Perioperative Versus Postoperative Glycemia Control in Cardiac Surgery Patients
Condition: Perioperative and Postoperative Hyperglycemia; Tight Glycemia Control
MeSH terms: Hyperglycemia
Study type: Interventional

Summary: 
      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.
    

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.
    

Intervention name(s): Intensive glycemia control
Intervention type(s): Procedure
Intervention description(s): 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 intervention name(s): Tight glycemia control; Blood glucose control
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Tight glycemia control; Model Predictive Control algorithm; Cardiac surgery patients