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Clinical Guidelines |

Use of Intensive Insulin Therapy for the Management of Glycemic Control in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians FREE

Amir Qaseem, MD, PhD, MHA; Linda L. Humphrey, MD, MPH; Roger Chou, MD; Vincenza Snow, MD; Paul Shekelle, MD, PhD, for the Clinical Guidelines Committee of the American College of Physicians
[+] Article and Author Information

 This paper, written by Amir Qaseem, MD, PhD, MHA; Linda L. Humphrey, MD, MPH; Roger Chou, MD; Vincenza Snow, MD; and Paul Shekelle, MD, PhD, was developed for the Clinical Guidelines Committee of the American College of Physicians: Paul Shekelle, MD, PhD (Chair); Roger Chou, MD; Paul Dallas, MD; Thomas D. Denberg, MD, PhD; Nick Fitterman, MD; Mary Ann Forciea, MD; Robert H. Hopkins Jr., MD; Linda L. Humphrey, MD, MPH; Tanvir P. Mir, MD; Holger J. Schünemann, MD, PhD; Donna E. Sweet, MD; and David S. Weinberg, MD, MSc. Approved by the ACP Board of Regents on 20 November 2010.


From the American College of Physicians, Philadelphia, Pennsylvania; Pfizer, Collegeville, Pennsylvania; Oregon Health & Science University and Portland Veterans Affairs Medical Center, Portland, Oregon; and West Los Angeles Veterans Affairs Medical Center, Los Angeles, California.


Note: Clinical practice guidelines are “guides” only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians' judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.

Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the U.S Department of Veterans Affairs.

Acknowledgment: The authors thank Melissa Starkey, PhD, for her help in putting together this document.

Financial Support: Financial support for the development of this guideline comes exclusively from the ACP operating budget.

Potential Conflicts of Interest: Any financial and nonfinancial conflicts of interest of the group members were declared, discussed, and resolved. Dr. Vincenza Snow was an employee of the American College of Physicians at the time of the writing of this guideline. Dr. Snow: Employment: American College of Physicians, Pfizer. Dr. Shekelle: Grants/grants pending (money to institution): Agency for Healthcare Research and Quality; Royalties: UpToDate. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2725.

Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106; email, aqaseem@acponline.org.

Current Author Addresses: Dr. Qaseem: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.

Dr. Humphrey: Portland Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97201.

Dr. Chou: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239.

Dr. Snow: Pfizer, 500 Arcola Road, Collegeville, PA 19426.

Dr. Shekelle: West Los Angeles Veterans Affairs Medical Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073.

Author Contributions: Conception and design: A. Qaseem, L.L. Humphrey, V. Snow, P. Shekelle.

Analysis and interpretation of the data: A. Qaseem, L.L. Humphrey, R. Chou.

Drafting of the article: A. Qaseem, V. Snow.

Critical revision of the article for important intellectual content: A. Qaseem, L.L. Humphrey, R. Chou, V. Snow, P. Shekelle.

Final approval of the article: A. Qaseem, L.L. Humphrey, R. Chou, V. Snow, P. Shekelle.

Administrative, technical, or logistic support: A. Qaseem.


Ann Intern Med. 2011;154(4):260-267. doi:10.7326/0003-4819-154-4-201102150-00007
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Description: The American College of Physicians (ACP) developed this guideline to present the evidence for the link between the use of intensive insulin therapy to achieve different glycemic targets and health outcomes in hospitalized patients with or without diabetes mellitus.

Methods: Published literature on this topic was identified by using MEDLINE and the Cochrane Library. Additional articles were obtained from systematic reviews and the reference lists of pertinent studies, reviews, and editorials, as well as by consulting experts; unpublished studies on ClinicalTrials.gov were also identified. The literature search included studies published from 1950 through March 2009. Searches were limited to English-language publications. The primary outcomes of interest were short-term mortality and hypoglycemia. This guideline grades the evidence and recommendations by using the ACP clinical practice guidelines grading system.

Recommendation 1: ACP recommends not using intensive insulin therapy to strictly control blood glucose in non–surgical intensive care unit (SICU)/medical intensive care unit (MICU) patients with or without diabetes mellitus (Grade: strong recommendation, moderate-quality evidence).

Recommendation 2: ACP recommends not using intensive insulin therapy to normalize blood glucose in SICU/MICU patients with or without diabetes mellitus (Grade: strong recommendation, high-quality evidence).

Recommendation 3: ACP recommends a target blood glucose level of 7.8 to 11.1 mmol/L (140 to 200 mg/dL) if insulin therapy is used in SICU/MICU patients (Grade: weak recommendation, moderate-quality evidence).

Hyperglycemia is a common finding among medical and surgical patients with or without known diabetes during hospital admission (12). Although the prevalence of hyperglycemia in hospitalized patients is not known with certainty, it is estimated to be around 40% (3). Poorly controlled hyperglycemia is associated with increased morbidity, mortality, and costs (4). Hyperglycemia is associated with poor immune response, increased cardiovascular events, thrombosis, inflammatory changes, delayed healing, and other problems (5). Achieving tight glycemic control safely in inpatients is labor intensive and often requires coordination of efforts involving a multidisciplinary team in a hospital setting (4). Most of the evidence on how to best achieve target blood glucose levels centers around the use of intensive insulin protocols.

The purpose of this American College of Physicians (ACP) guideline is to address the management of hyperglycemia and evaluate the benefits and harms associated with the use of intensive insulin therapy (IIT) to achieve tight glycemic control in hospitalized patients with or without diabetes mellitus. We defined “IIT” as use of intravenous insulin to achieve targeted blood glucose level with frequent blood glucose testing and adjustment of insulin doses. In intensive care unit (ICU) settings, the usual target of IIT is normoglycemia (blood glucose level, 4.4 to 6.1 mmol/L [80 to 110 mg/dL]), whereas targets in non-ICU settings have been more variable (ranging from normoglycemia to <11.1 mmol/L [<200 mg/dL]).

The target audience for this guideline includes all clinicians, and the target patient population comprises all adults with hyperglycemia in a hospital setting. These recommendations are based on a systematic evidence review by Kansagara and colleagues (6), from an evidence report sponsored by the Department of Veterans Affairs (5).

The objective of this guideline is to present the evidence for the following questions:

  1. Does the use of IIT to achieve tight glycemic control compared with less tight glycemic control improve important health outcomes in the following settings or patient populations: surgical intensive care unit (SICU), medical intensive care unit (MICU), general surgical ward, general medicine ward, patients with myocardial infarction or acute stroke, and patients in the perioperative setting?

  2. What are the harms of strict glycemic control in the above subpopulations?

The databases used for the literature search were MEDLINE and the Cochrane Database of Systematic Reviews; the search included studies published from database inception through January 2010. The literature search was supplemented by reviews of reference lists, suggestions from consulting experts, and searches on ClinicalTrials.gov for unpublished studies. Each article was reviewed by using the eligibility criteria outlined in the systematic review (6). Eligible articles were published in English and provided primary data relevant to the use of IIT in hospitalized patients. Studies evaluating fixed-dose insulin infusions, including trials of fixed-dose glucose–insulin–potassium infusions, were excluded. The primary outcome of interest was short-term mortality (preferential order: 28-day mortality, hospital mortality, ICU mortality). The major harm of interest was the rate of hypoglycemia, including effects of hypoglycemia on clinical outcomes and length of hospitalization. The quality of each study was rated as good, fair, or poor on the basis of 1) the comparability of treatment groups; 2) the adequacy of randomization; 3) whether treatment allocation was concealed; 4) whether eligibility criteria were specified; 5) whether patients, care providers, and outcome assessors were blinded; 6) whether the analysis was done on an intention-to-treat basis, conducted with postrandomization exclusions, or had extensive or differential loss to follow-up; and 7) whether clearly defined interventions and reliable outcome measurement were used. Given the importance of glucose control and hypoglycemia in assessing the effectiveness and safety of IIT, studies that did not fully report glucose levels achieved or overall hypoglycemia rates were rated as poor quality.

Three investigators reviewed the abstracts of citations identified from literature searches. When reviewers disagreed about the quality rating, consensus was reached through discussion with all authors. Details of the methods for the evidence review are provided in the evidence review (6).

This guideline rates the evidence and recommendations by using the ACP's guideline grading system, which is a slightly modified version of the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system (Table).

