This randomized controlled double-blinded study was conducted at Beni-Suef University Hospital from 20 November 2019 to 25 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. The study was registered at ClinicalTrials.gov with identification number NCT04151381 and date November 5, 2019, retrospectively, and adhered to CONSORT guidelines. The study included 45 patients of both sexes in the age group of 20–60 years and American Society Of Anesthesiology physical status I-II who were scheduled for pelvic-abdominal surgeries under general anaesthesia. Patients were excluded if their body mass index was more than 30 kg/m2 or if they had sensitivity to aminophylline or history of seizure, renal or hepatic impairment or coffee consumption (more than 2 cups/day). Patients with opioid addiction or patients treated with B agonists, tranquilizers, or antidepressants 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 performed. All results were within normal values. The patients were admitted to the anaesthesia preparation room where monitors were applied (pulse oximetry, 5-lead electrocardiography, noninvasive arterial blood pressure), the heart rate (HR) and mean arterial blood pressure (MAP) were recorded before and after study drug administration, a wide bore intravenous cannula was inserted and crystalloid fluid infusion was started, and intravenous injection of 4 mg ondansetron was administered. However, sedative premedication was not given to the patients, and the patients were allocated randomly to three groups (n = 15 for each group) using sealed, opaque envelopes (indicating the group of each patient, carried out by an independent anaesthesiologist) to receive the study drugs (over 10 min) half an hour before the induction of general anaesthesia. The study solutions were prepared in identical syringes labelled “study drug”, and the anaesthesia residents who administered the study drug and who were in charge of general anaesthesia and collecting the data were blinded to the study protocol). Group (C): the control patients received 100 ml of normal saline IV. Group (A1): the patients received 2 mg/kg intravenous (IV) aminophylline diluted in 100 ml of normal saline. Group (A2): the patients received 4 mg/kg intravenous (IV) aminophylline diluted in 100 ml of normal saline. In the operating room, monitors were applied (pulse oximetry, 5-lead ECG, end-tidal carbon dioxide, noninvasive arterial blood pressure, temperature probe and bispectral index (BIS) electrodes). Following preoxygenation, anaesthesia was induced by 2 μg/kg fentanyl, propofol infusion at 30 mg/kg/h was performed until a BIS value of 48 ± 2 was reached for 1 min (to ensure an adequate level of hypnosis) [12], and 1 mg/kg lignocaine and 0.5 mg/kg atracurium were administered to facilitate endotracheal intubation using a cuffed oral tube. Anaesthesia was maintained using 2% sevoflurane in an 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, and the neuromuscular block was reversed using 0.02 mg/kg atropine and 0.05 mg/kg neostigmine. Then, the patients were extubated, and after recovery, they were transferred to the PACU. For pain control, the following multimodal protocol was applied for all patients: at the end of surgery, IV paracetamol (perfalgan) at 1 g was administered, and infiltration of the surgical wound by bupivacaine hydrochloride (0.25%, 30 ml) was administered by the surgeon; no other opioids were administered to avoid affecting the ROC, extubation time or discharge time from the PACU once the patients were discharged to the surgical intensive care unit, where initiation of pain control was started according to the protocol planned by the SICU team.
The following data were recorded:
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Demographic data (age, sex, weight), ASA physical status (I or II) and duration of anaesthesia and surgery.
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Vital signs: Heart rate and mean arterial blood pressure were monitored continuously and recorded before and after study drug administration, after induction of general anaesthesia and then every 30 min for the duration of surgery.
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Adverse events after aminophylline administration (e.g., light-headedness, vomiting, chest discomfort, arrhythmia, hypotension or hypertension).
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The primary outcome: the ROC (in minutes), which is the time after discontinuation of anaesthesia until the response to a verbal command by eye opening, and time from propofol injection to the end point of hypnosis (defined as a sustained BIS value of 48 ± 2 for 1 min).
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The secondary outcomes: time for the BIS value to reach 80 after sevoflurane discontinuation [12], propofol dose (mg) until BIS reached 48 ± 2, time to tracheal extubation (in minutes) (which is the time from cessation of anaesthetic agent and recovery from neuromuscular blockage clinically and was monitored by a nerve stimulator), and 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).
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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 baseline reading, in case of tachycardia or hypertension the depth of anaesthesia was increased by increasing the concentration of the inhalational anaesthetics and administration of IV fentanyl at 50 μg, in case of hypotension; the concentration of the inhaled anaesthetic was reduced, and ephedrine was administered in 5 mg/kg increments, and causes of hypotension were excluded as intraoperative bleeding).
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The need for vasopressors or inotropes and fentanyl dose (μg).
Statistical analysis
Sample size calculation was performed using the comparison of time to ROC, as reported in a previous publication [5]; the mean ± SD of time to ROC in normal saline group was 12.2 ± 4.73 min, and in the 6 mg/kg aminophylline group, it was 6.18 ± 3.96 min. No results were found in the published literature on lower doses of aminophylline. Therefore, we assumed that the effect of 6 mg/kg was similar to that of 4 mg/kg, and the effect of the 2 mg/kg dose was half that of the 4 mg/kg dose. The minimum sample size was 13 patients in each group to reject the null hypothesis with 80% power at the α = 0.05 level using a one-way analysis of variance test. The number of cases was increased to 15 in each group in case of a drop in cases. G*Power software version 3.1.2 for MS Windows, Franz Faul, Kiel University, was used.
Data are described in terms of the mean ± standard deviation or frequencies. Numerical data were tested for a normal distribution using the Shapiro Wilk test. Comparison of numerical variables was performed using one-way analysis of variance (ANOVA) with post hoc multiple 2-group comparisons to compare normally distributed data and Kruskal-Wallis tests with post hoc multiple 2-group comparisons to compare non-normally distributed data. Categorical data were compared by the chi-square (χ2) test. If the expected frequency was < 5, Fisher’s exact test was used. p-values < 0.05 were considered statistically significant, and p-values < 0.01 were considered statistically highly significant. Statistical calculations were performed using Statistical Package for the Social Science; IBM Corp, Armonk, NY, USA) release 22 for Microsoft Window.
