Prevalence of Gastroesophageal Reflux in Cats During Anesthesia and Effect of Omeprazole on Gastric pH.

BACKGROUND: Gastroesophageal reflux (GER) is poorly characterized in anesthetized cats, but can cause aspiration pneumonia, esophagitis, and esophageal stricture formation. OBJECTIVE: To determine whether pre-anesthetic orally administered omeprazole increases gastric and esophageal pH and increases serum gastrin concentrations in anesthetized cats, and to determine the prevalence of GER using combined multichannel impedance and pH monitoring. ANIMALS: Twenty-seven healthy cats undergoing elective dental procedures. METHODS: Prospective, double-masked, placebo-controlled, randomized clinical trial. Cats were randomized to receive 2 PO doses of omeprazole (1.45-2.20 mg/kg) or an empty gelatin capsule placebo 18-24 hours and 4 hours before anesthetic induction. Blood for measurement of serum gastrin concentration was collected during anesthetic induction. An esophageal pH/impedance catheter was utilized to continuously measure esophageal pH and detect GER throughout anesthesia. RESULTS: Mean gastric pH in the cats that received omeprazole was 7.2 ± 0.4 (range, 6.6-7.8) and was significantly higher than the pH in cats that received the placebo 2.8 ± 1.0 (range, 1.3-4.1; P < .001). Omeprazole administration was not associated with a significant increase in serum gastrin concentration (P = .616). Nine of 27 cats (33.3%) had ≥1 episode of GER during anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Pre-anesthetic administration of 2 PO doses of omeprazole at a dosage of 1.45-2.20 mg/kg in cats was associated with a significant increase in gastric and esophageal pH within 24 hours, but was not associated with a significant increase in serum gastrin concentration. Prevalence of reflux events in cats during anesthesia was similar to that of dogs during anesthesia.

Pharmacokinetics of dexmedetomidine, MK-467, and their combination following intravenous administration in male cats.

This study characterized the pharmacokinetics of dexmedetomidine, MK-467, and their combination following intravenous bolus administration to cats. Seven 6- to-year-old male neutered cats, weighting 5.1 ± 0.7 kg, were used in a randomized, crossover design. Dexmedetomidine [12.5 (D12.5) and 25 (D25) µg/kg], MK-467 [300 µg/kg (M300)] or dexmedetomidine (25 µg/kg) and MK-467 [75, 150, 300 or 600 µg/kg-only the plasma concentrations in the 600 µg/kg group (D25M600) were analyzed] were administered intravenously, and blood was collected until 8 hours thereafter. Plasma drug concentrations were analyzed using liquid chromatography/mass spectrometry. A two-compartment model best fitted the data. Median (range) volume of the central compartment (mL/kg), volume of distribution at steady state (mL/kg), clearance (mL min/kg) and terminal half-life (min) were 342 (131-660), 829 (496-1243), 14.6 (9.6-22.7) and 48 (40-69) for D12.5; 296 (179-982), 1111 (908-2175), 18.2 (12.4-22.9) and 52 (40-76) for D25; 653 (392-927), 1595 (1094-1887), 22.7 (18.5-36.4) and 48 (35-60) for dexmedetomidine in D25M600; 117 (112-163), 491 (379-604), 3.0 (2.0-4.5) and 122 (99-139) for M300; and 147 (112-173), 462 (403-714), 2.8 (2.1-4.8) and 118 (97-172) for MK-467 in D25M600. MK-467 moderately but statistically significantly affected the disposition of dexmedetomidine, whereas dexmedetomidine minimally affected the disposition of MK-467.

Pharmacokinetics of tramadol following intravenous and oral administration in male rhesus macaques (Macaca mulatta).

Recently, tramadol and its active metabolite, O-desmethyltramadol (M1), have been studied as analgesic agents in various traditional veterinary species (e.g., dogs, cats, etc.). This study explores the pharmacokinetics of tramadol and M1 after intravenous (IV) and oral (PO) administration in rhesus macaques (Macaca mulatta), a nontraditional veterinary species. Rhesus macaques are Old World monkeys that are commonly used in biomedical research. Effects of tramadol administration to monkeys are unknown, and research veterinarians may avoid inclusion of this drug into pain management programs due to this limited knowledge. Four healthy, socially housed, adult male rhesus macaques (Macaca mulatta) were used in this study. Blood samples were collected prior to, and up to 10 h post-tramadol administration. Serum tramadol and M1 were analyzed using liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis was performed. Tramadol clearance was 24.5 (23.4-32.7) mL/min/kg. Terminal half-life of tramadol was 111 (106-127) min IV and 133 (84.9-198) min PO. Bioavailability of tramadol was poor [3.47% (2.14-5.96%)]. Maximum serum concentration of M1 was 2.28 (1.88-2.73) ng/mL IV and 11.2 (9.37-14.9) ng/mL PO. Sedation and pruritus were observed after IV administration.