Table Jump PlaceholderTable.  The American College of Physicians Guideline Grading System
Mortality

A meta-analysis of 21 trials (14 768 participants) found no benefit associated with IIT on short-term mortality (28-day, hospital, or ICU mortality) (relative risk [RR], 1.0 [95% CI, 0.94 to 1.1]) (6). Although the trials differed with regard to target glucose levels for ITT and control groups, achieved glucose levels, IIT protocols, and medical setting (for example, ICU vs. non-ICU), there was no statistical heterogeneity (I2 = 0%). Results were similar when trials were stratified according to blood glucose level achieved, the percentage of diabetic patients, definition of short-term mortality, or study quality. Meta-analysis also showed no benefit associated with IIT for 90- or 180-day mortality (13 trials; RR, 1.1 [CI 0.99 to 1.1]; I2 = 0%). Results in specific patient subgroups are described below.

ICUs
MICUs

Evidence from 5 fair-quality trials (711) and 1 poor-quality trial (12) of IIT (target glucose levels of normoglycemia [4.4 to 6.1 mmol/L {80 to 110 mg/dL}] compared with control values ranging from 7.8 to 11.1 mmol/L [140 to 200 mg/dL]) consistently found no mortality benefit associated with normoglycemia as a target. The overall quality of evidence that IIT with normoglycemia as a target in patients in the MICU does not improve mortality was rated as high.

SICUs

Three fair-quality trials (7, 9, 13) and 2 poor-quality trials (1415) of IIT (target glucose levels of 4.4 to 8.3 mmol/L [80 to 150 mg/dL] vs. control values ranging from 10.0 to 12.2 mmol/L [180 to 220 mg/dL]) conducted in SICUs showed no benefit of IIT on mortality (7, 9, 1315). The largest trial (2232 patients in the surgical subgroup) was the recent multicenter NICE-SUGAR (Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation) study (9), a fair-quality study with target glucose levels of 4.4 to 6.0 mmol/L (80 to 108 mg/dL) that showed an increase in mortality compared with a target less than 10.0 mmol/L (<180 mg/dL) (RR, 1.31 [CI, 1.07 to 1.61]). However, not all of the trials found no benefit. A large (1600 participants), fair-quality study showed a statistically significant reduction in all-cause ICU mortality in the IIT group (morning blood glucose level, 4.4 to 6.1 mmol/L [80 to 110 mg/dL]) compared with conventional therapy (morning blood glucose level, 10.0 to 11.1 mmol/L [180 to 200 mg/dL]); mortality rates were 4.6% and 8.0%, respectively (RR, 0.58 [CI, 0.38 to 0.78]) (16). The overall quality of evidence that IIT targeted at normoglycemia in patients in the SICU does not improve mortality was rated as moderate.

Mixed MICU and SICU Populations

Five fair-quality trials that included mixed MICU and SICU populations (glucose target for IIT ranging from 4.0 to 6.1 mmol/L [72 to 110 mg/dL] compared with control ranging from 7.8 to 11.1 mmol/L [140 to 200 mg/dL]) did not demonstrate an overall mortality benefit of IIT ((7, 9, 1718); Mackenzie I, Blunt M, Ingle S, Palmer C. GLYcaemic Control and Outcome in GENeral Intensive Care. Unpublished report). The largest trial (6104 participants), the NICE-SUGAR study, showed that IIT with target glucose levels of 4.4 to 6.0 mmol/L (80 to 108 mg/dL) was associated with an increase in 90-day mortality compared with a target level less than 10.0 mmol/L (<180 mg/dL) (RR, 1.14 [CI, 1.02 to 1.28]); there was approximately 1 excess death per 39 patients treated with IIT (9). The overall quality of evidence that IIT targeted at normoglycemia in mixed MICU/SICU populations does not improve mortality was rated as high.

General Medicine Ward

No studies evaluated IIT in patients on the general medical ward.

Patients With Myocardial Infarction

Evidence from 3 fair-quality studies (1921) and 2 poor-quality studies (2223) showed no reduction in mortality among patients with myocardial infarction who received IIT and adjustable-dose glucose–insulin–potassium infusions (target glucose levels ranging from 4.0 to 11.0 mmol/L [72 to 198 mg/dL] vs. unspecified target levels in control groups). One fair-quality trial (620 participants) that compared IIT (target glucose levels ranging from 7.0 to 11.0 mmol/L [126 to 198 mg/dL]) with long-term postdischarge insulin therapy found a mortality reduction at 1 year (18.6% vs. 26.1%, respectively; RR, 0.69 [CI, 0.49 to 0.96]; P = 0.027), but it was not possible to determine whether the results were due to IIT or the use of insulin after discharge (24). In addition, this trial was published about 10 years before the other trials, and given changes over time in management of myocardial infarction, its current applicability may be limited.

Variations in trial design, glucose level achieved, and concomitant therapy for myocardial infarction limit the strength of conclusions that can be drawn from these studies. The overall quality of evidence for IIT to achieve target glucose levels of 4.0 to 11.0 mmol/L (72 to 198 mg/dL) on mortality in patients with myocardial infarction was rated as low.

Patients With Stroke or Acute Brain Injury

Two fair-quality trials (2526) and 2 poor-quality trials (2729) that examined the efficacy of IIT (target glucose values ranging from 4.4 to 8.0 mmol/L [80 to 144 mg/dL]) in patients with stroke or brain injury showed no mortality benefit compared with higher targets (ranging from <10.0 to <17.0 mmol/L [<180 to <306 mg/dL]). The overall quality of evidence that IIT targeted to achieve glucose levels of 4.4 to 8.0 mmol/L (80 to 144 mg/dL) in patients with stroke does not improve mortality was rated as low.

Perioperative Care

Evidence from 1 fair-quality trial (30) and 2 poor-quality trials (3132) that evaluated IIT (glucose targets ranging from 3.9 to 10.0 mmol/L [70 to 179 mg/dL]) versus higher or unspecified target values during the immediate perioperative period (IIT was begun before, during, or immediately after surgery and was continued for less than 24 hours after surgery) did not show a beneficial effect on mortality.

The trials included patients undergoing surgery (mainly cardiac) and had small sample sizes, low event rates, and considerable differences in interventions used and blood glucose targets. The overall quality of evidence that IIT to achieve target glucose levels of 3.9 to 10.0 mmol/L (70 to 179 mg/dL) does not improve health outcomes in patients receiving perioperative care was rated as low.

Infection

Nine fair-quality trials (7, 9, 13, 17, 30, 3336) and 7 poor-quality trials (12, 1415, 29, 32, 3738) evaluated the effect of IIT on the incidence of infection in various patient populations. For sepsis, evidence from 9 trials (7, 9, 1214, 1617, 29, 36) showed a marginally significant reduction in the risk for sepsis (RR, 0.79 [CI, 0.62 to 1.00]). Seven other studies (15, 30, 3234, 38) reported the occurrence of wound infections, urinary tract infections, pneumonia, or a combination of these infections. A pooled analysis of these outcomes showed a non–statistically significant reduction in infection (RR, 0.68 [CI, 0.36 to 1.30]).

Length of Stay

Eight fair-quality trials ((7, 9, 18, 24, 30, 3334); Mackenzie I, Blunt M, Ingle S, Palmer C. GLYcaemic Control and Outcome in GENeral Intensive Care. Unpublished report) and 5 poor-quality trials (15, 3132, 37) reported the effects of IIT on hospital length of stay. Four trials ((7, 9, 18); Mackenzie I, Blunt M, Ingle S, Palmer C. GLYcaemic Control and Outcome in GENeral Intensive Care. Unpublished report) in the mixed MICU/SICU environment found a neutral effect of IIT on overall hospital length of stay (0.008 day [CI, −0.84 to 0.85 day) or ICU length of stay (−0.04 day [−0.34 to 0.26 day]; I2 = 0%). In contrast, 4 SICU studies (1315, 39) found that IIT was associated with a reduction in ICU length of stay (−1.5 days [CI, −2.2 to −0.73 day]; I2 = 50%; P = 0.11). The overall quality of evidence on effects of IIT on length of hospital or ICU stay in patients in the ICU was rated as moderate.

Two fair-quality perioperative trials (33, 40) showed neutral results for hospital length of stay, and 1 fair-quality trial (34) showed on average a 1-day reduction in length of stay. The overall quality of evidence was rated as low.

