Respiratory effects of quazepam and pentobarbital.

Quazepam is a new benzodiazepine that may provide good hypnotic action with negligible effect on motor coordination or respiration. Sleep laboratory studies on human volunteers have shown quazepam 15 mg to be an effective hypnotic dose, with the 30-mg dose being optimal. At these doses, there was no deterioration of motor performance, and the drug, when given nightly for two weeks, continued to exert hypnotic effects without serious adverse effects. Therefore, this study was designed to compare the respiratory effects of quazepam 15 and 30 mg to those of pentobarbital 50 and 150 mg and to placebo. Five adult male volunteers received each dose at separate times. A double-blind technique was employed for controlled rebreathing studies, to a ventilation of 40 L/min or a PETCO2 of 8%. Respiratory curves were compared with controls. The mean displacement curve at the 20-liter intercept showed a depressant effect for pentobarbital 150 mg at two hours and a stimulant effect for quazepam 15 mg at two hours but a slight depression effect for quazepam 30 mg at three hours compared with placebo. The slope of the respiratory curve was not affected.

Comparison of chemoreflex gains obtained with two different methods in cats.

This study investigates the correspondence between results of the ventilatory response to CO2 obtained using the technique of dynamic end-tidal CO2 forcing (DEF) and results obtained using the technique of artificial brain stem perfusion (ABP). The DEF technique separates the dynamic ventilatory response into a slow and fast component with gains g1 and g2 as well as the extrapolated CO2 tension at zero ventilation (Bk). The ABP technique results in steady-state central (Sc) and peripheral (Sp) chemoreflex gains and extrapolated CO2 tension at zero ventilation (B). Experiments were performed on 14 alpha-chloralose-urethan anesthetized cats. A wide range of relative peripheral chemosensitivities was obtained by subjecting eight cats to normoxic and three cats to hypoxic CO2 challenges and three cats to both conditions. Statistical analysis of the experimental data showed that the vectors (g1, g2, Bk) and (Sc, Sp, B) for each cat did not differ significantly (P = 0.56). This was also the case for the vectors [g2/(g1 + g2), Bk] and [Sp/(Sc + Sp), B] (P = 0.21). We conclude that in the DEF experiments the slow ventilatory response to isoxic changes in end-tidal CO2 can be equated with the central chemoreflex loop and the faster ventilatory response to the peripheral chemoreflex loop. The agreement between the two techniques is good.

Effect of intravenous dopamine on hypercapnic ventilatory response in humans.

This study assessed the effect of low-dose intravenous dopamine (3 micrograms X kg-1 X min-1) on the hypercapnic ventilatory response in humans. Six normal healthy subjects were studied. By manipulating the inspired carbon dioxide concentration, the end-tidal carbon dioxide tension was raised in a stepwise fashion from 41 to 49 Torr and held at this level for 4 min. The end-tidal CO2 tension was then lowered back to 41 Torr in a stepwise fashion. The end-tidal O2 tension was held constant at 106 Torr throughout the experiment. The ventilatory response to this normoxic hypercapnic stimulus was analyzed by fitting two exponential functions, allowing the response to be separated into slow and fast chemoreflex loops. Each loop is described by a gain, time constant, and time delay. A single eupneic threshold was used for both loops. Nine control experiments and eight experiments performed during dopamine infusion were analyzed. The dopamine infusion caused the fast loop gain to be significantly (P less than 0.05) reduced from 0.64 to 0.19 l X min-1 X Torr-1, while the slow loop gain was unchanged. The fast loop contribution was reduced from 28 to 11% of the total ventilatory response. None of the other model parameters were significantly affected by the dopamine infusion. Exogenously administered dopamine substantially reduces the sensitivity of the fast chemoreflex loop to carbon dioxide.

Reduction of hypoxic ventilatory drive by dopamine.

To define precisely the effects of dopamine on hypoxic ventilatory drive, two sets of experiments were performed in five healthy subjects. End-tidal CO2 was held constant in all experiments. First, a dopamine infusion (3 microgram/kg/min) was started in subjects already rendered hypoxic, causing an average sustained decrease in ventilation to 60% of the preinfusion ventilation. In the second group of experiments, the ventilatory response of subjects made hypoxic during a dopamine infusion was compared with the hypoxic ventilatory response without the dopamine infusion. Without dopamine, a sudden decrease in end-tidal O2 from 100 to 53 torr caused ventilation to increase from 11.9 to 20.9 L/min (p less than 0.01). During the dopamine infusion, only a statistically insignificant increase in ventilation (9.8 to 12.8 L/min) was seen with the same hypoxic stimulus. Low dose dopamine is a potent depressant of hypoxic ventilatory response.

