The Effect of Nitroglycerin Infusion Rate on Cerebral Rewarming During Hypothermic Coronary Artery Bypass Grafting

Study Overview
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Brief Summary
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Glyceryl trinitrate is used in coronary artery bypass grafting surgery. This surgery frequently employs hypothermic cardiopulmonary bypass, where the whole body is cooled down to 28-32 °C to arrest the heart, and protect the organs from ischemic insult. When the cardiac repair or grafting is done, the body is warmed to 37 °C. During this rewarming period, the heart has to beat against the vessels, all of which are constricted due to hypothermia. To overcome this constriction of the vessels, and decrease the workload of the heart, glyceryl trinitrate is infused. This drug causes significant dilatation in arteries and veins, which allows the heart to pump the blood with less force. The dilatation of the vessels also allows the body to rewarm more easily. The investigators' concern is whether increased infusion rates of glyceryl trinitrate may cause uncontrolled rewarming of the brain or not. The investigators will measure the temperature of the brain using a temperature probe located in the nasal cavity. The temperature will be recorded at each minute during the the rewarming period. Results of two commonly used infusion rates of glyceryl trinitrate will be compared.

Detailed Description
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Hypothermia had demonstrated potential benefits in myocardial infarction, organ transplantation, and cardiopulmonary bypass. The brain uses 2/3 of the oxygen it receives to support cerebral electrophysiological function, while the rest is used for maintenance of cellular integrity. Anesthetic drugs alter only the first portion, while temperature is the only agent known to affect both portions (the cerebral consumption of oxygen decreases 6-7 % per degree centigrade reduction in temperature). Although hypothermia is effectively used to protect the brain and myocardium from ischemia, studies report that rapid rewarming is correlated with brain injury. Therefore it is common practice to monitor the nasopharyngeal temperature and to keep the gradient between heat-exchanger and nasopharynx during rewarming at 2-3 °C. This study's main concern is that the infusion rate of glyceryl trinitrate may affect the rewarming rate of the body and the brain during te rewarming period. One possibility is that the increased vasodilatation resulting from glyceryl trinitrate may divert most of the heat to the body and protect the brain from overheating. The other possibility is that the increased partial pressures of carbon dioxide may render the brain more susceptible to the vasodilatatory actions of glyceryl trinitrate, which may cause the brain to overheat. This study will measure temperatures at several sites of the patient and the cardiopulmonary bypass machine: Nasopharynx: a probe inside the nasal cavity, located above the palate. Core temperature: a probe inside the esophagus, 12 cm distal from where the heart and breath sounds are heard best. Heat-exchanger: recorded as is supplied by the heat exchanger as the temperature of the water inside the heat exchanger. Returning blood: measured at the entrance of reservoir Blood leaving the oxygenator: measured at the outlet of the oxygenator All patients scheduled for cardiopulmonary bypass grafting surgery, and aortic arch surgery will be recruited. Data will be collected by an observer blinded to the glyceryl trinitrate dose used. Data management will be done via an electronic database including demographic data, anesthetic records, and bypass records of the patient. All data will be anonymized on a case-by-case fashion after the surgery. Data analysis will be performed using R statistical software. Any adverse events, including adverse drug reactions, and adverse patient outcomes associated with monitoring tools and patient management will be reported to the Ethics Committee. Should any change to the research protocol required, the Ethics Committee will be informed. Sample size for each sample is calculated (according to the primary outcomes of the study) as 48 to detect a 20 % difference in time to reach optimal body temperature (expected mean 30 ± 5 minutes, or a 0.3 °C difference in nasopharyngeal temperature when the esophageal temperature reached 37 °C. In case of missing data (such as due to equipment malfunction, inability to monitor the patient, data not reported, uninterpretable, or considered missing because of data inconsistency or out-of-range results), the participant will be excluded from the study. The statistical analysis will include descriptive statistics of patient demographics, comparison of both primary outcomes, and comparisons of adverse events.