Harms of Intensive Insulin Therapy: Hypoglycemia

The use of IIT was associated with an excess risk for hypoglycemia in almost all trials; critically ill patients receiving IIT aimed at achieving normoglycemia had the highest occurrence of hypoglycemia (RR, 5.32 [CI, 4.21 to 6.73]) (4144). The overall quality of evidence that IIT is associated with hypoglycemia in all subgroups except the general medical unit (for which there were no studies) was rated as high.

The consequences of hypoglycemia in hospitalized patients are unclear because few of the studies reviewed reported adverse effects and few studies have examined the long-term consequences of hypoglycemia. There is some evidence for excess mortality or extended length of stay among patients in the MICU experiencing 1 or more episodes of severe hypoglycemia related to IIT (78, 4546). However, it is unclear whether hypoglycemia was a causative factor or whether it was a marker for more severe disease. Some studies have suggested that hypoglycemia is associated with an increased risk for dementia in patients with type 2 diabetes (47) and a 2-fold increase in risk for mortality (48) and that it may induce transient ischemia and catecholamine surges (4951).

Implementation of Effective and Safe Intensive Insulin Therapy

Fair-quality evidence (5254) on the effects of different insulin infusion protocols on glycemic control differed in terms of patient characteristics, target glucose ranges, the time required to achieve the target glucose, the incidence and definition of hypoglycemia, the rationale or algorithm used for adjusting the insulin infusion rates, the methods used to assess effectiveness, and the methods of glucose monitoring. Two reviews suggested that in light of variability among protocols, each institution should individualize protocol implementation on the basis of its patient population, institutional resources, and provider resources (5253). A third review concluded that protocols that incorporate such factors as the rate of change in glucose level, current blood glucose level, and insulin infusion rate may be more effective than simple sliding-scale infusion protocols in decreasing blood glucose levels while maintaining relatively low rates of hypoglycemia (54). However, this conclusion is not based on direct comparisons of protocols.

Evidence evaluating subcutaneous sliding-scale insulin regimens suggests that this regimen may be relatively ineffective in achieving lower target blood glucose values (38, 5557).

Summary

Poorly controlled hyperglycemia is associated with increased morbidity, mortality, and worsening health outcomes in hospitalized patients. Most clinicians make efforts to prevent and control hyperglycemia in inpatient settings. However, the optimal blood glucose range to target in hospitalized patients is uncertain. Many trials have shown no effect of IIT targeted to different blood glucose levels on mortality, and pooling of trials does not suggest any trend toward benefit. Among patients in ICUs, in whom there are theoretical reasons to target normoglycemia or near-normoglycemia, the evidence also shows no mortality benefit associated with IIT for targeted glucose levels of 4.4 to 6.1 mmol/L (80 to 110 mg/dL). Although an SICU study (16) showed evidence supporting the link between reduced mortality and the use of IIT to targets of 4.4 to 6.1 mmol/L (80 to 110 mg/dL), the study used aggressive parenteral nutrition, which is not standard practice in many hospitals (16, 36, 58). Parenteral nutrition has been associated with hypertriglyceridemia, insulin resistance, increased infection rates, and increased mortality. Furthermore, this study had a relatively low event rate and was stopped early because of benefit, raising concerns that the reported treatment effect was larger than the “true” treatment effect (59). Finally, the results of this study have not been replicated in other settings. In contrast, several other trials were stopped early owing to an excess risk for hypoglycemia in the intervention groups. This raises the possibility that the lack of observed benefit may reflect inadequate power to detect health benefit (78).

The consequences of severe hypoglycemia in hospitalized patients have not been well studied. There is some evidence for excess mortality or extended length of stay among patients experiencing 1 or more episodes of hypoglycemia. However, from the currently available evidence, it cannot be established whether hypoglycemia was the causative factor.

The evidence evaluating insulin protocols that have achieved normoglycemic targets with low rates of hypoglycemia is sparse. The ability to achieve glucose targets safely probably depends on multiple factors, including the titration characteristics of the protocol, patient characteristics, staffing ratios, and provider acceptance. Characteristics of these studies suggest that several variables may be responsible for the lower rates of hypoglycemia: modest glucose targets (approximately 5.6 to 8.3 mmol/L [100 to 150 mg/dL]); an iterative, institution-based protocol development and deployment process; and innovations in insulin titration protocols.

Recommendation 1: ACP recommends not using intensive insulin therapy to strictly control blood glucose in non-SICU/MICU patients with or without diabetes mellitus (Grade: strong recommendation, moderate-quality evidence).

Current evidence does not show any reduction in mortality with a target blood glucose level of 4.4 to 10.0 mmol/L (80 to 180 mg/dL) compared with higher or unspecified targets using a variety of IIT regimens for patients with myocardial infarction, stroke, or acute brain injury or those under perioperative care. A nonsignificant reduction in the incidence of infection has also been observed. Although the target blood glucose levels in the current trials ranged widely, avoiding targets less than 7.8 mmol/L (<140 mg/dL) should be a priority because harms are likely to increase at lower blood glucose targets. Although the consequences of hypoglycemia in hospitalized patients are unclear, there is some evidence for increased mortality or extended length of stay among patients experiencing 1 or more episodes of hypoglycemia. However, optimal targets in patients not receiving care in the SICU or MICU cannot be precisely defined, because IIT was associated with an excess risk for hypoglycemia in almost all trials and no clear differences in mortality were observed at any target level.

Recommendation 2: ACP recommends not using intensive insulin therapy to normalize blood glucose in SICU/MICU patients with or without diabetes mellitus (Grade: strong recommendation, high-quality evidence).

Current evidence does not show a mortality benefit associated with use of IIT to achieve a target of normoglycemia (blood glucose levels of 4.4 to 6.1 mmol/L [80 to 110 mg/dL]). Evidence from some studies showed an increase in mortality associated with IIT and hypoglycemia. Data on the effects of IIT targeted to normoglycemia on reduction in length of ICU stay are mixed.

Recommendation 3: ACP recommends a target blood glucose level of 7.8 to 11.1 mmol/L (140 to 200 mg/dL) if insulin therapy is used in SICU/MICU patients (Grade: weak recommendation, moderate-quality evidence).

Although IIT to achieve targeted normoglycemia is not associated with improved health outcomes and increases the risk for hypoglycemia, poorly controlled hyperglycemia is associated with increased morbidity, mortality, and worsened health outcomes in patients in the ICU. While the evidence is not sufficient to give a precise range for blood glucose levels, target values of 7.8 to 11.1 mmol/L (140 to 200 mg/dL) is a reasonable option in patients in the ICU, because insulin therapy targeted at blood glucose levels of 7.8 to 11.1 mmol/L (140 to 200 mg/dL) is associated with similar mortality outcomes as IIT targeted at blood glucose levels of 4.4 to 6.1 mmol/L (80 to 110 mg/dL) and is associated with a lower risk for hypoglycemia. Current studies do not provide enough information to determine whether allowing blood glucose levels to increase above 10.0 to 11.1 mmol/L (180 to 200 mg/dL) is associated with similar outcomes to those seen at lower target levels.

Although the risk for hypoglycemia was higher in studies with lower target glucose values, hypoglycemia was also observed among patients who received insulin therapy with target blood glucose levels ranging from 7.8 to 11.1 mmol/L (140 to 200 mg/dL). Therefore, minimizing hypoglycemia associated with IIT is critical in institutions that choose to implement insulin therapy in patients in the ICU. Factors that may be associated with achievement of glucose targets with low rates of hypoglycemia include titration characteristics of the protocol, patient characteristics, staffing ratios, and clinician acceptance. Institutions that implement insulin therapy in patients in the ICU should incorporate quality improvement and training initiatives in order to achieve target glucose levels while minimizing rates of hypoglycemia.

See the Figure for a summary of the recommendations and clinical considerations. The Table describes the ACP's guideline grading system.

Grahic Jump Location
Figure.
The American College of Physicians guideline on the use of intensive insulin therapy for the management of glycemic control in hospitalized patients.

IIT = intensive insulin therapy; MICU = medical intensive care unit; SICU = surgical intensive care unit.

