Perioperative Versus Postoperative Glycemia Control in Cardiac Surgery Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Jan Blaha, MD, PhD., Charles University, Czech Republic
ClinicalTrials.gov Identifier:
NCT01548963
First received: February 25, 2012
Last updated: April 6, 2013
Last verified: April 2013
  Purpose

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.


Condition Intervention
Perioperative and Postoperative Hyperglycemia
Tight Glycemia Control
Procedure: Intensive glycemia control

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Perioperative Versus Postoperative Glycemia Control in Cardiac Surgery Patients

Resource links provided by NLM:


Further study details as provided by Charles University, Czech Republic:

Primary Outcome Measures:
  • Morbidity comparison of perioperative vs. postoperative glycemia control [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    Number of postoperative complications in 30 days following cardiac surgery.


Secondary Outcome Measures:
  • mortality [ Time Frame: in-hospital, 30 day ] [ Designated as safety issue: Yes ]
    in-hospital and 30-Day mortality, ICU time


Enrollment: 2384
Study Start Date: January 2007
Study Completion Date: June 2012
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 (4.2 - 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 (4.2 - 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 (4.2 - 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 (4.2 - 6.1 mmol/l)
Other Names:
  • Tight glycemia control
  • Blood glucose control

  Hide Detailed Description

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 mainly:

Time of weaning from ventilatory support and other respiratory complications Renal impairment (elevation of serum creatinine, glomerular filtration changes, needs of diuretics or CRRT) Hematologic and immunologic complications (No. of transfusions, changes in cell and plasmatic immunity) Infectious complications, wound healing Catecholamine and other drug treatment Scoring systems (Euroscore, TISS 28, APACHE II, SAPS3)

Secondary outcomes: in-hospital and 30-Day 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 (4.2 - 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 (4.2 - 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.

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 and 30-Day 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.

  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01548963

Locations
Czech Republic
General University Hospital Prague
Prague, Czech Republic, 128 51
Sponsors and Collaborators
Charles University, Czech Republic
Investigators
Principal Investigator: Jan Blaha, M.D., PhD. 1st Faculty of Medicine, Charles University in Prague
  More Information

Publications:
Responsible Party: Jan Blaha, MD, PhD., Principal Investigator, Charles University, Czech Republic
ClinicalTrials.gov Identifier: NCT01548963     History of Changes
Other Study ID Numbers: eMPC_long
Study First Received: February 25, 2012
Last Updated: April 6, 2013
Health Authority: Czech Republic: Ethics Committee

Keywords provided by Charles University, Czech Republic:
Tight glycemia control
Model Predictive Control algorithm
Cardiac surgery patients

Additional relevant MeSH terms:
Hyperglycemia
Glucose Metabolism Disorders
Metabolic Diseases

ClinicalTrials.gov processed this record on April 17, 2014