Ignite Creation Date:
2024-05-05 @ 10:05 PM
Last Modification Date:
2024-10-26 @ 10:13 AM
Study NCT ID:
NCT01022151
Status:
COMPLETED
Last Update Posted:
2010-11-19
First Post:
2009-11-26
Brief Title:
Aminophylline and Cognitive Function After Sevoflurane Anaesthesia
Sponsor:
King Faisal University
Organization:
King Faisal University
Study Overview
Official Title:
Aminophylline Improves Early Postoperative Cognitive Recovery After Sevoflurane Anaesthesia A Dose-Dependent Study
Status:
COMPLETED
Status Verified Date:
2010-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Early postoperative recovery of neurologic and cognitive functions is especially advantageous after fast-tracking ambulatory procedures to hasten home discharge after surgery1 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 volunteers2Hence rapid elimination of the volatile anaesthetics may help reduce postoperative confusion and cognitive impairment in surgical patients by facilitating a faster recovery from general anaesthesia3 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 metabolism4 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 barbiturates6-7Aminophylline in doses of 2-5 mgkg 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 disease8-11However the use of smaller doses of 2-3 mgkg is associated with less increases in heart rate 10-11 The use of 1 mgkg of Doxapram is comparable to 2 mgkg of aminophylline in improvement of early recovery from sevoflurane anaesthesia secondary to its central nervous system stimulating effect rather than increased ventilatory elimination of sevoflurane11 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 mgkg 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 mgkg of doxapram and 2 3 4 and 5 mgkg 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
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 barbiturates6-7Aminophylline in doses of 2-5 mgkg 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 disease8-11However the use of smaller doses of 2-3 mgkg is associated with less increases in heart rate 10-11 The use of 1 mgkg of Doxapram is comparable to 2 mgkg of aminophylline in improvement of early recovery from sevoflurane anaesthesia secondary to its central nervous system stimulating effect rather than increased ventilatory elimination of sevoflurane11 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 mgkg 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 mgkg of doxapram and 2 3 4 and 5 mgkg 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 authors 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 SOMCT12 at 30 minutes after extubation with a type-I error of 005 and type II error of 02 We added 10 more patients to account for patients dropping out during the study Participants were allocated randomly to six groups n30 for each to receive saline group P 1 mgkg of doxapram group D or 2 3 4 or 5 mgkg 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 Kgm2 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 112 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 Ringers solution was infused at a rate of 2-3 mLkgh Patients monitoring included electrocardiography pulse oximetry non-invasive blood pressure and nasopharyngeal temperature monitoring Datex-OhmedaTM S5TM Helsinki Finland RE and SE were monitored with the Datex-OhmedaTM S5 Entropy Module using a specific entropy sensor M-EntropyTM Datex-Ohmeda Division Instrumentarium Corporation Helsinki Finland The sensors were applied appropriately to the patients forehead according to the manufacturers 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 patients data General anaesthesia was induced with propofol 2-3 mgkg and fentanyl 2-3 µgkg Rocuronium 06 mgkg 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 05-1 MAC of sevoflurane in combination with 50 air in oxygen in a semi-closed circuit with total gas flow of 1 Lmin based on entropy reading where the end-points were SE of 50 and SE-RE difference less than 1013 The patients 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 mgkg for postoperative pain relief and granisetron 1 mg for postoperative nausea and vomiting PONV prevention
During skin closure neuromuscular blockade was antagonized with 50 µgkg neostigmine and 10 µgkg glycopyrrolate when the train of four ratio TOF ratio ranged between 03 and 05 At the last skin suture sevoflurane was discontinued T0 and the patients lungs were ventilated with 100 oxygen at 5 litresmin
Subjects were allocated randomly to six groups n30 for each by drawing sequentially numbered sealed opaque envelopes containing a computer-generated randomisation code to receive intravenous injection of 02 mLkg of a study solution containing either saline 09 solution group P doxapram 5 mgmL group D or 10 mgmL group A2 15 mgmL group A3 20 mgmL group A4 or 25 mgmL 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 patients 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 hisher 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 09 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 investigators 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 05 mgkg 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 patients 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 05 hour able to sit up without dizziness andor 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 recorded15 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 SpO290 were recorded
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 SOMCT12 at 30 minutes after extubation with a type-I error of 005 and type II error of 02 We added 10 more patients to account for patients dropping out during the study Participants were allocated randomly to six groups n30 for each to receive saline group P 1 mgkg of doxapram group D or 2 3 4 or 5 mgkg 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 Kgm2 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 112 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 Ringers solution was infused at a rate of 2-3 mLkgh Patients monitoring included electrocardiography pulse oximetry non-invasive blood pressure and nasopharyngeal temperature monitoring Datex-OhmedaTM S5TM Helsinki Finland RE and SE were monitored with the Datex-OhmedaTM S5 Entropy Module using a specific entropy sensor M-EntropyTM Datex-Ohmeda Division Instrumentarium Corporation Helsinki Finland The sensors were applied appropriately to the patients forehead according to the manufacturers 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 patients data General anaesthesia was induced with propofol 2-3 mgkg and fentanyl 2-3 µgkg Rocuronium 06 mgkg 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 05-1 MAC of sevoflurane in combination with 50 air in oxygen in a semi-closed circuit with total gas flow of 1 Lmin based on entropy reading where the end-points were SE of 50 and SE-RE difference less than 1013 The patients 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 mgkg for postoperative pain relief and granisetron 1 mg for postoperative nausea and vomiting PONV prevention
During skin closure neuromuscular blockade was antagonized with 50 µgkg neostigmine and 10 µgkg glycopyrrolate when the train of four ratio TOF ratio ranged between 03 and 05 At the last skin suture sevoflurane was discontinued T0 and the patients lungs were ventilated with 100 oxygen at 5 litresmin
Subjects were allocated randomly to six groups n30 for each by drawing sequentially numbered sealed opaque envelopes containing a computer-generated randomisation code to receive intravenous injection of 02 mLkg of a study solution containing either saline 09 solution group P doxapram 5 mgmL group D or 10 mgmL group A2 15 mgmL group A3 20 mgmL group A4 or 25 mgmL 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 patients 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 hisher 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 09 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 investigators 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 05 mgkg 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 patients 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 05 hour able to sit up without dizziness andor 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 recorded15 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 SpO290 were recorded
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2007 | OTHER | King Faisal University | None |