Effects of trazodone and dexmedetomidine on fentanyl-mediated reduction of isoflurane minimum alveolar concentration in cats.

OBJECTIVE: To screen modulators of biogenic amine (BA) neurotransmission for the ability to cause fentanyl to decrease isoflurane minimum alveolar concentration (MAC) in cats, and to test whether fentanyl plus a combination of modulators decreases isoflurane MAC more than fentanyl alone. STUDY DESIGN: Prospective, experimental study. ANIMALS: A total of six adult male Domestic Short Hair cats. METHODS: Each cat was anesthetized in three phases with a 1 week washout between studies. In phase 1, anesthesia was induced and maintained with isoflurane, and MAC was measured in duplicate using a tail clamp stimulus and standard bracketing technique. A 21 ng mL-1 fentanyl target-controlled infusion was then administered and MAC measured again. In phase 2, a single cat was administered a single BA modulator (buspirone, haloperidol, dexmedetomidine, pregabalin, ramelteon or trazodone) in a pilot drug screen, and isoflurane MAC was measured before and after fentanyl administration. In phase 3, isoflurane MAC was measured before and after fentanyl administration in cats co-administered trazodone and dexmedetomidine, the two BA modulator drugs associated with fentanyl MAC-sparing in the screen. Isoflurane MAC-sparing by fentanyl alone, trazodone-dexmedetomidine and trazodone-dexmedetomidine-fentanyl was evaluated using paired t tests with p < 0.05 denoting significant effects. RESULTS: The MAC of isoflurane was 1.87% ± 0.09 and was not significantly affected by fentanyl administration (p = 0.09). In the BA screen, cats administered trazodone or dexmedetomidine exhibited 26% and 22% fentanyl MAC-sparing, respectively. Trazodone-dexmedetomidine co-administration decreased isoflurane MAC to 1.50% ± 0.14 (p < 0.001), and the addition of fentanyl further decreased MAC to 0.95% ± 0.16 (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl alone does not affect isoflurane MAC in cats, but co-administration of trazodone and dexmedetomidine causes fentanyl to significantly decrease isoflurane requirement.

Analgesic effect of the mint terpenoid L-carvone in sheep.

OBJECTIVE: To determine whether L-carvone increases the voltage threshold response to a noxious electrical stimulus in sheep. STUDY DESIGN: Prospective, blinded, randomized, crossover experimental study. ANIMALS: A group of six healthy adult sheep. METHODS: Sheep were instrumented with cranial dorsothoracic subcutaneous copper electrodes. A stimulator delivered a 10 ms square-wave stimulus at 50 pps starting at 0.1 V with a 0.2 V second-1 ramp. The stimulus stopped once two observers who were blinded to treatment noted a behavioral pain response or when a 15 V cut-off was reached. Next, 0.15 mL kg-1 of either a 50% L-carvone solution or a saline-vehicle control was administered intramuscularly, and electrical threshold responses were measured every 5-15 minutes over a 6 hour period using methods identical to the baseline. One week following the first treatment (L-carvone or control), sheep were studied using identical methods with the second treatment (control or L-carvone). Drug and time effects were evaluated using a two-way repeated measures analysis of variance, and pairwise comparisons were evaluated with Holm-Sidák tests with values of p < 0.05 considered significant. RESULTS: L-carvone significantly increased voltage threshold responses for most time points up to 75 minutes compared with baseline and with saline control. The last time point with a significantly different response between L-carvone and saline treatments was 5 hours after drug administration. The saline-vehicle control decreased voltage threshold responses at several time points after 3 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Intramuscular L-carvone is analgesic in sheep, although the ethanol-propylene glycol vehicle may cause mild hyperalgesia. This study demonstrates that a food-derived compound can be used to relieve pain in a food-producing animal.

Anesthetic Pharmacology of the Mint Extracts L-Carvone and Methyl Salicylate.

