Study design
This double-blind randomized clinical trial study was conducted in Golestan Hospital, Ahvaz, Iran, from September 2018- December 2019 with Ethics code: IR.AJUMS.REC.1398.050 from Anesthesiology and Pain Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, and Trial registration number: IRCT20150216021098N5.
Sixty patients undergoing elective on-pump coronary artery bypass graft surgery. After clearly explaining the objective and potential risks and benefits of the study, a written consent form for participation in the study was obtained from all patients.
Setting and Patients: Inclusion criteria: Aged 30-70 years, ASA III, Both of sex, Ejection Fraction≥30 %, undergoing elective CABG.
Exclusion criteria included: Severe hepatic and renal disease, consumption of anti-inflammatory drugs or antipyretic drugs before the study, redo surgery, history of cerebrovascular accident (CVA), and thrombocytopenia
Randomization: randomization was performed using computer-generated random digits to ensure that patients and investigators were blind to the treatment assignment before study entry, and the allocation was done 1:1 to receive either ketorolac or Paracetamol. Randomization was not performed until electronically confirming the eligibility criteria in the web-based case report form. Randomization was performed centrally without stratification. The sequence was generated by an independent statistician using a random number generator with a 1:1 allocation using random block sizes of 2. In this study patients and researchers were blinded.
Sample size: The sample size of this study was calculated using the sample size estimation formula. The 95% confidence interval (CI) level was considered. The study population consisted of 90 patients. Based on the previous data [19]. After initial screening, 85 patients agreed to participate and provided informed consent. Among them, 25 patients did not have inclusion criteria (Five patients had EF<30%, Ten patients had complex surgery, the surgical procedure of Five patients turned into off-pump, Five patients were given antipsychotic drugs or history of seizure). Finally, 60 patients were enrolled in the study and were assigned into two groups of Paracetamol and ketorolac, 30 patients each (Figure1).
Anesthesia protocol
After arrival to the operation room, standard monitoring included five-lead electrocardiography, pulse oximetry and arterial line for continuous blood pressure monitoring and blood gases were inserted. A standard anesthesia technique was used for all patients. The anesthetic drug doses were calculated according to body weight; midazolam at 0.1 mg/kg was given as IV premedication. Induction of anesthesia was induced fentanyl 15 µg/kg, propofol 1mg/kg, and pancuronium 0.1–0.15 mg/kg). Anesthesia was maintained with a continues infusion of propofol 1-1.5mg/kg/h , fentanyl 4 µg/kg/h, 0.25 mg/kg/h midazolam, and 0.3 mg/kg/h cisatracurium until the end of surgery. Isoflurane supplementation was used at the discretion of the attending anesthesiologist. After induction of general anesthesia, a central venous catheter was introduced. For initiation of cardiopulmonary bypass, 350 u/kg heparin was injected to all patients. Heparin dosage was attuned based on goal ACT 450-480 second. After the bypass was terminated, protamine 1mg/kg was given for the reversal of heparin. Cardiac surgery and postoperative management were standardized.
After surgery, all the patients were admitted to the cardiovascular ICU, with a standard protocol for sedation, analgesia (propofol 0.5 mg/kg/h and morphine sulfate 0.1 mg/kg/h), and management of mechanical ventilation (SIMV mode of ventilation).
Intervention: Immediately after the transfer of patients to ICU, the intervention began. The patients in the ketorolac group were administered at a rate of 0.5 mg/kg IV admixed with 100 ml of normal saline each 6 hours for 24 hours. A bolus may be given at the start of therapy if desired. The patients in the Paracetamol group were given 10 mg/kg IV of Paracetamol (mixed with normal saline to a total volume of 100 ml) for 30 minutes each 6 hours for 24 hours. ( Dose of ketorolac determined based on Howard et.al study. [20]
Patients were extubated according to the following criteria: responsive and cooperative, pO2 of 80-100, oxygenation index of pO2/FiO2 > 300, and hemodynamic stability without any inotropes.
After extubation, the patients had access to morphine sulfate with a patient-controlled analgesia device (PCA device; Graseby 3300P, Hoyer, Bremen, Germany) using a standardized protocol: bolus dose of 2 mg, dose duration of 2 min, lockout interval of 13 min (15 min effective lockout time), and with no background infusion and no upper dose limit. Before commencing the PCA, the nurses in the PACU were allowed to give morphine sulfate 2mgIV before extubation for the treatment of pain if required. Morphine consumption was recorded from the PCA device at the end of the 48-h study period. Per protocol, the primary efficacy variable was cumulative morphine consumption (the combined amount administered via the PCA device and given as rescue doses) at the end of the 48-h postoperative period. If pain relief was insufficient (VAS score >3 at rest), nurses were allowed to give an extra bolus of morphine2 mg IV as a rescue analgesic once an hour. Renal function test (serum creatinine) were measured the evening before surgery and 72 hours after surgery. Bleeding after surgery was measured as chest tube drainage. The number of red cell units transfused was recorded.
Primary outcomes were: visual analog pain scale (VAS) at the time point immediately after extubation (baseline) and at 6, 12, 24 and 48 hours and the total dose of morphine consumption. Secondary outcomes included the hemodynamic variables, weaning time, postoperative bleeding, myocardial infarction, CVA, TIA , in-hospital mortality and postoperative serum creatinine.
VAS score assessment
Pain intensity levels were subjectively measured using a 10 cm visual analog pain scale (VAS, 0 = no pain to 10 = unbearable pain). We assessed VAS and hemodynamic variables (systolic blood pressure, diastolic blood pressure, heart rate and other parameters ) of each regimen immediately after extubation (baseline) and at 6, 12, 24, and 48 hours.
Statistical analysis
Numerical variables were reported as mean ± standard deviation (SD). Quantitative and qualitative variables were measured by independent t-test, and ANOVA test respectively. P value ≤ 0.05 was considered to be statistically significant. All analyses were performed using SPSS for Windows version 22.0 (SPSS Inc., Chicago, IL, USA)