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
PREFACE 

VA’s Health Services Research and Development Service (HSR&D) works to improve 

the cost, quality, and outcomes of health care for our nation’s veterans. Collaborating 

with VA leaders, managers, and policy makers, HSR&D focuses on important health care 

topics that are likely to have significant impact on quality improvement efforts. One 

significant collaborative effort is HSR&D’s Evidence-based Synthesis Program (ESP). 

Through this program, HSR&D provides timely and accurate evidence syntheses on 

targeted health care topics. These products will be disseminated broadly throughout VA 

and will: inform VA clinical policy, develop clinical practice guidelines, set directions for 

future research to address gaps in knowledge, identify the evidence to support VA 

performance measures, and rationalize drug formulary decisions. 

HSR&D provided funding for the two Evidence Based Practice Centers (EPCs) 

supported by the Agency for Healthcare Research and Quality (AHRQ) that also had an 

active and publicly acknowledged VA affiliation – Southern California EPC and 

Portland, OR EPC – so they could develop evidence syntheses on requested topics for 

dissemination to VA policymakers. A planning committee with representation from 

HSR&D, Patient Care Services, Office of Quality and Performance, and the VISN 

Clinical Management Officers, has been established to identify priority topics and to 

insure the quality of final reports. 

Comments on this evidence report are welcome and can be sent to Susan Schiffner, ESP 

Program Manager, at Susan.Schiffner@va.gov. 

ii 
TABLE OF CONTENTS 

BACKGROUND .....................................................................................................1 

 

METHODS

 Topic Development ..........................................................................................2 

 Search Strategy ...............................................................................................4 

 Study Selection ..............................................................................................4 

 Data Abstraction .....................................................................................................5 

 Rating the Body of Evidence ...............................................................................5 

 Data Synthesis ................................................................................................6 

 Peer Review ...................................................................................................6 

RESULTS

 Literature Flow ...............................................................................................6 

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

 control improve final health outcomes in the following patients? 

 Patients in Medical and Surgical Intensive Care Units .....................................................8 

 Acute Myocardial Infarction Patients .............................................................................14 

 Acute Stroke Patients ....................................................................................................16 

 Perioperative Patients ....................................................................................................19 

 General Medicine Ward Patients .....................................................................................23 

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

 subpopulations? ......................................................................................................................25 

 KEY QUESTION 3: What are the most effective and safest means of lowering blood 

 glucose in the above subpopulations? ....................................................................................32 

SUMMARY AND DISCUSSION .........................................................................................................34 

 Limitations .............................................................................................................................36 

 Future Research Recommendations .......................................................................................36 

CONCLUSIONS ...............................................................................................................................37 

REFERENCES ....................................................................................................41 

IN-TEXT TABLES AND FIGURES

 Figure 1. Analytic framework ..................................................................................................3 

 Figure 2. Management of inpatient hyperglycemia literature flow ..........................................7 

Figure 3. Individual and combined estimates of mortality in MICU/SICU studies 

 comparing intensive insulin with conventional therapy ........................................................11 

 Table 1. Trials in patients in medical and surgical intensive care units .................................12 

 Table 2. Trials in patients with acute MI or stroke ................................................................17 

 Table 3. Trials in patients undergoing cardiac surgery ..........................................................21 

 Figure 4. Individual and combined estimates of hypoglycemia in MICU/SICU 

 studies comparing intensive insulin with conventional therapy .............................................25 

 Table 4. Frequency of hypoglycemia in randomized controlled trials ..................................27 

 Table 5. Frequency of hypoglycemia in observational studies and trials not reporting 

 health outcomes .....................................................................................................................30 

 Table 6. Summary of Systematic Evidence Review, Key Question 1 ..................................38 

 Table 7. Summary of Systematic Evidence Review, Key Questions 2 and 3 .......................40 

vii 
viii 

APPENDIX A. Search strategy 

APPENDIX B. Inclusion/exclusion criteria 

APPENDIX C. Quality rating criteria 

APPENDIX D. Reviewer comments and responses 

APPENDIX E. Table of Quality Ratings 
BACKGROUND 

Hyperglycemia is a common finding among medical and surgical inpatients with and 

without known diabetes,(2, 3) and is associated with poor outcomes across a variety of 

inpatient subpopulations.(2, 4-8) The relationship between hyperglycemia and inpatient 

outcomes may be weaker in patients with diabetes than in patients without diabetes.(9, 

10) 

Hyperglycemia may be a marker of severe, acute illness, one of many physiological 

derangements associated with an abundance of counter-regulatory hormones, insulin 

resistance, and suppression of anabolic pathways.(11) On the other hand, many 

investigators believe that hyperglycemia itself may worsen outcomes by contributing to 

inflammation, oxidative stress, poor immune function, and endothelial dysfunction.(12) 

Interventions to control hyperglycemia in inpatients have largely centered on the use of 

adjustable insulin infusions to lower blood glucose. An early trial in myocardial 

infarction patients found that lowering blood glucose using intensive insulin therapy (IIT) 

reduced long-term mortality, though it remains unclear whether the inpatient or outpatient 

components of the intervention were responsible for the benefit.(13) An influential 

single-center observational study of cardiac surgery patients reported reduced wound 

infection and mortality rates after the introduction of an intensive care unit IIT 

protocol.(14, 15) Subsequently a single-center trial in critically ill surgical patients 

suggested a mortality benefit from IIT used to achieve normoglycemia.(16) 

These findings have fueled widespread interest in inpatient glycemic control 

strategies,(17, 18) and organizations have called for strict glycemic control strategies to 

be implemented in a variety of intensive care unit settings.(12, 19) More recently, new 

trials have been completed that may help clarify the balance of benefits and harms of 

widespread IIT implementation in intensive care units. We conducted a systematic 

review of trials and a critical appraisal of frequently cited observational studies to 

identify strengths of—and gaps in—the evidence supporting broad use of IIT to achieve 

glycemic control in inpatients. 

1 
2 

METHODS 

Topic Development 

The review was commissioned by the Department of Veterans Affairs’ Evidence-based 

Synthesis Program. We conferred with VA and non-VA experts to select the patients and 

subgroups, interventions, outcomes, and setting addressed in the review. 

The objectives of this review are to address the following questions: 

1. Does the use of intensive insulin therapy (IIT) to achieve tight glycemic control 

compared to less tight glycemic control improve final health outcomes in the following 

patients? 

 patients in the surgical intensive care unit 

 patients in the medical intensive care unit 

 patients in the perioperative setting 

 acute myocardial infarction patients 

 acute stroke patients 

 general surgical ward patients 

 general medicine ward patients 

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

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

subpopulations? 

Figure 1 illustrates the analytic framework that guided our review and synthesis.
Figure 1. Analytic Framework 

Intermediate outcomes: 

- glucose level - length of stay - renal failure (not 

requiring HD) 

Final 

- - - - - - - 

Treatment interventions: 

- strict glucose 

control: 

o insulin

Hyperglycemic inpatients – Subpopulations of interest: 

- MICU 

o AMI o other 

- SICU 

o CABG o other 

- General medicine - General surgery - CVA 

Harms of 

treatment 
Search Strategy 

We conducted a search in Medline and the Cochrane database of systematic reviews of 

literature published from 1950 through May 2008. Appendix A provides the search 

strategy in detail. We 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. All citations were imported 

into an electronic database (EndNote X1). 

Study Selection 

Three reviewers assessed for relevance the abstracts of citations identified from 

literatures searches. Full-text articles of potentially relevant abstracts were retrieved for 

further review. Each article retrieved was reviewed using the eligibility criteria shown in 

Appendix B. 

Eligible articles had English-language abstracts and provided primary data relevant to the 

key questions. Eligibility criteria varied depending on the question of interest, as 

described below. 

To evaluate the efficacy of intensive insulin therapy (IIT) in hospitalized patients, we 

considered prospective, controlled clinical trials of insulin-based protocols targeted to 

strict glycemic targets compared to those targeted to less strict glycemic targets. We also 

considered clinical trials of fixed-dose insulin-based treatment regimens in myocardial 

infarction patients. The studies had to report at least one prespecified final health 

outcome (Appendix B). Unpublished studies were included if the authors could provide 

enough information about the methodology and results to fully evaluate the study’s 

quality. We excluded insulin-based studies conducted in myocardial infarction patients 

prior to widespread availability of thrombolytics (i.e., enrolling patients prior to 

1990).(20) We categorized perioperative trials as those in which IIT was begun pre-, 

intra-, or immediately post-operatively, and was continued for less than 24 hours postoperatively. We considered patients in neurologic, neurosurgical, and coronary intensive 

care units separately from patients in general medical and surgical ICUs. Though 

observational studies using historic control groups were initially excluded from our 

review, after consultation with experts we decided to include a discussion and critique of 

frequently cited observational studies. 

To assess the risk of hypoglycemia associated with IIT, we included controlled trials and 

uncontrolled series that reported rates of hypoglycemia in ICU patients treated with IIT, 

even if they did not report health outcomes. In order to avoid studies with substantial 

selection bias, we included only interventional prospective cohort studies in which 

patients were consecutively enrolled and in which there was minimal loss to follow-up. 

Because tight glycemic control strategies require some personnel training and 

institutional acceptance, we included only studies in which the intervention was evaluated 

over a prolonged period of time (defined as 6 months for the purposes of this review) as 

we felt these studies were most likely to provide externally valid results. 

4 
To assess the effectiveness of specific inpatient blood glucose control strategies in 

lowering blood glucose, we evaluated fair to good quality systematic reviews of insulin 

infusion protocols. Because of the relative dearth of information guiding insulin 

management in general medical or surgical ward patients, we also included primary data 

from controlled clinical trials evaluating subcutaneous insulin management strategies in 

general medical or surgical ward patients (e.g., those that compared sliding scale insulin 

to scheduled insulin). 

Data abstraction 

From each study we abstracted the following: study design, objectives, setting, 

population characteristics (including sex, age, baseline morbidity), subject eligibility and 

exclusion criteria, number of subjects, years of enrollment, duration of follow-up, the 

study and comparator interventions, the method used to monitor blood glucose, the target 

range for blood glucose control, the outcomes measured, the analytic method used, the 

variables adjusted in the analysis, the results of the study and the mean blood glucose 

achieved in each group, information on concomitant therapy/nutrition, the occurrence of 

hypoglycemia in each group, and any other adverse events. 

