EAL

CI: Blood Glucose Control (2009)

Citation:

Mitchell I, Knight E, Gissane J, Tamhane R, Kolli R, Leditschke IA, Bellomo R, Finfer S; Australian and New Zealand Intensive Care Society Clinical Trials Group. A phase II randomised controlled trial of intensive insulin therapy in general intensive care patients. Crit Care Resusc. 2006; 8(4): 289-293.

PubMed ID: 17227263

Study Design:

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

NEUTRAL: See Quality Criteria Checklist below.

Research Purpose:

The research purpose was to determine safety and efficacy of intensive vs. conventional insulin therapy in the general ICU.

Inclusion Criteria:

Age 18 years or older
Predicted to stay in ICU for two or more days
Informed consent obtained from patient or surrogate.

Exclusion Criteria:

Age younger than 18 years
Expected ICU stay fewer than two days
Unwilling to give informed consent.

Description of Study Protocol:

Recruitment

All eligible patients admitted to ICU from March 2003 through December 2003.

Design

RCT.

Blinding used

Randomization though use of sealed envelopes balanced with permuted blocks of 10. It was not possible to blind nursing or medical staff to insulin regimen.

Intervention

Insulin treatment or conventional insulin treatment:

Intensive: insulin infusion commenced if BG reached 6.1mmol per L and titrated to maintain BG concentration at 4.6mmol per L to 6.1mmol per L
Conventional: insulin infusion commenced if BG reached 12mmol per L and titrated to maintain BG concentration at 10mmol per L to 11.1mmol per L.

Statistical analysis

Power analysis revealed that 31 patients per group were needed to detect a difference of two standard deviations of overall mean BG concentration between the two groups with 95% certainty at 80% power. Thus, target recruitment was 35 per group.
Numerical data presented as median and IQR; also used z tests
Categorical data presented as counts and percentages; also used chi-square tests.

Data Collection Summary:

Timing of Measurements

Baseline: demographic data, APACHE II score, diagnosis, BG value, pre-existing diabetes
After randomization: BG values, hourly insulin dosing, type and quantity of caloric intake.

Dependent Variables

Primary: median blood glucose concentration
Secondary:
- Hypoglycemia (≤2.2mmol per L)
- ICU mortality
- Hospital mortality.

Independent Variables

Insulin therapy
- Conventional: insulin infusion commenced if BG reached 12mmol per L, and titrated to maintain BG concentration at 10mmol per L to 11.1 mmol per L
- Intensive: insulin infusion commenced if BG reached 6.1mmol per L, and titrated to maintain BG concentration at 4.6mmol per L to 6.1mmol per L.

Control Variables

Enteral feeding started as soon as possible.

Description of Actual Data Sample:

Initial N

70 (60% male).

Attrition (final N)

70.

Age

Median age, 65.8 years (IQR 59-74.6).

Ethnicity

Australian and New Zealander.

Other relevant demographics

61% medical and 39% surgical
Intensive insulin group had:
- Higher APACHE II scores: Intensive insulin group, 26.1 (23.5-28.9 IQR); conventional insulin group, 22 (20-29 IQR) (P<0.01)
- Greater number of patients admitted with sepsis (P<0.001).

Anthropometrics

Intensive insulin group had higher BMI.

Location

Australia and New Zealand.

Summary of Results:

Variables	Intensive Insulin Treatment	Conventional Insulin	Statistical Significance of Group Difference
Median hourly blood glucose level (median; IQR)	5.4 (5.1-5.7)	7.9 (7.2-9.0)	P<0.0001
Hypoglycemia [number of patients with BG≤2.2mmol/L(%)]	5 (14.3%)	0	NS
ICU mortality	20%	6%	P=0.15
Hospital mortality (%)	26%	9%	P=0.11 RR 3.0 (95% CI 0.78-15.69)

Other Findings

Most common cause of death in intensive insulin treatment group was sepsis with multi-organ failure. Subjects in the intensive insulin treatment group had lower APACHE II scores and higher incidence of sepsis at admission than those in the conventional insulin treatment group.

Author Conclusion:

Intensive insulin treatment was effective in achieving target BG. The incidence of hypoglycemia was increased, but there was no detectable harm.

Funding Source:

University/Hospital:

The Canberra Hospital, Canberra ACT, Australia

Reviewer Comments:

This study received a neutral quality rating because at baseline the subjects in the intensive insulin treatment group differed significantly from those in the conventional insulin treatment group. The investigators did not use multi-variate analyses to account for the group differences.

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?		???
	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?	No
	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?		N/A
	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%.)	N/A
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	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?		No
	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?	No
	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)?	No
	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?	Yes
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