Perioperative Versus Postoperative Glycemia Control in Cardiac Surgery Patients

May 15, 2015 updated by: Jan Blaha, MD, PhD., Charles University, Czech Republic

It is known that acute stress of organism often leads to hyperglycemia even in nondiabetic patients. It is also known that pathophysiological mechanisms: enhanced gluconeogenesis, impaired insulin secretion and decreased insulin sensitivity due to anti-insulin effect of stress hormones and proinflammatory cytokines, or changes of glucose excretion and renal tubular resorption.

Many studies proved the negative effects of hyperglycemia to different tissues and organs, e.g. hearth (increasing size of myocardial necrosis, reducing coronary collateral blood flow, exaggerating ischemia-reperfusion injury, impairing ischemic preconditioning), vascular (increased risk of thrombosis, endothelial dysfunction, activation of systemic inflammation with destabilization of atherosclerotic plaques), kidneys and its association with infectious complications.

The first Leuven study (published in 2001) demonstrated that hyperglycemia in critical care patients significantly increases risk of organ complication and total mortality. Although the importance of postoperative tight glycemia control is now widely accepted, glycemia stability during cardiac surgery is often neglected. It is known that postoperative hyperglycemia has negative effects, but it is not known what effect has its peroperative elevation.

Goal of this study is to demonstrate, whether full perioperative intensive glycemia control can reduce the incidence of postoperative morbidity even more than postoperative glycemia control only.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

It has been for a long time a well known phenomenon that the acute stress of organism induced for instance by an extensive surgery often leads to hyperglycemia, even in patients without a previous history of diabetes. Also well known are the common pathophysiological mechanisms, which are responsible for this, such as enhanced hepatic gluconeogenesis, impaired insulin secretion and decreased insulin sensitivity due to anti-insulin effect of stress hormones and proinflammatory cytokines, or a change of glucose excretion and higher renal tubular resorption.

Many studies proved the negative effect of the elevated blood glucose level to different tissues and organs. Even short-term hyperglycemia has been found to markedly impair cardiovascular function in ischemic heart, increasing size of myocardial necrosis, reducing coronary collateral blood flow, exaggerating ischemia-reperfusion cellular injury and/or impairing ischemic preconditioning.

Also other studies have identified numerous hyperglycemia-induced abnormalities such as increased risk of thrombosis, endothelial disfunction or activation of systemic inflammation, with possible destabilization of atherosclerotic plaques leading to acute ischemic syndromes. Hyperglycemia also has effect to the extent of renal injury, e.g. in patients after cardiac surgery, and last but not least, hyperglycemia has been associated with increased postoperative infectious complications.

Despite all those facts hyperglycemia has been until recently considered as a "protective" mechanism for patients in critical condition, when the cells are offered a supranormal amount of easily accessible energy. This approach has been radically changed thanks to Leuven study published by prof.Van den Berghe and her colleagues in 2001 in New England Journal of Medicine. This fundamental study proved that a higher levels of blood glucose in intensive care patients significantly increase the risk of organ complications as well as an overall death rate, and that, on the contrary, we can significantly decrease both mortality, as well as the amount of organ complications connected with the critical state by an intensive insulin therapy aimed to keep normoglycemia. Such results were confirmed also by another study of prof.Van den Berghe and her colleagues (published in NEJM 2006), this time performed on non-surgery patients. This fact was quickly accepted by the intensivists and therefore it is nowadays commonplace for us to carefully monitor blood glucose levels in postoperative ICU, and keep it at normal levels.

Both the above-mentioned studies are even more significant for cardiac surgery patients, since the population of the patients in the first Leuven study (2001), where the results of intensive insulinotherapy were more distinct in comparison with non-surgery population (2006) mostly thanks to a 40% reduced mortality, consisted up to 63% from patients following cardiac surgery.