Rating the body of evidence 

We assessed the overall quality of evidence for outcomes using a method developed by 

the Grade Working Group.(1) The Grade method considers the consistency, coherence, 

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

studies to classify the grade of evidence across outcomes as follows: 

High = Further research is very unlikely to change our confidence on the estimate of 

effect. 

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

the estimate of effect and may change the estimate. 

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

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

Very Low = Any estimate of effect is very uncertain. 

The quality of each study was rated as good, fair, or poor based on the following criteria: 

the comparability of treatment groups; the adequacy of randomization; whether treatment 

allocation was concealed; whether eligibility criteria were specified; the use of blinding 

among patients, care providers, and outcome assessors; whether the analysis was 

intention-to-treat, or conducted with post-randomization exclusions, or with extensive or 

differential loss to follow-up; clearly defined interventions and reliable outcome 

measurement (Appendix C).(21) When reviewers disagreed, consensus was reached 

through discussion with all authors. 

5 
Data synthesis 

Because all ICU trials except one (22) were either small (n < 100) (23-25) or did not 

reach recruitment goals (16, 26-29), we performed a meta-analysis of trials conducted in 

critical care settings to estimate with greater power the effects of achieving 

normoglycemia using IIT on short-term mortality and hypoglycemia. The clinical 

heterogeneity of insulin interventions, glucose targets, and population characteristics 

precluded quantitative analysis within the perioperative, myocardial infarction, and stroke 

subgroups. We abstracted the number of events and total subjects from each treatment 

arm, and obtained a pooled estimate of relative risk (RR) using a random effects 

model.(30) Trials reporting hospital or 28-day mortality were included in the short-term 

mortality analysis. We performed sensitivity analyses to assess the effects of short-term 

mortality definition (i.e. hospital or 28 day mortality), as well as the effects of excluding 

trials using higher intervention glucose targets. 

2 Statistical heterogeneity was assessed by Cochran’s Q test and I statistic.(31) Because 

of the small number of trials that could be combined, we did not perform assessments for 

publication bias.(32) All analyses were performed using Stata 10.0 (StataCorp, College 

Station, TX, 2007). 

Peer review 

A draft version of this report was sent to the technical advisory panel and additional peer 

reviewers. Their comments and our responses are shown in Appendix D. 

RESULTS 

Literature Flow 

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

additional 44 from reference mining and recently published studies. We also identified 9 

unpublished or ongoing studies.(26-28, 33-38) Three of these studies have been 

completed and the authors provided enough information for us to quality rate and 

formally include the studies.(26-28) 

After applying inclusion/exclusion criteria at the abstract level, 356 full-text articles were 

reviewed, as shown in Figure 2. Of the full-text articles, we rejected 288 that did not 

meet our inclusion criteria. 

6 
Figure 2. Management of Inpatient Hyperglycemia Literature Flow 

Abstracts imported from MEDLINE

(1950‐May 2008)

N = 2313

Reference mining and recently

published studies Unpublished or ongoing studies

N = 9 N = 44

Total number of citations identified for review

N = 2366

Total number of articles retrieved

N = 356

1 SR

Total excluded articles = 288

KQ1 MI/Stroke

N=13

Study design or article type out of scope = 125 KQ1 MICU/SICU Non‐systematic or poor‐quality systematic

review = 67 N=9 8 RCTs

Study outcome not within scope = 30

Duplicate data = 25

GIK study pre‐thrombolytic era = 16

Intervention not within scope = 17 1 SR

Topic not within scope = 7

Study population not within scope = 1

12 RCTs

KQ3 Hyperglycemia

management protocols KQ1

Perioperative

1 SR

N=15

N=6

5 RCTs

2 RCTs 3 SRs

KQ2 Hypoglycemia

N=35

2 SRs

23 RCTs

10 observational

studies & trials without

health outcomes

10 observational

studies & trials without

health outcomes

Note:  Some studies

applied to multiple KQs

7 
KEY QUESTION #1. Does strict glycemic control compared to 

less strict glycemic control improve final health outcomes in the 

following patients? 

Patients in Medical and Surgical Intensive Care Units 

Eight unblinded randomized, controlled trials evaluated tight glycemic control using 

intensive insulin therapy (IIT) in critically ill patients (Table 1).(16, 22-24, 26-29) Two 

trials included critically ill surgical patients (SICU)(16, 24), two trials included critically 

ill medical patients (MICU),(22, 23) and four trials included a mixed SICU/MICU 

population.(26-29) All of the trials except for one(23) investigated the relative benefits 

of glucose targets in the normoglycemic range (80 – 110 mg/dL) compared to moderate 

glucose targets (140 – 200 mg/dL). Our combined analysis of all seven ICU studies(16, 

22, 24, 26-29) evaluating the use of intensive insulin therapy to achieve normoglycemia 

found the intervention had a neutral effect on short-term mortality (RR 0.90; 95% CI 0.78 

– 1.03, I

2 40.7%; Figure 3), and substantially increased the risk of hypoglycemia (RR 

5.32; 95% CI 4.21 – 6.73, I2 2.28%; Figure 4).(GRADE: Moderate = further research is 

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

change the estimate). 

SICU

In one influential trial, Van den Berghe et al randomized 1548 SICU patients to either a 

simple IIT protocol (Leuven protocol) targeted to normal blood glucose (80 – 110 mg/dL 

by morning blood glucose), or conventional therapy designed to keep blood glucose 180 

– 200 mg/dL. This study was terminated early after finding all-cause ICU mortality was 

significantly lower in the intensive insulin group (4.6% v. 8%, relative risk 0.58, 95% CI 

0.38-0.78)(Table 1).(16) The short-term mortality benefit was limited to the subgroup of 

patients requiring 5 or more days of ICU care (10.6 vs 20.2%, p = 0.005), and long-term 

mortality did not differ between the two groups.(39) The intervention group experienced 

a higher cumulative incidence of hypoglycemia (5% v. 0.76%; RR 6.65, 95 % CI 2.83 – 

15.62). 

This trial was conducted in a SICU that used intravenous glucose and TPN routinely, and 

monitored all patients with arterial blood sampling, a more accurate method than 

capillary blood sampling. These practices are not standard in most SICUs. These 

characteristics may limit the applicability of these results to nonsurgical patients, patients 

not receiving parenteral nutrition, and centers mainly relying on capillary blood 

samples.(40-42) Given the nature of the intervention and need for frequent monitoring, 

blinding of care providers was not possible in this or any of the other studies considered. 

Though outcomes assessors were blinded, it is possible that patients assigned to IIT 

received better overall management as a result of the intensive monitoring required for 

IIT. 

 

A poor quality trial conducted among 61 SICU patients found that establishing normal 

blood glucose levels (80 – 120 mg/dL) compared to a moderate glucose target (180 – 220 

8 
mg/dL) in surgical ICU patients using IIT similar to the Leuven protocol was associated 

with a 4-fold decrease in intravascular device and bloodstream infections (p<0.05), but 

not a decrease in mortality (Table 1).(24) The study had numerous methodologic flaws 

including lack of blinding of outcome assessors, poorly defined exclusion criteria, and 

failure to report numbers of patients excluded and reasons for exclusion. 

MICU 

The mortality benefits seen in Van den Berghe et al’s SICU trial have not been replicated 

in MICU populations.(16) A fair-quality trial by Van den Berghe et al included 1200 

adult patients admitted to a single medical ICU.(22) As with the other included trials, 

blinding of care providers was not feasible and could potentially have resulted in 

treatment bias. Those who were assumed to require less than three days of intensive care, 

specifically those who were able to receive oral nutrition, were excluded. The methods, 

insulin regimens and glucose targets were similar to Van den Berghe’s 2001 surgical ICU 

study, but both arterial and capillary blood samples were used in this study for glucose 

monitoring. Patients received just over 1200 kcal/day of nutritional support in both 

groups and the vast majority received most nutrition parenterally. Neither in-hospital nor 

ICU mortality was reduced in the overall intention to treat population, but in-hospital 

mortality was reduced from 52.5% to 43% (relative risk 0.82, 95% CI not given, 

p=0.009) in the prespecified subgroup of patients staying in the ICU for at least a third 

day. There was a nonsignificant mortality increase associated with intensive therapy 

(relative risk 1.09, 95% CI 0.9-1.32) amongst the 433 patients requiring less than 3 days 

of ICU care. The incidence of hypoglycemia was significantly higher in the intervention 

group (Table 4) and mortality was non-significantly higher among those who experienced 

at least one episode of hypoglycemia (66.7% v. 46.4%, p = 0.1). 

A small, poor quality trial in a single MICU examined the efficacy of targeting more 

moderate glucose goals: 110-140 mg/dl in the intensive group and 140-200 in the control 

group.(23) Neither ICU nor one month mortality were reduced, but the intervention 

group did have a reduced incidence of a combined outcome of cerebro- and 

cardiovascular events (12.2% v. 39.6%, p = 0.004). Methodologic details, including 

blinding of outcomes assessors and numbers of patients excluded, were not described. 

Mixed ICU populations 

Four recently completed trials including mixed MICU/SICU populations also 

consistently failed to demonstrate an overall mortality benefit of achieving 

normoglycemia using IIT. A recently published fair quality trial used a two-by-two 

factorial design to assess IIT as well as two different types of volume resuscitation in 

MICU patients with severe sepsis.(29) This multi-center study used the Leuven protocol 

and was stopped early because of an excess risk of severe hypoglycemia in the 

intervention group (17.0% v. 4.1%; RR 4.11, 95% CI 2.21 – 7.63), with many of the 

hypoglycemic events classified as life-threatening (Table 4). Hypoglycemia was 

independently associated with mortality (HR 3.31, 95% CI 2.23 – 4.90). There was no 

significant difference between the groups for the primary outcomes of death at 28 days 

and multi-organ failure. 

9 
Three of the trials have not yet been published, but each of the authors shared 

methodologic and outcome details complete enough to allow quality rating and inclusion 

in our quantitative and qualitative analyses.(26-28) GLUCONTROL is a recently 

completed fair quality randomized, multi-center trial that has been submitted for 

publication.(28) Using a insulin infusion protocol similar to the Leuven protocol, the IIT 

group was targeted to 80-110 mg/dl, and the comparator group was targeted to a more 

moderate range of 140-180 mg/dl. The trial was stopped after enrolling 1101 of a planned 

3500 patients because of an excess risk of hypoglycemia in the intervention group (14.5 

v. 3.9%; RR 3.64, 95% CI 2.30 – 5.75).(28) Of note, the median blood glucose 

achieved in the control group (134 mg/dL) was lower than that achieved in the control 

groups in any of the other trials, further reducing the power to detect a significant 

difference in outcome between the two groups.. The ICU mortality rate – the primary 

outcome – did not differ between the two groups, but one month mortality was 

nonsignificantly higher in the intervention group (24.5 v. 20.7%; RR 1.19, 95% CI 0.95 – 

1.48). There was no difference in patient-days on renal replacement therapy between the 

two groups (521 v. 526, p = NS). 