Grahic Jump Location
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Malmberg K, Rydén L, Wedel H, Birkeland K, Bootsma A, Dickstein K, et al. DIGAMI 2 Investigators.  Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005; 26:650-61.
PubMed
 
Rasoul S, Ottervanger JP, Timmer JR, Svilaas T, Henriques JP, Dambrink JH. et al.  One year outcomes after glucose-insulin-potassium in ST elevation myocardial infarction. The Glucose-insulin-potassium study II. Int J Cardiol. 2007; 122:52-5.
PubMed
 
Malmberg K, Rydén L, Efendic S, Herlitz J, Nicol P, Waldenström A. et al.  Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995; 26:57-65.
PubMed
 
Azevedo JR, Lima ER, Cossetti RJ, Azevedo RP.  Intensive insulin therapy versus conventional glycemic control in patients with acute neurological injury: a prospective controlled trial. Arq Neuropsiquiatr. 2007; 65:733-8.
PubMed
 
Bruno A, Kent TA, Coull BM, Shankar RR, Saha C, Becker KJ. et al.  Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial. Stroke. 2008; 39:384-9.
PubMed
 
Gray C, Hildreth A, Sandercock P, O'Connell JE, Johnston DE, Cartlidge NE, et al. GIST Trialists Collaboration.  Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol. 2007; 6:397-406.
PubMed
 
Walters MR, Weir CJ, Lees KR.  A randomised, controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients. Cerebrovasc Dis. 2006; 22:116-22.
PubMed
 
Yang M, Guo Q, Zhang X, Sun S, Wang Y, Zhao L. et al.  Intensive insulin therapy on infection rate, days in NICU, in-hospital mortality and neurological outcome in severe traumatic brain injury patients: a randomized controlled trial. Int J Nurs Stud. 2009; 46:753-8.
PubMed
 
Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, O'Brien PC. et al.  Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med. 2007; 146:233-43.
PubMed
 
Butterworth J, Wagenknecht LE, Legault C, Zaccaro DJ, Kon ND, Hammon JW Jr. et al.  Attempted control of hyperglycemia during cardiopulmonary bypass fails to improve neurologic or neurobehavioral outcomes in patients without diabetes mellitus undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2005; 130:1319.
PubMed
 
Smith A, Grattan A, Harper M, Royston D, Riedel BJ.  Coronary revascularization: a procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study. J Cardiothorac Vasc Anesth. 2002; 16:413-20.
PubMed
 
Barcellos Cda S, Wender OC, Azambuja PC.  Clinical and hemodynamic outcome following coronary artery bypass surgery in diabetic patients using glucose-insulin-potassium (GIK) solution: a randomized clinical trial. Rev Bras Cir Cardiovasc. 2007; 22:275-84.
PubMed
 
Subramaniam B, Panzica PJ, Novack V, Mahmood F, Matyal R, Mitchell JD. et al.  Continuous perioperative insulin infusion decreases major cardiovascular events in patients undergoing vascular surgery: a prospective, randomized trial. Anesthesiology. 2009; 110:970-7.
PubMed
 
van den Berghe G, Weekers F, Baxter RC, Wouters P, Iranmanesh A, Bouillon R. et al.  Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. J Clin Endocrinol Metab. 2001; 86:3217-26.
PubMed
 
Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I. et al.  Intensive insulin therapy in the medical ICU. N Engl J Med. 2006; 354:449-61.
PubMed
 
Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS.  Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation. 2004; 109:1497-502.
PubMed
 
Li JY, Sun S, Wu SJ.  Continuous insulin infusion improves postoperative glucose control in patients with diabetes mellitus undergoing coronary artery bypass surgery. Tex Heart Inst J. 2006; 33:445-51.
PubMed
 
Van den Berghe G, Wouters PJ, Kesteloot K, Hilleman DE.  Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients. Crit Care Med. 2006; 34:612-6.
PubMed
 
Ingels C, Debaveye Y, Milants I, Buelens E, Peeraer A, Devriendt Y. et al.  Strict blood glucose control with insulin during intensive care after cardiac surgery: impact on 4-years survival, dependency on medical care, and quality-of-life. Eur Heart J. 2006; 27:2716-24.
PubMed
 
Fischer KF, Lees JA, Newman JH.  Hypoglycemia in hospitalized patients. Causes and outcomes. N Engl J Med. 1986; 315:1245-50.
PubMed
 
Krinsley J.  Glycemic control in critically ill patients: Leuven and beyond [Editorial]. Chest. 2007; 132:1-2.
PubMed
 
Shilo S, Berezovsky S, Friedlander Y, Sonnenblick M.  Hypoglycemia in hospitalized nondiabetic older patients. J Am Geriatr Soc. 1998; 46:978-82.
PubMed
 
Vriesendorp TM, van Santen S, DeVries JH, de Jonge E, Rosendaal FR, Schultz MJ. et al.  Predisposing factors for hypoglycemia in the intensive care unit. Crit Care Med. 2006; 34:96-101.
PubMed
 
Devos P, Preiser J, Melot C.  Impact of tight glucose control by intensive insulin therapy on ICU mortality and the rate of hypoglycaemia: final results of the GLUCONTROL study. Intensive Care Med. 2007; 33:S189.
 
Krinsley JS.  Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc. 2003; 78:1471-8.
PubMed
 
Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV.  Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009; 301:1565-72.
PubMed
 
Svensson AM, McGuire DK, Abrahamsson P, Dellborg M.  Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J. 2005; 26:1255-61.
PubMed
 
Desouza C, Salazar H, Cheong B, Murgo J, Fonseca V.  Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring. Diabetes Care. 2003; 26:1485-9.
PubMed
 
Lindström T, Jorfeldt L, Tegler L, Arnqvist HJ.  Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus. Diabet Med. 1992; 9:536-41.
PubMed
 
Spyer G, Hattersley AT, MacDonald IA, Amiel S, MacLeod KM.  Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes. Lancet. 2000; 356:1970-4.
PubMed
 
Nazer LH, Chow SL, Moghissi ES.  Insulin infusion protocols for critically ill patients: a highlight of differences and similarities. Endocr Pract. 2007; 13:137-46.
PubMed
 
Wilson M, Weinreb J, Hoo GW.  Intensive insulin therapy in critical care: a review of 12 protocols. Diabetes Care. 2007; 30:1005-11.
PubMed
 
Meijering S, Corstjens AM, Tulleken JE, Meertens JH, Zijlstra JG, Ligtenberg JJ.  Towards a feasible algorithm for tight glycaemic control in critically ill patients: a systematic review of the literature. Crit Care. 2006; 10:R19.
PubMed
 
Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M. et al.  Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care. 2007; 30:2181-6.
PubMed
 
Datta S, Qaadir A, Villanueva G, Baldwin D.  Once-daily insulin glargine versus 6-hour sliding scale regular insulin for control of hyperglycemia after a bariatric surgical procedure: a randomized clinical trial. Endocr Pract. 2007; 13:225-31.
PubMed
 
Dickerson LM, Ye X, Sack JL, Hueston WJ.  Glycemic control in medical inpatients with type 2 diabetes mellitus receiving sliding scale insulin regimens versus routine diabetes medications: a multicenter randomized controlled trial. Ann Fam Med. 2003; 1:29-35.
PubMed
 
Needham P, Burton A, Jayne D.  Artificial nutrition in UK intensive care units: a review of current practice. Proc Nutr Soc. 2008; 67:152.
 
Montori VM, Devereaux PJ, Adhikari NK, Burns KE, Eggert CH, Briel M. et al.  Randomized trials stopped early for benefit: a systematic review. JAMA. 2005; 294:2203-9.
PubMed
 

Figures

Grahic Jump Location
Figure.
The American College of Physicians guideline on the use of intensive insulin therapy for the management of glycemic control in hospitalized patients.

IIT = intensive insulin therapy; MICU = medical intensive care unit; SICU = surgical intensive care unit.

Grahic Jump Location

Tables

Table Jump PlaceholderTable.  The American College of Physicians Guideline Grading System

References

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PubMed
CrossRef
 
Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE.  Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002; 87:978-82.
PubMed
 
Clement S, Braithwaite S, Magee M, Ahmann A, Smith EP, Schafer RG, et al. American Diabetes Association Diabetes in Hospitals Writing Committee.  Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004; 27:553-91.
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Kansagara D, Fu R, Freeman M, Wolf F, Helfand M.  Systematic review: intensive insulin therapy in hospitalized patients. Ann Intern Med. 2011; 154:268-xx.
 