Potency, duration of action and pA2 in man of intravenous naloxone measured by reversal of morphine-depressed respiration.

Placebo and morphine (5 and 10 mg) alone and in combination with naloxone (0.2, 0.4 and 0.8 mg) were administered i.v. to six volunteers. Respiratory responses curves obtained by the rebreathing method were obtained before and 15, 30, 45, 60, 90, 120, 180 and 240 min after the drug infusions. At each time, morphine dose-effect curves, alone and with naloxone, were constructed. Dose ratios and thus the apparent pA2 of these drugs were determined from these curves. The pA2 ia a measure of the affinity of an antagonist for its receptor. The peak effects of both morphine and naloxone occurred at 0.5 hr. Morphine effect showed no significant fall up to 4 hr after infusion. The duration of naloxone appears to be dose-related, statistically significant up to approximately 1.5 hr. The apparent pA2 at each time was calculated by three methods; these values were used, in turn, to calculate the pA2 by a time-dependent method. The apparent pA2 and T1/2 of naloxone in man were determined to be approximately 8.37 and 0.32 hr, respectively. A clinical measure of naloxone potency, the cA2, is proposed.

Effects of nefopam on visual tracking.

The effects of 2 doses of nefopam, d-amphetamine, pentazocine, and placebo were studied in healthy male sleep-deprived volunteers to determine whether the drugs improved or impaired coordination and whether they induced subjective effects. A critical tracking task was used to study hand-eye coordination. D-amphetamine, 10 mg orally, significantly improved tracking performance and made subjects feel better able to perform tasks but more anxious. It also made them feel more alert, steady, sociable, and strong. Pentazocine, 45 mg intramuscularly, caused deterioration in tracking performance and was followed by reports of depression, gloominess, dreaminess, nausea, and injection site pain. There was no significant change in tracking performance or subjective effects after both doses of nefopam and placebo.

The respiratory effects of dezocine and pentazocine in man.

The respiratory effects of dezocine and pentazocine were studied in five volunteers. Based on their effects over a 3-hour period, it was found that dezocine was 8.6 times as potent as pentazocine in terms of their respiratory depressant effects. The clinical significance of these findings remains to be determined.

Relative potencies and durations of action with respect to respiratory depression of intravenous meperidine, fentanyl and alphaprodine in man.

Fentanyl, 0.7 and 1.4 microgram/kg, alphaprodine, 0.135 and 0.270 mg/kg meperidine, 0.564 and 1.127 mg/kg, and placebo were administered intravenously over 2.6 min by infusion to five healthy adult males. The crossover study was of incomplete Latin square design with at least 1 week between administrations of each study drug. The subjects breathed from a mixing chamber the gas composition of which was servo-controlled so as to produce CO2 ramps in the end-tidal gases. Each experiment was composed of: 1) control CO2 ramps, 2) a 25-min isocarbic run during which the drug was infused and 3) CO2 ramps at half-hour intervals for 3 hr postinfusion. The 20-liter intercept (the PETCO2 at which ventilation was 20 liters/min) was used as the measure of respiratory drive; the change in 20-liter intercept measured drug effect. The potency ratios at peak effect were: fentanyl/meperidine, 679; alphaprodine/meperidine, 3.68; fentanyl/alphaprodine, 179. With the area under the time-effect curves, the potency ratios of mean effect were: fentanyl/meperidine, 45c; alphaprodine/meperidine, 3.00; fentanyl/alphaprodine, 141. Thus, both fentanyl and alphaprodine are shorter-acting than meperidine, and fentanyl is shorter-acting than alphaprodine. The time-effect curves were fitted to linear and mono- and bi-exponential models. The time constants were compatible with the above relative durations of action.

Effect of hypercapnia on hypoxic ventilatory drive in carotid body-resected man.