Another fair-quality MICU/SICU trial also found no significant difference in hospital 

mortality after adjusting for differences in baseline characteristics, notably a significantly 

smaller proportion of diabetic patients in the IIT group (Hospital mortality: 27.1% versus 

32.3%, p=0.19).(26) Hypoglycemia occurred more often in the intensive group (9.1/100 

treatment days versus 0.9/100 treatment days, p<0.0001). There was no difference 

between groups in any of the secondary outcomes, including hospital mortality, ICU or 

hospital length of stay, duration of mechanical ventilation, need for renal replacement 

therapy or PRBC transfusion. 

Finally, a poor quality trial found in-hospital mortality was similar between the two 

groups (I v. C, 32.3 v. 39.5%, p = 0.28).(27) Nearly 75% of patients admitted to the two 

ICUs were excluded, most because the length of stay was projected to be < 48 hours. 

The incidence of hypoglycemia was higher in the intensive group: 6.7% versus 0.8%, 

p=0.02 by morning whole blood glucose measures, and 41.3% v. 7.6%, p < .0001 by 

bedside glucometer measures. There were significantly more patients with liver disease 

in the control group which may have contributed to the higher hypoglycemia rates. 

Meta-analysis 

Our combined analysis of all seven ICU studies(16, 22, 24, 26-29) evaluating the use of 

intensive insulin therapy targeted to normoglycemia found the intervention had a neutral 

effect on short-term mortality (Figure 3, RR 0.90; 95% CI 0.78 – 1.03, I2 40.7%). A 

sensitivity analysis including the study that evaluated a more moderate glucose target 

(110 – 140 mg/dL compared to 140 – 200 mg/dL) produced similar short-term mortality 

results (RR 0.92; 95% CI 0.80 – 1.05, I2

 38.7%). 

10 
11 

Figure 3. Individual and combined estimates of mortality in MICU/SICU studies comparing 

intensive insulin with conventional therapy 

Study

One good-quality meta-analysis of 29 trials evaluating tight glycemic control in critically 

ill patients was just published and similarly found no hospital mortality advantage (21.6 

vs 23.3%; RR 0.93, 95% CI 0.85 – 1.03, I2 18%) or decrease in need for renal 

replacement therapy (11.2 vs 12.1%; RR 0.96, 95% CI 0.76 – 1.20, I2 25%) from IIT 

compared to usual care, but did find a reduced incidence of septicemia in the IIT group 

(10.9 vs 13.4%; RR 0.76, 95% CI 0.59 – 0.97, I2 35%).(43) The authors included studies 

from a variety of settings which we considered separately, including neurologic, 

neurosurgical, and cardiac intensive care units. They also combined trials which used 

different intervention group glucose targets: a sensitivity analysis limited to trials 

achieving normoglycemia in the intervention groups found similar results. 

In-progress trials 

Several trials investigating the efficacy of achieving normoglycemia with IIT in critically 

ill patients are in progress.(33, 36, 37) Of note, the NICE-SUGAR multi-center trial will 

be the largest to date and has randomized nearly 6000 medical and surgical ICU patients 

with results expected in early 2009.(33, 44) 

Risk ratio

.125 .25 .5 1 2

 Risk ratio (95% CI) % Weight

 Van den Berghe 2001 0.66 (0.48,0.92) 12.5

 Grey 2004 0.53 (0.17,1.69) 1.4

 Van den Berghe 2006 0.93 (0.81,1.08) 27.3

 Arabi 2008 0.84 (0.64,1.09) 16.1

 Mackenzie 2008 0.82 (0.58,1.15) 11.7

 Preiser 2008 1.20 (0.93,1.55) 16.8

 Brunkhorst 2008 0.95 (0.71,1.27) 14.3

 Overall (95% CI) 0.90 (0.78,1.03)
Table 1. Trials in patients in medical and surgical intensive care units 

Inpatient 

BG 

achieved, 

Population, 

Setting, N, 

% DM 

Glucose 

target, T v. C 

(mg/dL) 

Glucose 

monitoring 

method 

Conco

Study Mortality, T v. C (RR, 95% CI) 

therapy

T v. C 

(mg/dL) 

On adm, all 

glc; next day 

enteral, or e

no sig diff be

(16) SICU 

n=1548 

13% DM 

80-110 

v. 180-200 

Arterial blood

samples 

103 v. 153* ICU mortality 4.6 v. 8% (p=0.005 

unadjusted) 

RR 0.42 (95% CI 0.22-0.62); 

(p<0.001) 

Hospital mortality: 7.2 v. 10.9% (p = 0.01) 

RR 0.66; 95% CI 0.48 – 0.92; 85.2 % recei

calories thro

nutr

New renal replacement: 4.8 v. 8.2% (p = 

0.007) 

Sepsis: 4.2 vs 7.8% (p = 0.003) 

(24) SICU 

n=61 

15% DM 

80-120 

v. 180-220 

Not reported 125 v. 179† Hospital mortality: 11 v. 21% (p=0.50) RR 

0.53; 95% CI 0.17 – 1.69 

(p<0.001) 

Sepsis: 4 fold increased risk of 

bloodstream infections in control group, 

numbers not provided 

Mean kcal/d: 

12

(22) MICU 

n=1200 

16% DM 

80-110 

180-200 

Arterial and 

capillary 

blood 

samples 

111 v. 153* ICU mortality: 24.2 v. 26.8% (p=0.31) 

(p<0.001) Hospital mortality: 37.3 v. 40.0% (p = 

0.33) RR 0.93; 95% CI 0.81 – 1.08 

90 d mortality: 

35.9 v. 37.7% (p=0.53) 

85.2 % recei

calories thro

nutr

New renal replacement: 20.8 vs 22.7% (p 

= 0.5) 

(23) MICU, n=89 

DM: 48.8% T, 68.8% 

C (p = NS) 

110-140 

v. 140-200 

Not reported 142 v. 174† ICU mortality: 39 v. 31.3% (NS) 

28d mortality: 53.6 v. 45.8% (NS) RR 

1.17; 95% CI 0.77 – 1.78 

(p<0.001) 

Sepsis: 26.8 vs 35.4% (p = NS) 
Study 

Population, 

Setting, N, 

% DM 

Glucose 

target, T v. C 

(mg/dL) 

Glucose 

monitoring 

method 

Inpatient 

BG 

achieved, 

T v. C 

(mg/dL) 

Mortality, T v. C (RR, 95% CI) Conco

therapy

(29) Septic patients in 18 

MICUs, n=537 

30% DM 

80-110 

v. 180-200 

Arterial and 

capillary 

blood 

samples 

112 v. 151* 

(p<0.001) 

28 d mortality: 

24.7 v. 26% (p=0.74) 

RR 0.95, 95% CI 0.70-1.28 

90 day mortality: 39.7 v. 35.4% (p = 0.31) 

New renal replacement: 27.5 vs 22.5% (p 

= 0.19) 

Mean daily 

kcal/d 1236+

(28) MICU/SICU 

n=1101 

DM: 16.5% T, 21.8% 

C (p=0.031) 

80-110 

v. 140-180 

Arterial and 

capillary 

blood 

samples 

108 v. 134* 

(p=nr) 

ICU mortality: 16.7 v. 15.2% 

28-day mortality: 24.5 v. 20.7%; 

RR 1.19; 95% CI 0.95 – 1.48 

Days on renal replacement: 521 vs 526 (p 

= NS) 

Percentage oparenteral nu44 % (T), 27 +

(26) MICU/SICU 

N=523 

DM: 32.0% T, 47.9% 

C (p = 0.0002) 

80-110 

v. 180-200 

Arterial and 

capillary 

blood 

samples 

115 v. 171† 

(p<0.0001) 

ICU mortality: 13.5 v. 17.1% (p=0.70) RR 

1.09, 95% CI 0.70-1.72§ 

Hospital mortality: 27.1 v. 32.3% (p=0.19) 

RR 0.84; 95% CI 0.64 – 1.09§ 

New renal replacement: 

11.7 v. 12.1% (p=0.89)§ 

Mean daily 

kcal/d 916+/

5

>75% 

(27) MICU/SICU - two 

centers 

n=240 

14-19% DM 

72-108 

180-198 

Whole blood 

monitoring 

126 v. 151* 

113 v. 144‡ 

(p<0.0001) 

ICU mortality: 19 v. 22.7% (p=0.53) 

Hospital mortality: 32.2 v. 39.5% (p=0.28) 

RR 0.82; 95% CI 0.58 – 1.15 

* Morning blood glucose † Average of blood glucose measurements, not otherwise specified ‡ Time-weighted mean blood glucose § Adjusted for chronic liver disease, traumatic brain injury,APACHE II and INR.

ԡData from combined analysis of Van den Berghe SICU and MICU trials(45), data not reported in individual trials 

¶The full quality rating for each study is provided in Appendix E. 
Acute Myocardial Infarction Patients 

Adjustable dose insulin infusions 

Six unblinded trials have examined tight glycemic control using adjustable dose insulinbased regimens (Table 2).(13, 46-50) As a body of evidence, these studies lacked 

coherence and did not consistently demonstrate a benefit of adjustable dose insulin-based 

regimens in acute myocardial infarction patients. 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.) 

Three trials of insulin-glucose infusions in patients with acute myocardial infarction had 

conflicting findings.(13, 46, 47) The DIGAMI study was a fair quality trial,(13) in which 

intervention patients were maintained on an insulin infusion with the target plasma 

glucose 126 – 198 mg/dL for at least 24 hours and were subsequently transitioned to a 

multi-dose outpatient insulin regimen. The control group did not routinely receive 

insulin. Both groups were markedly hyperglycemic on admission (intervention mean 277 

mg/dL, control mean 282 mg/dL, p = NS), but the intervention group achieved better inhospital glucose control (172.8 mg/dL v. 210.6 mg/dL, p < .001) and maintained better 

glycemic control at one year of follow-up. The three-month mortality rate did not differ 

significantly between groups, but the intervention group had lower mortality by one year 

(18.6% v. 26.1%, RR 0.69, 95% CI 0.49 – 0.96, p = .027). It is unclear whether the 

benefit was related to the acute intervention or the longer-term insulin therapy. 

