Aminophylline and Cognitive Function After Sevoflurane Anaesthesia
Condition: Anaesthesia
Study type: Interventional
Phase: Phase 2

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.

      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, non-invasive blood pressure and nasopharyngeal
      temperature 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 according to the manufacturer's instructions.
      Neuromuscular block were monitored by a train-of-four (TOF) stimulation of the ulnar nerve.

      The attending anaesthesiologists who gave the anaesthetic were not involved 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 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 in a semi-closed circuit with
      total gas flow of 1 L/min, based on entropy reading where the end-points were SE of ≤ 50 and
      SE-RE difference less than 10.13 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. Normothermia was maintained using forced-air
      warming blankets. No supplementary dose of muscle relaxant was administered 30 minutes before
      the end of the surgery.

      During surgery, patients received lornixicam 16 mg and paracetamol 15 mg/kg for postoperative
      pain relief and granisetron 1 mg for postoperative nausea and vomiting (PONV) prevention.

      During skin closure, neuromuscular blockade was antagonized with 50 µg/kg neostigmine and 10
      µg/kg glycopyrrolate when the train of four ratio (TOF ratio) ranged between 0.3 and 0.5. At
      the last skin suture, sevoflurane was discontinued (T0) and the patient's lungs were
      ventilated with 100% oxygen at 5 litres/min.

      Subjects were allocated randomly to six groups (n=30 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], doxapram 5 mg/mL [group D], or 10 mg/mL [group A2], 15 mg/mL [group A3],
      20 mg/mL [group A4], or 25 mg/mL [group A5] of aminophylline. 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 looked identical and contained normal
      saline, doxapram or aminophylline. They were prepared in identical syringes labelled 'study
      drug', before induction of anaesthesia by an independent anaesthesiologist who was not
      involved in the study. The attending anaesthesiologists who were blinded to the study
      protocol and the patient's randomization code gave the anaesthetic, study solution and
      established awakening. All staff in the operating room, post anaesthesia care unit (PACU),
      and day-case surgery ward was unaware of the randomization code.

      All measurements were made by the same investigator who was not involved in the management of
      the patient and who was blinded to the study drugs. Therefore, the patient did not know
      his/her assigned treatment group. All data, including RE, SE, (RE-SE), the MAC and end-tidal
      concentration (EtSevo) of sevoflurane, heart rate (HR), and mean arterial blood pressure
      (MAP) was recorded every 1 min after administration of the study drug (T0) for 15 min.

      Tracheal extubation was performed immediately after suctioning when all extubation criteria
      were achieved (TOF ratio ≥ 0.9, spontaneous ventilation and the ability to follow verbal
      commands, eye opening, head lift ≥ 5 seconds, and handgrip), at the discretion of the
      anaesthetist who was involved in the intraoperative management of the patient. The level of
      consciousness was assessed using simple verbal commands ('open your eyes', 'move your hand')
      and was repeated up to three times with increasing forcefulness if the subject failed to
      respond.

      Recovery from anaesthesia was assessed by the times to eyes opening (time from T0 to
      spontaneous eye opening), response time (time from T0 to squeeze the investigator's hand on
      command), and the time to extubation (time from T0 to tracheal extubation).

      After awakening, patients were transferred to the PACU and physical recovery was assessed
      using the modified Aldrete score14 every 5 minutes after extubation until it reached at least
      9 points and the time to reach a score ≥ 9 was recorded. Postoperative analgesia was provided
      with 0.5 mg/kg intravenous boluses of meperidine as needed to achieve a visual analog pain
      scale less than 4 points. Heart rate (HR), mean arterial blood pressure (MAP), respiratory
      rate, peripheral oxygen saturation, and the degree of sedation (four-point verbal rating
      scores (VRS): awake, drowsy, rousable or deep sleep) were recorded on the patient's arrival
      and every 15 min until discharge to the ward.

      Early postoperative cognitive function was assessed using the SOMCT test, 30 min before
      induction and 30, 60 and 90 minutes after extubation.

      Discharge of patients from the PACU was determined by clinical criteria at the discretion of
      the attending anaesthetists and no attempt was made to speed up this process. These criteria
      included alertness and orientation to time and place, conversant and cooperative, stable
      vital signs for at least 0.5 hour, able to sit up without dizziness and/or nausea, tolerable
      pain, and a modified Aldrete score ≥ 9. Home readiness was determined by specific clinical
      criteria, included stable vital signs for at least 1 h, controllable pain by oral analgesics,
      absent or mild nausea or emesis, ability to walk without dizziness, and ability to retain
      oral fluids. Actual discharge time was also recorded.15 Times to reach a PACU discharge, home
      readiness and home discharge and the cost of the study medications were recorded.
      Postoperative complications included arrhythmia, tremors, vomiting, nausea, seizures,
      shivering, agitation, or hypoxemia (SpO2<90%) were recorded.
    

Intervention name(s): 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]; Doxapram 1 mg/kg [group D]
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): receive intravenous injection of 0.2 mL/kg of saline 0.9%L [group P]. All study solutions were injected within 1 min at T0 after discontinuation of sevoflurane. No stimulation was applied to patients during this period.; receive intravenous injection of 0.2 mL/kg of aminophylline 10 mg/mL [group A2]. All study solutions were injected within 1 min at T0 after discontinuation of sevoflurane. No stimulation was applied to patients during this period.; receive intravenous injection of 0.2 mL/kg of aminophylline 15 mg/mL [group A3]. All study solutions were injected within 1 min at T0 after discontinuation of sevoflurane. No stimulation was applied to patients during this period.; receive intravenous injection of 0.2 mL/kg of aminophylline 20 mg/mL [group A4]. All study solutions were injected within 1 min at T0 after discontinuation of sevoflurane. No stimulation was applied to patients during this period.; receive intravenous injection of 0.2 mL/kg of 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.; receive intravenous injection of 0.2 mL/kg of doxapram 5 mg/mL [group D]. All study solutions were injected within 1 min at T0 after discontinuation of sevoflurane. No stimulation was applied to patients during this period.
Intervention MeSH terms: Aminophylline; Doxapram
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Aminophylline; sevoflurane; anaesthesia; recovery; cognitive function; entropy