Aminophylline for Entropy Recovery After Sevoflurane Anaesthesia

03:47 EDT 2nd April 2015 | BioPortfolio


The use of general anaesthesia in fast-tracking outpatient setting represents a great challenge because the residual anaesthetic effects may delay home discharge after surgery.

Sevoflurane has been advocated for the routine anesthesia for ambulatory surgery patients. Sevoflurane activates adenosine A1 receptors in primary rat hippocampal cultures through the liberation of adenosine secondary to the interaction of with adenosine transport or key enzymes in adenosine metabolism. Aminophylline is a hydrophilic cyclic adenosine mono-phosphate (cAMP) dependent phosphodiesterase inhibitor, which has been used for long time to relieve bronchospasm. It has been shown that aminophylline antagonizes morphine, diazepam, and barbiturates sedation. Aminophylline in doses of 3-5 mg/kg hastens recovery from sevoflurane anaesthesia and improved bispectral index scores (BIS), with associated significant increases in heart rate.

The investigators hypothesized that the use of lower doses of aminophylline [2-3 mg/kg] may hasten the recovery from sevoflurane anaesthesia with the avoidance of significant tachycardia.

The aim of the present study was to investigate the effects of 2, 3, 4, and 5 mg/kg of aminophylline on response entropy (RE) state entropy (SE), (RE-SE), end-tidal sevoflurane concentration, haemodynamics, the times to eyes opening and to extubation, vigilance score and degree of sedation after sevoflurane anaesthesia in patients undergoing ambulatory surgery.


This randomised double-blinded placebo-controlled study after obtaining of the approval of Institutional Ethical Committee of author's institution and a written informed consent from the participants. Based upon our preliminary data, a prior power analysis indicated that 30 patients in each group was a sufficiently large sample size to detect a 20% changes in SE values, with a type-I error of 0.05 and a power of approximately 85%. We added 10% more patients to account for patients dropping out during the study. Participants were allocated randomly to five groups (n=35 for each) to receive saline [group P] or aminophylline 2, 3, 4 or 5 mg/kg [groups A2, A3, A4, and A5, respectively] at the end of surgery.

No premedications were given. A cannula was inserted in a forearm vein and Lactated Ringer's solution was infused at a rate of 2-3 mL/kg/h. Patients monitoring included electrocardiography, pulse oximetry and non-invasive blood pressure monitoring (Datex-OhmedaTM S/5TM, Helsinki, Finland). RE and SE were monitored with the Datex-OhmedaTM S/5 Entropy Module using a specific entropy sensor (M-EntropyTM, Datex-Ohmeda Division, Instrumentarium Corporation, Helsinki, Finland). The sensors were applied appropriately to the patient's forehead. Neuromuscular block was monitored by a train-of-four (TOF) stimulation of the ulnar nerve.

Anaesthesiologists who gave the anaesthetic did not involve in the collection of the patient's data. General anaesthesia was induced with propofol (2-3 mg/kg) and fentanyl (2-3 µg/kg). Rocuronium (0.6 mg/kg) was given and tracheal intubation was carried out at the development of maximum block of the TOF. After tracheal intubation, the minimum alveolar concentration (MAC), the inspiratory and end-tidal concentrations of sevoflurane (EtSevo) and end-tidal concentrations of carbon dioxide (EtCO2) were monitored. Anaesthesia was maintained with 0.5-1 MAC of sevoflurane in combination with 50% air in oxygen based on entropy reading where the end-point was SE 50 and SE-RE difference less than 10.9 The patient's lungs were ventilated mechanically to maintain the EtCO2 at 35-40 mm Hg. Rocuronium increments were given to maintain suppression of the second twitch using a train-of-four stimulation. No supplementary dose of muscle relaxant was administered 30 minutes before the end of the surgery.

During skin closure, neuromuscular blockade was antagonized with 50 µg/kg neostigmine and 10 µg/kg glycopyrrolate when the fourth twitch to the first twitch (T4/T1) ratio ranged between 30% and 50%. At the last skin suture, sevoflurane was discontinued (T0) and the patient's lungs were ventilated with 100% oxygen at 5 litre/min.

