Nitroglycerin Infusion During Rewarming in Cardiac Surgery and Its Effects on Tissue Perfusion and Coagulation
Phase: NA
Conditions: Lactic Acidosis, Blood Glucose, High
Sponsor: Tri-Service General Hospital

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Title: Nitroglycerin Infusion During Rewarming in Cardiac Surgery and Its 
Effects on Tissue Perfusion and Coagulation 
TSGHIRB 1-102-05-049, valid from June 10, 2013 to June 27, 2017. 
 
ClinicalTrials: NCT01901419, actual study from July 8, 2013 to June 8, 2017. 
 
Protocol version: May 4, 2016 
 

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Methods 
Patients 
This study was registered with ClinicalTrials.gov as NCT01901419 after obtaining 
approval of Tri-Service General Hospital Institutional Review Board (TSGHIRB-1-102-05-
049). Patients receiving elective cardiac surgery with cardiopulmonary bypass were recruited 
and signed the written informed consent. Those with complicated comorbidities were excluded, 
such as chronic hepatic or renal insufficiency, or acute cardiopulmonary failure requiring 
mechanical ventilation, intra-aortic balloon pump, or extracorporeal membrane oxygenation. 
Patients were randomly assigned to receive either NTG infusion 1-5 mcg/kg/min (NTG group), 
the dose labelled to maintain intraoperative hypotension, or 0-0.1 mcg/kg/min (control group), 
the dose labelled for acute cardiac insufficiency, during rewarming of hypothermic CPB. 
Those undergoing normothermic CPB decided by the surgeon intraoperatively were not 
analyzed. 
Anesthesia and cardiopulmonary bypass 
Routine physiologic monitoring, including three-lead electrocardiogram, pulse oximetry 
and an invasive arterial blood pressure monitoring were set up immediately before anesthesia 
induction. In addition, cardiac output was continuously monitored (FloTrac; Edwards 
Lifesciences, Irvine, CA, USA). Cerebral oximetry (Fore-Sight oximeter; CASMED, Branford, 
CT, USA), based on near-infrared spectroscopy technology, was applied on the forehead until 
the end of surgery. 
All patients received general anesthesia with midazolam 5 mg, fentanyl 1.5-3.0 mcg/kg, 
propofol 0.5-1.5 mg/kg, and cisatracurium 0.1-0.2 mg/kg for induction, as well as sevoflurane 
or isoflurane for maintenance after tracheal intubation. A pulmonary artery catheter (Swan-
Ganz Thermodilution catheter 7.5 Fr; Edwards Lifesciences, CA, USA) was placed through 
right internal jugular vein for postoperative monitoring. Transesophageal echocardiography 

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was used to monitor real-time cardiac performance throughout the whole procedure. Minute 
ventilation was adjusted to maintain end-tidal CO2 40 ± 5 mmHg, confirmed by serial arterial 
blood gas analyses. After achieving anticoagulation (activated clotting time >350 seconds) by 
intravenous administered heparin 300 U/kg prior to cannulation, standard hypothermic CPB 
(Sarns 8000, Terumo, Ann Arbor, MI) with an extracorporeal membrane oxygenator 
(Capiox®SX 18, Terumo, Ann Arbor, MI) were carried out in sequence to maintain the body 
temperature at 26-30 ºC during surgery. The perfusionist adjusted the pump flow to obtain an 
adequate output of 2.2 l/m2 of body surface area and adjusted sevoflurane concentration on the 
vaporizer, to keep mean arterial blood pressure 50-80 mmHg.  
Treatment protocol 
Before rewarming, the patients were randomly assigned to NTG group with NTG infusion 
1-5 mcg/kg/min or control group with 0-0.1 mcg/kg/min. The infusion rate would be tapered if 
there was profound hypotension (mean arterial pressure <40 mmHg) or cerebral desaturation 
(absolute saturation value <60 or relative drop to <80% of baseline value each side). Following 
standard rewarming and deaerating, the pump flow was reduced to 0.5 l/min for release of 
aortic clamp and was weaned with routine inotropic support, including dopamine 3-8 
mcg/kg/min and additional dobutamine, epinephrine, or norepinephrine infusion for acceptable 
cardiac output. Further intra-aortic balloon pump or extracorporeal membrane oxygenation 
would be applied for cardiopulmonary support, if needed. Heparin effect was neutralized with 
protamine sulfate after stop of bypass. All patients were transferred to the cardiovascular 
surgical intensive care unit (ICU) with endotracheal intubation after the operations were 
finished. According to the routine criteria, extubation was performed after obtaining oriented 
consciousness, normothermia (patient rewarmed and shivering controlled), and hemodynamic 
stability with no uncontrolled arrhythmias and no excessive bleeding (as defined by loss of < 
100 ml/h). 

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Data collection 
Arterial blood gas analysis was routinely examined perioperatively, including before 
incision, after heparin administration, before aortic unclamping, after aortic unclamping, after 
protamine administration, and immediately upon ICU admission by GEM Premier 3000 
(Instrumentation Laboratory, Lexington, MA, USA), including plasma lactate (detectable limit, 
0.3 to 20 mmol/L) and glucose (detectable limit, 20-500 mg/dL) levels. The activated clotting 
(or coagulation) time was tested by ACT Plus (Medtronic, Minneapolis, MN, USA) after 
heparin administration, during CPB, after protamine administration, and before the end of 
surgery (if needed). The perioperative variables were collected, including acid-base status, 
glucose level, and urine output. Postoperative inotropic use, time to extubation, lengths of ICU 
and hospital stay, and 30-day mortality were also recorded from the hospital’s registry 
database.  
Statistical analysis 
All values were expressed as mean ± SD or number unless otherwise stated. The Student 
t-test was applied to compare means of continuous variables. Pearson’s Chi-square test or 
Fisher’s exact test was used for categorical variables. All statistical tests were two-tailed, with 
the level of significance set at P values <0.05. Data analysis was performed using the SPSS for 
Windows.