Eugene P. Steffey

Toxicity of sevoflurane in rats.

Sevoflurane, an experimental potent volatile anesthetic with a low blood/gas partition coefficient, degrades in the presence of soda lime to products the toxicity of which is unknown. We tested whether toxic products were produced by the passage of sevoflurane through soda lime, and a comparison was made of the toxicity of sevoflurane passed through soda lime with the toxicity of other potent volatile anesthetics in current clinical use. Halothane, isoflurane, sevoflurane (all in 1-MAC concentrations), or no anesthetic (control) were passed through soda lime for 4 hr with 12, 14, or 300% oxygen to groups of rats with hepatic microsomal enzyme induction. Separate groups of 12–13 rats were given 1 MAC of sevoflurane that had not passed through soda lime and either 14 or 100% oxygen. Sevoflurane was no more toxic than isoflurane and both of these anesthetics were less toxic than halothane. Soda lime was not a factor in any toxicity produced. Hepatic injury with all agents varied inversely with the oxygen concentration administered during anesthesia.

Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs

OBJECTIVE To determine the anesthetic-sparing effect of maropitant, a neurokinin 1 receptor antagonist, during noxious visceral stimulation of the ovary and ovarian ligament in dogs. ANIMALS Eight 1-year-old female dogs. PROCEDURES Dogs were anesthetized with sevoflurane. Following instrumentation and stabilization, the right ovary and ovarian ligament were accessed by use of laparoscopy. The ovary was stimulated with a traction force of 6.61 N. The minimum alveolar concentration (MAC) was determined before and after 2 doses of maropitant. RESULTS The sevoflurane MAC value was 2.12 ± 0.4% during stimulation without treatment (control). Administration of maropitant (1 mg/kg, IV, followed by 30 μg/kg/h, IV) decreased the sevoflurane MAC to 1.61 ± 0.4% (24% decrease). A higher maropitant dose (5 mg/kg, IV, followed by 150 μg/kg/h, IV) decreased the MAC to 1.48 ± 0.4% (30% decrease). CONCLUSIONS AND CLINICAL RELEVANCE Maropitant decreased the anesthetic requirements during visceral stimulation of the ovary and ovarian ligament in dogs. Results suggest the potential role for neurokinin 1 receptor antagonists to manage ovarian and visceral pain.

Nitrous Oxide Intensifies the Pulmonary Arterial Pressure Response to Venous Injection of Carbon Dioxide in the Dog

To determine the effect of nitrous oxide on the bodys response to venous carbon dioxide (CO2) embolization, the authors compared changes in mean pulmonary arterial pressure (MPAP) following intravenous injections of CO2 in pentobarbital-anesthetized dogs breathing 100 per cent oxygen (O2) or nitrous oxide–oxygen, 79:21 per cent (N2O). When CO2 was infused intravenously in seven dogs at a rate of 3 ml/kg/min the volume of injected CO2 needed to increase MPAP to 40 per cent above control during breathing of O2 was approximately 5.5 times the volume necessary during inhalation of N2O. In a second group of eight dogs, breathing N2O, compared with O2 or air, resulted in a significantly greater increase and duration of increase in MPAP following a bolus injection of CO2 of 20, 40 or 80 ml. The data suggest that breathing nitrous oxide intensifies and prolongs the effect of CO2 bubbles in blood. While the magnitude of insult following intravenous injection of CO2 is about 6.5 times less than that for a similar volume of air, avoidance of nitrous oxide should be considered in management of patients in whom CO2 embolism is possible.