Official Title
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The Effect of Two Different Rates of Nitroglycerin Infusion on Cerebral Rewarming During Rewarming Period of Hypothermic Cardiopulmonary Bypass

Conditions
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Coronary Artery Bypass, Cardiopulmonary Bypass

Intervention / Treatment
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* Drug: Glyceryl trinitrate 0.2
* Drug: Glyceryl trinitrate 0.5


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients who are scheduled for on-pump coronary artery bypass grafting surgery Exclusion Criteria: Administration of vasopressors during rewarming period

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Intervention type is drug dosage. Patients will be assigned to 2 arms, where they will receive different doses of the same drug. The study will end when both of the arms will have at least 48 patients each.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Glyceryl trinitrate 0.2<br>Drug Intervention Generic name: Glyceryl trinitrate Dosage form: Ampoule for intravenous infusion Dosage: 0.2 mcg/kg/minute Frequency and duration: The infusion will start as soon as the rewarming period starts, will continue throughout the operation and throughout the first 24 hours of the postoperative period. | Drug: Glyceryl trinitrate 0.2<br>* These patients will receive glyceryl trinitrate infusion at a rate of 0.2 mcg/kg/min throughout the rewarming period of cardiopulmonary bypass, which usually lasts for 30-45 minutes.<br>* Other names: Nitroglycerin, Perlinganit;|
| Active Comparator: Glyceryl trinitrate 0.5<br>Drug Intervention Generic name: Glyceryl trinitrate Dosage form: Ampoule for intravenous infusion Dosage: 0.5 mcg/kg/minute Frequency and duration: The infusion will start as soon as the rewarming period starts, will continue throughout the operation and throughout the first 24 hours of the postoperative period. | Drug: Glyceryl trinitrate 0.5<br>* These patients will receive glyceryl trinitrate infusion at a rate of 0.5 mcg/kg/min throughout the rewarming period of cardiopulmonary bypass, which usually lasts for 30-45 minutes.<br>* Other names: Nitroglycerin, Perlinganit;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nasopharyngeal temperature > 37 °C | If the nasopharyngeal temperature is > 37 °C by the time the esophageal temperature reached 37 °C. | Rewarming period of cardiopulmonary bypass, usually 30 - 45 minutes | 
| Time to 37 °C | Time required to reach an esophageal temperature of 37 °C. | Rewarming period of cardiopulmonary bypass, usually 30 - 45 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event: Regional cerebral oxygen saturation | Occurrence and degree of significant drop in regional cerebral oxygen saturation | Rewarming period of cardiopulmonary bypass, usually 30 - 45 minutes | 
| Length of Intensive Care Unit stay | Outcome criteria for coronary artery bypass surgery: length of intensive care unit stay | Postoperative period from entrance to Intensive Care Unit until the date of death from any cause or discharge from Intensive Care Unit, whichever came first, assessed up to 1 month | 
| Length of hospital stay | Outcome criteria for coronary artery bypass surgery: length of intensive care unit stay | Postoperative period from entrance to Intensive Care Unit until the date of death from any cause or discharge from hospital, whichever came first, assessed up to 3 months | 
| Frequency of atrial fibrillation | Outcome criteria for coronary artery bypass surgery: occurrence of atrial fibrillation | Postoperative period from entrance to Intensive Care Unit until the date of death from any cause or discharge from hospital, whichever came first, assessed up to 3 months | 
| Frequency of low cardiac output syndrome | Outcome criteria for coronary artery bypass surgery: occurrence of low cardiac output syndrome | Postoperative period from entrance to Intensive Care Unit until the date of death from any cause or discharge from hospital, whichever came first, assessed up to 3 months | 
| Frequency of stroke | Outcome criteria for coronary artery bypass surgery: occurrence of stroke | Postoperative period from entrance to Intensive Care Unit until the date of death from any cause or discharge from hospital, whichever came first, assessed up to 3 months | 
| Frequency of delirium | Outcome criteria for coronary artery bypass surgery: occurrence of postoperative delirium | Postoperative period from entrance to Intensive Care Unit until the date of death from any cause or discharge from hospital, whichever came first, assessed up to 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peak temperature, rewarming rate, surgical outcomes