Subcutaneous insulin therapy in the hospital setting: issues, concerns, and implementation
Magee MF, Clement S. Endocr Pract. 2004;10 Suppl 2:81-8. PMID: 15251645

Hospital management of diabetes: Beyond the sliding scale
Moghissi E. Cleveland Clin J Med.2004;71:801-808. PMID: 15529485

Hospital Management of Diabetes
Moghissi ES, Hirsch IB. Endocrinol Metab Clin N Am 34 (2005) 99-116. PMID: 15752924

Hyperglycemia in the hospital. Diabetes Spectrum
Thompson CL, Dunn KC, Menon MC, Kearns LE, Braithwaite SS. 2005;18:20-27.

Management of Hyperglycemia in the Hospital Setting
Inzucchi S. N Engl J Med 2006;355:1903-11. PMID: 17079764

Trials of SC insulin regimens / protocol interventions.

Basal versus sliding-scale regular insulin in hospitalized patients with hyperglycemia during enteral nutrition therapy.
Umpierrez GE. Diabetes Care. 2009 Apr;32(4):751-3. PMID: 19336641 No abstract available.

Insulin therapy and glycemic control in hospitalized patients with diabetes during enteral nutrition therapy: a randomized controlled clinical trial.
Korytkowski MT, Salata RJ, Koerbel GL, Selzer F, Karslioglu E, Idriss AM, Lee KK, Moser AJ, Toledo FG. Diabetes Care. 2009 Apr;32(4):594-6. PMID: 19336639 

Performance Improvement: Reducing Hyperglycemia Hospitalwide: The Basal-Bolus Concept
Murphy DM, Vercruysse R, Bertucci TM, et al. Jt Comm J Qual Patient Saf. 2009 Apr;35(4): 216-223. No Abstract Available

Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial).
Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, Puig A, Mejia R. Diabetes Care 30:2181–2186, 2007. PMID: 17513708

A recent study demonstrated the safety and efficacy of using basal-bolus insulin therapy utilizing weight-based dosing in insulin-naïve hospitalized patients with type 2 diabetes (301). Glycemic control, defined as a mean blood glucose <140 mg/dl, was achieved in 68% of patients receiving basal-bolus insulin versus only 38% of those receiving sliding-scale insulin alone. There were no differences in hypoglycemia between the two groups. It is important to note that the patients in this study were obese, and the doses used in this study (0.4–0.5 units · kg^–1 · day^–1) are higher that what may be required in patients who are more sensitive to insulin, such as those who are lean or who have type 1 diabetes.

Comparison of Inpatient Insulin Regimens with Detemir plus Aspart versus NPH plus Regular in Medical Patients with Type 2 Diabetes.
Umpierrez GE, Hor T, Smiley D, Temponi A, Umpierrez D, Ceron M, Munoz C, Newton C, Peng L, Baldwin D. J Clin Endocrinol Metab. 2008 Nov 18. [Epub ahead of print]. PMID: 19017758

Detemir / aspart and NPH / regular achieved equivalent control and hypoglycemia in this randomized trial, but the hypoglycemia rate was much higher than that seen in the RABBIT2 trial above, and higher than that clinically seen using a regimen similar to the RABBIT 2 trial in clinical practice (see next reference).

Effects of a subcutaneous insulin protocol, clinical education, and computerized order set on the quality of inpatient management of hyperglycemia: Results of a clinical trial
Ndumele CD, Liang CL, Pendergrass ML. Schnipper JL, Ndumele CD, Liang CL, Pendergrass ML.J Hosp Med. 2009 Jan;4(1):16-27.
PMID: 19140191

The two articles above show how quality improvement interventions can improve glycemic control on the wards without intensive use of endocrinologists or a diabetes management service. The Maynard article is important because it reduced the rate of both hyper- and hypoglycemia.

Improving glycemic control in medical inpatients: A pilot study
Trujillo JM, Barsky EE, Greenwood BC, Wahlstrom SA, Shaykevich S, Pendergrass ML, Schnipper JL.J Hosp Med. 2008 Jan;3(1):55-63. PMID: 18257047

Indication Based Ordering: A New Paradigm for Glycemic Control in Hospitalized Inpatients
Lee J, Clay B, Ziband Z, Clay B, Maynard G. J Diabetes Science Tech May 2008, Vol 2 (3) 349 – 356.

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VII. Iatrogenic Hypoglycemia and Sliding Scale Insulin

Glycemic Control and Sliding Scale Insulin Use in Medical Inpatients with Diabetes Mellitus
Queale et al. Arch Intern Med. 1997;157:545-552. PMID: 9066459
In a study by Queale and colleagues, 171 patients admitted to one of 6 medical services were 3 times more likely to experience hyperglycemia with either a conservative or aggressive sliding scale regimen over a 4 day period post-admission. Moreover, blood glucose levels in these patients were highly variable as 23% of patients experienced hypoglycemic episodes and 40% experienced glycemic excursions > 300 mg/dL. Furthermore, there was no significant change in glycemic control over the 4 day period.