Applicability of the study results to current MI populations may be limited: only 50% of 

patients received revascularization therapy, the trial predates widespread statin use, and a 

large proportion (42 %) of eligible patients were excluded because of lack of willingness 

or ability to comply with a complex insulin regimen. 

The DIGAMI II trial was a poor quality trial designed to determine whether the mortality 

benefit seen in the earlier trial was related to use of a tight glycemic control strategy 

during the acute hospital setting or the outpatient follow-up period.(47) There were two 

intervention groups: one received an insulin-glucose infusion and was transitioned to an 

insulin-based outpatient regimen, and the other received only the insulin-glucose infusion 

with subsequent diabetes care left to the discretion of the physician. The trial was 

stopped early due to slow enrollment and the difference in blood glucose achieved at 24 

hours between groups was smaller than anticipated (163.8 v. 180 mg/dL, p < .001). 

Adjusted long-term mortality (mean follow-up 2.1 years) did not differ among the 

groups, though one analysis did suggest those treated with outpatient insulin during 

follow-up had a significantly higher risk of non-fatal myocardial infarction or stroke 

compared to those on oral glucose-lowering treatments (adjusted HR 1.71; 95% CI 1.25 – 

2.35).(51) 

A third fair quality trial investigated intensive insulin therapy given only during the acute 

post-infarct period with a moderate glucose target (72 – 180 mg/dL).(46) The difference 

14 
in blood glucose achieved during hospitalization between the two groups did not achieve 

significance (149.2 v. 162 mg/dL). There was no difference in inpatient, 3 month, or 6 

month mortality between the intervention and control groups. Though there was a 

suggestion of reduced cardiac events and CHF in the intervention group, these reductions 

were not consistent across the follow-up period. 

One small fair quality trial compared a normoglycemic to a moderate glucose target in 

survivors of ventricular fibrillation cardiac arrest.(48) Insulin infusion dosing was left to 

the discretion of the nurse without a strict protocol. The trial was stopped early after an 

interim analysis failed to provide any evidence of benefit. The authors found no 

difference in 30 day mortality, but the group randomized to a normoglycemic target did 

experience a higher incidence of moderate hypoglycemia (blood glucose < 54 mg/dL; 

18% v. 2 %, p < .0001). 

Two trials investigated the use of adjustable dose insulin as part of a glucose-insulinpotassium (GIK) infusion (Table 2).(49, 50) Van der Horst et al investigated a high-dose 

GIK infusion with a broad glucose target range in 940 patients with acute ST elevation 

myocardial infarction, approximately ten percent of whom had known diabetes.(49) 

There was no significant difference in blood glucose achieved between the two groups. 

There was no reduction in 30 day mortality in the overall group. The large prespecified 

subgroup of patients without signs of heart failure did experience a mortality benefit from 

GIK infusion (RR 0.28, 95% CI 0.1 - 0.75, ARR 3.0), but there were a large number of 

prespecified subgroups. A poor quality trial included a similar number of patients, with a 

similar proportion of diabetics, and found no difference in 30 day or one-year mortality 

rates between the two groups.(50, 52) The insulin infusion was targeted to a moderate 

glucose range, but the authors did not report blood glucose achieved or hypoglycemia 

rates in the two groups. 

Fixed dose insulin infusions 

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 (not shown in 

table).(GRADE: High = Further research is unlikely to change out confidence on the 

estimate of effect.) An analysis combining results from two large fair-quality multicenter trials included nearly 23,000 patients and found no difference at 30 days in 

mortality (HR 1.04; 95% CI, 0.96 – 1.13; p = .33), development of congestive heart 

failure (HR 0.99; 95% CI, 0.93 – 1.06; p = .82), or reinfarction (HR 0.99; 95% CI, 0.84 – 

1.17; p = .93).(53-55) Of note, in both trials the post-randomization glucose was higher 

in the GIK group, and the combined analysis showed an increase in 3 day mortality in the 

GIK group (HR 1.13; 95% CI, 1.02 - 1.26). 

Three small trials of fixed high-dose GIK infusions reported clinical outcomes. One 

study of poor quality reported found no difference in mortality at 6 months.(56) Another 

fair-quality trial found a reduction in a composite outcome of short- (10.0 vs 32.5%, RR 

0.24; 95% CI 0.09 – 0.63) and long-term (13.0 vs 40.0%, RR 0.22; 95% CI 0.09 – 0.55) 

15 
16 

cardiac events.(57) One small, poor quality study, hampered by poor reporting of followup, randomization, and allocation concealment, showed a reduction in congestive heart 

failure incidence.(58) Additionally, one fair-quality trial examined a fixed low-dose 

GIK infusion and found an excess in 35 day and 6 month mortality in the intervention 

group, with many of the excess deaths occurring within the first three days of the 

trial.(59) 

One good-quality meta-analysis included 24 studies of insulin use in acute myocardial 

infarction patients.(60) The vast majority (n = 21) of these trials examined insulin in the 

form of fixed-dose GIK infusions, and 15 of these were conducted during the prethrombolytic era (pre-1990). When all studies, regardless of the form of insulin used or 

study date, were combined, there was a non-significant reduction in mortality (RR 0.89, 

95% CI, 0.76 – 1.03). The pre-thrombolytic era studies seemed to account for most of 

this borderline benefit: when the 15 pre-thrombolytic era GIK studies were combined, 

there was a similar mortality reduction of borderline significance (RR 0.84, 95% CI, 0.71 

– 1.00) while the six post-thrombolytic era trials found a neutral effect of GIK infusion 

on mortality (RR 1.02, 95% CI, 0.75 – 1.39). Three non-GIK trials included the two 

DIGAMI trials detailed above and a third smaller trial conducted prior to widespread 

thrombolytic use.(20) The authors could not pool these results because DIGAMI II did 

not report 30 day mortality outcomes. 

Acute Stroke Patients 

There is very little fair or good-quality evidence investigating tight glycemic control in 

patients who have suffered a cerebrovascular accident (Table 2). (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.) The largest trial to date was poor 

quality and reported largely negative results.(61) The intervention group’s glycemic 

target was very strict (72 – 126 mg/dL) while the control group only received insulin if 

blood glucose ranged above 300 mg/dL. The intervention group did achieve a lower 24 

hour mean blood glucose (mean glucose difference 10.3 mg/dL; 95% CI 4.9 - 15.5), 

though this data was only available in half the population. The intervention did not 

reduce mortality or severe disability at 90 days. The trial was stopped early because of 

low participation rates. 

A second much smaller fair-quality trial in patients with subarachnoid hemorrhage failed 

to find a long-term clinical benefit from tight glycemic control, but did find a reduced 

infection rate in the short-term (27% v. 42%, p < .001).(62) A small poor quality study 

included a subgroup of acute brain injury patients from a larger ICU trial.(63) 

Intervention patients received an insulin infusion but failed to achieve normoglycemic 

targets, and control patients received little insulin but received low glucose enteral feeds 

and intravenous fluids. There was no difference in ICU mortality or rates of neurologic 

recovery.
Table 2. Trials in patients with acute MI or stroke 

Inpatient blood 

glucose achieved 

mean (SD), T v. C 

(mg/dL) 

Population 

n 

% DM 

Glucose 

target, T v. 

C (mg/dL) 

Glucose 

monitoring 

method 

Mortality, T v. C (RR, 95% 

CI) 

Concomittant the

Study T v. C 

Insulin-glucose infusions

(46) acute MI 

n = 240 

DM 49% 

T: 72 - 180 

C: < 288 

capillary blood 

glucose 

T: 149.4 (39.6) 

C: 162 (50.4) 

p = NS 

Inpatient mortality: 4.8% v. 

3.5%, p = .75 

3 month mortality: 7.1% v. 

4.4%, p = .42 

percutaneous corona

v. 39; thromboly

most patient receiv

blockers and statin

(13) acute MI 

n = 620 

DM 39% 

T: 126 - 

198 

C: NR 

whole blood 

samples, 

bedside 

reflectance 

meter 

monitoring 

24 hours: 3 month mortality: 

12.4% v. 15.6%, p = NS 

1 year mortality: 

18.6% v. 26.1 %, RR 0.69; 

95% CI 0.49 – 0.96 

thrombolytic

T: 172.8 (59.4) heparin - 

C: 210.6 (73.8) 

p < .001 

aspirin at d/

beta blockers a

insulin treatment at o

49% (p < 

(47) acute MI, n = 1253 

DM 77%* (with 

established DM, 

23% had "newly 

diagnosed DM <1y) 

group 1 

and 2: 126 

- 180 

group 3: 

NR 

NR 24 hours: 

group 1: 163.8 (54.0), group 2: 163.8 (50.4), 

group 3: 180.0 (64.8)

p = .0001 

Adjusted 2-year morality HR 

(95% CI): Group 1 v. group 

3 = 1.19 (0.86 - 1.64) 

Group 2 v. group 3 = 1.23 

(0.89 - 1.69) 

percutaneous corona

(gr 1) v. 40 (gr 2

thrombolysis: 3

Aspirin at d/c: 8

Beta-blocker at d/c

Lipid lowering at d/c

(48) Ventricular 

fibrillation survivors 

T: 72 – 

108 

arterial blood 

glucose 

I = 90 (81 - 104.4) 30 day mortality: Therapeutic h

C = 115.2 (99 - 133.2), 

p < .0001 

33% v. 35%, p = 0.85 

n = 90 C: 108 – 

DM 11% 144 

(63) Acute brain injury T: 80 – 

120 

Capillary blood 

glucose 

Mean (inter-quartile 

range: 

ICU mortality: 25.8 v. 35.2, 

p = 0.5 

Enteral nutrition; con

formula had lower % 

N = 48 

DM % NR C: < 180 T: 138.9 (125.6 - 

174), C: 148.4 (131.5 

- 188.6), p = .16 

64.5% with CVA 
Study 

Population 

n 

% DM 

Glucose 

target, T v. 