Subjects were allocated randomly to five groups (n=35 for each) by drawing sequentially numbered sealed opaque envelopes containing a computer-generated randomisation code to receive intravenous injection of 0.2 mL/kg of a study solution containing either saline 0.9% solution [group P], aminophylline 10 mg/mL [group A2], aminophylline 15 mg/mL [group A3], aminophylline 20 mg/mL [group A4] or aminophylline 25 mg/mL [group A5]. All study solutions were injected within 1 min at T0 after discontinuation of sevoflurane. No stimulation was applied to patients during this period. The test solutions were prepared in identical syringes labelled 'study drug' by an independent anaesthesiologist who was not included in the study, before induction of anaesthesia, and contained either aminophylline or normal saline. Other anaesthesiologists who were blinded to the study solution gave the anaesthetic, and established awakening. All staff in the operating room was unaware of the randomization code.

Tracheal extubation was performed immediately after suctioning when all extubation criteria were met (TOF recovery to ≥ 90%, spontaneous ventilation and the ability to follow verbal commands, eye opening, head lift ≥ 5 seconds, and handgrip), at the discretion of the anaesthetist in charge of the patient. The level of consciousness was assessed using simple verbal commands ('open your eyes', 'move your hand') repeated up to three times with increasing forcefulness if the subject failed to respond.

RE, SE, (RE-SE), the MAC and end-tidal concentration (EtSevo) of sevoflurane, T4/T1 ratio, heart rate (HR), mean arterial blood pressure (MAP), respiratory frequency (RR), and peripheral oxygen saturation (SpO2) were recorded every 1 min after administration of the study drug (T0) for 15 min.

Recovery from anaesthesia was assessed by the time to eyes opening (time from T0 to spontaneous eye opening), the time to extubation (time from T0 to tracheal extubation) and the assessment of vigilance score every 3 min after extubation until the patient's transfer to the post-anaesthesia care unit (PACU). All measurements were made by an investigator blinded to the study drugs. Vigilance score included ten separate variables to assess the recovery of cognitive complex functions from sevoflurane anaesthesia. Each successfully accomplished response to a question scored one point.10 [Appendix (A)] Appendix (A): Vigilance score (each successfully accomplished action=1 point) Eye opening - spontaneous or upon command Limb movements - spontaneous or upon command Answering questions Showing tongue on command Coherent speech Recall of age Recall of date of birth Recall of address Recall of telephone number Simple arithmetic 2x3, 12÷4, 7+4, 13-5, etc.) In the PACU, vigilance score, HR, MAP, RR, SpO2, and the degree of sedation (four-point verbal rating scores (VRS): awake, drowsy, rousable or deep sleep); were recorded on the patient's arrival, every 15 min for 60 min, and thereafter every 30 min until discharge to the ward. Postoperative complications included arrhythmia, tremors, vomiting, nausea, seizures, shivering, or hypoxaemia (SpO2<90%) were recorded. Discharge of patients from the PACU was at the discretion of the attending anaesthetists and no attempt was made to speed up this process.


Data were tested for normality using the Kolmogorov-Smirnov test. Repeated-measures analysis of variance was used for analysis of serial changes in the data at different times after administration of study solution. Fisher exact test was used for Categorical Data. Repeated measure analysis of variance (ANOVA) was used for continuous parametric variables and the differences were then calculated by post-hoc Tukey's HSD (honestly significant difference). The Kruskal-Wallis one-way ANOVA was performed for intergroup comparisons for the non-parametric values and post hoc pairwise comparisons was done using the Wilcoxon rank sum t test. Data were expressed as mean (SD), number (%), or median [range]. A value of p < 0.05 was considered to represent statistical significance.

Study Design

Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment




Placebo [group P], 0.2 mL/kg of aminophylline 10 mg/mL [group A2], 0.2 mL/kg of aminophylline 15 mg/mL [group A3], 0.2 mL/kg of aminophylline 20 mg/mL [group A4], 0.2 mL/kg of aminophylline 25 mg/mL [group A5]


King Faisal University
Saudi Arabia




King Faisal University

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