INTRODUCTION: Hydrocarbons with sufficient water solubility allosterically modulate anesthetic-sensitive ion channels. Mint extracts L-carvone and methyl salicylate water solubility exceeds modulation cutoff values for γ-amino butyric acid type A (GABAA) receptors, N-methyl-D-aspartate (NMDA) receptors, and type-2 voltage-gated sodium (Nav1.2) channels. We hypothesized that mint extracts modulate these channels at concentrations that anesthetize rats. METHODS: Channels were expressed separately in frog oocytes and studied using 2-electrode voltage clamp techniques at drug concentrations up to 10 mM. Normalized current effects were fit to Hill equations. Mint compounds were formulated in a lipid emulsion and administered IV to rats. When unresponsive to the tail clamp, rats were exsanguinated, and plasma drug concentrations were measured. RESULTS: Both mint compounds caused concentration-dependent inhibition of all channels except for methyl salicylate which inhibited GABAA receptors at low concentrations and potentiated at high concentrations. Plasma drug concentrations in anesthetized rats were 7.9 mM for L-carvone and 2.7 mM for methyl salicylate. This corresponded to ≥53% NMDA receptor inhibition and ≥78% Nav1.2 channel inhibition by both compounds and 30% potentiation of GABAA receptors by methyl salicylate. CONCLUSION: L-Carvone and methyl salicylate allosterically modulate cell receptor targets important to molecular actions of conventional anesthetics at concentrations that also induce general anesthesia in rats.

Pharmacokinetics and pharmacodynamics of a high concentration of buprenorphine (Simbadol) in conscious horses after subcutaneous administration.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of high-concentration formulation of buprenorphine (1.8 mg mL-1; Simbadol) following subcutaneous (SC) administration in horses. STUDY DESIGN: Prospective, randomized, crossover trial. ANIMALS: A group of six healthy adult horses weighing 521-602 kg. METHODS: On three occasions, Simbadol (0.005 mg kg-1; treatment S5), (0.0025 mg kg-1; treatment S2.5) or saline (treatment SAL) were administered SC at least 7 days apart in random order. Electrical nociceptive threshold (ENT) measured on the neck region, physiologic variables, locomotor activity, degree of restlessness and presence of excitatory signs were measured at baseline and for up to 48 hours after injection. Blood was collected for pharmacokinetic analysis at the same time intervals and plasma buprenorphine concentration (Cp) measured using liquid chromatography-tandem mass spectrometry. RESULTS: Buprenorphine was quantifiable in all horses from 15 minutes after administration up to 8-12 hours. ENT was significantly increased in treatment S2.5 compared with treatment SAL at 0.75-6 hours after treatment. Increase in locomotor activity and compulsive behavior were recorded in all horses after Simbadol, and degree of restlessness was significantly higher in treatment S5 than SAL for a sustained time. Gastrointestinal motility significantly decreased in all horses after Simbadol and returned to baseline by 16 hours after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, SC Simbadol was rapidly absorbed and Cp decreased rapidly. Side effects commonly seen in horses after opioids were observed in both Simbadol treatments, but degree of opioid-induced excitement lasted significantly longer in treatment S5. Simbadol (0.0025 mg kg-1) SC has the potential to be used clinically to treat pain in horses. However, at this dose, duration of antinociceptive effects was not longer than that reported for conventional buprenorphine, and side effects, including reduction in gastrointestinal motility and increased locomotor activity, were documented.

Phenylpiperidine opioid effects on isoflurane minimum alveolar concentration in cats.

Different structurally related phenylpiperidine opioids exhibit different isoflurane-sparing effects in cats. Because minimum alveolar concentration (MAC) in cats is affected only by very high plasma concentrations of some phenylpiperidine opioids, we hypothesized these effects are caused by actions on nonopioid receptors. Using a prospective, randomized, crossover design, six cats were anesthetized with isoflurane, intubated, ventilated, and instrumented. Isoflurane MAC was measured in triplicate using a tail-clamp and bracketing technique. A computer-controlled intravenous infusion using prior pharmacokinetic models targeted plasma concentrations of 60 ng/ml fentanyl, 10 ng/ml sufentanil, or 500 ng/ml alfentanil, and isoflurane MAC was measured in duplicate. Next, naltrexone 0.6 mg/kg was administered to cats hourly during the opioid infusion, and isoflurane MAC was measured in duplicate. Blood was collected during MAC determinations to measure opioid concentrations. Responses were analyzed using repeated measures ANOVA with significance at p < .05. Alfentanil and sufentanil decreased isoflurane MAC by 16.4% and 6.4%, respectively, and these effects were completely reversed by naltrexone. Fentanyl had no significant effect on isoflurane MAC. Alfentanil and sufentanil modestly reduce isoflurane MAC via agonist effects on opioid receptors. However, these effects are too small to justify clinical use of phenylpiperidine opioids as single agents to reduce MAC in cats.