Arabi YM, Dabbagh OC, Tamim HM, Al-Shimemeri AA, Memish ZA, Haddad SH. et al.  Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med. 2008; 36:3190-7.
PubMed
 
Brunkhorst F, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. German Competence Network Sepsis (SepNet).  Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008; 358:125-39.
PubMed
 
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D. et al.  Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009; 360:1283-97.
PubMed
 
Van den Berghe G, Wilmer A, Milants I, Wouters PJ, Bouckaert B, Bruyninckx F. et al.  Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes. 2006; 55:3151-9.
PubMed
 
Savioli M, Cugno M, Polli F, Taccone P, Bellani G, Spanu P. et al.  Tight glycemic control may favor fibrinolysis in patients with sepsis. Crit Care Med. 2009; 37:424-31.
PubMed
 
Farah R, Samokhvalov A, Zviebel F, Makhoul N.  Insulin therapy of hyperglycemia in intensive care. Isr Med Assoc J. 2007; 9:140-2.
PubMed
 
Bilotta F, Caramia R, Paoloni FP, Delfini R, Rosa G.  Safety and efficacy of intensive insulin therapy in critical neurosurgical patients. Anesthesiology. 2009; 110:611-9.
PubMed
 
Grey NJ, Perdrizet GA.  Reduction of nosocomial infections in the surgical intensive-care unit by strict glycemic control. Endocr Pract. 2004; 10:Suppl 246-52.
PubMed
 
Kirdemir P, Yildirim V, Kiris I, Gulmen S, Kuralay E, Ibrisim E. et al.  Does continuous insulin therapy reduce postoperative supraventricular tachycardia incidence after coronary artery bypass operations in diabetic patients? J Cardiothorac Vasc Anesth. 2008; 22:383-7.
PubMed
 
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M. et al.  Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001; 345:1359-67.
PubMed
 
De La Rosa Gdel C, Donado JH, Restrepo AH, Quintero AM, González LG, Saldarriaga NE, et al. Grupo de Investigacion en Cuidado intensivo: GICI-HPTU.  Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial. Crit Care. 2008; 12:R120.
PubMed
 
Preiser JC, Devos P, Ruiz-Santana S, Mélot C, Annane D, Groeneveld J. et al.  A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009; 35:1738-48.
PubMed
 
Cheung NW, Wong VW, McLean M.  The Hyperglycemia: Intensive Insulin Infusion in Infarction (HI-5) study: a randomized controlled trial of insulin infusion therapy for myocardial infarction. Diabetes Care. 2006; 29:765-70.
PubMed
 
Oksanen T, Skrifvars MB, Varpula T, Kuitunen A, Pettilä V, Nurmi J. et al.  Strict versus moderate glucose control after resuscitation from ventricular fibrillation. Intensive Care Med. 2007; 33:2093-100.
PubMed
 
van der Horst IC, Zijlstra F, van 't Hof AW, Doggen CJ, de Boer MJ, Suryapranata H, et al. Zwolle Infarct Study Group.  Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial. J Am Coll Cardiol. 2003; 42:784-91.
PubMed
 
Malmberg K, Rydén L, Wedel H, Birkeland K, Bootsma A, Dickstein K, et al. DIGAMI 2 Investigators.  Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005; 26:650-61.
PubMed
 
Rasoul S, Ottervanger JP, Timmer JR, Svilaas T, Henriques JP, Dambrink JH. et al.  One year outcomes after glucose-insulin-potassium in ST elevation myocardial infarction. The Glucose-insulin-potassium study II. Int J Cardiol. 2007; 122:52-5.
PubMed
 
Malmberg K, Rydén L, Efendic S, Herlitz J, Nicol P, Waldenström A. et al.  Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995; 26:57-65.
PubMed
 
Azevedo JR, Lima ER, Cossetti RJ, Azevedo RP.  Intensive insulin therapy versus conventional glycemic control in patients with acute neurological injury: a prospective controlled trial. Arq Neuropsiquiatr. 2007; 65:733-8.
PubMed
 
Bruno A, Kent TA, Coull BM, Shankar RR, Saha C, Becker KJ. et al.  Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial. Stroke. 2008; 39:384-9.
PubMed
 
Gray C, Hildreth A, Sandercock P, O'Connell JE, Johnston DE, Cartlidge NE, et al. GIST Trialists Collaboration.  Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol. 2007; 6:397-406.
PubMed
 
Walters MR, Weir CJ, Lees KR.  A randomised, controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients. Cerebrovasc Dis. 2006; 22:116-22.
PubMed
 
Yang M, Guo Q, Zhang X, Sun S, Wang Y, Zhao L. et al.  Intensive insulin therapy on infection rate, days in NICU, in-hospital mortality and neurological outcome in severe traumatic brain injury patients: a randomized controlled trial. Int J Nurs Stud. 2009; 46:753-8.
PubMed
 
Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, O'Brien PC. et al.  Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med. 2007; 146:233-43.
PubMed
 
Butterworth J, Wagenknecht LE, Legault C, Zaccaro DJ, Kon ND, Hammon JW Jr. et al.  Attempted control of hyperglycemia during cardiopulmonary bypass fails to improve neurologic or neurobehavioral outcomes in patients without diabetes mellitus undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2005; 130:1319.
PubMed
 
Smith A, Grattan A, Harper M, Royston D, Riedel BJ.  Coronary revascularization: a procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study. J Cardiothorac Vasc Anesth. 2002; 16:413-20.
PubMed
 
Barcellos Cda S, Wender OC, Azambuja PC.  Clinical and hemodynamic outcome following coronary artery bypass surgery in diabetic patients using glucose-insulin-potassium (GIK) solution: a randomized clinical trial. Rev Bras Cir Cardiovasc. 2007; 22:275-84.
PubMed
 
Subramaniam B, Panzica PJ, Novack V, Mahmood F, Matyal R, Mitchell JD. et al.  Continuous perioperative insulin infusion decreases major cardiovascular events in patients undergoing vascular surgery: a prospective, randomized trial. Anesthesiology. 2009; 110:970-7.
PubMed
 
van den Berghe G, Weekers F, Baxter RC, Wouters P, Iranmanesh A, Bouillon R. et al.  Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. J Clin Endocrinol Metab. 2001; 86:3217-26.
PubMed
 
Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I. et al.  Intensive insulin therapy in the medical ICU. N Engl J Med. 2006; 354:449-61.
PubMed
 
Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS.  Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation. 2004; 109:1497-502.
PubMed
 
Li JY, Sun S, Wu SJ.  Continuous insulin infusion improves postoperative glucose control in patients with diabetes mellitus undergoing coronary artery bypass surgery. Tex Heart Inst J. 2006; 33:445-51.
PubMed
 
Van den Berghe G, Wouters PJ, Kesteloot K, Hilleman DE.  Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients. Crit Care Med. 2006; 34:612-6.
PubMed
 
Ingels C, Debaveye Y, Milants I, Buelens E, Peeraer A, Devriendt Y. et al.  Strict blood glucose control with insulin during intensive care after cardiac surgery: impact on 4-years survival, dependency on medical care, and quality-of-life. Eur Heart J. 2006; 27:2716-24.
PubMed
 
Fischer KF, Lees JA, Newman JH.  Hypoglycemia in hospitalized patients. Causes and outcomes. N Engl J Med. 1986; 315:1245-50.
PubMed
 
Krinsley J.  Glycemic control in critically ill patients: Leuven and beyond [Editorial]. Chest. 2007; 132:1-2.
PubMed
 
Shilo S, Berezovsky S, Friedlander Y, Sonnenblick M.  Hypoglycemia in hospitalized nondiabetic older patients. J Am Geriatr Soc. 1998; 46:978-82.
PubMed
 
Vriesendorp TM, van Santen S, DeVries JH, de Jonge E, Rosendaal FR, Schultz MJ. et al.  Predisposing factors for hypoglycemia in the intensive care unit. Crit Care Med. 2006; 34:96-101.
PubMed
 
Devos P, Preiser J, Melot C.  Impact of tight glucose control by intensive insulin therapy on ICU mortality and the rate of hypoglycaemia: final results of the GLUCONTROL study. Intensive Care Med. 2007; 33:S189.
 
