Does the achievement of an intermediate glycemic target reduce organ failure and mortality? A post hoc analysis of the Glucontrol trial

doi:10.1016/j.jcrc.2014.01.013

Journal of Critical Care

Volume 29, Issue 3, June 2014, Pages 374-379

https://doi.org/10.1016/j.jcrc.2014.01.013 Get rights and content

Abstract

Objective

This research evaluates the impact of the achievement of an intermediate target glycemic band on the severity of organ failure and mortality.

Methods

Daily Sequential Organ Failure Assessment (SOFA) score and the cumulative time in a 4.0 to 7.0 mmol/L band (cTIB) were evaluated daily up to 14 days in 704 participants of the multicentre Glucontrol trial (16 centers) that randomized patients to intensive group A (blood glucose [BG] target: 4.4-6.1 mmol/L) or conventional group B (BG target: 7.8-10.0 mmol/L). Sequential Organ Failure Assessment evolution was measured by percentage of patients with SOFA less than or equal to 5 on each day, percentage of individual organ failures, and percentage of organ failure–free days. Conditional and joint probability analysis of SOFA and cTIB 0.5 or more assessed the impact of achieving 4.0 to 7.0 mmol/L target glycemic range on organ failure. Odds ratios (OR) compare the odds risk of death for cTIB 0.5 or more vs cTIB less than 0.5, where a ratio greater than 1.0 indicates an improvement for achieving cTIB 0.5 or more independent of SOFA or glycemic target.

Results

Groups A and B were matched for demographic and severity of illness data. Blood glucose differed between groups A and B (P < .05), as expected. There was no difference in the percentage of patients with SOFA less than or equal to 5, individual organ failures, and organ failure–free days between groups A and B over days 1 to 14. However, 20% to 30% of group A patients failed to achieve cTIB 0.5 or more for all days, and significant crossover confounds interpretation. Mortality OR was greater than 1.0 for patients with cTIB 0.5 or more in both groups but much higher for group A on all days.

Conclusions

There was no difference in organ failure in the Glucontrol study based on intention to treat to different glycemic targets. Actual outcomes and significant crossover indicate that this result may not be due to the difference in target or treatment. Odds ratios–associated achieving an intermediate 4.0 to 7.0 mmol/L range improved outcome.

Introduction

Rate, severity, and lack of resolution of organ failure are strongly associated with increased morbidity and mortality in intensive care unit (ICU) patients [1]. Organ failure is typically assessed daily by the Sequential Organ Failure Assessment (SOFA) score [2], [3], [4]. Van den Berghe et al [5] suggested that glucose control could improve organ failure, and, recently, cumulative time in an intermediate glycemic band (4.0-7.0 mmol/L) (cTIB) was associated with improved rate and severity of organ failure, based on a different study [6]. However, glycemic control and targets are contentious [7], [8]. Although decreased mortality was found in some studies [5], [6], [9], others did not [10], [11], [12], and many saw no difference [13], [14], [15]. Therefore, moderate targets are currently recommended [16], [17], despite evidence that intermediate target ranges could favorably influence organ failure rate and severity.

This study evaluates the impact and interaction of organ failure and glycemic control in the Glucontrol trial [10] that compared separate glycemic target bands, one of which is entirely within the 4.0 to 7.0 mmol/L band used by Chase et al [18], whereas the others did not overlap. This randomized trial data provide a further opportunity to examine the interaction of glycemic level and organ failure and how initial results [18] generalize over an independent cohort.

Section snippets

Glucontrol

Glucontrol was a prospective, randomized, multicenter controlled glucose control trial implemented in 19 centers (21 ICUs) from November 2004 to May 2006 [10]. The 1078 patients were randomized to group A (target: 4.4-6.1 mmol/L) or group B (target: 7.8-10.0 mmol/L). Insulin infusion dosing was defined using sliding scales, with blood glucose (BG) measured hourly when not in the target range. For limited variation (≤ 50%) of BG levels, 2 hourly and 4 hourly measurements were allowed. Details are

Results

Table 3 shows initial and maximum SOFA score, and initial BG is equivalent over groups (P ≥ .4). Group A has lower BG levels than patients from group B (P < .05), more hypoglycemia, and greater per-patient cTIB, as in Chase et al [18] and thus as expected.

Fig. 2 shows SOFA improves slightly for both groups over the first 12 to 14 days. Table 4 shows patient numbers per day in each group in Fig. 2. The difference in SOFA less than or equal to 5 between groups A and B is not significant for any

Discussion

The results show no clinically significant difference in the evolution of organ failure severity or rate between groups A and B from Glucontrol. Sequential Organ Failure Assessment less than or equal to 5 is not significant for any of days 1 to 14, although low patient numbers underpower the comparison on days13 to 14 (Table 4). These results are supported by the OFFD and IOF results. Glycemic outcome was examined independently for its impact on mortality. Patients in groups A and B who

Conclusions

This study presents results from a unique analysis of a randomized glycemic control trial that evaluates the impact of glycemic control and target range in terms of daily organ failure status. Two main conclusions are drawn.

First, there was no difference in the rate or severity of organ failure between the lower intensive (group A) and higher conventional (group B) groups. However, significant patient crossover between groups with very low per-patient percent BG in both groups target band

Key messages

•
There was no difference in the rate or severity of organ failure between the lower intensive (group A) and higher conventional (group B) treated groups.
•
Examining mortality with respect to achieving a cTIB more than 50% had improved OR (of survival) on all days of stay.
•
Cohort differences may play a role in assessing the impact of glycemia on organ failure.
•
Cumulative time in band seems to be an effective and novel glycemic target for control.

Authors’ information

1.
MSc, Cardiovascular Research Centre, Institut de Physique, Université de Liege, Institut de Physics, Allée du 6 Août, 17 (Bât B5), B4000 Liege, Liege, Belgium.
2.
PhD, Cardiovascular Research Centre, Institut de Physique, Université de Liege, Institut de Physics, Allée du 6 Août, 17 (Bât B5), B4000 Liege, Liege, Belgium.
3.
PhD, Department of Mechanical Engineering, Centre for Bio-Engineering, University of Canterbury, Christchurch, Private Bag 4800, 8054, New Zealand.
4.
BE (Hons), Department of

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^☆: Competing interests: The authors declare that they have no competing interests.

^☆☆: Authors’ contribution: JCP and CM conducted the trial and made the acquisition of data during the Glucontrol study. All authors were involved in the analysis and interpretation of data. The manuscript was originally drafted by SP, JGC, and JCP, but all authors made contributions through the entire process, including reading and final approval of this manuscript.

^★: Financial support: Fonds National de la Recherche Scientifique (F.R.S.-FNRS, Belgium) and Department of Mechanical Engineering, Scholarship Grant, University of Canterbury, Christchurch, New Zealand.

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Clinical StudyDoes the achievement of an intermediate glycemic target reduce organ failure and mortality? A post hoc analysis of the Glucontrol trial☆,☆☆,★

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Glucontrol

Results

Discussion

Conclusions

Key messages

Authors’ information

J Crit Care

Best Pract Res

Mayo Clin Proc

Chest

Endocr Pract

Mayo Clin Proc

The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on sepsis-related problems of the European Society of Intensive Care Medicine

Intensive Care Med

Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine

Crit Care Med

Organ dysfunction in patients with severe sepsis

Surg Infect (Larchmt)

Intensive insulin therapy in the critically ill patients

N Engl J Med

Implementation and evaluation of the SPRINT protocol for tight glycaemic control in critically ill patients: a clinical practice change

Clinical Study
Does the achievement of an intermediate glycemic target reduce organ failure and mortality? A post hoc analysis of the Glucontrol trial☆,☆☆,★