In vitro and in vivo GABAA Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid.

BACKGROUND: Propanidid is a γ-aminobutyric acid type A (GABAA) receptor agonist general anesthetic and its primary metabolite is 4-(2-[diethylamino]-2-oxoethoxy)-3-methoxy-benzeneacetic acid (DOMBA). Despite having a high water solubility at physiologic pH that might predict low-affinity GABAA receptor interactions, DOMBA is reported to have no effect on GABAA receptor currents, possibly because the DOMBA concentrations studied were simply insufficient to modulate GABAA receptors. Our objectives were to measure the propanidid and DOMBA concentration responses on -GABAA receptors and to measure the behavioral responses of DOMBA in mice at concentrations that affect GABAA receptor currents in vitro. METHODS: GABAA receptors were expressed in oocytes using clones for the human GABAA α1, ß2 and γ2s subunits. The effects of DOMBA (0.2-10 mmol/L) and propanidid (0.001-1 mmol/L) on oocyte GABAA currents were studied using standard 2-electrode voltage clamp techniques. Based on in vitro results, 6 mice received -DOMBA 32 mg intraperitoneal and were observed for occurrence of neurologic effects and DOMBA plasma concentration was measured by liquid chromatography tandem mass spectrometry. RESULTS: DOMBA both directly activates GABAA receptors and antagonizes its GABA-mediated opening in a concentration-dependent manner at concentrations between 5-10 and 0.5-10 mmol/L respectively. In vivo, DOMBA produced rapid onset sedation at plasma concentrations that correlate with direct GABAA receptor activation. CONCLUSION: DOMBA modulation of GABAA receptors is associated with sedation in mice. Metabolites of propanidid analogues currently in development may similarly modulate GABAA, and impaired elimination of these metabolites could produce clinically relevant neurophysiologic effects.

Investigation of perioperative and anesthetic variables affecting short-term survival of horses with small intestinal strangulating lesions.

OBJECTIVE: To determine if preoperative and intraoperative physiologic variables, and surgical factors correlate with survival to anesthetic recovery or hospital discharge, repeat celiotomy, and postoperative nasogastric intubation (NGT) in horses undergoing exploratory celiotomy for small intestinal (SI) strangulating lesions. STUDY DESIGN: Retrospective case series. ANIMALS: Horses that had surgical correction of SI strangulating lesions (n = 258). METHODS: Medical records (January 2000-December 2014) of horses that had surgical correction of SI strangulating lesions were reviewed. Data collection included signalment, preoperative physical examination variables, hematologic values, presence of gastric reflux, peritoneal fluid analysis, intraoperative physiologic variables, intraoperative findings/treatments, and arterial blood gas values. Risk factors for survival to anesthetic recovery and hospital discharge were determined using exact logistic regression. RESULTS: Survival to anesthetic recovery was 76% and survival to discharge after anesthetic recovery was 79%. The difference between abdominal and peripheral lactate concentrations and intraoperative tachycardia were associated with not surviving to anesthetic recovery or hospital discharge. Intraoperative hypotension, hypocapnia, and low intraoperative packed cell volume (PCV) were negative predictors of survival to anesthetic recovery. Low intraoperative PCV was also associated with NGT postoperatively. Performing resection-anastomosis and jejunocecostomy were associated with repeat celiotomy and with not surviving to hospital discharge. CONCLUSION: Several hematological and cardiorespiratory variables show good correlation with short-term survival in horses undergoing surgery for SI strangulating lesions. These variables are easily measured and could be useful for prognosticating survival in horses presenting with SI strangulating lesions.

Anesthetic synergy between two n-alkanes.