C (mg/dL) 

Glucose 

monitoring 

method 

Inpatient blood 

glucose achieved 

mean (SD), T v. C 

(mg/dL) 

Mortality, T v. C (RR, 95% 

CI) 

Concomittant the

T v. C 

Insulin-glucose infusions, continued

(61) acute CVA 

n = 933 

DM 17% 

T: 72 - 126 

C: < 306 

capillary blood 

glucose 

24 hour mean 

difference I v. C (95% 

CI): 10.3 (4.9 - 15.5), 

p < .0001 

90 day mortality: 

30.0% v. 27.3%, OR (95% 

CI) = 1.14 (0.86 - 1.51) 

90 day severe disability: 

35.1% v. 36.0%, OR (95% 

CI) = 0.96 (0.70 - 1.32) 

NR 

(62) subarachnoid 

hemorrhage 

n = 78 

DM 10% 

T: 80 - 120 

C: 80-220 

arterial blood 

glucose 

NR 6 month mortality: 

15.0% v. 18.4%, p = NS 

Total infection rate: 

27% v. 42%, p < .001 

Intracranial aneu

intravenous calciu

Adjustable GIK infusions 

(49) acute MI 

undergoing PTCA 

n = 940 

DM 11% 

T: 126 

- 198 

C: NR 

whole blood 

samples 

16 hours: 

T: 138.6 

C: 145.8 

p = NS 

30 day mortality: 

4.8 v. 5.8, RR 0.82; 95% CI 

0.46 - 1.46 

Percutaneous coron

91.6 v. 

CABG: 4.

(50) acute MI 

n = 864 

DM 10% 

T: 108 

- 180 

C: NR 

NR NR One year mortality: 

5.3% v. 3.9%, p = .33 

Recurrent MI: 

4.6% v. 4.6%, p = .99 

Percutaneous corona

v. 9

Thrombolys

Aspirin at d/c

Beta-blocker at 

Statin at d/c: 

*The full quality rating for each study is provided in Appendix E. 
Perioperative Patients 

Overall, the evidence, including five RCTs conducted in patients undergoing cardiac 

surgery,(64-68) is methodologically limited, evaluates heterogenous treatment 

approaches, and does not provide clear, consistent evidence of benefit from tight 

glycemic control strategies in the perioperative setting (Table 3). (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.) 

Two fair-quality trials were designed to evaluate the efficacy of achieving intraoperative 

normoglycemia using IIT during cardiopulmonary bypass.(65, 66) One trial which 

excluded diabetic patients found no significant differences between groups in rates of 

neurologic morbidity or mortality, but did find a trend toward increased hypoglycemia in 

the intervention group (11.7% v. 6.2%, p = 0.07).(65) In the second trial only the 

intervention group was targeted to normoglycemia during surgery, but both groups 

received insulin infusions with normoglycemic targets during the post-operative 

period.(66) More patients in the intensive insulin group than the control group died (2% 

v. 0%, p=0.06) or suffered a stroke (4% v. 1%, p=0.02) within 30 days after surgery. 

Two RCTs examined the effect of GIK infusion administered just before surgery and 

maintained for 6-12 hours after surgery, using an adjustable-dose GIK infusion with a 

moderate glucose target range.(67, 68) One was a fair-quality trial (n=141) that found no 

significant differences in short-term mortality or MI, although GIK-treated patients had 

significantly higher cardiac indices (2.9 v. 2.4 L/min/m2

 after GIK infusion was 

discontinued at 18 h), less need for pacing (14% v. 39%, p=0.001), a lower incidence of 

infections (0 v. 13%, p=0.01), and shorter postoperative hospital stays (6.5 v. 9.2 days, 

p=0.003).(67) Survival at 2 years was marginally better among GIK patients in this 

study (p=0.04). The other study was a poor-quality pilot trial in 44 patients without 

diabetes, and found no differences between groups in wound infection, length of stay, or 

30-day mortality.(68) 

A poor-quality trial including CABG patients with diabetes (n=93) compared use of an 

insulin infusion to subcutaneous sliding scale insulin in order to achieve a moderate 

glucose target (150-200 mg/dL) in the immediate post-operative period.(64) The insulin 

infusion group achieved a lower post-operative mean blood glucose level (195 v. 288 

mg/dL, p<0.001). There were no between-group differences in mortality, length of ICU 

stay, or frequency of sternal wound infections. 

One good quality systematic review and meta-analysis included a large number of trials 

with patients receiving some form of insulin intraoperatively, perioperatively, and/or 

postoperatively.(69) The majority of trials included patients undergoing CABG, although 

a handful of trials examined other surgical populations. The authors included studies of 

GIK and insulin-alone infusions, and studies with and without a glucose target. Most 

trials were of poor to fair quality. We had excluded a number of these trials from our 

own review that did not examine prespecified health outcomes,(70-83) or that examined 

an insulin-based intervention without a glucose target.(70, 71, 73-76, 83, 84) When all 

19 
20 

14 trials reporting mortality outcomes were combined, there was a 31% reduction in 

mortality (RR 0.69, 95% CI, 0.51 – 0.94). However, when the Van den Berghe SICU 

trial(22) was excluded from the meta-analysis, the authors found no mortality difference 

between the two groups (RR 0.92, 95% CI, 0.57 – 1.48). The Van den Berghe trial 

examined a qualitatively different intervention (ie – tight glycemic control throughout the 

ICU stay) and is extensively discussed along with the other trials examining glucose 

control in critically ill patients. 
Table 3. Trials in patients undergoing cardiac surgery 

Glucose 

monitoring 

method 

Glucose 

target, T v. 

C (mg/dL) 

Population 

Setting, N, 

% DM 

Inpatient BG achieved, T v. 

C (mg/dL) 

Mortality, T v. C 

(% per group) 

Intervention and 

comparator Study 

10055 wwhe<70 

(65) CABG with CPB 

0% DM n = 188 intensive IT; 193 saline placebo 

T: Insulin infusion during surgery, if glucose > 100. C: saline placebo infusion. BG was measured for analysis. 

Arterial blood samples 

T: 70-100 C: not specified 

T v. C levels were significantly lower (p<0.01), values not reported 

In-hospital 2.1 v. 1.6% (p=ns) 6-month 3.2% v. 2.6% (p=ns) 

30 days after surgery: 

Dursurggivemedclea

Arterial blood samples 

T: 80 -100 C: <200 

After CPB, T v. C (mg/dL): 123 v. 148 (p=<.001) At arrival in ICU: 114 v. 157 (p<0.001) In ICU, both groups received IIT. After 24 hrs in ICU: 103 v. 104 mg/dL (p=0.72) 

T: Insulin infusion during surgery, if glucose > 100. C: IV bolus of insulin if glucose >200; infusion if >250. Both groups received insulin infusion on arrival in ICU. 

(66) 48% CABG 

52% other cardiac surgery 20% DM n = 188 intensive IT; 191 conventional IT 

2 v. 0% (p=0.06) 

(67) CABG 

100% DM n = 72 GIK; 69 no-GIK 

T: GIK infusion started just before surgery; continued 12h after arrival in ICU. C: SQ sliding scale insulin 

Not reported 

T: 126 - 200 C: <250 

12 hours post surgery mean (SD) in mg/dL: T = 134.3 (3.7) C = 266.8 (6.3) 

30 days: 0 v. 0%

2 yrs: 0 v. 10% (p=0.04) 

Nonpreo(oraafteper

(68) CABG 

0%DM n= 22 GIK; 22 D5W 

T: GIK infusion started just before surgery; continued until 6h after reperfusion C: D5W placebo infusion, with no glucose monitoring 

Serum T: 89-179 

C: not specified 

NR No deaths 

occurred within 30 days in either group 
Study 

Population 

Setting, N, 

% DM 

Intervention and 

comparator 

Glucose 

monitoring 

method 

Glucose 

target, T v. 

C (mg/dL) 

Inpatient BG achieved, T v. 

C (mg/dL) 

Mortality, T v. C 

(% per group) 

(64) CABG 

100% DM n = 51 CII; 42 SQI 

CII v. SQI. Not 

reported 

T: 150 - 200 C: 150 - 200 

Post-op day 1 mean in mg/dL (SD NR): I = 195.0, C = 229.1, p <.001 

Mortality: 3.9 v. 2.4% (p = ns) 

Mosora1st dayinjeinstinfubeg

*The full quality rating for each study is provided in Appendix E. Abbreviations: CII = Continuous insulin infusion; C = Comparator; DM = Diabetes mellitus; SQI = subcutaneous insulin; T = Treatment 
General Medicine Ward Patients 

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

control in general medical ward patients. 

Observational Studies 

The following observational studies did not meet our initial inclusion criteria but we 

discuss them in further detail because they report health outcomes, have been cited 

frequently, and have informed clinical practice. 

The Portland Diabetic Project was a single-center observational study of diabetic cardiac 

surgery patients treated between 1987 and 2005.(14, 15) The control group consisted of 

patients treated between 1987-1991 during which time subcutaneous insulin was used to 

maintain blood glucose at or below 200 mg/dL. An insulin infusion protocol was 

subsequently introduced in a graded fashion with glucose targets gradually lowered over 

time in an effort to improve staff/institutional acceptance and lower the risk of 

hypoglycemia. Compared with the historic control group, the first intervention cohort, 

which was maintained on a peri- and postoperative insulin infusion with a moderate 

glucose target (150-200 mg/dL), had a significantly lower risk of deep sternal wound 

infections (DSWI) (0.8% v. 2.0%, p = .01) even after controlling for patient level and 

surgical confounding variables.(17) A subsequent analysis reported a lower cardiac 

mortality in the over 4500 patients enrolled during the insulin infusion era compared 

with historic controls (1.1% v. 4.4%, p < .001). The overall incidence of hypoglycemia 

was not reported. 

In 2007 D’Alessandro et al used the EuroSCORE risk stratification algorithm to compare 

expected and observed mortality rates in diabetic patients undergoing cardiac 

surgery.(85-88) Between 2003 and 2004 patients were treated with an intra- and postoperative insulin infusion protocol similar to that of Furnary et al with target blood 

glucose 150-200mg/dL and a post-operative target of < 140 mg/dL. Observed and 

expected mortalities in the historical controls were similar, while patients treated during 

the protocol era had a lower observed mortality than expected (OR 0.28; 95% CI, 0.09 – 

0.82). Morbidity rates, including DSWI, did not differ between the two groups. The 

hypoglycemia rate was not reported. 