Krinsley JS.  Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc. 2003; 78:1471-8.
PubMed
 
Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV.  Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009; 301:1565-72.
PubMed
 
Svensson AM, McGuire DK, Abrahamsson P, Dellborg M.  Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J. 2005; 26:1255-61.
PubMed
 
Desouza C, Salazar H, Cheong B, Murgo J, Fonseca V.  Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring. Diabetes Care. 2003; 26:1485-9.
PubMed
 
Lindström T, Jorfeldt L, Tegler L, Arnqvist HJ.  Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus. Diabet Med. 1992; 9:536-41.
PubMed
 
Spyer G, Hattersley AT, MacDonald IA, Amiel S, MacLeod KM.  Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes. Lancet. 2000; 356:1970-4.
PubMed
 
Nazer LH, Chow SL, Moghissi ES.  Insulin infusion protocols for critically ill patients: a highlight of differences and similarities. Endocr Pract. 2007; 13:137-46.
PubMed
 
Wilson M, Weinreb J, Hoo GW.  Intensive insulin therapy in critical care: a review of 12 protocols. Diabetes Care. 2007; 30:1005-11.
PubMed
 
Meijering S, Corstjens AM, Tulleken JE, Meertens JH, Zijlstra JG, Ligtenberg JJ.  Towards a feasible algorithm for tight glycaemic control in critically ill patients: a systematic review of the literature. Crit Care. 2006; 10:R19.
PubMed
 
Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M. et al.  Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care. 2007; 30:2181-6.
PubMed
 
Datta S, Qaadir A, Villanueva G, Baldwin D.  Once-daily insulin glargine versus 6-hour sliding scale regular insulin for control of hyperglycemia after a bariatric surgical procedure: a randomized clinical trial. Endocr Pract. 2007; 13:225-31.
PubMed
 
Dickerson LM, Ye X, Sack JL, Hueston WJ.  Glycemic control in medical inpatients with type 2 diabetes mellitus receiving sliding scale insulin regimens versus routine diabetes medications: a multicenter randomized controlled trial. Ann Fam Med. 2003; 1:29-35.
PubMed
 
Needham P, Burton A, Jayne D.  Artificial nutrition in UK intensive care units: a review of current practice. Proc Nutr Soc. 2008; 67:152.
 
Montori VM, Devereaux PJ, Adhikari NK, Burns KE, Eggert CH, Briel M. et al.  Randomized trials stopped early for benefit: a systematic review. JAMA. 2005; 294:2203-9.
PubMed
 

Letters

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Comments

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Comment on the ACP Guidelines for the Management of Glycemic Control in Hospitalized Patients
Posted on February 16, 2011
Rajesh Garg
Harvard Medical School
Conflict of Interest: None Declared

Dear Editor,

The American College of Physicians' clinical practice guidelines for the management of hyperglycemia in hospitalized patients are confusing and may do more harm than good. The guidelines recommend against use of intensive insulin therapy (IIT) in the intensive care unit (ICU) as well in the non-ICU setting irrespective of the diabetes status. The IIT is defined as the use of intravenous insulin infusion. If intravenous insulin infusion should not be used in the ICU, what should be used to keep blood glucose levels in 140-200 mg/dL range? Should it be the oral agents, multiple subcutaneous insulin injections or a sliding scale insulin regimen? Many physicians consider multiple subcutaneous insulin injections also an IIT. This is especially true in the non-ICU setting where intravenous insulin is rarely used. Therefore, if following these guidelines, many hospitalized patients will be given only sliding scale insulin. This is potentially dangerous for all type 1 diabetic patients and many type 2 diabetic patients. Moreover, no upper limit for blood glucose levels has been set for the non-ICU patients. I think ACP guidelines should be more explicit and explain what should be done and not just what should not be done.

Rajesh Garg, M.D. Assistant Professor of Medicine Division of Endocrinology, Diabetes and Hypertension Brigham and Women's Hospital, Harvard Medical School 221 Longwood Ave, RF 393 Boston, MA 02115 rgarg@partners.org

Conflict of Interest:

None declared

Intensive Insulin Therapy in hospitalized patients.
Posted on February 17, 2011
Gauranga C. Dhar
Bangladesh Institute of Family Medicine And Research, USTC
Conflict of Interest: None Declared

In diabetics, sudden fall of blood glucose causes sympathetic and adrenergic activation. Direct effects of catecholamine and sympathetic system activation as well as catecholamine induced hypokalemia through Na+K+ATPase system leads to long QTc and QTd; ventricular tachy-arrhythmia (Torsade de pointes) and death. Patients either in SICU or MICU may present with hyperglycemia where blood glucose equal or >180mg/dl (10mmol/L) frequently indicates previously undiagnosed of existing diabetes. On the other hand non-diabetics with moderate hyperglycemia (<180mg/dl) in ICU may be found as a result of altered carbohydrate metabolism, glycogenolysis, gluconeogenesis and lipolysis associated with stress with the involvement of corticotrophin releasing hormone-arginine-vasopressin-catecholamine system. It has long been known that poorly controlled hyperglycemia among hospitalized patients is associated with increased morbidity and mortality but stringent glycemic control with intensive insulin therapy (IIT) leading to normoglycemia (4.4mmol/L to 6.1mmol/L) is associated with increased mortality due to hypoglycemia. Although to reduce such adverse outcomes, altered target of IIT; 7.8mmol/L to 11.1mmol/L in such contingent of patients also associated with similar mortality. Currently we do not have enough evidence that more relaxed target; 10mmol/L to 11.1mmol/L provides with better outcomes. As defined by American Diabetes Association, hypoglycemia, at blood glucose level <3.9mmol/L (<4.0mmol/L according to Canadian Diabetes Association), counter regulatory sympatho-adrenal activation starts to take place where catecholamine play one of the crucial roles. Same pathophysiological factor applies to any person with hyperglycemia experiencing "any sudden fall" of blood glucose irrespective of initial/baseline glucose level (relative hypoglycemia) as a result of IIT. More vulnerable are hospitalized non-diabetic individuals in whom corticotrophin releasing hormone-arginine-vasopressin-catecholamine system is already been activated before additional adrenal activation takes place after IIT. For better outcomes, no doubt glycemic control is necessary in patients in ICU but not at the cost of hypoglycemia and blood glucose target, if even IIT is used, may not be fixed but should be individualized which depends upon patient's present condition, age, duration of diabetes, existing medications and concomitant illness.

Conflict of Interest:

None declared

Appples v Pears
Posted on February 18, 2011
Lynn Bentson
Samaritan Health Physicians
Conflict of Interest: None Declared

I appreciate the extensive review of in hospital glucose targets Pehaps I misunderstand, but I think the stated goal of 140-200 includes all blood glucose levels . It appears in looking at the references that most of them dealt with patients who are NPO, whether because they are critically ill, postoperative or have had recent neurological events . Most of the time in the hospital, if a patient is eating we check PREprandial capillary glucose. If the PREprandial blood glucose is 200, the post meal sugar will be higher, outside the target range.I don't interpret this review as suggesting that mealtime insulin coverage is not needed if the pre-meal sugar is <200. This is the interpretation of many of my collegues. Please clarfy this

Conflict of Interest:

None declared

Defining the Glycemic Targets for Hospitalized Patients
Posted on February 24, 2011
Mary T. Korytkowski
University of Pittsburgh
Conflict of Interest: None Declared

The American College of Physicians (ACP) Clinical Practice Guideline on inpatient glucose control recommends against intensified insulin therapy (IIT) in medical and surgical patients in the hospital (1). This recommendation is based on a systematic review finding no consistent evidence to support strict glycemic control, defined as glucose targets of 4.4-6.1 mmol/L (80-110 mg/dL) (1, 2). The use of intensive insulin therapy to achieve these targets is associated with an increase in risk for hypoglycemia, which is related to an increased risk of hospital complications and mortality (3).

The ACP guideline also recommends that the upper glycemic target be changed to include blood glucose levels as high as 11.1 mmol/L (200 mg/dL) in ICU and non-ICU settings (1). Evidence from observational and randomized controlled trials has shown that glucose levels above 10 mmol/L (180 mg/dL) impair neutrophil function, increase risk for infections, prolong length of hospital stay and increase mortality in ICU patients (3). In addition, recent randomized control trials in non-ICU patients have shown that targeting pre-meal and random glucose levels between 6.1- 10 mmol/L (110-180 mg/dL), respectively, decrease the risk for infectious and other complications (4).