OBJECTIVE: N-butane and n-pentane can both produce general anesthesia. Both compounds potentiate γ-aminobutyric acid type A (GABAA) receptor function, but only butane inhibits N-methyl-d-aspartate (NMDA) receptors. It was hypothesized that butane and pentane would exhibit anesthetic synergy due to their different actions on ligand-gated ion channels. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of four Xenopus laevis frogs and 43 Sprague-Dawley rats. METHODS: Alkane concentrations for all studies were determined via gas chromatography. Using a Xenopus oocyte expression model, standard two-electrode voltage clamp techniques were used to measure NMDA and GABAA receptor responses in vitro as a function of butane and pentane concentrations relevant to anesthesia. The minimum alveolar concentrations (MAC) of butane and pentane were measured separately in rats, and then pentane MAC was measured during coadministration of 0.25, 0.50 or 0.75 times MAC of butane. An isobole with 95% confidence intervals was constructed using regression analysis. A sum of butane and pentane that was statistically less than the lower-end confidence bound isobole indicated a synergistic interaction. RESULTS: Both butane and pentane dose-dependently potentiated GABAA receptor currents over the study concentration range. Butane dose-dependently inhibited NMDA receptor currents, but pentane did not modulate NMDA receptors. Butane and pentane MAC in rats was 39.4±0.7 and 13.7±0.4 %, respectively. A small but significant (p<0.03) synergistic anesthetic effect with pentane was observed during administration of either 0.50 or 0.75×MAC butane. CONCLUSIONS: Butane and pentane show synergistic anesthetic effects in vivo consistent with their different in vitro receptor effects. CLINICAL RELEVANCE: Findings support the relevance of NMDA receptors in mediating anesthetic actions for some, but not all, inhaled agents.

Pharmacokinetics and pharmacodynamics of intravenous romifidine and propranolol administered alone or in combination for equine sedation.

OBJECTIVE: Propranolol has been suggested for anxiolysis in horses, but its sedation efficacy and side effects, both when administered alone and in combination with α2-adrenoceptor agonists, remain undetermined. This study aimed to document the pharmacokinetics and pharmacodynamics of propranolol, romifidine and their combination. STUDY DESIGN: Randomized, crossover study. ANIMALS: Six adult horses weighing 561 ± 48 kg. METHODS: Propranolol (1 mg kg-1; treatment P), romifidine (0.1 mg kg-1; treatment R) or their combination (treatment PR) were administered intravenously with a minimum of 1 week between treatments. Alertness, behavioral responsiveness (visual and tactile) and physiologic variables were measured before and up to 960 minutes after drug administration. Blood was collected for blood gas and acid-base analyses and measurement of plasma drug concentrations. Data were analyzed using repeated-measures analysis of variance or Friedman with Holm-Sidak and Wilcoxon rank-sum tests (p < 0.05). RESULTS: Systemic clearance significantly decreased and the area under the concentration-time curve significantly increased for both drugs in PR compared with P and R. Both PR and R decreased behavioral responsiveness and resulted in sedation for up to 240 and 480 minutes, respectively. Sedation was deeper in PR for the first 16 minutes. Heart rate significantly decreased in all treatments for at least 60 minutes, and PR significantly increased the incidence of severe bradycardia (<20 beats minute-1). CONCLUSIONS AND CLINICAL RELEVANCE: Although not associated with reduced behavioral responsiveness or sedation alone, propranolol augmented romifidine sedation, probably through alterations in romifidine pharmacokinetics, in horses administered PR. The occurrence of severe bradycardia warrants caution in the co-administration of these drugs at the doses studied.

GABAA Receptor Modulation by Phenyl Ring Compounds Is Associated with a Water Solubility Cut-Off Value.