If normoglycemia is commonplace in postoperative intensive care, then the stability of glycemia during cardiac surgery is usually neglected. There is no clear recommendation regarding when it is suitable to start intensive control of glycemia, whether to do so after the surgery or already during the surgery. We know that postoperative hyperglycemia has many negative effects on the organism, however, we do not know yet whether the peroperative rise of blood glucose itself during cardiac or other extensive surgery with postoperative maintenance of normoglycemia has negative or benefiting effects on the organism. Until now, there has not yet been a valid study performed that would answer this concrete question.

THE GOALS OF THE PROJECT:

The goal of this study is to prove whether by full perioperative intensive control of glycemia, the occurrence of organ complications will be decreased even more significantly than by only postoperative normalization of hyperglycemia, what has already been proved by published studies. This proposed study is aiming at complementing the fundamental Leuven study with perioperative data and therefore answering the question, when to start the control of glycemia by an intensified insulinotherapy in patients undergoing cardiac surgery.

A decisive factor for the success of the project is also a quality protocol of glycemia control in perioperative care. During the previous years there were a number of various insulin protocols that more or less successfully tried to keep the levels of blood glucose in normoglycemia. Thanks to the European study of CLINICIP (Closed Loop Insulin Infusion for Critically Ill Patients) our Department took part in as a clinical partner, the investigators had the possibility to evaluate several European protocols and to compare them with the computer algorithm MPC (Model Predictive Control). The comparison of the possibilities to keep the levels of blood glucose in normoglycemia ended positively in favors of eMPC algorithm compare to the standard protocols. Therefore the investigators decided to use its adaptative version also in this project for glycemia control.

THE HYPOTHESIS AND EXPECTED RESULTS:

The investigators hypothesize, that if the postoperative normalization of already started hyperglycemia can significantly decreases the occurrence of postoperative complications, then absolute perioperative glycemia control, thanks to complete blockage of the negative influences of even the short term hyperglycemia, can even further emphasize the reduction of the postoperative complications.

OUTCOME MEASURES:

Primary outcome - to prove, whether the full blocking of the perioperative blood glucose elevation will reach a lower occurrence of postoperative organ complications, than in patients with a temporary peroperative rise of glycemia. The investigators will observe a number of adverse events (newly developed organ dysfunctions) from any cause during the postoperative hospital stay:

cardiovascular (LCO, postoperatively initiated inotropic support or intra-aortic balloon counterpulsation, acute myocardial ischemia, moderate to severe arrhythmias, cardiopulmonary resuscitation), respiratory (acute pneumonia, fluidothorax > 300 ml, reintubation, acute respiratory distress syndrome/acute lung injury), neurological (stroke, transient ischemic attack), gastrointestinal (ileus, gastric ulcer, gastrointestinal bleeding, hepatopathy, acute pancreatitis, need of parenteral nutrition), renal (acute kidney injury defined by RIFLE criteria - stage Injury and above) infections defined by clinical picture and the need of systemic antibiotic therapy Scoring systems (Euroscore, TISS 28, APACHE II, SAPS3)

Secondary outcomes:

in-hospital mortality, ICU time further development of MPC algorithm

TIME SCHEDULE:

Year 1- starting the project, establishment of a database, recruitment of patients (800) and processing of partial results Year 2- project review, recruitment of patients (800) and processing of partial results and their presentation Year 3- project review, recruitment of patients (800), final results processing and their publication, study ending

METHODS:

Type of the study: prospective, randomized, controlled, double blinded Inclusion criteria: patients undergoing cardiac surgery, men and women aged 18-90 years, signed informed consent Exclusion criteria: patient's dissent, allergy to insulin or other components added to insulin solution Reasons for exclusion during study: repeated (twice) major hypoglycemia Randomization: on admission to OR into two equally large groups (A, B), after signed informed consent

A = Group of intensive glycemia control: blood glucose level will be maintained by continuous insulin infusion (Actrapid, Novo Nordisk A/S, Bagsvaerd, Danemark - 50 IU/50 ml FR) according to actual glycemia to keep it within normoglycemia limits (4.4 - 6.1 mmol/l) since patient's admission to operating room. Samplings will be taken in 1 to 4 hours intervals in accordance with glycemia stability and MPC algorithm suggestions.