Steplike end-tidal hypoxic drives (PETCO2 = 53 Torr) lasting for 5 min were generated in a group of normal subjects and a group of carotid body-resected subjects when end-tidal CO2 was maintained constant under eucapnic (PETCO2 = 39 Torr) and hypercapnic (PETCO2 = 49 Torr) conditions. The hypoxic ventilatory response of the normal subjects was prompt and significant in eucapnia and was enhanced in the hypercapnic state, evidencing CO2-O2 interaction. In contrast, the carotid body-resected subjects did not respond to eucapnic hypoxia but did demonstrate a small but significant ventilatory response to hypoxia against the hypercapnic background. This suggests that the aortic bodies in man may contribute a small component of the hypoxic ventilatory drive under hypercapnic conditions, although the possibility of neuromalike ending regeneration cannot be excluded.

Diazepam and lorazepam for intravenous surgical premedication.

Diazepam, 10 and 20 mg, and 2 and 4 mg lorazepam were studied as intravenous surgical premedicants in 120 patients. Relief of anxiety, sedation, patient acceptance, lack of recall, and side effects were the variables evaluated. Both diazepam and lorazepam proved to be excellent surgical premedicants. The basic difference between the two drugs is temporal. Both medications produce similar relief of anxiety, sedation, patient acceptance, and lack of recall. The clinical effects of intravenous diazepam peaks in 2 to 3 minutes and diminishes thereafter. Intravenous lorazepam has a latent period of 8 to 15 minutes, with increasing effects at 15 to 30 minutes.

Lorazepam, hyoscine and atropine as i.v. surgical premedicants.

Lorazepam 2 and 4 mg alone and in combination with atropine 0.4 mg and hyoscine 0.4 mg were studied as i.v. surgical premedicants in 150 patients. Relief of anxiety, sedation, patient acceptance, lack of recall and side-effects were evaluated. Hyoscine was found to improve the relief of anxiety and sedation associated with lorazepam, but did not significantly increase lack of recall or patient acceptance. The addition of atropine to lorazepam did not significantly alter its effects. A high frequency of agitation and restlessness in patients receiving lorazepam and hyoscine make this combination undesirable for surgical premedication.

Arousal reactions during anesthesia in man.

Power-spectrum analysis of the electroencephalogram and inhaled-exhaled concentrations of halothane (when used), nitrous oxide, and carbon dioxide of 36 patients during surgical operations under general anesthesia were monitored. Electroencephalographic arousal reactions were detected in 24 patients and these were accompanied by irregular respirations in nine patients. Cardiac arrhythmias occurred following an arousal reaction in eight patients. The authors conclude that this electroencephalographic arousal phenomenon occurs frequently and deserves further investigation to define its clinical implications and how it might be avoided.

Morphine and promethazine as intravenous premedicants.

Two hundred seventy patients received morphine 5 mg or 10 mg alone or with promethazine 6.25 mg, 12.5 mg, or 25 mg. Promethazine 25 mg alone also was studied. All drugs were given intravenously. Anxiety relief, sedation, patient acceptance, lack of recall, and side effects were the variables examined. Promethazine improved relief of anxiety, sedation, and patient acceptance when added to morphine. Doses of promethazine larger than 12.5 mg intravenously failed to improve these effects. Memory remained unaffected by any of the drugs.

Comparison of i.v. diazepam and hydroxyzine as surgical premedicants.

Diazepam and hydroxyzine as i.v. surgical premedicants were compared. A double-blind randomized sequence was used employing 7.5 and 15 mg of diazepam v. 75 and 150 mg of hydroxyzine. Each group consisted of 35 patients. Anxiety relief, sedation, lack of recall and patient acceptance were the principal assessments. Diazepam was superior to hydroxyzine in all respects. No serious side-effects were noted with either drug.

Meperidine and morphine as intravenous surgical premedicants.

Morphine 5 mg and 10 mg and meperidine 50 mg and 100 mg were studied as intravenous surgical premedicants in 160 patients. Relief of anxiety, sedation, lack of recall and side effects were the variables evaluated. Neither morphine nor meperidine proved to be particularly good surgical premedicants. There appeared to be no significant differences between the two drugs, but what differences there were tended to favor meperidine.

Evaluation of intravenous diazepam as a surgical premedicant.

Intravenous diazepam was administered to 4 groups of 35 patients as a surgical premedicant, double blind and according to a randomized sequence. Four dosages were used: 2.5, 5, 10, and 20 mg. Amnesia, relief of anxiety, sedation, and patient acceptance were primarily evaluated. While a significant linear dose effect was found for sedation, anxiety releief, and patient acceptance, this was not true for anmesia, which was clinically present only with doses of 10 and 20 mg. No significant adverse effects were noted at any dosage, and vital signs remained stable in all patients studied.