Another observational study included mixed medical and surgical ICU patients admitted 

between 1999 and 2006 (89). Mortality was compared before and after a protocol to 

maintain glucose between 80 and 140mg/dl was instituted in 2003. The protocol 

prompted subcutaneous insulin use when blood glucose ranged 140-199 mg/dL and an 

insulin infusion when blood glucose exceeded 200mg/dL (the thresholds were lowered 

during the last year of the study). The mean (SD) blood glucose was 124.4 mg/dL (51.3) 

and 154.0 mg/dL (87.5) in the post- and pre-protocol eras, respectively. The authors 

found a lower mortality rate during the tight glycemic protocol era (OR 0.68; 95% CI 

0.57-0.80, p<0.001) and most of this benefit was seen in nondiabetic patients. The rate of 

23 
severe hypoglycemia was relatively low overall, but increased during the protocol era 

(1.50 v. 2.26%, p = .051). 

These studies have several important strengths: large size, consecutive enrollment, 

thorough follow-up, and an attempt to control for severity of illness and other 

confounding factors. They also provide important insights into the feasibility of 

establishing various glycemic control strategies in “real-world” settings. However, these 

studies also have several important weaknesses which temper their use in drawing 

conclusions about the efficacy of tight glycemic control in improving health outcomes 

and the use of specific glucose targets. Observational studies may overestimate 

magnitude of treatment effect when compared to randomized studies.(90) Because of the 

use of historic controls, it is difficult to ascertain the proportion of the health outcome 

improvement that was attributable to the insulin-based glycemic control strategies. For 

example, one study found a 25% drop in mortality within the subset of patients with the 

poorest glycemic control.(89) A number of interventions and quality improvement 

initiatives may contribute to improved outcomes in surgical and critically ill patients.(91, 

92) The change efforts heralded by a glycemic control strategy may also improve 

provider and institutional acceptance of other quality improvement intitiatives and may 

reduce variation in practice around efforts such as infection control.(93) Also, as in the 

reviewed randomized trials, these single-center studies were necessarily unblinded and 

some improvement attributable to increased vigilance, more intensive training of staff, 

and more intensive data registry use is certainly possible. Finally, two of the studies did 

not report overall hypoglycemia rates, making it more difficult to draw conclusions about 

protocol safety. 

24 
KEY QUESTION #2. What are the harms of strict blood glucose 

control in the above subpopulations? 

The highest occurrence of hypoglycemia appeared among critically ill patients receiving 

IIT aimed at achieving normoglycemia (Figure 4, RR 5.32; 95% CI 4.21 – 6.73, I2

2.28%; Table 4), especially those in the MICU, of whom a large proportion had risk 

factors for hypoglycemia such as sepsis, malnutrition, liver disease, congestive heart 

failure, and renal insufficiency.(94-97) 

Figure 4. Individual and combined estimates of hypoglycemia in MICU/SICU studies comparing 

intensive insulin with conventional therapy 

 Risk ratio

Study

A recent fair quality meta-analysis included several of the same ICU trials(16, 22, 29) as 

well as several that did not prespecify health outcomes(98-101) and found a similar risk 

of hypoglycemia (RR 4.97; 95% CI, 3.65 – 6.76, p < .001).(102) Another recent good 

quality meta-analysis examined perioperative insulin infusions, many of which used 

higher glucose targets in the intervention groups: 20/34 included studies reporting 

hypoglycemia rates found that insulin-infusion was associated with a two-fold increased 

risk of hypoglycemia (RR 2.07, 95% CI, 1.29 – 3.32).(69) 

The consequences of hypoglycemia in hospitalized patients are unclear. There were few 

reported in-hospital adverse effects of hypoglycemia during intensive insulin therapy in 

the reported RCTs (Table 4), though many critically ill patients included in these studies 

were sedated thus limiting the completeness of neurologic assessment. One study 

Risk ratio

.5 1 2 4 6 16 32

 (95% CI) % Weight

 Van Den Berghe 2001 6.65 (2.83,15.62) 11.5

 Grey 2004 4.37 (1.06,18.06) 7.9

 Van Den Berghe 2006 5.94 (3.70,9.54) 13.9

 Arabi 2006 9.18 (4.52,18.63) 12.5

 Farah 2007 1.17 (0.78,1.75) 14.3

 Brunkhorst 2008 4.11 (2.21,7.63) 13.1

 Mackenzie 2008 5.46 (2.82,10.60) 12.8

 Preiser 2008 3.64 (2.31,5.75) 14.0

 Overall (95% CI) 4.33 (2.44,7.68)

25 
26 

reported a case of cardiac asystole related to treatment-induced hypoglycemia.(103) 

Several MICU studies found an excess mortality risk or extended length of stay among 

patients experiencing one or more episodes of severe hypoglycemia, though it is unclear 

if hypoglycemia was a causative factor or simply a marker for more severe disease.(10, 

26, 28, 29) 

Most of the observational studies and trials without health outcomes that we examined 

used more conservative blood glucose targets and found far lower rates of hypoglycemia 

(Table 5). There was little information about hypoglycemia rates in general 

medical/surgical ward patients where staffing ratios, patient heterogeneity and diet may 

vary substantially. 

Few studies have examined the long-term consequences of hypoglycemia. Svensson et 

al investigated the association between in-hospital hypoglycemia and 2 year all-cause 

mortality in a cohort of over 700 diabetic patients admitted with acute coronary 

syndrome. Hypoglycemia, defined as blood glucose < 55 mg/dL, occurred in 6.4% of 

patients and was associated with an almost 2-fold risk of 2 year all cause mortality (HR 

1.93, 95% CI 1.18 – 3.17). Though comorbidities and other prognostic factors were 

controlled for, the study was observational and cannot explain whether hypoglycemia 

was simply a marker of more severe disease, or whether treatment-induced hypoglycemia 

itself can lead to adverse consequences. Several small studies(104-106) have suggested 

that hypoglycemia may induce transient ischemia and catecholamine surges, but these 

effects have not been well-studied in large groups of inpatients with the power to 

investigate downstream clinical consequences. 
Table 4. Frequency of hypoglycemia in randomized controlled trials 

Hypoglycemia 

definition 

(mg/dL) 

Frequency of hypoglycem

episode/persons s

Intervention Glucose target (mg/dL) Study Population (T: treatment, C: control) Adverse events due 

(22) MICU Insulin infusion in both groups*‡ T: 80-110mg/dl 

C: 180-200mg/dl 

<40 18.7% v. 3.1%

(23) MICU Insulin infusion in both groups*‡ T: 110-140 

C: 140-200 

< 40 Total # of hypoglycemic epis

AEs n

(29) MICU Insulin infusion in both groups*‡ T: 80-110 

C: 180-200 

<60 17% v. 4.1%, RR 4.11; 

More episodes (T v. C) describ

2.1%, p = 0.05) and requiring 

(2.4 v. 0.3%, 

(16) SICU Insulin infusion in both groups*‡ T: 80-110mg/dl 

C: 180-200mg/dl 

<40 5% v. 0.76%, RR 6.65; 

AEs N

(24) SICU Insulin infusion in both groups*‡ T: 80-120mg/dl 

C: 180-220mg/dl 

<60 32% v. 7.4%, RR 4.37; 

AEs n

(26) Mixed 

MICU/SICU 

Insulin infusion in both groups*‡ T: 80-110 

C: 180-200 

< 40 28.6 v. 3.1, p 

ICU mortality in patients with 

13.7%, 

P=0.02. Among pts w

mortality in IIT v. control 

(27) Mixed 

MICU/SICU 

Insulin infusion in both groups*‡ T: 72 – 108 < 40 41.3 v. 7.6%, 

C: < 198 One case of cardiac asystol

dextrose infusion in hy

(28) Mixed 

MICU/SICU 

Insulin infusion in both groups*‡ T: 80 – 110 < 40 14.5 v. 3

C: 140 – 180 ICU mortality in patients with hy

(p<.0

(13) Acute MI T: Insulin infusion*† for 24 hours then 

multidose insulin regimen for at least 3 

months. C: usual care 

T: 126 - 198 mg/dL 

C: not specified 

<54 15.0 v. 0%, p < .

(46) Acute MI T: insulin infusion* for 24 h. C: usual 

care, supplemental insulin if glucose > 

288 mg/dL 

T: 72 - 180 mg/dL 

C: not specified 

< 63 10.3 v. 1.8%, p = 
Hypoglycemia 

definition 

(mg/dL) 

Frequency of hypoglycem

episode/persons s

Intervention Glucose target (mg/dL) Study Population (T: treatment, C: control) Adverse events due 

(47) Acute MI T: Int 1 - insulin infusion*† and outpatient 

multidose insulin, Int 2 - insulin infusion 

only. C: usual care 

T: 126 - 180 mg/dL 

C: not specified 

< 54 Gr 1 v. Gr2 v. Gr3: 

1/3 of patients with hypoglyce

reported adverse 

(50, 

107) 

Acute MI T: adjustable high-dose GIK* T: 108 - 180 mg/dL 

C: not specified 

NR NR; AE

C: usual care 

(49) Acute MI T: adjustable high-dose GIK*† T: 128 - 198 mg/dL 

C: not specified 

NR 0 v. 0; AE

C: usual care 

(48) Ventricular 

fibrillation 

survivors 

Insulin infusion in both groups, no 

protocol 

T: 72 – 108 < 54 18 vs 2; A

C: 108 – 144 

(61) Stroke T: Adjustable GIK infusion* T: 72 - 126 

C: < 306 

< 72 for > 

30 mins 

15.7, control group ra

C: saline infusion, insulin allowed if 

glucose > 306 mg/dL 

(63) Acute brain injury T: Insulin infusion‡ T: 80 – 120 < 40 6.4 vs 5.8; 

C: regular insulin if glucose >180 mg/dL; 

lower carbohydrate enteral formula 

C: < 180 

(62) Neurosurgical 

ICU, 

subarachnoid 

hemorrhage 

Insulin infusion in both groups T: 80- 120 

C: 80-220 

NR NR

AEs N

(64) Perioperative, 

CABG 

T: Insulin infusion*† T: 150 - 200 

C: 150 - 200 

NR NR 

C: subcutaneous insulin 

(65) Perioperative, 

CABG 

T: Intra-operative insulin infusion* 

C: saline infusion. 

T: 70-100 

C: not specified 

<70 11.7% v. 6.2% (p=
Study Population Intervention (T: treatment, C: control) Glucose target (mg/dL) 

Hypoglycemia 

definition 

(mg/dL) 

Frequency of hypoglycem

episode/persons s

Adverse events due 

(66) Perioperative, 

cardiac surgery 

T: Intra-operative insulin infusion* 

C: IV bolus of insulin if BG >200; infusion 

if >250. 