BACKGROUND: The modulation of N-methyl-D-aspartate receptors is associated with a molar water solubility cut-off effect of approximately 1.1 mmol/l and hence are unaffected by significantly less soluble compounds. However, compounds with this molar water solubility are still able to modulate x03B3;-aminobutyric acid type A (GABAA) receptors. We hypothesized that GABAA receptor modulation by phenolic compounds would exhibit cut-off at a molar water solubility value less than 1.1 mmol/l. METHODS: GABAA receptors consisting of human α1 and rat ß2 and x03B3;2s subunits were expressed in Xenopus laevis oocytes, and drug responses were measured using standard 2-electrode voltage clamp techniques. Twenty substituted phenols and benzenes of similar size and molecular volume were studied at saturated aqueous concentrations. Reversible and statistically significant change in GABAA receptor current that was 10% or greater in magnitude from the baseline response defined a positive drug effect. RESULTS: All phenyl ring compounds with a molar water solubility value equal to or greater than 0.46 mmol/l positively modulated GABAA receptor currents. No compounds with a molar water solubility value equal to or less than 0.10 mmol/l had any effect on GABAA receptor currents. Saturated solutions of phenols with 2,6-dimethyl and 2,6-diisopropyl substituents also caused channel opening in the absence of GABA. CONCLUSIONS: The molar water solubility cut-off for GABAA receptor modulation by phenyl ring compounds lies between 0.10 and 0.46 mmol/l. Data suggest that hydrocarbons, perhaps including inhaled anesthetics, might modulate GABAA receptors by displacing water from one or more low-affinity amphipathic binding sites to induce conformational changes that increase ion conductance.

Hilar closure using staplers or Hem-o-lok clips in a rabbit model.

BACKGROUND: Lung lobectomy is necessary in neonatal patients for the treatment of a variety of congenital bronchopulmonary malformations. The working space required for traditional stapling devices limits their use in pediatric video-assisted thoracoscopic (VATS) lung lobectomy. The use of Hem-o-lok clips (Teleflex Medical Inc. Research Triangle Park, NC) has been described for a number of applications in minimally invasive surgery and may provide an alternative to traditional stapling devices for bronchial closure. MATERIALS AND METHODS: Twenty-four New Zealand White rabbits were used in the study. The hilus of each cranial lung lobe was sealed with the Endo GIA (Covidien Inc, Mansfield, MA) stapler or 2 Hem-o-lok clips and the lung lobe was removed. Lung inflation to leakage point was induced by incrementally increasing tidal volume. Side of leakage, volume at leakage, and airway pressure before leakage were recorded. RESULTS: Fourteen rabbits were included in the data analysis. Leakage of air was first observed at the Hem-o-lok closure site in five rabbits and from the Endo GIA site in three rabbits. In the remaining six, both resection sites leaked simultaneously. The mean pressure before failure was 16.39 ± 7.35 mm Hg for the Hem-o-lok clips, 17.98 ± 11.12 mm Hg for the Endo GIA stapler, and 16.95 ± 3.48 mm Hg for the simultaneous failures. No statistical differences were detected in airways pressures before leakage between hilar closure devices. CONCLUSIONS: Despite advances in VATS, options for bronchial closure in pediatric patients undergoing VATS lung lobectomy remain limited. Hem-o-lok clips require less working space than traditional stapling devices and may represent an equally efficacious alternative to traditional stapling devices.

Feline herpesvirus-1-related multiple respiratory eosinophilic nodules in an adult cat receiving long-term oral prednisolone.

Case summary: A 10-year-old male castrated domestic shorthair cat was presented for evaluation of a 3-day history of increased inspiratory effort. The cat had received prednisolone 1 mg/kg PO q24h for 1 year due to chronic diarrhea. On physical examination, the patient exhibited severe stridor, intermittent open-mouth breathing and bilateral mucopurulent nasal discharge. Subcutaneous emphysema was palpated over the dorsal cervical region. Mild hypoventilation (PvCO2 55.1 mmHg; approximate reference interval 35-45 mmHg) was identified. Cervicothoracic radiographs showed marked gas tracking within cervical soft tissues with concurrent laryngeal thickening, pulmonary nodules, a bronchial pulmonary pattern, pneumomediastinum and aerophagia. The cat was hospitalized and treated overnight with oxygen and intravenous fluid therapy before anesthesia the next day. On laryngoscopy, a large tracheal mass was observed arising from the right subglottic region and was removed using biopsy forceps. CT revealed an additional mass at the level of the tracheal bifurcation causing marked luminal narrowing of the trachea and proximal main bronchi. The cat made a good initial recovery, although moderate stridor persisted. Five days later, the cat was re-examined due to recurrence of respiratory distress and orthopnea, and the owner elected euthanasia. Histopathology revealed severe nodular obstructive eosinophilic plasmacytic laryngotracheitis with intranuclear inclusion bodies positive for feline herpesvirus-1 on immunohistochemistry. Relevance and novel information: This report describes the presentation and management of a cat with respiratory distress secondary to intratracheal eosinophilic masses caused by feline herpesvirus-1. Although the outcome was ultimately unsatisfactory, to the authors' knowledge, this clinical presentation has not been previously reported.