B = Group of standard glycemia control: blood glucose level will be maintained by continuous insulin infusion (see above) within normoglycemia limits (4.4 - 6.1 mmol/l) after patient's admission to ICU after cardiac surgery. During surgery hyperglycemia will not be interfered before it will reach level of 10 mmol/l, then i.v. bolus of 1-2 IU of rapid-acting insulin was administered in order to keep glucose values under this threshold.

Data collection: demographic and clinical characteristics, BMI, standard laboratory findings, perioperative organ complications (respiratory, renal, hematologic, immunologic, infection, wound healing), weaning from ventilatory support, use of catecholamine, in-hospital mortality, scoring (Euroscore, TISS 28, APACHE II, SAPS)

CONCLUSION:

The answer the question when is the optimal time to start glycemia control in patients with in advance known beginning of acute stress reaction would give us a chance, if our hypothesis will be confirmed, to block on time negative effects of hyperglycemia and thereby to decrease number of postoperative organ complications, what would have a significant importance not only medical, but also socio-economical.

Also further eMPC improvement based on clinical data from this study will give to intensivists instrument for markedly simpler and mainly more accurate glycemia normalization and glycemia control in critically ill patients then recent glycemia protocols enable.

Study Type

Interventional

Enrollment (Actual)

2384

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Czech Republic
      • Prague, Czech Republic, 128 51
        • General University Hospital Prague

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • patients undergoing cardiac surgery
  • men and women
  • aged 18-90 years
  • signed informed consent

Exclusion Criteria:

  • patient's dissent
  • allergy to insulin or other components added to insulin solution

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Perioperative glycemia control
Group of perioperative intensive glycemia control: blood glucose level will be maintained by continuous insulin infusion (Actrapid, Novo Nordisk A/S, Bagsvaerd, Danemark - 50 IU/50 ml FR) according to actual glycemia to keep it within normoglycemia limits (4.4 - 6.1 mmol/l) since patient's admission to operating room. Samplings will be taken in 1 to 4 hours intervals in accordance with glycemia stability and MPC algorithm suggestions.
Procedure: Intensive glycemia control
Blood glucose levels will be maintained by continuous insulin infusion (Actrapid, Novo Nordisk A/S, Bagsvaerd, Danemark - 50 IU/50 ml FR) within normoglycemia limits (4.4 - 6.1 mmol/l)
Other Names:
  • Tight glycemia control
  • Blood glucose control
Active Comparator: Postoperative glycemia control
Group of standard glycemia control: blood glucose level will be maintained by continuous insulin infusion (see above) within normoglycemia limits (4.4 - 6.1 mmol/l) after patient's admission to ICU after cardiac surgery. During surgery hyperglycemia will not be interfered before it will reach level of 10 mmol/l.
Procedure: Intensive glycemia control
Blood glucose levels will be maintained by continuous insulin infusion (Actrapid, Novo Nordisk A/S, Bagsvaerd, Danemark - 50 IU/50 ml FR) within normoglycemia limits (4.4 - 6.1 mmol/l)
Other Names:
  • Tight glycemia control
  • Blood glucose control

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Morbidity comparison of perioperative vs. postoperative glycemia control
Time Frame: in-hospital
Number of adverse events from any cause during the postoperative hospital stay
in-hospital

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
mortality
Time Frame: in-hospital
in-hospital mortality, ICU time
in-hospital

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Charles University, Czech Republic

Investigators

  • Principal Investigator: Jan Blaha, M.D., PhD., 1st Faculty of Medicine, Charles University in Prague

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2007

Primary Completion (Actual)

December 1, 2010

Study Completion (Actual)

June 1, 2012

Study Registration Dates

First Submitted

February 25, 2012

First Submitted That Met QC Criteria

March 6, 2012

First Posted (Estimate)

March 8, 2012

Study Record Updates

Last Update Posted (Estimate)

May 18, 2015

Last Update Submitted That Met QC Criteria

May 15, 2015

Last Verified

May 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • eMPC_long

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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