Both groups received 24h postop insulin 

infusion in ICU 

T: 80 -100 

C: <200 

< 60 1% v. 1% (p=1

(67) Perioperative, 

CABG 

T: Intra- and 12h postoperative GIK 

infusion* 

C: SQ sliding scale insulin 

T: 126 - 200 

C: <250 

NR NR; AE

(68) Perioperative, 

CABG 

T: Intra- and 6h postoperative GIK 

infusion* 

C: D5W placebo infusion, with no 

glucose monitoring 

T: 89-179 

C: not specified 

NR NR; AE

*Insulin infusion rate was based on current blood glucose †Rate of change in glucose level was also included in adjusting insulin infusion rate ‡Factors included in insulin infusion rate calculations not reported, or protocol allows for dosing based on provder discretion§Excess risk of severe hyperglycemia (BG>350 mg/dL) occurred in intervention group Abbreviations: AEs = adverse events; NR = not reported 
Table 5. Frequency of hypoglycemia in observational studies and trials not reporting health ou

Frequency of 

hypoglycemia 

(% with 1+ 

episode/ 

persons 

studied) 

Hypoglycemia 

definition 

(mg/dL) 

CT, 

HC,or 

Obs. 

Study 

Factors included in 

insulin infusion rate 

calculations 

Glucose 

target 

(mg/dL) 

Mean glucose 

achieved 

mg/dL (SD) 

Population C

Obs. MICU/SICU (no 

cardiothoracic surgery) 

Current glucose 75-120 133.5 (43.9) <40 0.09* All patients re

dextrose solutio

higher than int

consecutive p

included, but it is 

chos

(108) Rate of change in 

glucose 

<60 1.0* 

49.5% DM 

n = 90 Current insulin rate 

Obs. SICU (47% 

cardiothoracic surgery) 

35.5% DM 

n = 276 

Current glucose 80 – 110 135.3 (49.9) <60 1.5* Included only glu

consult patients

goal (mean cap

(109) Rate of change in 

glucose 

Obs. CTICU (2 centers) Current glucose 100 – 139 Non-DM 

patients: 120.0 

(14.0) 

< 60 0.2* Overall mean glu

(110) 34.0% DM Rate of change in 73% within 

N = 118 glucose 

Current insulin rate DM patients: 

122.0 (9.0) 

Obs. ICU (66% med, 28% 

surg, 6% trauma) 

21.4% DM 

n=2699 

Current glucose 80-140 124.4 (51.3) <40 0.58* 

(89) <70 1.78* 

Obs. Burn-Trauma ICU Current glucose < 120 115.9 – 119.5 < 60 5.0 All consecutive 

included, but it is 

chos

(111) 33% DM 

N = 30 

Obs. Trauma ICU Current glucose < 110 118.9 (27.3) <50 0 All consecutive 

included, but it is 

chos

(112) % DM NR Rate of change in 

glucose 

<70 2.0* 

n = 24 

Current insulin rate 

Estimated insulin 

sensitivity 
CT, 

HC,or 

Obs. 

Study 

Population 

Factors included in 

insulin infusion rate 

calculations 

Glucose 

target 

(mg/dL) 

Mean glucose 

achieved 

mg/dL (SD) 

Hypoglycemia 

definition 

(mg/dL) 

Frequency of 

hypoglycemia 

(% with 1+ 

episode/ 

persons 

studied) 

C

CT 

(113) 

Trauma ICU 

8.6% DM 

N=243 

Computerized algorithm 

Current glucose 

Current insulin rate 

80-110 116.0 (37.0) <40 7.8 Computer algorit

based protocol w

was nonsignifica

HC 

(114) 

MICU/SICU (5 ICUs 

across 2 centers) 

% DM NR 

n = 2398 

Computerized 

algorithm; current 

glucose; rate of change 

in glucose; 

Estimated insulin 

sensitivity 

80 – 110 106.5 (39.1) < 50 

< 70 

0.4* 5.0* 

Treating physi

infusion protoco

insulin sensitiv

HC 

(98) 

MICU/SICU 

32.0 % DM 

n = 44 

Current glucose 

Rate of change in 

glucose 

90-144 128.0 (32.0) <40 

<72 

0.2* 3.8* 

All consecutive 

included, but it is 

chos

HC 

(115) 

CTICU 

32.0 % DM 

N = 168 

Current glucose 

Current insulin rate 

Presence of diabetes or 

steroids 

80 - 150 NR 

% glucose 

within range: 61 

< 40 < 65 

7.1 

16.7 

Patients receive

nutrition for first 

*rate reported as # hypoglycemic occurences/# total glucose measurements Abbreviations: CT = Controlled trial; HC = study using historical control; Obs = Observational study
KEY QUESTION #3. What are the most effective and safest means of 

lowering blood glucose in hospitalized patients? 

Insulin infusions 

We evaluated three recent fair-quality systematic reviews,(116-118) of studies evaluating 

the effects of different insulin infusion protocols (IIPs) on glycemic control. There were 

no completed studies directly comparing these protocols, though we found two inprogress comparative effectiveness trials.(34, 35) 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. One review stressed that, given this variety of factors, each 

institution should individualize its approach to protocol implementation based on its 

patient population as well as its institutional and provider resources.(116) Another 

review focusing on ICU protocols used computer simulations to model patterns of insulin 

administration and similarly concluded that the variability amongst protocols precludes 

dissemination of a single protocol.(118) The authors suggest the better protocols 

incorporate bolus insulin doses, account for the direction and rate of glucose change, and 

make allowances for “off-protocol” adjustments. A third review concludes protocols that 

incorporate factors such as the rate of glucose change, the current blood glucose and 

insulin rate may be more effective than simple sliding scale infusion protocols in 

lowering blood glucose while maintaining relatively low rates of hypoglycemia, though 

this conclusion is not based on direct comparisons of protocols.(117) 

Protocols used in observational studies and trials not examining health outcomes that we 

assessed are summarized in Table 5.(89, 98, 108-111, 113-115, 119, 120)  Protocols used 

in the efficacy trials varied across subpopulations as detailed in Tables 1, 2, and 3. In 

general, protocols that were successful in targeting normoglycemia were also associated 

with a substantially elevated risk of hypoglycemia (Table 4). One observational study 

found a computerized insulin infusion protocol which incorporated factors such as insulin 

sensitivity achieved its normoglycemic target with relatively low rates of 

hypoglycemia.(114) 

Subcutaneous insulin 

Subcutaneous sliding scale insulin (SSI) regimens have a number of theoretical 

disadvantages when used as the sole method for inpatient glycemic control and authors 

have called for a reduction in the widespread use of sliding scale subcutaneous 

insulin.(121) A limited body of small, mainly single-center controlled trials suggest 

subcutaneous sliding scale insulin regimens may be relatively ineffective in targeting 

lower blood glucose. A prospective, multi-center trial compared a basal bolus regimen 

with SSI in general medical ward patients with type 2 diabetes and found the basal-bolus 

regimen led to longer duration of time within the target glucose range, from 38% to 66%, 

with no differences in the incidence of hypoglycemia.(122) A trial in patients with a 

glucose of more than 144 mg/dl after Roux-en-Y gastric bypass randomized the subjects 

32 
(n=81) to SSI or insulin glargine.(123) Mean glucose was 154 versus 134 mg/dl in the 

SSRI and glargine groups, respectively, p<0.01. Hypoglycemia defined as glucose 

<60mg/dl occurred in only 3 of the 926 readings (2 in glargine and 1 in SSI). A 

randomized controlled trial of 153 diabetic patients admitted to a family medicine service 

found that the addition of a subcutaneous sliding scale insulin regimen to routine diabetes 

medications (oral agents or scheduled insulin) led to no difference in the time spent in the 

hyper- or hypoglycemic range (124). A second trial randomized 93 post-operative 

cardiac surgery patients to either an insulin infusion or to a subcutaneous sliding scale 

regimen. Mean blood glucoses of less than 200mg/dl occurred in more often in the 

infusion group (28.6 to 64.7%, p<0.001). (64). 

33 
SUMMARY AND DISCUSSION 

 

Observational and biologic plausibility studies suggest an association between 

hyperglycemia and worsening health outcomes in hospitalized patients. However, trial 

evidence of the efficacy of tight, compared to less tight, glycemic control strategies using 

IIT in various inpatient subpopulations is limited. Current evidence does not 

conclusively support existing guideline recommendations to routinely maintain a blood 

glucose ≤ 110 mg/dL in ICU patients, and there is very little data on the health outcome 

benefits of achieving more moderate blood glucose control (eg – 110 – 180 mg/dL) 

compared to less strict targets in various inpatient subpopulations.(125) 

Single-center evidence from one group of investigators had shown a mortality and 

morbidity benefit from IIT in subgroups of patients requiring prolonged ICU stays, (16, 

22) while our meta-analysis of seven ICU studies showed that achieving normoglycemia 

using a relatively simple insulin infusion protocol had no effect on short-term mortality 

but did substantially increase the risk of hypoglycemia. 

