Evidence-based Synthesis Program 

Management of Inpatient 

Hyperglycemia: A Systematic 

Review

Department of Veterans Affairs

Health Services Research & Development Service

October 2008

Investigators:

Devan Kansagara, MD

Principal Investigator

Fawn Wolf, MD

Investigator

Michele Freeman, MPH

Research Associate

Mark Helfand, MD, MPH

Director

Prepared for: 

Department of Veterans Affairs

Veterans Health Administration

Health Services Research & Development Service

Washington, DC 20420 

Prepared by:

Portland Veterans Affairs Healthcare System

Oregon Evidence-based Practice Center

Portland, OR
EXECUTIVE SUMMARY 

BACKGROUND 

Hyperglycemia is a common finding in hospitalized patients and has been associated with 

worsened outcomes in a variety of inpatient subpopulations. The use of insulin to control 

blood glucose has been advocated as a way to improve health outcomes in hospitalized 

patients with hyperglycemia, but the evidence for the efficacy of this approach and the 

thresholds for initiating insulin management are unclear. 

The key questions were: 

1. Does strict blood glucose control compared to less strict blood glucose control 

improve final health outcomes in the following patients? 

 patients in the medical intensive care unit 

 patients in the surgical intensive care unit 

 acute myocardial infarction patients 

 acute stroke patients 

 post coronary artery bypass graft patients 

 general surgical ward patients 

 general medicine ward patients 

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

3. What are the most effective and safest means of normalizing blood glucose in the 

above subpopulations? 

METHODS 

We conducted searches in Medline and the Cochrane database of systematic reviews of 

literature published from 1950 through May 2008, and obtained additional articles from 

systematic reviews, reference lists of pertinent studies, reviews, editorials, and by 

consulting experts. We also searched for information about unpublished studies on 

clinicaltrials.gov and included these studies if the authors provided enough detail to 

enable quality rating. Reviewers trained in the critical analysis of literature assessed for 

relevance the abstracts of citations identified from literatures searches. Full-text articles 

of potentially relevant abstracts were retrieved for further review. We assessed the 

overall quality of evidence for outcomes by considering the consistency, coherence, and 

applicability of a body of evidence, as well as the internal validity of individual studies, 

using a method developed by the Grade Working Group.(1) We performed a metaanalysis of trials conducted in critical care settings to estimate the effects of achieving 

normoglycemia using intensive insulin therapy on short-term mortality and risk of 

hypoglycemia. 

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RESULTS

We reviewed 2313 titles and abstracts from the electronic search, an additional 44 from 

reference mining and recently published studies, and also 9 unpublished studies. We 

retrieved 356 full-text articles for further review. We included 26 RCTs and 3 systematic 

reviews in synthesizing evidence for key question 1. For key question 2, we evaluated 

the results of 23 RCTs, 2 systematic reviews, and 10 studies that were either 

observational studies or trials without health outcomes. To address key question 3, we 

included 3 systematic reviews and 2 RCTs, as well as the 10 observational studies and 

trials without health outcomes. 

KEY QUESTION #1. Does strict glycemic control compared to less strict 

glycemic control improve final health outcomes in the following patients? 

Very little intervention data is available to help clearly define a glucose threshold that 

should prompt glucose lowering efforts in various inpatient subpopulations. The benefits 

of achieving normoglycemia with aggressive insulin use are inconsistent and may be 

limited to subgroups of critically ill patients receiving aggressive nutrition and in whom 

reliable glucose monitoring methods are used. Use of insulin to achieve normoglycemia 

is associated with a considerable risk of hypoglycemia. Higher glucose targets can likely 

be relatively safely achieved in inpatients, though the impact of this practice on health 

outcomes is uncertain. 

Patients in Medical and Surgical Intensive Care Units 

 

We found eight unblinded randomized, controlled trials examining the efficacy of tight 

glycemic control using intensive insulin regimens in critically ill patients, including two 

in the medical ICU (MICU) setting, two in the surgical ICU (SICU) setting, and four in 

mixed MICU/SICU settings. Single-center evidence had initially shown a mortality and 

morbidity benefit from IIT in subgroups of patients requiring prolonged ICU stays, but 

the applicability of these data to other ICUs may be limited and subsequent trials have 

not confirmed this benefit. Our meta-analysis found the use of intensive insulin therapy 

to achieve normoglycemia had a neutral effect on short-term mortality, but increased the 

risk of hypoglycemia more than five-fold. (GRADE: Moderate = further research is 

likely to have an important impact on our confidence in the estimate of effect and may 

change the estimate.) 