Effects of intravenous administration of lidocaine on the minimum alveolar concentration of sevoflurane in horses

OBJECTIVE To determine effects of a continuous rate infusion of lidocaine on the minimum alveolar concentration (MAC) of sevoflurane in horses. ANIMALS 8 healthy adult horses. PROCEDURES Horses were anesthetized via IV administration of xylazine, ketamine, and diazepam; anesthesia was maintained with sevoflurane in oxygen. Approximately 1 hour after induction, sevoflurane MAC determination was initiated via standard techniques. Following sevoflurane MAC determination, lidocaine was administered as a bolus (1.3 mg/kg, IV, over 15 minutes), followed by constant rate infusion at 50 μg/kg/min. Determination of MAC for the lidocaine-sevoflurane combination was started 30 minutes after lidocaine infusion was initiated. Arterial blood samples were collected after the lidocaine bolus, at 30-minute intervals, and at the end of the infusion for measurement of plasma lidocaine concentrations. RESULTS IV administration of lidocaine decreased mean ± SD sevoflurane MAC from 2.42 ± 0.24% to 1.78 ± 0.38% (mean MAC reduction, 26.7 ± 12%). Plasma lidocaine concentrations were 2,589 ± 811 ng/mL at the end of the bolus; 2,065 ± 441 ng/mL, 2,243 ± 699 ng/mL, 2,168 ± 339 ng/mL, and 2,254 ± 215 ng/mL at 30, 60, 90, and 120 minutes of infusion, respectively; and 2,206 ± 329 ng/mL at the end of the infusion. Plasma concentrations did not differ significantly among time points. CONCLUSIONS AND CLINICAL RELEVANCE Lidocaine could be useful for providing a more balanced anesthetic technique in horses. A detailed cardiovascular study on the effects of IV infusion of lidocaine during anesthesia with sevoflurane is required before this combination can be recommended.

Cardiovascular, respiratory, and analgesic effects of fentanyl in unanesthetized rhesus monkeys

&NA; To determine the suitability of the rhesus monkey as a model for investigation of opioids, we examined the analgesic, respiratory, and cardiovascular effects of fentanyl in six adult male rhesus monkeys. Fentanyl was administered in sequential bolus injections of 2, 4, 16, 64, and 128 μg/kg, with 10 min between each dose. Arterial plasma fentanyl concentrations and blood gas tensions were measured 3 and 9 min after each dose and 1, 2, 5, 20, 60, and 120 min after the final dose. At the same time periods, mean systemic arterial, pulmonary arterial, central venous, and pulmonary capillary wedge pressures, cardiac output, heart rate, and respiratory rate were measured. Analgesia was quantified as the time required for tail withdrawal from a standardized noxious stimulus. Tail latency response time increased significantly after the 4‐μg/kg dose (plasma fentanyl concentration = 2.7 ± 0.9 ng/mL). Maximum tail latency response time was attained after the 64‐μg/kg dose (43.4 ± 26.0 ng/mL) Respiratory rate decreased significantly after the 2‐μg/kg dose, and Paco2 increased significantly after the 4‐μg/kg dose. All animals became apneic, requiring tracheal intubation and controlled ventilation, after the 64‐μg/kg dose. Also, mean arterial pressure and cardiac output decreased significantly after the 64‐μg/kg dose. There were no other significant cardiovascular changes. Peak plasma fentanyl concentration after the 128‐μg/kg dose was 117.0 ± 49.6 ng/mL. It appears that plasma concentrations of approximately 40 ng/mL are sufficient to reach the full cardiovascular, respiratory, and analgesic effects of fentanyl in the rhesus monkey. Significant respiratory and analgesic effects are evident at concentrations as low as 3 ng/mL. These effects of fentanyl are similar to those previously reported in humans.

Comparison of the cardiovascular effects of equipotent anesthetic doses of sevoflurane alone and sevoflurane plus an intravenous infusion of lidocaine in horses