Several factors may account for the discrepancy in results between the Van den Berghe 

trials and data from other centers. The aggressive use of parenteral nutrition, especially 

in the SICU study showing benefit,(16) differs from practice in many centers.(126) 

Parenteral nutrition has been associated with hypertriglyceridemia, insulin resistance, 

increased infection rates and mortality, leading to speculation that the observed benefits 

of intensive insulin in this population actually reflect a reduction in harm from aggressive 

nutrition practices.(127-131) It is unclear whether the control group mortality rate in this 

study was higher than expected. The authors of the study have reported mortality rates 

lower than expected based on the EuroSCORE of the cardiac surgery patients, though a 

review of EuroSCORE performance characteristics found that scores in the range 

reported in the trial may underestimate mortality by almost 3 %.(85, 132) On the other 

hand, a post-hoc analysis using combined data from both the Van den Berghe SICU and 

MICU studies found a mortality benefit in subgroups receiving the highest and lowest 

amounts of parenteral glucose.(45) 

The exclusive use of arterial blood sampling in the Van den Berghe SICU study also has 

implications for the applicability of results across diverse ICU settings since very few 

medical centers use arterial blood sampling to monitor glucose control. Capillary blood 

sampling is more commonly used and is less dependable in critically ill patients, due to a 

number of factors including vasopressor therapy, perfusion pressure, pH, and others.(133-

135) There is a very low rate of agreement between capillary and whole blood glucose 

samples, particularly in the hypoglycemic range.(99, 136) 

Finally, this SICU study had a relatively low event rate and was stopped early for benefit 

with less than half the projected number of participants recruited, raising the possibility 

that the reported treatment effect was larger than the “true” treatment effect.(137) 

Indeed, the effect size decreased substantially, though remained significant, after the 

authors adjusted for the repeated interim analyses which had prompted the early 

recruitment discontinuation.(138) 

34 
Three of the trials that failed to show a mortality benefit from achieving normoglycemia 

in critically ill patients were stopped early due to an excess risk of hypoglycemia in the 

intervention groups, thus raising the possibility that the lack of observed benefit may 

actually reflect inadequate power to detect a health benefit.(26, 28, 29) However, the 

trials did not demonstrate a consistent trend towards benefit and combining these studies 

in our meta-analysis should increase the power to detect a health benefit if one were 

present. Furthermore, the inability to implement the insulin infusion protocol in various 

settings without high rates of hypoglycemia may underscore problems with feasibility 

and generalizability across institutions. It is unclear whether the high hypoglycemia rates 

are due to insulin infusion protocol characteristics, staffing characteristics, patient 

comorbidities, or the very tight glucose target itself. Since the health consequences of 

insulin-induced hypoglycemia in hospitalized patients are as yet unclear, interventions 

associated with high rates of hypoglycemia should demonstrate compelling benefit across 

a variety of institutions before being widely implemented. 

The current body of trial evidence in perioperative patients is heterogenous and 

inconclusive. The most dramatic evidence of health outcome benefits from tight 

glycemic control in the perioperative setting comes from retrospectively controlled 

observational studies with methodologic flaws.(14, 15, 88) Well-designed controlled 

clinical trials in this population would add substantially to our body of knowledge. 

Evidence supporting the efficacy of tight glycemic control in myocardial infarction 

populations is similarly limited and inconsistent. One trial showed a mortality reduction 

from moderate inpatient and outpatient glucose control in severely hyperglycemic 

myocardial infarction patients, but this older trial was conducted prior to the widespread 

use of cholesterol lowering therapies and mechanical revascularization techniques.(13) 

More recent studies have been negative, but methodologic considerations limit the 

strength of conclusions drawn from these trials.(46, 47) There is very little fair-good 

quality empiric data in general surgical or medical ward settings, or in stroke patients. 

The ability to achieve glucose targets safely is likely to depend on multiple factors 

including the titration characteristics of the protocol, patient characteristics, as well as 

staffing ratios and provider acceptance. A number of mainly single-center observational 

studies and trials that did not examine health outcomes found relatively low rates of 

hypoglycemia. Characteristics of these studies suggest there may be several variables 

responsible for the lower rates of hypoglycemia: modest glucose targets (approximately 

100 – 180 mg/dL), an iterative, institution-based protocol development and deployment 

process, and insulin protocol titration innvovations. There is relatively little information 

on insulin protocols that have achieved normoglycemic targets with low rates of 

hypoglycemia. 

35 
Limitations 

Our review has several potential limitations. We did not exclude individual trials based 

on quality rating alone. Thus the strength of our conclusions is inherently limited by the 

quality variation among included studies. We did make an effort to note particular 

methodologic limitations, and each study was closely reviewed for overall quality using a 

rigorously developed approach. The studies included in our quantitative synthesis 

differed in some important respects: population studied and the attendant differences in 

event rates (ie – SICU v. MICU), interval of outcome reporting, and glucose monitoring 

method. The applicability of results from the included studies is limited by a variety of 

factors: patient characteristics, event rates, concomitant therapy, institution 

characteristics, and monitoring methodology. Most of these were single-center studies, 

yet the relative success or failure of an insulin-based intervention is likely to depend, to a 

significant extent, on systems characteristics which are unique to a given institution or 

health system. Finally, the included trials relied on glucose measurements from a defined 

reference time, rather than 24 hour glucose levels achieved, thus potentially obscuring the 

inherent variability in glucose control through the course of intensive care.(139) 

Future research recommendations 

The bulk of efficacy evidence comes from studies in critically ill populations. Even 

amongst these studies, the patient characteristics, underlying event rates, and risk of 

hypoglycemia varied substantially. There is almost no empiric data available to guide 

glucose management practice in non-ICU settings. Future trials should enroll general 

medical and surgical ward patients. 

 

The current body of evidence has not defined a glucose threshold that should prompt 

more aggressive intervention in various subpopulations. Given the observed risk of 

hypoglycemia in patients exposed to insulin therapy designed to normalize blood glucose, 

and the relatively low hypoglycemia rates in observational studies using less strict 

targets, the efficacy of higher glucose targets should be examined prospectively in 

various subpopulations. 

As discussed, there are a variety of insulin titration protocols. Those that take into 

account a patient’s insulin sensitivity and rate of glucose change are theoretically 

attractive, but future studies should rigorously evaluate these protocols and compare them 

to simpler protocols. 

Individual institutions describing their experience implementing intensive insulin 

protocols suggest that the increase in nursing workload and fear of hypoglycemia were 

significant, but surmountable, barriers to implementation.(140, 141) The cost of attaining 

normal blood glucose in critically ill patients is unclear. Van der Berghe et al found that 

IIT targeted to normoglycemia was cost-saving using data from their SICU study.(142) 

Cost analyses using more recent data have not yet been conducted. Since insulin 

therapy can be resource intensive, future studies should examine the real cost and the 

36 
37 

opportunity cost of such treatment, as well as patient and staff acceptance across a variety 

of settings. 

 

Transitions of care (e.g., ICU to ward, hospital to home) are fraught with uncertainty and 

there is likely a high rate of adverse events during these transitions, including an 

increased risk of post-discharge hypoglycemia.(143, 144) Studies should examine the 

safest and most effective ways to adapt insulin management in patients transitioning from 

one level of care to another. 

 

There is a relative dearth of evidence evaluating the safety and efficacy of non-infusion 

based insulin protocols. Trials evaluating subcutaneous insulin protocols with moderate 

glucose targets in the medical ward setting would be of great use to clinicians. 

 

Finally, newer technologies may enhance the safety and efficacy of inpatient glycemic 

management. Innovations such as continuous blood glucose monitoring systems and 

computer-based algorithms should be evaluated in various inpatient subpopulations. 

CONCLUSIONS 

The use of intensive insulin therapy to achieve normoglycemia in critically ill patients 

does not clearly result in health outcome benefits and is associated with high rates of 

hypoglycemia. More moderate blood glucose control to targets above the 

normoglycemic range can likely be safely achieved, though the health outcome benefit of 

this practice has not been well studied. Tables 6 and 7 summarize the findings of this 

systematic review for each key question. 
Table 6. Summary of Systematic Evidence Review, Key Question 1: Does strict glycemic contr

less strict glycemic control improve final health outcomes in the following patients? 

Patient 

subgroup 

Type of 

Evidence 

Quality (GRADE) of 

Evidence Comments 

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

We found good quality evidence that insulin used as part of a fixed-doinsulin-potassium infusion does not consistently improve final health oacute myocardial infarction patients, and may increase short-term mor

2 systematic 

reviews; 

Acute myocardial infarction patients 

10 RCTs 

Several trials examined tight glycemic control using adjustable dose inregimens, and failed to demonstrate consistent evidence of benefit in myocardial infarction patients. Variation in trial design, achievement ogoals, glucose level achieved, and concomitant therapy for myocardiathe strength of this conclusion. 

Low = Further research is very likely to have an important impact on our confidence in the estimate of effect and may change the estimate. 

There is very little good-quality evidence investigating tight glycemic cpatients who have suffered a cerebrovascular accident. 

3 RCTs 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 

8 RCTs Moderate = Further research 

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

Patients in medical and/or surgical intensive care units 

Single-center evidence had initially shown a mortality and benefit from IIT in subgroups of patients requiring prolon

stays, but the applicability of these data to other ICUs may and subsequent trials have not confirmed this benefit. Ouanalysis found the use of intensive insulin therapy to achienormoglycemia had a neutral effect on short-term mortalitincreased the risk of hypoglycemia more than five-fold. 
Patient 

subgroup 

Type of 

Evidence 

Quality (GRADE) of 

Evidence Comments 

Overall, there is no clear evidence showing a benefit of tight glycemic strategies in the perioperative setting, but the trial evidence is methodlimited. The studies varied widely in design, blood glucose levels attainclusion of patients with diabetes, limiting the comparability of results Several studies were underpowered to evaluate health outcomes. Thevidence of benefit comes from the single-center SICU study discussesection. 

Perioperative patients 

1 systematic 

review; 

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.

5 RCTs 

None Very Low = Any estimate of 

effect is very uncertain.

There were no studies evaluating a tight glycemic control strategy to leglycemic control in general medical ward patients. 

General medicine ward patients

* (+) benefit; (–) harm; (÷) mixed findings/no effect; (0) no evidence 
Table 7. Summary of Systematic Evidence Review, Key Questions 2 and 3. 

KQ# Key question Type of Evidence Grade of Evidence Comments 

2 What are the harms of 

strict glycemic control in the above subpopulations? 

1 systematic review; 

15 RCTs; 

12 observational 

studies 

Moderate = Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

There is a considerable risk of hypoglycemia in mtreated with intensive insulin protocols designed tglucose. This risk was lower in surgical ICU patietherapy, and in myocardial infarction, stroke, and in whom the target glucose level was generally neuglycemia. Observational studies suggest a mocan be safely achieved with modest glucose targprotocol design. Some studies suggest hypoglycpatients may be associated with excess mortality and long-term consequences of hypoglycemia hastudied. 

3 What are the most 

effective and safest means of lowering blood glucose in the above subpopulations? 

2 systematic 

reviews; 

2 RCTs 

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.

A number of insulin infusion protocols (IIPs) have comparative effectiveness data are lacking. Protglucose targets appeared most feasible and were lowest hypoglycemia risk. Dynamic protocols thathe patient’s insulin sensitivity and that have guidhelp prevent hypoglycemia may be preferred. Thintroduction of insulin infusion protocols in a giveiterative and multi-disciplinary endeavor. Basal binsulin regimens may be more effective than, and sliding scale regimens, though there is very limitemethods of blood glucose control in ward patients
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