Ketamine: review of its pharmacology and its use in pediatric anesthesia.

The management of the uncooperative pediatric patient undergoing minor surgical procedures has always been a great challenge. Several sedative techniques are available that will effectively alleviate anxiety, but short of general anesthesia, no sedative regimen is available that will enable treatment of the uncooperative child. Ketamine produces a unique anesthetic state, dissociative anesthesia, which safely and effectively enables treatment of these children. The pharmacology, proposed mechanisms of action, and clinical use of ketamine (alone and in combination with other agents) are reviewed and evaluated.

Accuracy of clinical examination versus computed tomography in detecting occult lymph node involvement in patients with oral epidermoid carcinoma.

PURPOSE: To determine the accuracy of clinical examination versus computed tomography (CT) scanning in detecting positive cervical lymph nodes (N) in patients with epidermoid carcinomas of the oral cavity, 27 patients with epidermoid carcinomas were reviewed. PATIENTS AND METHODS: The patients underwent 40 neck dissections, 20 with N- and 20 with N+ necks histologically. All patients were examined by the same clinician, and all CT scans were read by the same radiologist. Patients with clinical and CT N- necks underwent neck dissection only if the neck had to be entered to resect the primary tumor or if the primary tumor was T3 or T4 with a high probability of microscopic metastasis. RESULTS: Of the 20 necks that were histologically N-, 16 (80%) were clinically diagnosed as N- and 4 (20%) N+ versus 18 (90%) N- and 2 (10%) N+ diagnosed by CT scan. Of the 20 histologically N+ necks, 12 (60%) were clinically diagnosed as N+ and 8 (40%) N- versus 11 (55%) N+ and 9 (45%) N- diagnosed by CT scan. All lymph nodes diagnosed as N- by both clinical examination and CT scan were less than 1 cm in diameter. Overall, clinical examination of the neck was correct in 28 patients (70%) and the CT scan was correct in 29 patients (73%). Both clinical examination and CT scan were more accurate in diagnosis of N- necks. In 31 necks (78%), the CT and clinical examination were in agreement. Of these, 10 of 10 (100%) were correctly positive. Of the 21 in which both were negative, 14 were histologically N-, and 14 (67%) were correct. Overall, in those cases in which both CT and clinical examination were in agreement, the diagnosis was correct in 24 of 31 (77%). CONCLUSION: These results suggest that there is no significant difference in the accuracy of clinical examination versus CT scanning in detecting both positive and negative cervical nodes. When both CT and clinical examination agree, positive cervical nodes are almost always correctly diagnosed. However, one third of the negative cervical nodes were incorrectly diagnosed. Improved methods for detecting occult disease are still needed.

Immediate mandibular stabilization following resection of advanced oral cavity carcinoma using the Joe Hall Morris external fixation device.

Internal mandibular fixation after resection of advanced oral cavity carcinoma with mandibulectomy has a significant complication rate. We placed the Joe Hall Morris (JHM) external mandibular appliance in 29 patients undergoing mandibulectomy for advanced oral cavity carcinoma. Fourteen patients received postoperative radiation therapy (RT). Three of 29 patients (10%) had complications associated with the JHM appliance: one patient had a broken connecting bar, a second had loosening of a single pin, and a third had loss of fixation requiring complete replacement of the appliance. Complications not associated with the appliance occurred in 8 patients (28%) including mandibular exposure (1), orocutaneous fistula (2), partial flap dehiscence (4), and flap necrosis (1). Oral continence was maintained in 26 patients, and occlusion was normal in 27. The appliance was removed in 12 weeks to 6 months in all patients. The JHM appliance allows for a reliable and rapid immediate fixation of the mandible with acceptable functional and aesthetic results, and no delay or interference with postoperative radiotherapy. Since the life expectancy of these patients is short, most do not require subsequent permanent fixation after removal of the appliance.

Imipramine-fentanyl antinociception in a rabbit tooth pulp model.

Antinociception of imipramine (I) and its effect in combination with fentanyl (F) was evaluated in rabbits using electrically-induced lick chew responses via tooth pulp stimulation as the model of nociception. Acute i.v. injections of I elicited a graded dose response comparable to i.v. morphine (M) with I ED 50 = 4.35 mg/kg (2.31-8.14, 95% CL) and M ED 50 = 1.81 mg/kg (1.11-3.90), with no differences in the slopes between the two curves. The lethal dose of I was 10 mg/kg. An i.v. dose of I twice the ED 50 elicited an antinociceptive effect of more than 50% maximum possible effect (MPE) for 90 minutes with peak effect of 82% MPE occurring at 15 minutes. These effects of I were not reversed by a morphine-reversal dose of naloxone (0.1 mg/kg i.v.) but were reversed with a ten fold dose of naloxone. F ED 50 values (mcg/kg) were lowered from 11.35 to 2.70, 0.74 and 0.33 with increasing pretreatment doses of I (1.0, 2.1 and 3.2 mg/kg). These magnitudes of potency increases of F were 4.2, 15.3 and 34.4 fold respectively. A single i.v. ED 50 dose of I extended the time to 50% MPE of an ED 90 dose of F from 26 minutes to 77 minutes; of a 2 X ED 50 dose of F from 17 minutes to 28 minutes. Data points for three different combinations of I and F fell significantly within the synergistic field of an ED 50 isobologram and a polynomial equation described the curve best fitting the data points. F alone (i.v. ED 50 dose) increased the PaCO2 values to 74% above controls and three different combinations with I showed no increases in PaCO2 values above controls. I alone did not significantly cause any change in PaCO2 values from controls.