OBJECTIVE To compare cardiovascular effects of sevoflurane alone and sevoflurane plus an IV infusion of lidocaine in horses. Animals-8 adult horses. PROCEDURES Each horse was anesthetized twice via IV administration of xylazine, diazepam, and ketamine. During 1 anesthetic episode, anesthesia was maintained by administration of sevoflurane in oxygen at 1.0 and 1.5 times the minimum alveolar concentration (MAC). During the other episode, anesthesia was maintained at the same MAC multiples via a reduced concentration of sevoflurane plus an IV infusion of lidocaine. Heart rate, arterial blood pressures, blood gas analyses, and cardiac output were measured during mechanical (controlled) ventilation at both 1.0 and 1.5 MAC for each anesthetic protocol and during spontaneous ventilation at 1 of the 2 MAC multiples. RESULTS Cardiorespiratory variables did not differ significantly between anesthetic protocols. Blood pressures were highest at 1.0 MAC during spontaneous ventilation and lowest at 1.5 MAC during controlled ventilation for either anesthetic protocol. Cardiac output was significantly higher during 1.0 MAC than during 1.5 MAC for sevoflurane plus lidocaine but was not affected by anesthetic protocol or mode of ventilation. Clinically important hypotension was detected at 1.5 MAC for both anesthetic protocols. CONCLUSIONS AND CLINICAL RELEVANCE Lidocaine infusion did not alter cardiorespiratory variables during anesthesia in horses, provided anesthetic depth was maintained constant. The IV administration of lidocaine to anesthetized nonstimulated horses should be used for reasons other than to improve cardiovascular performance. Severe hypotension can be expected in nonstimulated horses at 1.5 MAC sevoflurane, regardless of whether lidocaine is administered.

Effects of high plasma fentanyl concentrations on minimum alveolar concentration of isoflurane in horses

OBJECTIVE To verify the isoflurane anesthetic minimum alveolar concentration (MAC)-sparing effect of a previously administered target plasma fentanyl concentration of 16 ng/mL and characterize an anticipated further sparing in isoflurane MAC associated with higher target plasma fentanyl concentrations. ANIMALS 8 horses. PROCEDURES Horses were assigned 2 of 3 target plasma fentanyl concentrations (16, 24, and 32 ng/mL), administered in ascending order. Following determination of baseline MAC, horses received a loading dose of fentanyl followed by a constant rate infusion; MAC determination was performed in triplicate at baseline and at each fentanyl concentration. Venous blood samples were collected throughout the study for determination of actual plasma fentanyl concentrations. Recovery from anesthesia was monitored, and behaviors were rated as excellent, good, fair, or poor. RESULTS Mean + or - SD fentanyl plasma concentrations were 13.9 + or - 2.6 ng/mL, 20.1 + or - 3.6 ng/mL, and 24.1 + or - 2.4 ng/mL for target concentrations of 16, 24, and 32 ng/mL, respectively. The corresponding changes in the MAC of isoflurane were -3.28%, -6.23%, and +1.14%. None of the changes were significant. Recovery behavior was variable and included highly undesirable, potentially injurious excitatory behavior. CONCLUSIONS AND CLINICAL RELEVANCE Results of the study did not verify an isoflurane-sparing effect of fentanyl at a plasma target concentration of 16 ng/mL. Furthermore, a reduction in MAC was not detected at higher fentanyl concentrations. Overall, results did not support the routine use of fentanyl as an anesthetic adjuvant in adult horses.

Evaluation of infusions of xylazine with ketamine or propofol to modulate recovery following sevoflurane anesthesia in horses

OBJECTIVE To determine whether infusion of xylazine and ketamine or xylazine and propofol after sevoflurane administration in horses would improve the quality of recovery from anesthesia. ANIMALS 6 healthy adult horses. PROCEDURES For each horse, anesthesia was induced by administration of xylazine, diazepam, and ketamine and maintained with sevoflurane for approximately 90 minutes (of which the last 60 minutes were under steady-state conditions) 3 times at 1-week intervals. For 1 anesthetic episode, each horse was allowed to recover from sevoflurane anesthesia; for the other 2 episodes, xylazine and ketamine or xylazine and propofol were infused for 30 or 15 minutes, respectively, after termination of sevoflurane administration. Selected cardiopulmonary variables were measured during anesthesia and recovery. Recovery events were monitored and subjectively scored. RESULTS Cardiopulmonary variables differed minimally among treatments, although the xylazine-propofol infusion was associated with greater respiratory depression than was the xylazine-ketamine infusion. Interval from discontinuation of sevoflurane or infusion administration to standing did not differ significantly among treatments, but the number of attempts required to stand successfully was significantly lower after xylazine-propofol infusion, compared with the number of attempts after sevoflurane alone. Scores for recovery from anesthesia were significantly lower (ie, better recovery) after either infusion, compared with scores for sevoflurane administration alone. CONCLUSIONS AND CLINICAL RELEVANCE Xylazine-ketamine or xylazine-propofol infusion significantly improved quality of recovery from sevoflurane anesthesia in horses. Xylazine-ketamine or xylazine-propofol infusions may be of benefit during recovery from sevoflurane anesthesia in horses for which a smooth recovery is particularly critical. However, oxygenation and ventilation should be monitored carefully.

