This randomized controlled double -blinded study was conducted at Beni-Suef University hospital from 20/ November/ 2019 to25/ February/ 2020 in compliance with the Helsinki Declaration after approval of the Research Ethical Committee of Beni-Suef University Hospitals (FMBSUREC/01102019/Rashwan) and obtaining written informed consent from the patients, and was registered at ClinicalTrials.gov with Identification number : NCT04151381, date November 5, 2019, retrospectively, and adheres to CONSORT guidelines, it included 45patients of both sex, in the age group 20–60 years and of American Society Of Anesthesiology physical status I- II who were scheduled for pelvi-abdominal surgeries under general anesthesia. Patients were excluded if the body mass index more than 30 kg/m2),,sensitivity to aminophylline or have history of seizure, renal or hepatic impairment and coffee consumption ( more than 2 cupps/day), patients with opioid addiction or treated with B agonists, tranquilizers, antidepressant were also excluded.The patients were subjected to preoperative assessment and preoperative investigations [complete blood count, coagulation profile, liver and renal function tests, chest x ray and electrocardiogram (if indicated)] were done.All investigations were within normal values.0;The patients were admitted to the anesthesia preparation room where monitors were applied (pulse oximetry,5 leads electrocardiography, noninvasive arterial blood pressure ), the heart rate(HR) and mean arterial blood pressure(MAP) were recorded before and after study drug administration, wide bore intravenous cannula was inserted and crystalloid fluid infusion was started, sedative premedication were not given to the patients and the patients were allocated randomly to three groups (n = 15for each group) using sealed, opaque envelopes (indicating the group of each patient, carried out by an independent anesthesiologist) to receive the study drugs (over 10 minutes ) half an hour before the induction of general anesthesia .The study solutions were prepared in identical syringes labeled “study drug”,the anesthesia residents who administrated the study drug and who were in charge of general anesthesia and collecting the data were blinded to the study protocol).Group (C): the control group : received 100 ml of normal saline IV .
Group (A1): received 2 mg/kg intravenous (IV) aminophylline diluted in 100 ml normal .Group (A2): received 4 mg/kg intravenous (IV) aminophylline diluted in 100 ml normal saline[ 11].At the operating room, monitors were applied (pulse oximetry,5leads ECG, end-tidal carbon dioxide, non-invasive arterial blood pressure .(the vital signs were continuously monitored to ensure homodynamic stability, normovolemia was also maintained), temperature probe and Bispectral index (BIS)electrodes were connected.Following preoxygenation; anaesthesia was induced by 2 µg/kg fentanyl, propofol infusion 30 mg/kg/h till the BIS value of 48 ± 2 for 1 minute( to ensure adequate level of hypnosis),lignocaine 1 mg/kg and 0.5 mg/kg atracurium to facilitate endotracheal intubation using cuffed oral tube. Anesthesia was maintained using sevoflurane 2 % in O2/air mixture and mechanical ventilation was adjusted to maintain the end-tidal carbon dioxide at 36–40 mmHg.Normothermia was maintained by warming the IV fluids and using hot air convection. At the end of the surgery, the inhalation of sevoflurane was discontinued, the neuromuscular block was reversed then the patients were extubated and after recovery they were transferred to the PACU.
The following data were recorded:
Demographic data (age,sex,weight),ASA physical status (I or II) and duration of anesthesia and surgery
Vital signs:heart rate and mean arterial blood pressure were monitored continuously, and recorded before and after study drug administration, after induction of general anesthesia then every 30minutes for the duration of surgery(to maintain hemodynamic stability and euvolemia)
Adverse events after aminophylline administration(e.g.light-headedness,vomiting,chest discomfort ,arrhythmia,hypotension or hypertension).
The primary out come:the ROC (in minutes), which is the time after discontinuation of anesthesia till the response to a verbal command by eyes opening, time from propofol injection to the end point of hypnosis (defined as sustained BIS value of 48 ± 2 for 1 min), the secondary out comes :time for BIS value to reach 80 after sevoflurane discontinuation , propofol dose (mg) till BIS 48 ± 2, time to tracheal extubation (in minutes) (which is the time from cessation of anaesthetic agent and recovery from neuromuscular blockage clinically, and monitored by a nerve stimulator),time to discharge from the PACU ( in minutes) (which is the time from arrival of the patient to the PACU till the modified Aldrete score reached ≥ 9 points.
intraoperative cardiovascular complications(e.g.sinus tachycardia :20% increase in the heart rate from the baseline reading ,hypotension or hypertension :20% increase/decrease in the mean arterial pressure from the base line reading, in case of tachycardia or hypertension the depth of anesthesia was increased by increasing the concentration of the inhalational anesthetics and administration of fentanyl 50 ug IV, in case of hypotension ;the concentration of the inhales anesthetic was reduced, and ephedrine was administrated in 5 mg/kg increments, and causes of hypotension were excluded as intraoperative bleeding)
the need for vasopressors or inotropes and fentanyl dose (ug)
Sample size calculation was done using the comparison of time to ROC,as reported in previous publication (5), the mean ± SD of time to ROC in normal saline group was 12.2 ± 4.73 minutes, in 6 mg/kg aminophylline group it was 6.18 ± 3.96 minutes.No results were found in the published literatures on lower dose of aminophylline. Therefore we assumed that the effect of 6 mg/kg is similar to the 4 mg/kg, and the effect of the 2 mg/kg dose is half the 4 mg/kg dose effect, the minimum sample size was 13 patients in each group to be able to reject the null hypothesis with 80% power at α = 0.05 level using one way analysis of variance test.The number of cases was increased to 15 in each group in case of drop of cases. G*Power software version 3.1.2 for MS Windows, Franz Faul, Kiel University.
Data were described in terms of mean ± standard deviation, or frequencies. Numerical data were tested for the normal assumption using the Shapiro Wilk test. Comparison of numerical variables was done using one-way analysis of variance (ANOVA) test with Post-hoc multiple 2-group comparisons for comparing normally distributed data and Kruskal Wallis test with Post-hoc multiple 2-group comparisons for comparing not normal data. Categorical data were compared by Chi-square (χ2) test. Ifthe expected frequency is < 5. Fisher's" Exact test was used. p -values < 0.05 was considered statistically significant.Statistical calculations were done using Statistical Package for the Social Science; IBM Corp, Armonk, NY, USA) release 22 for Microsoft Window.