Pregabalin produces similar effects as gabapentin for preanesthetic sedation in cats.

OBJECTIVE: To compare the effects of oral pregabalin versus gabapentin on sedation quality and anesthesia recovery times in cats in a typical perioperative setting. ANIMALS: 50 healthy cats with > 1 kg body weight presenting for elective surgery. METHODS: In this randomized, prospective clinical trial, cats presenting to the University of California-Davis Veterinary Medical Teaching Hospital were assigned to receive buprenorphine 0.02 mg/kg IM followed by 1 of 2 oral sedation treatments: pregabalin 4 mg/kg or gabapentin 10 mg/kg. Cats were then anesthetized using a standardized protocol. Physical examination parameters and behavioral scores were measured by 2 treatment-blinded veterinarians to compare sedation levels before and after drug administration. Inadequate sedation for handling or IV catheter placement was addressed by dexmedetomidine administration. After surgery was completed, anesthesia recovery times and quality were assessed by the same veterinarians. The effects of pregabalin versus gabapentin on body temperature, respiratory rate, and heart rate were analyzed using Student t tests; behavioral assessments were analyzed using Wilcoxon signed-rank tests; and drug treatment effects on dexmedetomidine sedation rescue and frequency of delirium during anesthetic recovery were analyzed using Fisher exact tests. A P < .05 indicated statistical significance. RESULTS: There was no significant difference in change of physiologic parameters or sedation scores before and after sedation between groups. The need for rescue sedation for IV catheter placement and the incidence of emergence delirium were infrequent and similar for both treatments. CLINICAL RELEVANCE: At the doses studied, oral pregabalin and gabapentin produced indistinguishable effects as adjunctive perioperative sedation agents in cats.

Use of physiologic and arterial blood gas variables to predict short-term survival in horses with large colon volvulus.

OBJECTIVE: To determine if preoperative physical examination and blood work values, intraoperative physiologic variables, and intraoperative treatments can be correlated with survival to anesthetic recovery and short-term survival to hospital discharge in horses that undergo exploratory celiotomy for large colon volvulus (LCV) with and without colon resection. STUDY DESIGN: Retrospective case series. ANIMALS: Horses (n = 156) undergoing exploratory celiotomy for correction of LCV ≥ 360(ο) . METHODS: Medical records (January 2000-December 2009) of horses that had surgical correction of LCV ≥ 360(ο) were reviewed. Data collection included signalment, preoperative physical examination variables and hematologic values as well as intraoperative physiologic variables, intraoperative treatments, and arterial blood gas values. Risk factors for survival to anesthetic recovery and hospital discharge were determined using exact logistic regression. RESULTS: High preoperative heart rate and packed cell volume were associated with not surviving to anesthetic recovery or hospital discharge. A low intraoperative total serum protein concentration was associated with not surviving to anesthetic recovery or to hospital discharge. Intraoperative tachycardia and hypercapnia were associated with not surviving to hospital discharge. Intraoperative hypotension was a negative predictor of survival to anesthetic recovery. There was no increase in death for horses in which a resection and anastomosis was performed compared with those having manual correction. CONCLUSIONS: Several hematologic and cardiorespiratory variables that are easily measured preoperatively and intraoperatively show good correlation with postanesthetic survival in horses undergoing surgical correction of LCV. These measurements might be useful for prognosticating survival in horses admitted for correction of LCV ≥ 360(ο) .

Naltrexone does not affect isoflurane minimum alveolar concentration in cats.

