Neither IT neostigmine alone nor IV ketamine or fentanyl alone increased the time for first request of rescue analgesic medication (P = 0.178406, P = 0.799933, and P = 1, respectively). The ketamine group (KG), FNG, and KNG requested fewer rescue analgesic medications during the first 24 h of observation compared with the CG (P < 0.01). However, only the KNG reported statistically lower 24-h VAS scores compared with the CG (P = 0.021848).
The number of patients having intraoperative nausea and vomiting, the overall intraoperative nausea and vomiting scores, and the overall 24-h VAS nausea and vomiting scores are shown in Table 3. Fifty percent of the patients from the FNG had intraoperative nausea and vomiting compared with 0% from the CG and KG (P = 0.026718); these patients complained of an overall intraoperative nausea and vomiting VAS assessment score of 2.4 +/- 2.6 compared with the CG (VAS = 0) and KG (VAS = 0) (P = 0.011238).
Other intraoperative adverse effects included bradycardia, hypotension, cardiac arrhythmia, and fecal incontinence. One patient from the CG and two from the KG had hypotension 30, 18, and 25 min after the spinal anesthesia, respectively, and were treated with IV ephedrine. Two patients from the NCG had bradycardia 65 and 80 min after the spinal anesthesia and were successfully treated with atropine. One patient from the KNG had bradycardia at 21 min and other cardiac arrhythmias (ventricular extrasystoles) 20 min after the spinal anesthesia and was successfully treated with 160 mg IV lidocaine divided in two equal bolus doses. This last ASA physical status II patient had a past history of occasional cardiac arrhythmia. Three patients from the FNG had bradycardia at 15, 40, and 45 min after the spinal anesthesia. Another patient from the FNG opened the bowel and urinated 35 min after the spinal anesthesia; this particular patient vomited frequently during the procedure.
Apart from postoperative nausea and vomiting, which was similar among groups (P = 0.8437), one ASA physical status II patient (past history of hypertension) from the CG had a grand mal seizure in the recovery room 195 min after the spinal anesthesia and was successfully treated with 5 mg IV midazolam. She was the third patient from the study, and at that time we had opened her personal code to discover which group she was in. Because she was from the CG, we were confident in performing this double-blind study.
We have shown that the administration of a small dose of IV ketamine with IT neostigmine results in prolonged postoperative analgesia (mean > 7 hours) similar to that with IV fentanyl administered with IT neostigmine. However, IV ketamine results in less nausea and vomiting than does the combination of a small dose of IV 1 micro gram/kg fentanyl and 50 micro gram IT neostigmine.
While neither IV ketamine alone nor IV fentanyl alone increased the time for first request for analgesic medications, their administration with IT neostigmine showed a clear analgesic effect. Morphine given intrathecally is thought to improve IT neostigmine analgesia. Isobolographic analysis revealed a simple additivity between IT neostigmine and morphine in rats . Other authors have demonstrated that the combination of IT morphine and neostigmine produces moderate analgesia in a model of noxious thermal stimuli in rats . In another study, in patients undergoing vaginoplasty, IT morphine and neostigmine also produced a moderate synergistic analgesic effect .
This is the first time that IV ketamine has been shown to improve IT neostigmine analgesia in patients. Although systemically administered ketamine has a local anesthetic action, as well as spinal effects , the IV dose used in this study (0.2 mg/kg) was not large enough to have any local anesthetic action, as demonstrated by similar pinprick levels at 5 and 10 minutes and similar anesthetic times, as measured by the Bromage scale.
Although ketamine's primary antinociceptive site of action appears to be the phencyclidine receptor on the N-methyl-D-aspartate receptor complex , additional activity on opiate  and quisqualate receptors  is suggested. It is interesting that ketamine appears to exert its analgesic effect after the channel coupled to the N-methyl-D-aspartate receptor complex has been opened , but small doses of IV ketamine were successfully used preemptively, combined with general anesthesia, to provide postoperative analgesia . Ketamine also inhibits central temporal nociceptive somation and has a marked hypoalgesic effect on high-intensity nociceptive electrical and mechanical stimuli . Nevertheless, ketamine also profoundly inhibited both the central and peripheral muscarinic signaling within the clinically relevant concentration range . It could be argued that the stimulation of spinal cord muscarinic receptors results in antinociceptive effects [2,7]. However, the ketamine analgesic effect observed could be due to a direct antispasmodic effect on the viscera through muscarinic receptors. If so, this is another example of an association between central cholinergic effects and peripheral anticholinergic effects in the treatment of postoperative pain .
Among the adverse effects observed, nausea and vomiting were the most troublesome in the FNG. One patient from the FNG also opened the bowels and urinated 35 minutes after the spinal anesthesia. This could be an effect of spinal neostigmine, although the etiology of bowel incontinence is uncertain, and there is no evidence that spinal cholinergic stimulation causes this effect . We have previously shown that spinal bupivacaine combined with IT fentanyl and IT neostigmine were effective as anesthetics in patients undergoing abdominal hysterectomy . Interestingly, while the association of IT fentanyl with IT neostigmine resulted in minimal adverse effects , the association of IV fentanyl with a similar spinal neostigmine dose resulted in an unacceptable incidence of nausea and vomiting. It is been suggested that the emetic effect of opioids is expressed at the chemoreceptor trigger zone through delta-opioid receptor subtype binding, while binding to the mu-receptor subtype at the vomiting center expresses an antiemetic effect [23,24]. One explanation could be that IV fentanyl expresses emesis, through a predominant binding at the chemoreceptor trigger zone, whereas IT fentanyl would be acting mainly at the vomiting center expressing an antiemetic effect. Nevertheless, the doses used in both studies were different (1 micro gram/kg IV and 25 micro gram IT). Whether a smaller IV dose of fentanyl would retain the analgesic potentiation of spinal neostigmine with an acceptable incidence of adverse effects is already under investigation.
In our study, one of the patients had a clinical seizure 195 minutes after the spinal anesthesia, which was promptly and successfully treated with IV midazolam. Fortunately, she was from the CG; otherwise, this study and many others would have been compromised, and spinal antinociceptive neostigmine could have been partially discredited.
In conclusion, the administration of a small dose of IV ketamine enhances the spinal neostigmine antinociceptive effect without increasing the incidence of side effects, showing it to be an efficient alternative postoperative pain therapy for vaginoplasty surgery.
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© 1996 International Anesthesia Research Society
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