EAL

CI: Blood Glucose Control (2009)

Citation:

Arabi YM, Dabbagh OC, Tamim HM, Al-Shimemeri AA, Memish ZA, Haddad SH, Syed SJ, Giridhar HR, Rishu AH, Al-Daker MO, Kahoul SH, Britts RJ, Sakkijha MH. Intensive versus conventional insulin therapy: A randomized controlled trial in medical and surgical critically ill patients. Crit Care Med. 2008 Dec; 36(12): 3,190-3,197.

PubMed ID: 18936702

Study Design:

Randomized control trial.

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

To investigate whether intensive insulin therapy (IIT) reduces mortality in medical and surgical ICU patients.

Inclusion Criteria:

Age 18 or older
Serum glucose greater than 110mg per dL (6.1mmol per L) during the first 24 hours of ICU admission.

Exclusion Criteria:

Type I diabetes
Diabetic ketoacidosis
Documented hypoglycemia on ICU admission or in the same hospitalization
Brain death
Do-not-resuscitate status
Terminal illness with expected survival less than four weeks
Post-cardiac arrest
Seizures within the last six months
Pregnancy
Liver transplantation
Burn victims
Re-admission to ICU within same hospitalization
Enrollment in a competing trial
Expected ICU length of stay less than 24 hours
Inability to obtain consent within 24 hours of ICU admission.

Description of Study Protocol:

Recruitment

Consecutive patients were checked for eligibility by an investigator not involved in the randomization process.

Design

Nurse coordinator randomized enrolled patients into intensive insulin therapy (IIT) or conventional insulin therapy (CIT) based on computer-generated random permuted blocks of 20 patients each
Stratified randomization performed for post-operative and nonoperative patients.

Intervention

Patients received either ICC to maintain blood glucose between 80mg to 110mg per dL (4.4mmol to 6.1mmol per L) or conventional insulin therapy to maintain a blood glucose level of 180mg to 200mg per dL (10.0mmol to 11.1mmol per L).

Statistical Analysis

Sample size calculated to show 50% relative risk reduction or 8% absolute risk reduction; 258 patients in each group, using a Type 1 error of 5% and power of 80%
Intention-to-treat analysis
Baseline characteristics and outcome variables were compared using a T-test, chi-square, and proportional tests, as appropriate
Adjusted intervention effects were calculated with well-known and clinically relevant baseline characteristics in a time-to-death multivariate stepwise Cox regression models
Absence of colinearity checked by calculating variance inflation factors
Missing information was replaced by median values
Results expresses as adjusted hazards ratios (AHR) and 95% confidence intervals
Continuous variables stratified into two groups based on median values
For outcomes presented as rates, such as hypoglycemia, Z-approximation was used to compare IIT with CIT.

Data Collection Summary:

Timing of Measurements

Baseline recording of demographics, anthropometrics, scores and treatments
Blood glucose checked hourly using arterial or capillary whole blood samples
When blood glucose value was less than or equal to 3.2mmol per L, blood glucose was checked every 20 minutes.

Dependent Variables

Primary: ICU mortality
Secondary:
- Causes of death
- Hospital mortality
- ICU length of stay
- Hospital length of stay
- Mechanical ventilation
- Number of hypoglycemic episodes (glucose less than or equal to 40mg per dL or 2.2mmol per L)
- Rate of hypoglycemic episodes per 100 days
- ICU-acquired infections
- Sepsis, severe sepsis, and septic shock, defined according to the 2001 International Sepsis Definitions conference
- Nosocomial infections defined according to the National Nosocomial Infections Surveillance System.

Independent Variables

Intensive insulin therapy or conventional insulin therapy.

Description of Actual Data Sample:

Initial N: 523 enrolled (75% male); 266 assigned to IIT group and 257 assigned to CIT group
Attrition final N: 523 (no attrition)
Age: Mean 50.6±22.6 for IIT; 54.3±20.5 for CIT
Ethnicity: Saudi Arabian.

Other relevant demographics:

Mixed ICU of medical and surgical patients.

**Comparison of CIT and IIT Groups**
	CIT group	IIT group	P-Value
age (mean ±SD)	54.3±20.5	50.6±22.6	0.05
baseline blood glucose (mean ±SD)	11.7±4.5	10.8±4.3	0.01
history of diabetes	47.9%	32%	0.0002
SOFA score (mean ±SD)	8.8±3.5	8.7±3.5	0.59
APACHE II score (mean ±SD)	23.1±8.4	22.5±7.9	0.41

Anthropometrics

Mean BMI 27.9±8.1 for CIT and 26.8±6.9 for IIT (P=0.10).

Location

Riyadh, Saudi Arabia.

Summary of Results:

Variables	IIT Group	CIT Group	P-Value
*ICU mortality, %	13.5	14.3	0.70
Hospital mortality %	27.1	32.3	0.19
ICU Length of Stay (days) mean ±SD	9.6±8.5	10.8±11.3	0.18
Hospital Length of Stay (days) mean ±SD	54.1±84.1	57.5±77.1	0.63
Mechanical ventilation (days) mean ±SD	8.3±7.1	9.7±11.0	0.11
Any ICU-acquired infection per 1000 ICU days	56	59	0.69
ICU-acquired sepsis, N (%)	98 (36.9%)	105 (40.9)	0.35
New renal replacement therapy, N (%)	31 (11.7)	31 (12.1)	0.89

Other Findings

*After adjusting for baseline characteristics IIT was not associated with decreased mortality when compared to CIT (Adjusted Hazard Ratio 1.09, 95% CI 0.7 to 1.72). No significant difference in secondary endpoints (LOS, mechanical ventilation, infection, renal replacement therapy).
IIT was associated with significant increase in hypoglycemia incidence. 26.8% of IIT patients had as least one hypoglycemia episode compared to 3.1% in CIT patients (P<0.0001)
Patients with hypoglycemia had higher ICU mortality than those who did not (23.8% compared to 13.7%, P=0.02).

Author Conclusion:

Intensive insulin therapy put ICU patients at risk for hypoglycemia and did not improve survival. ICU and hospital length of stay, days on mechanical ventilation, or ICU-acquired infectious complications were not reduced by the IIT.

Funding Source:

University/Hospital:

King Abdulaziz Medical City ICU Research Fund

Reviewer Comments:

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?	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?		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?	N/A
	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?	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