OBJECTIVE: To test whether naltrexone, an opioid receptor antagonist, affects the minimum alveolar concentration (MAC) of isoflurane in cats, a species that is relatively resistant to the general anesthetic sparing effects of most opioids. STUDY DESIGN: Randomized, crossover, placebo-controlled, blinded experimental design. ANIMALS: Six healthy adult cats weighing 4.9 ± 0.7 kg. METHODS: The cats were studied twice. In the first study, baseline isoflurane MAC was measured in duplicate. The drug (saline control or 0.6 mg kg(-1) naltrexone) was administered IV every 40-60 minutes, and isoflurane MAC was re-measured. In the second study, cats received the second drug treatment using identical methods 2 weeks later. RESULTS: Isoflurane MAC was 2.03 ± 0.12% and was unchanged from baseline following saline or naltrexone administration. CONCLUSION AND CLINICAL RELEVANCE: Minimum alveolar concentration was unaffected by naltrexone. Because MAC in cats is unaffected by at least some mu-opioid agonists and antagonists, spinal neurons that are directly modulated by mu-opioid receptors in this species cannot be the neuroanatomic sites responsible for immobility from inhaled anesthetics.

Inhaled anesthetics in horses.

Inhaled agents represent an important and useful class of drugs for equine anesthesia. This article reviews the ether-type anesthetics in contemporary use, their uptake and elimination, their mechanisms of action, and their desirable and undesirable effects in horses.

Solubility of haloether anesthetics in human and animal blood.

BACKGROUND: Anesthetic blood solubility predicts pharmacokinetics for inhaled agents and is essential for determination of blood anesthetic concentrations from end-tidal gas concentrations using Henry's Law. Though used to model anesthetic effects in humans, there are limited interspecies solubility comparisons that include modern haloethers. This study aimed to measure hematocrit-adjusted blood:gas anesthetic partition coefficients (λ B:G) for desflurane, sevoflurane, isoflurane, and methoxyflurane in humans and animals. METHODS: Whole blood was collected from 20 rats, 8 horses, and 4 each of cats, cattle, humans, dogs, goats, pigs, rabbits, and sheep. Plasma or cell volume was removed to adjust all samples to a packed cell volume of 40%. A single-agent calibration gas headspace was added to blood in a glass syringe and was mixed and equilibrated at 37°C for 2 h. Agent concentrations in the calibration gas and syringe headspace were measured using gas chromatography. Anesthetic solubility in saline, citrate-phosphate-dextrose-adenine, and olive oil were similarly measured. RESULTS: Except for goats, all animal species had at least one λ B:G measurement that differed significantly from humans. For each agent, λ B:G positively correlated with serum triglyceride concentrations, but this only explained 25% of interspecies variability. Desflurane was significantly less soluble in blood than sevoflurane in some species (e.g., humans) but not in others (e.g., rabbits). CONCLUSIONS: Anesthetic partition coefficients differ significantly between humans and most animals for haloether anesthetics. Because of their similar λ B:G values, goats may be a better animal model for inhaled anesthetic pharmacokinetics in people.

Increased NMDA receptor inhibition at an increased Sevoflurane MAC.

BACKGROUND: Sevoflurane potently enhances glycine receptor currents and more modestly decreases NMDA receptor currents, each of which may contribute to immobility. This modest NMDA receptor antagonism by sevoflurane at a minimum alveolar concentration (MAC) could be reciprocally related to large potentiation of other inhibitory ion channels. If so, then reduced glycine receptor potency should increase NMDA receptor antagonism by sevoflurane at MAC. METHODS: Indwelling lumbar subarachnoid catheters were surgically placed in 14 anesthetized rats. Rats were anesthetized with sevoflurane the next day, and a pre-infusion sevoflurane MAC was measured in duplicate using a tail clamp method. Artificial CSF (aCSF) containing either 0 or 4 mg/mL strychnine was then infused intrathecally at 4 µL/min, and the post-infusion baseline sevoflurane MAC was measured. Finally, aCSF containing strychnine (either 0 or 4 mg/mL) plus 0.4 mg/mL dizocilpine (MK-801) was administered intrathecally at 4 µL/min, and the post-dizocilpine sevoflurane MAC was measured. RESULTS: Pre-infusion sevoflurane MAC was 2.26%. Intrathecal aCSF alone did not affect MAC, but intrathecal strychnine significantly increased sevoflurane requirement. Addition of dizocilpine significantly decreased MAC in all rats, but this decrease was two times larger in rats without intrathecal strychnine compared to rats with intrathecal strychnine, a statistically significant (P < 0.005) difference that is consistent with increased NMDA receptor antagonism by sevoflurane in rats receiving strychnine. CONCLUSIONS: Glycine receptor antagonism increases NMDA receptor antagonism by sevoflurane at MAC. The magnitude of anesthetic effects on a given ion channel may therefore depend on the magnitude of its effects on other receptors that modulate neuronal excitability.