Acute Myocardial Infarction Patients 

We found good evidence that insulin used as part of a fixed-dose glucose-insulinpotassium infusion does not consistently improve final health outcomes in acute 

myocardial infarction patients, and may increase short-term mortality. (GRADE: High = 

Further research is unlikely to change our confidence on the estimate of effect.) 

Six trials have examined tight glycemic control using adjustable dose insulin-based 

regimens. As a body of evidence, these studies fail to demonstrate consistent evidence 

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of the benefits of adjustable dose insulin-based regimens in acute myocardial infarction 

patients, but variation in trial design, achievement of recruitment goals, glucose level 

achieved, and concomitant therapy for myocardial infarction limit the strength of this 

conclusion. (GRADE: Low = Further research is very likely to have an important impact 

on our confidence in the estimate of effect and may change the estimate.) 

Acute Stroke Patients 

The largest trial to date in stroke patients reported largely negative results, but was 

hampered by low participation rates and incomplete data reporting. A second much 

smaller fair-quality trial in patients with subarachnoid hemorrhage failed to find a longterm clinical benefit from tight glycemic control, but did find a reduced infection rate in 

the short-term. Thus there is very little good-quality evidence investigating tight 

glycemic control in patients who have suffered a cerebrovascular accident. (GRADE: 

Low = Further research is very likely to have an important impact on our confidence in 

the estimate of effect and may change the estimate.) 

Post Coronary Artery Bypass Graft Patients and General Surgical Ward 

Patients 

We found five trials which varied widely in design, blood glucose levels attained, and in 

the inclusion of patients with diabetes, limiting the comparability of results across 

studies. Several studies were underpowered to evaluate the outcomes of interest in this 

review. Neither insulin infusion nor GIK infusion given perioperatively provided a clear 

benefit among cardiac surgery patients in any of the studies. One good-quality metaanalysis reviewed a diverse group of GIK and insulin infusion studies in peri- and 

postoperative settings and found largely negative results when the largest trial (reviewed 

under the ICU section above) was excluded. 

Overall, there is no clear evidence showing a benefit of tight glycemic control strategies 

in the perioperative setting, but the trial evidence is methodologically limited. (GRADE: 

low = Further research is likely to have an important impact on our confidence in the 

estimate of effect and is likely to change the estimate.) 

General Medicine Ward Patients

There were no studies evaluating a tight glycemic control strategy to less tight glycemic 

control in general medical ward patients. Thus, the overall level of evidence in this 

subpopulation is very low (GRADE: Very Low = Any estimate of effect is very 

uncertain.) 

KEY QUESTION #2. What are the harms of strict blood glucose control in 

the above subpopulations? 

There is a considerable risk of hypoglycemia in medical ICU patients treated with 

intensive insulin protocols designed to normalize blood glucose. This risk was lower in 

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surgical ICU patients receiving similar therapy, and in myocardial infarction, stroke, and 

perioperative patients in whom the target glucose level was generally not aimed at strict 

normoglycemia. Data from numerous mainly single-center observational studies and 

trials not examining health outcomes suggest the incidence of hypoglycemia may be 

considerably lower when less strict glucose targets are used. There was very little 

evidence that hypoglycemia from tight glycemic control protocols resulted in short-term 

adverse health outcomes, but the long-term effects of inpatient hypoglycemia have not 

been well studied. 

KEY QUESTION #3. What are the most effective and safest means of 

normalizing blood glucose in the above subpopulations?

A number of insulin infusion protocols (IIPs) have been evaluated, but comparative 

effectiveness data are lacking. The protocols 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 rates, 

the methods used to assess effectiveness and the methods of glucose monitoring. Given 

this variety of factors, reviewers have suggested each institution should individualize its 

approach to protocol implementation based on its patient population as well as its 

institutional and provider resources. Based on comparisons across studies, some 

reviewers speculate better protocols incorporate bolus insulin doses, account for the 

direction and rate of glucose change, and make allowances for “off-protocol” 

adjustments, although this conclusion is not based on direct comparisons of protocols. 

Basal bolus subcutaneous insulin regimens may be more effective in lowering blood 

glucose than sliding scale regimens, though there is very limited evidence comparing 

methods of blood glucose control in ward patients. 

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