Aminophylline Improves Early Postoperative Cognitive Recovery After Sevoflurane Anaesthesia: A Dose-Dependent Study
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- King Faisal University
- Enrollment
- 180
- Locations
- 1
- Primary Endpoint
- early postoperative cognitive function
Study Overview
Brief Summary
Early postoperative recovery of neurologic and cognitive functions is especially advantageous after fast-tracking ambulatory procedures to hasten home discharge after surgery.1 It is well known that volatile anaesthetic agents may generate adverse postoperative cognitive effects and even traces of it may affect task performance in healthy volunteers.2Hence, rapid elimination of the volatile anaesthetics may help reduce postoperative confusion and cognitive impairment in surgical patients by facilitating a faster recovery from general anaesthesia.3 Sevoflurane has been advocated for the routine anesthesia for ambulatory surgery patients. It 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.4 However; sevoflurane anaesthesia is associated with slower emergence and delayed early postoperative cognitive recovery than desflurane5 and xenon2 anaesthesia.
Aminophylline, which is a hydrophilic cyclic adenosine mono-phosphate (cAMP) dependent phosphodiesterase inhibitor has been used for long time to antagonize the sedative effects of morphine, diazepam, and barbiturates.6-7Aminophylline in doses of 2-5 mg/kg shortens the recovery from sevoflurane anaesthesia and improves bispectral index scores (BIS) with concurrent increases in heart rate which might have a detrimental effect in patients with ischaemic heart disease.8-11However, the use of smaller doses of 2-3 mg/kg is associated with less increases in heart rate. 10-11 The use of 1 mg/kg of Doxapram is comparable to 2 mg/kg of aminophylline in improvement of early recovery from sevoflurane anaesthesia secondary to its central nervous system stimulating effect rather than increased ventilatory elimination of sevoflurane.11 Currently, there is no available published studies have investigated the effects of either theophylline or doxapram on early postoperative cognitive recovery after balanced anaesthesia with sevoflurane.
We hypothesized that the use of small doses of aminophylline [2-3 mg/kg] may be comparable to larger doses in improvement of the early postoperative cognitive recovery from sevoflurane anaesthesia with associated non-significant increases in heart rate.
The present study investigated the effects of 1 mg/kg of doxapram, and 2, 3, 4, and 5 mg/kg of aminophylline on the early postoperative cognitive recovery using the Short Orientation Memory Concentration Test (SOMCT), response entropy (RE) state entropy (SE), difference between RE and SE (RE-SE), end-tidal sevoflurane concentration, haemodynamics, the times to eyes opening and to extubation and degree of sedation after sevoflurane anaesthesia in patients undergoing ambulatory surgery.
Detailed Description
One-hundred-eighty ASA I-II patients aged 18-55 years scheduled for elective ambulatory general surgery with a duration >1 h under general anaesthesia were enrolled in this double-blinded placebo-controlled randomised study after obtaining of the approval of Institutional Ethical Committee of author's centre and a written informed consent from the participants.
Based upon our preliminary data, a prior power analysis indicated that 27 patients in each group was a sufficiently large sample size to detect a 20% difference on the Short Orientation Memory Concentration Test (SOMCT)12 at 30 minutes after extubation, with a type-I error of 0.05 and type II error of 0.2. We added 10% more patients to account for patients dropping out during the study. Participants were allocated randomly to six groups (n=30 for each) to receive saline [group P], 1 mg/kg of doxapram [group D] or 2, 3, 4 or 5 mg/kg of aminophylline [groups A2, A3, A4, and A5, respectively] at the end of surgery.
Patients with history of significant cardiovascular, respiratory, cognitive dysfunction, cerebrovascular disease, neurological or psychiatric diseases, pregnancy, and obesity (body mass index ≥ 30 Kg/m2), recent history of infection or recent fever, or adverse reaction to aminophylline or sevoflurane, alcoholism, drug dependence or those receiving xanthines, ß-agonist, anticholinergic, tranquilizers, anticonvulsants or antidepressants or those who has habitual coffee consumption exceeding 2 cups per day, are unable to read, or are suffering from serious hearing or vision impairment were excluded from the study. All operations were performed by the same surgeons.
Primary outcome variable included early postoperative cognitive function. Secondary outcome variables included changes in entropy variables, end-tidal sevoflurane and recovery pattern.
The SOMCT is a patient-based test designed to assess cognitive function in terms of level of orientation, memory, and concentration, The SOMCT requires subjects to recall the current year, and one sentence, and to repeat in numerical order and reverse order the sequence of the months through the year. These six variables yield scores ranging from 0 to 28, with higher scores indicating better function and scores more than 20 were considered normal (Appendix 1).12 A blind investigator who was not involved in the management of the patient and who was blinded to the study drugs explained the SOMCT to the participant and applied it 30 min before induction. All patients received the same explanation of the test by the same investigator.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 55 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •ASA I-II patients
- •aged 18-55 years
- •scheduled for elective ambulatory surgery
- •duration >1 h under general anaesthesia
Exclusion Criteria
- •cardiovascular diseases
- •respiratory diseases
- •neurological diseases
- •psychiatric diseases
- •adverse reaction to aminophylline or sevoflurane
- •receiving xanthines, ß-agonist, anticholinergic
- •history of cognitive dysfunction
- •cerebrovascular disease
- •recent history of infection or recent fever
- •adverse reaction to aminophylline or sevoflurane
- •drug dependence
- •those receiving xanthines, ß-agonist, anticholinergic, tranquilizers, anticonvulsants or antidepressants
- •those who has habitual coffee consumption exceeding 2 cups per day
- •unable to read
- •suffering from serious hearing or vision impairment
- •those who had not completed primary school
Arms & Interventions
Placebo [group P]
Intervention: Placebo [group P] (Drug)
Aminophylline 2 mg/Kg [group A2]
Intervention: 0.2 mL/kg of aminophylline 10 mg/mL [group A2] (Drug)
Aminophylline 3 mg/Kg [group A3]
Intervention: 0.2 mL/kg of aminophylline 15 mg/mL [group A3] (Drug)
Aminophylline 4mg/Kg [group A4]
Intervention: 0.2 mL/kg of aminophylline 20 mg/mL [group A4] (Drug)
Aminophylline 5 mg/Kg [group A5]
Intervention: 0.2 mL/kg of aminophylline 25 mg/mL [group A5] (Drug)
Doxapram 1 mg/kg [group D]
Intervention: Doxapram 1 mg/kg [group D] (Drug)
Outcomes
Primary Outcomes
early postoperative cognitive function
Time Frame: 30 min before induction and 30, 60 and 90 minutes after extubation.
The SOMCT is a patient-based test designed to assess cognitive function in terms of level of orientation, memory, and concentration.
Secondary Outcomes
- changes in entropy variables, and end-tidal concentration (EtSevo) of sevoflurane, heart rate (HR), and mean arterial blood pressure (MAP) and recovery pattern(1 min after administration of the study drug (T0) for 15 min.)