Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01548963 |
| Other study ID # |
eMPC_long |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
February 25, 2012 |
| Last updated |
May 15, 2015 |
| Start date |
January 2007 |
| Est. completion date |
June 2012 |
Study information
| Verified date |
May 2015 |
| Source |
Charles University, Czech Republic |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Czech Republic: Ethics Committee |
| Study type |
Interventional
|
Clinical Trial 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.
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.
