EAL

CI: Blood Glucose Control (2009)

Citation:

Finfer S, Chittock DR, et al, for the The Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) Investigators. Intensive versus conventional glucose control in critically ill patients. NEJM. 2009; 360(13): 1,283.

PubMed ID: 19318384

Study Design:

Randomized Crossover Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

The purpose of the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial was to test the effect of tight blood glucose control in critically ill patients on mortality at 90 days.

Inclusion Criteria:

Critically ill and admitted to one of 42 participating ICUs in Australia, New Zealand and Canada
Expected to require treatment for a minimum of three consecutive days
Informed consent.

Exclusion Criteria:

Not critically ill
Expected ICU stay less than three days
Unable to obtain informed consent.

Description of Study Protocol:

Recruitment: Admitted to ICU with expected stay of at least three days
Design: Parallel group PRCT
Blinding Used: Two interim analyses performed by an independent statistician.

Intervention

Randomized to receive either:

Tight glucose control (81mg to 108mg per dL)
Conventional glucose control (insulin started at 180mg per dL and discontinued when BG dropped below 144mg per dL.

Statistical Analysis

Multivariate analyses; tests used included log-rank test, Pearson's, Wilcoxon-rank sum, Kaplan-Meier estimates for probability of survival
Discussion stated that statistical power was higher than Van den Berghe studies.

Data Collection Summary:

Timing of Measurements

Recorded all blood glucose values
Insulin administration per algorithms used all participating ICUs.

Dependent Variables

Mortality
Length of stay in ICU
Total hospital length of stay
Days on mechanical ventilation
Renal-replacement therapy.

Independent Variables

Blood glucose control (tight or conventional).

Control Variables

BG determined via arterial catheters when possible
Trial discontinued once patient was eating or discharged from ICU, but resumed if readmitted to ICU within 90 days.

Description of Actual Data Sample:

Initial N

6,104 (64% male):

3,054 intensive insulin control
3,050 conventional group.

Final N

5,575 (7.5% attrition due to consent withheld or withdrawn):

2,750 intensive insulin control
2,825 conventional group.

Age

Mean age 60.

Other Relevant Demographics

Groups were similar in all demographics:

Mean APACHE score 21.1
About 20% of patients had history of diabetes mellitus
About 21% of patients had severe sepsis at randomization
About 15% were trauma patients
About 30% had APACHE II score at least 25.

Anthropometrics

Both groups had mean weight of 80kg.

Location

Multi-center trial of 42 ICUs in Australia, New Zealand and Canada.

Summary of Results:

Variables	Conventional BG Treatment	Intensive BG Treatment	Statistical Significance of Group Difference
Death at 90 days (percent)	24.9%	27.5% (Adjusted OR 1.14; 1.01 to 1.29)	P=0.04
Length of stay (median days; IQR)	6 (2 to 11)	6 (2 to 11)	P=0.84
Days on mechanical ventilation	6.6±6.6	6.6±6.5	P=0.56
Renal-replacement therapy	14.5%	15.4%	P=0.34
Severe hypoglycemia	0.5%	6.8%	P<0.001

Other Findings

Deaths from cardiovascular causes more common in the intensive control group (41.6%) than in the conventional control group (35.8%); absolute difference, 5.8 percentage points; P=0.02
No difference in new organ failures (P=0.11).

Author Conclusion:

A goal to normalize blood glucose in critically ill patients does not benefit patients and may be harmful.

Funding Source:

Government:

Australian National Health and Medical Research Council, Health Research Council of New Zealand, Canadian Institutes for Health Research

Reviewer Comments:

This paper has an excellent discussion section.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes