Safer glycemic control using isomaltulose-based enteral formula: A pilot randomized crossover trial

doi:10.1016/j.jcrc.2009.07.006

Journal of Critical Care

Volume 25, Issue 1, March 2010, Pages 90-96

https://doi.org/10.1016/j.jcrc.2009.07.006 Get rights and content

Abstract

Purpose

Preventing harmful hyperglycemia is important in critical illness. However, insulin therapy increases the risk of hypoglycemia. In patients with diabetes, isomaltulose-based enteral formula (IF) feeding has been shown to reduce glycemia. This randomized controlled crossover study was conducted to determine whether IF feeding improves glycemia in postoperative critically ill patients.

Material and Methods

Eight patients who developed hyperglycemia (>150 mg/dL) after esophagectomy were included. Patients were randomized to either the IF or the standard feeding formula (SF) arm. After 16 hours of administration of randomized formula and 8 hours of washout, patients crossed over to the other formula for the next 16 hours. Continuous glucose measurement using STG-22 (Nikkiso, Tokyo, Japan) was performed during the trial.

Results

Maximum blood glucose concentration was 181 mg/dL with IF, significantly lower than the 206 mg/dL with SF (P = .001). Mean glycemia during feeding periods was 162 mg/dL with IF, significantly lower than the 176 mg/dL with SF (P = .0001). Seven (87.5%) patients taking SF exceeded 180 mg/dL compared with 3 (37.5%) patients taking IF (P = .005). This effect was seen without any risk of hypoglycemia and complication.

Conclusions

Isomaltulose-based enteral formula might be useful for safer glycemic control in postoperative critically ill patients. Further study to determine clinical benefit of IF feeding is justified.

Introduction

Hyperglycemia is common in critically ill patients [1], [2], and its control is considered important [3], [4], [5], [6]. Recently, lowering glycemia has been recommended to improve patient outcome [7], [8]. However, using insulin increases the risk of hypoglycemia [9], [10], [11], [12], [13], [14]. Severe or prolonged hypoglycemia can result in cardiac arrhythmias, convulsions, irreversible brain damage, and death [15], [16], [17]. Accordingly, hypoglycemia is of great concern when delivering continuous insulin infusions, especially to sedated patients in the intensive care unit (ICU). In recently published large randomized controlled studies, mortality rates in patients with hypoglycemia using intensive insulin therapy increased by a factor of 2 to 3.3 when compared with patients who did not [18]. The Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation trial also reported that an episode of hypoglycemia was associated with increased mortality [19], [20]. Thus, it would be important to avoid hypoglycemia as much as hyperglycemia.

Isomaltulose is a naturally occurring disaccharide composed of α-1,6-linked glucose and fructose [21]. An isomaltulose-based enteral formula (IF) (Inslow/MHN-01, Meiji Dairy Products, Tokyo, Japan) (Table 1) has been shown to improve insulin resistance [22] and reduce glycemia [23], [24], [25], [26]. Thus, IF feeding might also improve blood glucose control without any risk of hypoglycemia in postoperative critically ill patients [27]. However, there was limited information on the effects of IF feeding in critically ill patients.

Accordingly, we conducted a randomized controlled crossover study comparing IF to standard feeding formula (SF) (Table 1) in postesophagectomy patients requiring intensive care. The aim of this study was to compare the efficacy and safety of IF with those of SF in such a cohort.

Section snippets

Subjects and methods

This study was conducted between January and December 2007 in the ICU of a tertiary teaching hospital. The human research ethics committee of Okayama University Hospital approved this study. Written informed consent was obtained from all patients.

Results

Thirty patients admitted to the ICU after esophagectomy during the study period were enrolled in the study. One of those 30 patients was excluded because of alternation of operation plan. The remaining 29 patients underwent postoperative feeding and were screened for hyperglycemia. Nine (31.0%) patients developed hyperglycemia (>150 mg/dL [8.3 mmol/L]) under the E₁₀₀ of SF feeding and were randomized. Of those 9 patients, 8 completed crossover feeding (16 feeding periods). One patient completed

Discussion

We conducted a pilot randomized controlled crossover study comparing the safety and efficacy of IF for glycemia in postesophagectomy patients admitted to the ICU. This is the first study to test the effect of IF in critically ill patients. Our investigation revealed that IF, compared with SF, reduces glycemia, HGI [31], and glucose variability [30] during feeding.

Lowering blood glucose levels has been recommended in international consensus guidelines as a means of improving patient outcomes in

Acknowledgments

Dr Egi developed the study designs, conducted the data analysis, and wrote and revised the manuscript. Drs Arai, Yamatsuji, and Naomoto developed the study designs and critiqued successive drafts of the manuscript. Drs Toda, Yokoyama, and Katayama collected original data and critiqued successive drafts of the manuscript. Dr Morita critiqued successive drafts of the manuscript. Dr Michael Bailey conducted additional analysis and proof reading. Dr Egi had full access to all of the data in the

References (47)

WolfeR.R. et al.
Glucose metabolism in man: responses to intravenous glucose infusion
Metabolism
(1979)
ShangrawR.E. et al.
Differentiation between septic and postburn insulin resistance
Metabolism
(1989)
MalmbergK. et al.
Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year
J Am Coll Cardiol
(1995)
MitchellI. et al.
A phase II randomised controlled trial of intensive insulin therapy in general intensive care patients
Crit Care Resusc
(2006)
FinferS. et al.
The NICE-SUGAR (Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) Study: statistical analysis plan
Crit Care Resusc
(2009)
LinaB.A. et al.
Isomaltulose (palatinose): a review of biological and toxicological studies
Food Chem Toxicol
(2002)
AchtenJ. et al.
Exogenous oxidation of isomaltulose is lower than that of sucrose during exercise in men
J Nutr
(2007)
AraiH. et al.
Effects of a palatinose-based liquid diet (Inslow) on glycemic control and the second-meal effect in healthy men
Metabolism
(2007)
FujiwaraT. et al.
Effects of a novel palatinose based enteral formula (MHN-01) carbohydrate-adjusted fluid diet in improving the metabolism of carbohydrates and lipids in patients with esophageal cancer complicated by diabetes mellitus
J Surg Res
(2007)
AraiH. et al.
Effect of a novel palatinose-based liquid balanced formula (MHN-01) on glucose and lipid metabolism in male Sprague-Dawley rats after short- and long-term ingestion
Metabolism
(2004)

RobinsonL.E. et al.

Insulin resistance and hyperglycemia in critical illness: role of insulin in glycemic control

AACN Clin Issues

(2004)

CoursinD.B. et al.

Perioperative diabetic and hyperglycemic management issues

Crit Care Med

(2004)

MalmbergK.

Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group

Bmj

(1997)

DellingerR.P. et al.

Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock

Crit Care Med

(2004)

DellingerR.P. et al.

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008

Intensive Care Med

(2007)

BilottaF. et al.

Intensive insulin therapy after severe traumatic brain injury: a randomized clinical trial

Neurocritical Care

(2008)

BrunkhorstF.M. et al.

Intensive insulin therapy and pentastarch resuscitation in severe sepsis

N Engl J Med

(2008)

OksanenT. et al.

Strict versus moderate glucose control after resuscitation from ventricular fibrillation

Intensive Care Med

(2007)

Van den BergheG. et al.

Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm

Diabetes

(2006)

van den BergheG. et al.

Intensive insulin therapy in critically ill patients

N Engl J Med

(2001)

BhatiaA. et al.

Hypoglycemia and cardiac arrest in a critically ill patient on strict glycemic control

Anesth Analg

(2006)

BilottaF. et al.

Glycemia management in neurocritical care patients: a review

J Neurosurg Anesthesiol

(2009)

OddoM. et al.

Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study

Crit Care Med

(2008)

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Additionally, we were unable to extract outcome data from five studies [35,37,39,43,44], despite multiple but fruitless attempts to contact authors for data requests. Notably, meta-analyzable data of CoV and glucose SD were measured but not reported in two [37,43] and three studies [39,43,44], respectively. With regards to the GRADE assessment, we had multiple reasons for rating down the quality of evidence.
To evaluate the association of glycemic-control formulae (GCF) with measurements of glycemic control and clinical outcomes compared to standard enteral formulae (SF) in critically ill patients.
MEDLINE, EMBASE, Scopus and the Cochrane Central Register of Controlled Trials were searched from inception up to January, 2021.
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Ten studies (12 reports, 685 patients) were included. The use of GCFs was associated with lower blood glucose (WMD, −16.06 mg/dL; 95% CI -23.48 to −8.63; I² = 47%) and lower daily administered insulin (WMD, −7.20 IU; 95% CI -13.92 to −0.48; I² = 53%). Glycemic variability, measured by the coefficient of variation, was also associated with the use of GCFs (WMD, −6.84%; 95% CI, −13.57 to −0.11; I² = 95%). In contrast, analyses for length of ICU stay (WMD, −0.12, 95% CI -1.77 to 1.52; I² = 0%), duration of MV (WMD, −0.34 days; 95% CI, −1.72 to 1.04; I² = 0%) and mortality (RR, 1.13; 95% CI 0.82 to 1.56; I² = 0%) were not statistically significant. Quality of evidence ranged from low to very low, and only one study was judged as at low risk of bias.
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Isomaltulose (IM) is a naturally occurring disaccharide composed of alpha-1,6-linked glucose and fructose monomers. IM is gaining interest as an alternative sweetener to sucrose primarily because of its low glycaemic index (GI) properties. Low GI has been implicated in the prevention and management of chronic diseases such as cardio-metabolic diseases and cancers. The low glycaemic potential of IM has fuelled the many recent in-vitro, animal and human studies including randomised-controlled trials and cohorts. This review discusses the chemical and physiological properties of IM in relation to its potential health effects, with a focus on its prebiotic properties. Research health findings from existing literature published within the last 10 years were compiled and summarised. The novel applications of products formulated with IM in improving health, cognition and nutrition are highlighted in this review. This review also evaluates the prebiotic potential of IM, an emerging alternative sweetener.
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^☆: Study sites: Department of Anesthesiology and Resuscitology, Okayama University Medical School, Okayama, Japan.

^☆☆: Funding: Supported by grants-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan.

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Glucose ControlSafer glycemic control using isomaltulose-based enteral formula: A pilot randomized crossover trial☆,☆☆

Abstract

Purpose

Material and Methods

Results

Conclusions

Introduction

Section snippets

Subjects and methods

Results

Discussion

Acknowledgments

Metabolism

Metabolism

J Am Coll Cardiol

Crit Care Resusc

Crit Care Resusc

Food Chem Toxicol

J Nutr

Metabolism

J Surg Res

Metabolism

Insulin resistance and hyperglycemia in critical illness: role of insulin in glycemic control

AACN Clin Issues

Perioperative diabetic and hyperglycemic management issues

Crit Care Med

Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group

Bmj

Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock

Crit Care Med

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008

Intensive Care Med

Intensive insulin therapy after severe traumatic brain injury: a randomized clinical trial

Neurocritical Care

Intensive insulin therapy and pentastarch resuscitation in severe sepsis

N Engl J Med

Strict versus moderate glucose control after resuscitation from ventricular fibrillation

Intensive Care Med

Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm

Diabetes

Intensive insulin therapy in critically ill patients

N Engl J Med

Hypoglycemia and cardiac arrest in a critically ill patient on strict glycemic control

Anesth Analg

Glycemia management in neurocritical care patients: a review

J Neurosurg Anesthesiol

Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study

Crit Care Med

Glucose Control
Safer glycemic control using isomaltulose-based enteral formula: A pilot randomized crossover trial☆,☆☆