GABAmimetics diminish antinociception of meperidine under conditions which enhance other opioid mu-agonists.

This study investigated the effects of pretreatment with muscimol (GABA-agonist) or diazepam (indirect GABAmimetic) on i.v. meperidine, fentanyl, alphaprodine and morphine, using rabbit tooth pulp and mouse hot plate assays. A previous study reported that the ED50 values for fentanyl in rabbits were significantly lowered by 0.25 mg/kg of muscimol (13.8 to 1.8 micrograms/kg) and by 1.5 mg/kg of diazepam (13.1 to 1.1 micrograms/kg). ED50 values for meperidine in rabbits in this study were increased by muscimol (1.2 to 3.2 mg/kg) and diazepam (1.5 to 3.1 mg/kg). ED50 values for fentanyl in mice were significantly lowered by 0.25 mg/kg of muscimol (23.0 to 8.9 micrograms/kg) and 1.0 mg/kg of diazepam (23.3 to 12.8 micrograms/kg). ED50 values for meperidine in mice were significantly increased by muscimol (2.1 to 5.0 mg/kg) and diazepam (2.0 to 4.8 mg/kg). ED50 values for alphaprodine and morphine were significantly lowered by muscimol and diazepam in mice. A higher dose of muscimol (1.0 mg/kg) had no effect on the ED50 values of meperidine in mice. The antinociception of a submaximal dose of meperidine in rabbits was significantly reduced by a 10 min pretreatment with i.v. diazepam (1.5 mg/kg) at 15, 20, 30 and 45 min after i.v. meperidine. The antinociception of a submaximal dose of fentanyl in rabbits was significantly increased by a 10 min pretreatment with i.v. diazepam (1.5 mg/kg) at 5, 10, 15 and 20 min after i.v. fentanyl. Pretreatment with 0.1 mg/kg of scopolamine enhanced the antinociceptive effect of a submaximal dose of fentanyl in both animal models. Diazepam reduced the antinociception produced by the combination scopolamine-fentanyl to that of fentanyl-vehicle control in both animal models. Pretreatment with 0.1 mg/kg of scopolamine did not change the magnitude of antinociception of a submaximal dose of meperidine in rabbits. Since meperidine possesses inherent anticholinergic activity, it is suggested that this anticholinergic activity may be involved in the reduction effects by muscimol and diazepam.

Effects of midazolam on fentanyl antinociception and respiration in a rabbit model.

Clinical antinociception is difficult to assess because of difficulties with controls and the incorporation of bias. The rabbit antinociceptive model is highly sensitive and predictive of analgesia in humans. We found that the combination of midazolam with fentanyl enhanced antinociception compared with fentanyl alone. In addition, with this model there were relatively unimportant increases in respiratory depression.

Diazepam enhances fentanyl and diminishes meperidine antinociception.

A rabbit tooth pulp antinociceptive model was used to investigate the effect of prior administration of diazepam or muscimol on the potency and duration of fentanyl and meperidine Potency experiments compared ED(50) values in all-or-none dose-response assays between both muscimol (0.25 mg/kg) and saline, and diazepam (1.5 mg/kg) and propylene glycol vehicle. An all-or-none effect was defined as doubling of voltage threshold to elicit a lick/chew evoked response. Duration experiments compared time (minutes) to 50% maximum possible effect (MPE) of an ED(90) dose of fentanyl (0.04 mg/kg) and to 50% and 20% MPE of an ED(98) dose of meperidine (17 mg/kg) 10 minutes after pretreatment with diazepam (1.5 mg/kg). Prior (10 minutes) injection of diazepam (1.5 mg/kg) increased the ED(50) value for meperidine (3.06 mg/kg) compared with its control (1.48 mg/kg), indicating a decrease in antinociceptive potency. The same dose of diazepam decreased the ED(50) value for fentanyl (1.1 µg/kg) compared with its control (13.1 µg/kg), indicating an increase in antinociceptive potency. Muscimol also had a similar effect on fentanyl (ED(50), 1.8 µg/kg) compared with saline control (ED(50), 13.8 µg/kg). Diazepam, vehicle, and muscimol by themselves had no effect on voltage thresholds to elicit a lick/chew response. Time to 50% MPE for diazepam-fentanyl was 38 minutes vs. 25 minutes for vehicle-fetanyl; time to 20% MPE for diazepam-meperidine was 38 minutes vs. 54 minutes for vehicle-meperidine (maximum percentage of MPE produced by diazepam-meperidine was 40% compared with 100% MPE for vehicle-meperidine). Percentages of MPE for diazepam-meperidine were significantly lower than those for vehicle-meperidine at all time intervals, whereas percentages of MPE for diazepam-fentanyl were significantly greater than those for vehicle-fentanyl over time.

Low dose naloxone enhances buprenorphine in a tooth pulp antinociceptive assay.

Low dose naloxone was reported to produce analgesia of long duration in patients who received buprenorphine. A rabbit tooth pulp antinociceptive model was utilized to evaluate a possible interaction of buprenorphine and naloxone. Naloxone (0.001 mg/kg i.v.) 210 min after buprenorphine (0.10 mg/kg i.v.) significantly increased the % MPE from 48 +/- 5% to 78 +/- 6%. This increased activity occurred within 90 min after naloxone injection and had a duration of 2 hr. Naloxone, 0.1 mg/kg, or saline 0.1 ml/kg did not increase nor reduce the buprenorphine antinociceptive effect. Naloxone alone (0.001 mg/kg) produced a peak antinociceptive effect of 43 +/- 14% MPE which was significantly greater than that of the saline control group. Using a graded dose response paradigm in the rabbit tooth pulp model, the graded dose response curve of buprenorphine was significantly shifted upwards after preadministration of 0.001 mg/kg naloxone. The slopes of both the ascending and descending limbs of the biphasic buprenorphine dose response curves were not significantly different. The peak % MPE achieved by buprenorphine in the presence of 0.001 mg/kg naloxone (62 +/- 8%) was significantly greater than the buprenorphine-saline control (23 +/- 4%). It appears that a low dose of naloxone produces antinociception which enhances that of buprenorphine.

The benzodiazepine receptor.

The benzodiazepines are among the most widely used drugs in the world. When first introduced, little was known about their mechanism of action. However, in the last 20 years, our understanding of the chemistry and function of the central nervous system (CNS) has increased substantially. This knowledge has shed some light on the mechanism of action of the benzodiazepines and other centrally acting drugs. It is well established that the benzodiazepines act by combining with specific receptors in the central nervous system. These receptors are anatomically in close association with gamma amino butyric acid (GABA) receptors and appear to reside on the neuronal membrane in the same supramolecular protein complex. GABA is the major inhibitory neurotransmitter of the CNS. The benzodiazepines act by increasing the affinity of the GABA receptor for its ligand, thereby augmenting the inhibitory effect of a given concentration of GABA. Two hypotheses of benzodiazepine ligand-receptor interactions in this supramolecular protein complex have been proposed: (1) multiple receptor subtypes analogous to the opioid receptors; (2) single receptor with multiple conformations. The multiple receptor hypothesis suggests that each pharmacologic effect of the benzodiazepines (i.e., anxiolysis) is mediated by interaction with a specific receptor subtype. On the other hand, the alternative hypothesis suggests that only one receptor exists which has a dynamic conformation. Experimental evidence in support of each hypothesis is presented and critically evaluated.

Relief of dental surgery pain: a controlled 12-hour comparison of etodolac, aspirin, and placebo.

Single doses of the study drugs were evaluated for 12 hours by 201 out-patients reporting moderate or severe pain following oral surgery. The results of this double-blind study indicated that 50, 100, and 200 mg of etodolac as well as 650 mg of aspirin were significantly more effective than placebo. A dose-response relationship was found for the three doses of etodolac, which was significant for summed pain relief scores for up to 8 hours. In terms of total analgesic effect, etodolac 200 mg was significantly superior to placebo for 8 hours, while aspirin and the two lower doses of etodolac were similarly effective in the range of 3-6 hours postdrug. All doses showed a favorable onset of analgesia (½-1 hour). Etodolac 200 mg resulted in a duration of action which was approximately twice as long as aspirin's and also produced a peak pain relief which was significantly greater than the lower doses of etodolac and aspirin. All study medications were well tolerated with no reports of significant adverse side effects. No dose-related effects were observed with etodolac

Dental extractions in patients with acute nonlymphocytic leukemia.

Dental extractions in patients with leukemia are controversial, since they may lead to hemorrhage, delayed wound healing and infection. However, the retention of diseased teeth in these patients may also lead to infectious complications during chemotherapy. With adequate hematologic values and specific surgical techniques, 119 extractions were performed on 28 patients with acute nonlymphocytic leukemia. No serious adverse sequelae occurred, and the prevalence of other adverse affects was comparable with that in nonleukemic patients. It is concluded that with proper precautions, extractions can be performed on these patients.