The ACP guides practice for the majority of internal medicine physicians across the United States and beyond. It is of concern that these guidelines were published without reference to either a recent Consensus Statement or the 2011 Clinical Practice recommendations for hospitalized patients which advocate glycemic targets of 7.8-10 mmol/L (140 to 180 mg/dL) for the majority of critically and non-critically ill hospitalized patients (3, 5). These are levels can be safely achieved without increasing risk for hypoglycemia.

It is our concern that variability in recommendations for glycemic targets by different professional organizations can result in both confusion and clinical inertia among those who deliver this care. Publications such as the ACP Clinical Guideline has the potential for misinterpretation with a weakening of current efforts to achieve reasonable glycemic goals that have been demonstrated to reduce risks of undertreated hyperglycemia in hospitalized patients.

References

1. Qaseem A, Humphrey L, Chou R, Snow V, Shekelle P, for the Clinical Guidelines Committee of the American College of Physicians. Use of Intensive Insulin Therapy for the Management of Glycemic Control in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians. Annals of Internal Medicine. 2011;154(4):260-267.

2. Kansagara D, Fu R, Freeman M, Wolf F, Helfand M. Intensive Insulin Therapy in Hospitalized Patients: A Systematic Review. Annals of Internal Medicine. 2011;154(4):268-282.

3. Moghissi ES, Korytkowski MT, DiNardo MM, et al. American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control. Diabetes Care. 2009;32(6):1119- 1131.

4. Umpierrez GE, Smiley D, Jacobs S, et al. Randomized Study of Basal- Bolus Insulin Therapy in the Inpatient Management of Patients With Type 2 Diabetes Undergoing General Surgery (RABBIT 2 Surgery). Diabetes Care. 2011;34(2):256-261.

5. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. . Diabetes Care. 2011;34(Suppl 1).

Conflict of Interest:

None declared

Misguided Guideline
Posted on February 26, 2011
Anthony P. Furnary
Starr-Wood Cardiac Group
Conflict of Interest: None Declared

To the editor:

I read with interest the clinical practice guideline on intensive insulin therapy published by the ACP (1). Specifically in regards to coronary artery bypass (CABG) patients with diabetes, ACP recommendations 2 and 3 are unfounded and not supported by the data cited. Only two of the 14 RCTs used for the ACP meta-analysis included CABG patients (2,3). In both, intensive insulin therapy-directed tight glycemic control (IIT-TGC) significantly reduced in-hospital mortality and surgical wound infection rates. All of the remaining studies considered in the meta-analysis excluded cardiac surgical patients by design. Those studies should not be used to broadly "over-rule" the significant effects of ITT-TGC that have been repeatedly proven in diabetes CABG patients.

To dilute the positive effects of these two cardiac surgical RCTs with 12 medical/non-cardiac surgical studies of IIT-TGC, which were ineffective in reducing mortality and infection, and then broadly claim that IIT-TGC should not be performed in all patients - including diabetes CABG patients -- is both irresponsible and dangerous.

The detrimental effects of hyperglycemia on mortality and surgical wound infections were first elucidated in the diabetes cardiac surgery patient population in the 1990's by our large (now >8000 patients) prospective observational studies from the Portland Diabetes Project. (4,5) These detrimental effects were proven to persist for 3 full days from the time of open-heart surgery, regardless of patient location within the hospital (SICU or ward). Eradication of hyperglycemia with ITT-TGC for 3 full days eliminated the increased risks of mortality and surgical site infection in this prominent portion (31%) of the cardiac surgery population. Kirdemir subsequently confirmed these same findings in a RCT (2). A sub-analysis of cardiac surgical patients from the Leuven SICU study re-confirmed the protective causal effects of IIT-TGC in cardiac surgical patients (6). Even the neurosurgical RCT by Bilotta confirmed the effects of tight IIT on surgical wound infections.

Hypoglycemia is an obvious potential detrimental consequence of IIT, but it is highly dependent on the protocol used, patient population studied and hospital environment in which it is used. The Portland Protocol at a target range of 70-110 carries a 1.0% risk (per patient) of severe hypoglycemia (<40) in the diabetes CABG patients on whom it is used for 3 days, even in the non-ICU ward (7). This is far lower than any other protocol assessed in the ACP meta-analysis.

The ACP and the AIM should withdraw its recommended guidelines with respect to CABG patients with diabetes; re-examine ALL of the evidence specific to this important patient cohort; and revise its guidelines appropriately and with haste... lest more patients die or become injured as a result of this misguided guideline becoming widely adopted in the wrong patient population.

Anthony P. Furnary, MD Senior Cardiothoracic Surgeon Starr-Wood Cardiac Group Director, Portland Diabetes Project Portland, OR

References

1. Qaseem A, Humphrey LL, Chou r,SnowV, Shekelle P for the Clinical Guidelines Committee of the American College of Physicians : Use of Intensive Insulin Therapy for the Management of Glycemic Control in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2011;154:260-267.

2. Kirdemir P, Yildirim V, Kiris I, Gulmen S, Kuralay E, Ibrisim E, et al. Does continuous insulin therapy reduce postoperative supraventricular tachycardia incidence after coronary artery bypass operations in diabetic patients? J Cardiothorac Vasc Anesth. 2008;22:383- 7. [PMID: 18503925]

3. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359-67. [PMID: 11794168]

4. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg Feb 1999; 67:352-362.

5. Furnary AP, Gao G, Grunkemeier GL, Wu YX, Zerr KJ, Bookin SO, Floten HS, Starr A. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. May 2003; 125(5):1007-21.

6. Vanhorebeek I; Ingels C; Van den Berghe G. ?Intensive insulin therapy in high-risk cardiac surgery patients: evidence from the Leuven randomized study. Seminars in thoracic and cardiovascular surgery 2006;18(4):309-16.

7. Furnary A, Wu YX. 2011 Arnold O Beckman Conference: Glycemic Control in the Hospital: Evidence, Issues and Future Directions -- The Portland Studies. Upcoming presentation San Diego, CA 4/12/2011.

Conflict of Interest:

None declared

Excellent guideline but requires little modifications
Posted on March 5, 2011
Gauranga C. Dhar
Bangladesh Institute of Family Medicine And Research, USTC
Conflict of Interest: None Declared

I like to draw our attention to a brief discussion on the pathophysiology and consequences of hypoglycemia and role of a physician towards the prevention of such a dreadful endocrine emergency. There are two basic causes of mortality in case of hypoglycemia. 1.Cardiac death 2.Brain death. In case of blood glucose when goes 3.9mmol/L or below, body's defense mechanism; sympathetic, adrenal and combined sympatho-adrenal effects become activated targeting to restore blood glucose back to normal through glycogenolysis and gluconeogenesis. In the individuals with comparatively intact vasculature (without endothelial dysfunction); persons without diabetes, or in persons with diabetes at young age and without any comorbid illness, such compensatory responses go unnoticed without any detectable symptoms of hypoglycemia or adverse outcomes. In patients with long standing diabetes, hyperglycemia is associated with high level of advanced glycosylated end products (AGEs) e.g. HbA1C and production of increased level of reactive oxygen species (ROS), which along with high level of proinflammatory cytokines (TNF-alpha, IL-6, PAI-1, angiotensinogen, hs-CRP, homocysteine etc.) lead to decrease of endothelial nitric oxide synthase (eNOS) through replacement of L-arginine by asymmetric dimethylarginine (ADMA) with ultimate deficiency of NO. On the other hand, high level of ROS lead to the production of high level of ox-LDL-P which are readily engulfed by macrophages at the subendothelial layer leading to expedite atherosclerosis. In addition to these, hyperglycemia is also associated with renin-angiotensin-aldosterone-system (RAAS) activation. All these factors cause endothelial dysfunction. Longer duration of hyperglycemia associated with higher rate of endothelial dysfunction. Patients with severely affected endothelium can not cope with both adrenergic and cholinergic activation [1] resulting adverse cardiovascular outcomes; myocardial infarction, ischemic stroke, severe ventricular tachycardia and death. Such activation may take place during any sudden drop of blood glucose from any baseline level e.g. relative hypoglycemia. Gradual loss of effective epinephrine counter regulatory mechanism in patients with long standing diabetes [2] may lead to neuroglycopenia and brain death without any apparent adrenergic or cholinergic symptoms. Diabetes patients under beta-blocker may also found to have diminished sympatho-adrenal activation resulting hypoglycemia unawareness leading to neuroglycopenia [3]. Recently published 5-years result of ACCORD trial showed that intensive glycemic control reduced 5-year nonfatal MI but increased 5-year mortality where author recommends not going for stringent glycemic control in patients with advanced type 2 diabetes [4]. Gerstein in this result noted that persons having lower HbA1C and less hyperglycemic at baseline appeared to have greater benefit from intensive glycemic control in terms of cardiovascular outcomes. Increased mortality was found in intensive arm, only in whom, whose on-treatment baseline A1C was higher. Previously, Matthew C. Riddle MD, Professor of Medicine at Oregon Health and Science University told in his article [5] that rapid reduction of blood glucose not resulted in increased mortality who maintained A1C around 6% but rate of mortality increased linearly with increase of A1C from 6% to 9% at baseline. From basic to practice. Here is a big lesson for physician. We should not forget about the baseline A1C during IIT, if required, in patients in ICU presenting with hyperglycemia. According to my opinion recent 3-part clinical practice guideline from ACP about the IIT in hospitalized patients is a very good recommendation but some modifications are required. 1.Same glycemic target should not be applied to all patients. Glycemic target should be individualized. 2.Such target should depend upon baseline HbA1C, age, duration of hyperglycemia, presence of any comorbid illness specifically cardiovascular and concomitant medication if any.