Effects of hypercapnic hyperpnea on recovery from isoflurane or sevoflurane anesthesia in horses.

OBJECTIVE: To test the hypothesis that hypercapnic hyperpnea produced using endotracheal insufflation with 5-10% CO(2) in oxygen could be used to shorten anesthetic recovery time in horses, and that recovery from sevoflurane would be faster than from isoflurane. STUDY DESIGN: Randomized crossover study design. ANIMALS: Eight healthy adult horses. METHODS: After 2 hours' administration of constant 1.2 times MAC isoflurane or sevoflurane, horses were disconnected from the anesthetic circuit and administered 0, 5, or 10% CO(2) in balance O(2) via endotracheal tube insufflation. End-tidal gas samples were collected to measure anesthetic washout kinetics, and arterial and venous blood samples were collected to measure respiratory gas partial pressures. Horses recovered in padded stalls without assistance, and each recovery was videotaped and evaluated by reviewers who were blinded to the anesthetic agent and insufflation treatment used. RESULTS: Compared to isoflurane, sevoflurane caused greater hypoventilation and was associated with longer times until standing recovery. CO(2) insufflation significantly decreased anesthetic recovery time compared to insufflation with O(2) alone without significantly increasing PaCO(2) . Pharmacokinetic parameters during recovery from isoflurane with CO(2) insufflation were statistically indistinguishable from sevoflurane recovery without CO(2). Neither anesthetic agent nor insufflation treatment affected recovery quality from anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Hypercapnic hyperpnea decreases time to standing without influencing anesthetic recovery quality. Although the lower blood gas solubility of sevoflurane should favor a shorter recovery time compared to isoflurane, this advantage is negated by the greater respiratory depression from sevoflurane in horses.

Continuous measurement of arterial oxygenation in mechanically ventilated horses.

BACKGROUND: The possibility of accurately and continuously measuring arterial oxygen partial pressure (PaO2 ) in horses may facilitate the management of hypoxaemia during general anaesthesia. OBJECTIVES: The aim of this study was to evaluate the ability of a novel fibreoptic sensor to measure PaO2 (PaO2Sensor ) continuously and in real time in horses undergoing ventilatory manoeuvres during general anaesthesia. STUDY DESIGN: In vivo experimental study. METHODS: Six adult healthy horses were anaesthetised and mechanically ventilated in dorsal recumbency. A fibreoptic sensor was placed in one of the facial arteries through a catheter to continuously measure and record PaO2Sensor . After an alveolar recruitment manoeuvre, a decremental positive end-expiratory pressure (PEEP) titration using 20-minute steps of 5 cm H2 O from 20 to 0 cm H2 O was performed. An arterial blood sample was collected at 15 minutes of ventilation at each PEEP level for PaO2 measurement using an automated blood gas machine (PaO2Ref ). The agreement between PaO2Sensor and PaO2Ref was assessed by Pearson's correlation, Bland-Altman plot and four-quadrant plot analysis. In the last minute of ventilation at each PEEP level, a slow tidal inflation/deflation manoeuvre was performed. RESULTS: The mean relative bias between PaO2Sensor and PaO2Ref was 4% with limits of agreement between -17% and 29%. The correlation coefficient between PaO2Sensor and PaO2Ref was 0.98 (P < .001). The PaO2Sensor and PaO2Ref concordance rate for changes was 95%. Measurements of PaO2Sensor during the slow inflation/deflation manoeuvre at PEEP 15 and 10 cm H2 O were not possible because of significant noise on the PaO2 signal generated by a small blood clot. MAIN LIMITATIONS: Small sample size. CONCLUSION: The tested fibreoptic probe was able to accurately and continuously measure PaO2Sensor in anaesthetised horses undergoing ventilatory manoeuvres. A heparinised system in the catheter used by the fibreoptic sensor should be used to avoid blood clots and artefacts in the PaO2 measurements.