Causes of hyperglycemia and hypoglycemia in adult inpatients
Smith WD, Winterstein AG, Johns T, et al. Am J Health-Syst Pharm 2005;62:714-719. PMID: 15790798

Hospital hypoglycemia: not only treatment but also prevention
Braithwaite SS. Buie MM. Thompson CL. Baldwin DF. Oertel MD. Robertson BA. Mehrotra HP. Endocrine Practice 2004: 10 Suppl 2:89-99. PMID: 15251646

Hypoglycemia: An Excuse for Poor Glycemic Control?
Saleh M, Grunberger G. Clin Diabetes. 2001;19(4): 161-167.

Provider response to insulin-induced hypoglycemia in hospitalized patients.
Garg R, Bhutani H, Jarry A, Pendergrass M. J Hosp Med. 2007 Jul;2(4):258-60. PMID: 17705211

Hypoglycemia in hospitalized patients treated with antihyperglycemic agents.
Varghese P, Gleason V, Sorokin R, Senholzi C, Jabbour S, Gottlieb JE. J Hosp Med. 2007 Jul;2(4):234-40. PMID: 17702035

Iatrogenic Inpatient Hypoglycemia: Risk Factors, Treatment, and Prevention: Analysis of Current Practice at an Academic Medical Center With Implications for Improvement Efforts.
Maynard GA, Huynh MP, Renvall M. Diabetes Spectr 2008;21 241-247.

Hypoglycemia in patients with type 2 diabetes mellitus.
Miller C, Phillips L, Ziemer D, Gallina D. Arch Intern Med. 2001;161:1653-1659. PMID: 11434798

Relationship Between Spontaneous and Iatrogenic Hypoglycemia and Mortality in Patients Hospitalized with Acute Myocardial Infarction
Kosiborod M, Inzucchi SE, Goyal A, Krumholz HM, Masoudi FA, Xiao L, Spertus JA. JAMA. 2009 Apr 15;301(15):1556-64. PMID: 19366775

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VIII. Financial Aspects of Inpatient Glycemic Control

Practical strategies for developing the business case for hospital glycemic control teams 
Magee M.F., Beck A.J Hosp Med. 2008 Sep;3(5 Suppl):76-83. PMID: 18951388

Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients
Van den Berghe G. Wouters PJ. Kesteloot K. Hilleman DE. Critical Care Medicine.2006 34(3):612-616. PMID: 16521256

Cost Analysis of Glycemic Control in Critically Ill Adult Patients
Krinsley JS, Jones RL. Chest 2006:129:644-650. PMID: 16537863

American Hospital Directory
Medicare Prospective Payment System. Accessed 12-1-06 at http://www.ahd.com/pps.html.

ICD-9-CM Professional. 6th Edition

Management of diabetes and hyperglycemia in hospitals
Clement S, Braithwaite SS, Magee MF, et al on behalf of the American Diabetes Association Diabetes in Hospitals Writing Group. Diabetes Care 2004; 27:553-91. PMID: 14747243

Financial Implications of Glycemic Control: Results of an Inpatient Diabetes Management Program
Newton CA, Young S. Endocrine Practice. 2006;12(S3): 43-48. PMID: 16905516

Impact of Endocrine and Diabetes Team Consultation on Hospital Length of Stay for Patients with Diabetes
Levetan CS, Salas JR, Wilets IF, Zumoff B. AJM. 1995; 99: 22-28. PMID: 7598138

Effect of Hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland diabetes project
Furnary AP, Wu Y, Bookin S. Endocr Pract. 2004;10:21-33. PMID: 15251637

Reduction of Surgical Mortality and Morbidity in Diabetic Patients Undergoing Cardiac Surgery with with a Combined Intravenous and Subcutaneous Insulin Glucose Management Strategy
Schmeltz LR, DeSantis AJ, Thiyagarajan V, Schmidt K, O'Shea E, Johnson D, Henske J, McCarthy PM, Gleason TG, McGee EC, Molitch ME. Diabetes. 2006; Abstract for ADA Annual Meeting.

Inpatient Management of Hyperglycemia: the Northwestern Experience
DeSantis AJ, Schmeltz LR, Schmidt K, O'Shea-Mahler E, Rhee C, Wells A, Brandt S, Peterson S, Molitch M. Endocrine Practice. 2006;12: 491-505. PMID: 17002924

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