References:

1.Diabetes. 2011 Feb;60(2):602-6.

2.Diabetes.Technol.Ther.2011 Jan;13(1):11-7.

3.Indian Heart J. 2010 Mar-Apr;62:101-10

4.The ACCORD Study Group. N Engl J Med 2011; 364:818-828 March 3, 2011.

5.Riddle MC. Diabetes Care. 2010;33:983-990.

Conflict of Interest:

None

Re:Comment on the ACP Guidelines for the Management of Glycemic Control in Hospitalized Patients
Posted on March 25, 2011
Romesh Khardori
Southern Illinois University School of Medicine, Springfield, Illinois
Conflict of Interest: None Declared

ACP guidelines are timely since there is no replicable convincing evidence that intensified insulin therapy in ICU's or outside the ICU setting reduce mortality and morbidity in magnitudes reported earlier. There is a compelling need to get away from the exclusive glucocentric view. There may indeed be subsets of patients such as those post CABG where intensified glucose control offers distinct advantage. Understanding of pathobiology of diabetes is still far from complete, and it should be no surprise that we still may not have good handle on how to manage it in all different situations. Till there is conclusive irrevocable evidence we should not stray from our primary charge - First do no harm.

Romesh Khardori, MD.,PhD

Conflict of Interest:

None declared

Author Response
Posted on April 14, 2011
Amir Qaseem
ACP
Conflict of Interest: None Declared

We thank Drs. Bentson, Furnary, Garg, and Korytkowski for their comments regarding the American College of Physicians' recent clinical guideline on inpatient glycemic control [1].

Dr. Bentson assumes that our guideline should not be interpreted as meaning that patients on oral diets should not get insulin if a pre- prandial glucose is less than 200 mg/dl. He is correct. While this population of hospitalized patients has not been specifically studied in terms of target thresholds, our guideline was about the use of intensive insulin therapy to keep blood sugars below a low threshold, such as 110 mg/dl, primarily in very ill hospitalized patients on parenteral nutrition. It should not be interpreted as meaning that diabetic patients on insulin should not use their normal dosing of insulin while in the hospital, for example, the use of pre-meal insulin as part based on the pre-prandial measurement of blood glucose.

We agree with Dr. Furnary that the evidence base for CABG patients is relatively limited. However, the evidence that is available in cardiac surgery patients specifically and operative patients more broadly does not convincingly show consistent evidence of benefit from the use of IIT to achieve very strict glucose targets, while there is some evidence of harm. The van den Berghe SICU study did indeed find that IIT was associated with both lower mortality and rate of septicemia, but IIT was not associated with lower rates of septicemia in the subgroup of cardiac surgery patients to which Dr. Furnary refers, and surgical wound infection rates were not reported [2, 3]. The potential reasons for discrepancies between the van den Berghe SICU study and subsequent studies are described in the evidence report [4]. Kirdemir et al reported a dramatic 92% reduction in the risk of sternal wound infection associated with IIT use which seems disproportionate to the very modest reductions in average blood glucose in the intervention group (172 vs 195 mg/dL). Of note, this study's quality was limited by important baseline differences between groups and unclear blinding of outcome assessors. An additional poor-quality study examining two groups of CABG patients found no infection risk reduction from perioperative IIT [5]. On the other hand, a prespecified subgroup analysis of operative patients in the NICE-SUGAR trial found significantly higher mortality associated with IIT titrated to very strict glucose targets (RR 1.31; 95% CI 1.07 - 1.61) [6]. The Portland Protocol is an observational study and was therefore not included in the analysis of health outcome data. We agree, however, that its ability to achieve low rates of hypoglycemia - at least in the selected patients tolerating the protocol for three or more days - highlights significant lessons about the importance of gradual implementation and nursing buy-in, but it may also reflect selective reporting of patients least likely to be harmed [7]. Factors such as protocol, hospital, and implementation characteristics probably contribute to the safety of IIT use and these issues are summarized in the evidence report appendix and discussed in the guideline [1, 4].

As far as Dr. Garg's comments are concerned, our guideline does not mean that insulin should not be used to control blood sugar, rather insulin should not be used to try and achieve "tight control" as defined in the RCTs that have assessed this, usually meaning glucose consistently under 110mg/dL. These RCTs have generally found few, if any, benefits for tight control yet certainly an increase in the risk of hypoglycemic events.

Dr. Korytkowski raises the question about the discrepancy between various guidelines regarding the upper limit of the blood glucose level. This discrepancy probably exists because there are no data from trials that unequivocally establish the threshold above which the benefits from glucose control exceed the harms. ACP based its choice on the glucose values attempted or achieved in the "control" groups in the studies of intensive insulin infusions, most of which failed to show appreciable benefits for the intervention [4]. We concluded that there was no evidence to support attempting to achieve better glucose levels than that achieved in the "control" groups of these studies (blood glucose target levels ranged from 140 to 200mg/dL). The very recently published RABBIT 2 trial referenced by Dr. Korytkowski was not designed to assess the relative benefits of a strict vs. less strict glucose target as glucose targets were the same in both groups. However, the group randomized to the basal-bolus strategy did achieve lower mean blood glucose and appeared to have a lower incidence of wound infections at the expense of a higher risk of hypoglycemia.

Current Addresses of Authors:

Devan Kansagara, MD, MCR Veterans Affairs Medical Center 3710 SW U.S. Veterans Hospital Road, Mailcode R&D 71, Portland, OR 97239

Paul Shekelle, MD, PhD Greater Los Angeles VA Health Center/RAND 1776 Main Street, Santa Monica, CA 90401

Amir Qaseem, MD, PhD, MHA American College of Physicians 190 N. Independence Mall West, Philadelphia, PA 19106

References

1. Qaseem, A., et al., Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 154(4): p. 260-7.

2. van den Berghe, G., et al., Intensive insulin therapy in the critically ill patients. New England Journal of Medicine, 2001. 345: p. 1359-1367.

3. Vanhorebeek I, Ingels C, and Van den Berghe G, Intensive insulin therapy in high-risk cardiac surgery patients: evidence from the Leuven randomized study. Seminars in thoracic and cardiovascular surgery, 2006. 18(4): p. 309-16.

4. Kansagara, D., et al., Intensive insulin therapy in hospitalized patients: a systematic review. Ann Intern Med. 154(4): p. 268-82.

5. Smith, A., et al., Coronary revascularization: a procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study. Journal of Cardiothoracic & Vascular Anesthesia, 2002. 16: p. 413-420.

6. Nice-Sugar Study, et al., Intensive versus conventional glucose control in critically ill patients. New England Journal of Medicine, 2009. 360: p. 1283-1297.

7. Furnary AP, Wu Y, and Bookin SO, Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocrine Practice, 2004. 10 Suppl 2(21- 33).

Conflict of Interest:

None declared

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