Deep sedation and mechanical ventilation without paralysis for 3 weeks in normal beagles: exaggerated resistance to metocurine in gastrocnemius muscle.

BACKGROUND Patients in the intensive care unit may have muscle weakness in the recovery phase, and disuse atrophy may play a role in this weakness. To assess this problem, the authors measured changes in the potency of the nondepolarizing neuromuscular blocking agent metocurine in a canine model that involved 3 weeks of intensive care, nonparalyzing anesthesia with pentobarbital, and positive-pressure ventilation. METHODS Six dogs were anesthetized with pentobarbital to a sufficient depth that spontaneous and reflex muscle movements were absent. Their tracheas were intubated, their lungs were mechanically ventilated, and they received round-the-clock intensive medical and nursing care for 3 weeks. Transduced gastrocnemius muscle responses to metocurine were determined weekly. A 4- to 15-min infusion of 148-4,300 microg/min (longer durations and greater concentrations on progressive weeks) yielded more than 80% paralysis. Serial metocurine plasma concentrations during the onset of the block and recovery provided data to determine pharmacokinetics using NONMEM. Metocurine plasma concentrations and the degree of paralysis were used to model the effect compartment equilibration constant, and the Hill equation was used to yield the slope factor and potency within the effect compartment. RESULTS The metocurine effect compartment concentration associated with a 50% diminution of twitch height after 3 weeks was 1,716+/-1,208 ng/ml (mean +/- SD), which was significantly different from 257+/-34 ng/ml, the value on day 0. There were no pharmacokinetic differences. CONCLUSION The absence of muscle tone and reflex responsiveness for 3 weeks was associated with exaggerated resistance to the neuromuscular blocker metocurine.

Ventilatory effects of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) in swine.

Nonimmobilizers (inhaled compounds that do not suppress movement in response to a noxious stimulus) resemble anesthetics in their capacity to suppress memory, but unlike anesthetics, they can cause convulsions.Higher concentrations of nonimmobilizers may cause death, even with apparent suppression of convulsions by the concurrent administration of conventional inhaled anesthetics. We hypothesized that nonimmobilizers can depress ventilation and can cause death by adding to the depression of ventilation produced by conventional anesthetics. To test these hypotheses, we administered 1,2-dichlorohexafluorocyclobutane (2N) to four pigs anesthetized with desflurane. The addition of 2N decreased PaCO (2) and tended to increase the slope of the ventilatory response to imposed increases in PETCO2. Limited results from study of two other nonimmobilizers (2,3-dichlorooctafluorobutane and perfluoropentane), in two pigs each, were consistent with the findings for 2N. However, experimental limitations (e.g., toxicity of 2,3-dichlorooctafluorobutane, and hypoxia from perfluoropentane) confound interpretation of these latter results. Our findings do not support our hypotheses-2N (and presumably all nonimmobilizers) seems to be a respiratory stimulant, not a depressant. Implications: A new class of inhaled compounds, nonimmobilizers, allow tests of how inhaled anesthetics act. Nonimmobilizers may act like anesthetics (e.g., impair learning) or may not (e.g., do not prevent movement in response to a noxious stimulus). The present work shows that, unlike anesthetics, nonimmobilizers do not depress breathing.