Pharmacokinetics of buprenorphine following intravenous and buccal administration in cats, and effects on thermal threshold.

This study reports the pharmacokinetics of buprenorphine, following i.v. and buccal administration, and the relationship between buprenorphine concentration and its effect on thermal threshold. Buprenorphine (20 µg/kg) was administered intravenously or buccally to six cats. Thermal threshold was determined, and arterial blood sampled prior to, and at various times up to 24 h following drug administration. Plasma buprenorphine concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to the time-concentration data. Pharmacokinetic/pharmacodynamic models were fitted to the concentration-thermal threshold data. Thermal threshold was significantly higher than baseline 44 min after buccal administration, and 7, 24, and 104 min after i.v. administration. A two- and three-compartment model best fitted the data following buccal and i.v. administration, respectively. Following i.v. administration, mean ± SD volume of distribution at steady-state (L/kg), clearance (mL·min/kg), and terminal half-life (h) were 11.6 ± 8.5, 23.8 ± 3.5, and 9.8 ± 3.5. Following buccal administration, absorption half-life was 23.7 ± 9.1 min, and terminal half-life was 8.9 ± 4.9 h. An effect-compartment model with a simple effect maximum model best predicted the time-course of the effect of buprenorphine on thermal threshold. Median (range) ke0 and EC50 were 0.003 (0.002-0.018)/min and 0.599 (0.073-1.628) ng/mL (i.v.), and 0.017 (0.002-0.023)/min and 0.429 (0.144-0.556) ng/mL (buccal).

Impact of the blood sampling site on time-concentration drug profiles following intravenous or buccal drug administration.

The aim of this study was to examine the effect of the sampling site on the drug concentration-time profile, following intravenous or buccal (often called 'oral transmucosal') drug administration. Buprenorphine (20 µg/kg) was administered IV or buccally to six cats. Blood samples were collected from the carotid artery and the jugular and medial saphenous veins for 24 h following buprenorphine administration. Buprenorphine concentration-time data were examined using noncompartmental analysis. Pharmacokinetic parameters were compared using the Wilcoxon signed rank test, applying the Bonferroni correction. Significance was set at P < 0.05. Following IV administration, no difference among the sampling sites was found. Following buccal administration, maximum concentration [jugular: 6.3 (2.9-9.8), carotid: 3.4 (1.9-4.9), medial saphenous: 2.5 (1.7-4.1) ng/mL], area under the curve [jugular: 395 (335-747), carotid: 278 (214-693), medial saphenous: 255 (188-608) ng·min/mL], and bioavailability [jugular: 47 (34-67), carotid: 32 (20-52), medial saphenous: 23 (16-55)%] were higher in the jugular vein than in the carotid artery and medial saphenous vein. Jugular venous blood sampling is not an acceptable substitute for arterial blood sampling following buccal drug administration.

Pharmacokinetics of buprenorphine following intravenous and intramuscular administration in male rhesus macaques (Macaca mulatta).

This study reports the pharmacokinetics of buprenorphine in conscious rhesus macaques (Macaca mulatta) after intravenous (i.v.) and intramuscular (i.m.) administration. Four healthy, opioid-naïve, socially housed, adult male macaques were used. Buprenorphine (0.03 mg/kg) was administered intravenously as a bolus or intramuscularly on separate occasions. Blood samples were collected prior to, and up to 24 h, postadministration. Serum buprenorphine concentrations were analyzed with liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis was performed with commercially available software. Mean residence time in the i.v. study as compared to the i.m. study was 177 (159-189) vs. 185 (174-214) min, respectively [median (range)]. In the i.v. study, concentration back-extrapolated to time zero was found to be 33.0 (16.8-57.0) ng/mL [median (range)]. On the other hand, the maximum serum concentration found in the i.m. study was 11.8 (6.30-14.8) ng/mL [median (range)]. Rhesus macaques maintained concentrations >0.10 ng/mL for over 24 h in the i.v. study and over 12 h in the i.m. study. Bioavailability was found to be 68.1 (59.3-71.2)% [median (range)]. No significant adverse effects were observed in the monkeys at the 0.03 mg/kg dose of buprenorphine during either study.

Bioavailability of morphine, methadone, hydromorphone, and oxymorphone following buccal administration in cats.

Buccal administration of buprenorphine is commonly used to treat pain in cats. It has been argued that absorption of buprenorphine through the buccal mucosa is high, in part due to its pKa of 8.24. Morphine, methadone, hydromorphone, and oxymorphone have a pKa between 8 and 9. This study characterized the bioavailability of these drugs following buccal administration to cats. Six healthy adult female spayed cats were used. Buccal pH was measured prior to drug administration. Morphine sulfate, 0.2 mg/kg IV or 0.5 mg/kg buccal; methadone hydrochloride, 0.3 mg/kg IV or 0.75 mg/kg buccal; hydromorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal; or oxymorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal were administered. All cats received all treatments. Arterial blood was sampled immediately prior to drug administration and at various times up to 8 h thereafter. Bioavailability was calculated as the ratio of the area under the time-concentration curve following buccal administration to that following IV administration, each indexed to the administered dose. Mean ± SE (range) bioavailability was 36.6 ± 5.2 (12.7-49.5), 44.2 ± 7.9 (18.7-70.5), 22.4 ± 6.9 (6.4-43.4), and 18.8 ± 2.0 (12.9-23.5)% for buccal administration of morphine, methadone, hydromorphone, and oxymorphone, respectively. Bioavailability of methadone was significantly higher than that of oxymorphone.

Pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats.

The aim of this study was to compare the pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats. Six adult cats were used. Anesthesia was induced and maintained with isoflurane in oxygen. End-tidal isoflurane concentration was set at 2% and adjusted as required due to spontaneous movement. Fentanyl (10 µg/kg), alfentanil (100 µg/kg), or sufentanil (1 µg/kg) was administered intravenously as a bolus, on separate days. Blood samples were collected immediately before and for 8 h following drug administration. Plasma drug concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to concentration-time data. A 3-compartment model best fitted the concentration-time data for all drugs, except for 1 cat in the sufentanil group (excluded from analysis). The volume of the central compartment and the volume of distribution at steady-state (L/kg) [mean ± SEM (range)], the clearance (mL/min/kg) [harmonic mean ± pseudo-SD (range)], and the terminal half-life (min) [median (range)] were 0.25 ± 0.04 (0.09-0.34), 2.18 ± 0.16 (1.79-2.83), 18.6 ± 5.0 (15-29.8), and 151 (115-211) for fentanyl; 0.10 ± 0.01 (0.07-0.14), 0.89 ± 0.16 (0.68-1.83), 11.6 ± 2.6 (9.2-15.8), and 144 (118-501) for alfentanil; and 0.06 ± 0.01 (0.04-0.10), 0.77 ± 0.07 (0.63-0.99), 17.6 ± 4.3 (13.9-24.3), and 54 (46-76) for sufentanil. Differences in clearance and volume of distribution result in similar terminal half-lives for fentanyl and alfentanil, longer than for sufentanil.

The influence of esomeprazole and cisapride on gastroesophageal reflux during anesthesia in dogs.

BACKGROUND: Gastroesophageal reflux (GER) is common in anesthetized dogs and can cause esophagitis, esophageal stricture, and aspiration pneumonia. OBJECTIVE: To determine whether preanesthetic IV administration of esomeprazole alone or esomeprazole and cisapride increases esophageal pH and decreases the frequency of GER in anesthetized dogs using combined multichannel impedance and pH monitoring. ANIMALS: Sixty-one healthy dogs undergoing elective orthopedic surgery procedures. METHODS: Prospective, randomized, placebo-controlled study. Dogs were randomized to receive IV saline (0.9% NaCl), esomeprazole (1 mg/kg) alone, or a combination of esomeprazole (1 mg/kg) and cisapride (1 mg/kg) 12-18 hours and 1-1.5 hours before anesthetic induction. An esophageal pH/impedance probe was utilized to measure esophageal pH and detect GER. RESULTS: Eight of 21 dogs in the placebo group (38.1%), 8 of 22 dogs in the esomeprazole group (36%), and 2 of 18 dogs in the combined esomeprazole and cisapride group (11%) had ≥ 1 episode of GER on impedance testing during anesthesia (P < .05). Esomeprazole was associated with a significant increase in gastric and esophageal pH (P = .001), but the drug did not significantly decrease the frequency of GER (P = .955). Concurrent administration of cisapride was associated with a significant decrease in the number of reflux events (RE) compared to the placebo and esomeprazole groups (P < .05). CONCLUSIONS AND CLINICAL RELEVANCE: Preanesthetic administration of cisapride and esomeprazole decreases the number of RE in anesthetized dogs, but administration of esomeprazole alone was associated with nonacid and weakly acidic reflux in all but 1 dog.

Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats.

This study reports the effects of dexmedetomidine on the minimum alveolar concentration of isoflurane (MAC(iso) ) in cats. Six healthy adult female cats were used. MAC(iso) and dexmedetomidine pharmacokinetics had previously been determined in each individual. Cats were anesthetized with isoflurane in oxygen. Dexmedetomidine was administered intravenously using target-controlled infusions to maintain plasma concentrations of 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, and 20 ng/mL. MAC(iso) was determined in triplicate at each target plasma dexmedetomidine concentration. Blood samples were collected and analyzed for dexmedetomidine concentration. The following model was fitted to the concentration-effect data: [Formula in text] where MAC(iso.c) is MAC(iso) at plasma dexmedetomidine concentration C, MAC(iso.0) is MAC(iso) in the absence of dexmedetomidine, I(max) is the maximum possible reduction in MAC(iso), and IC(50) is the plasma dexmedetomidine concentration producing 50% of I(max). Mean ± SE MAC(iso.0), determined in a previous study conducted under conditions identical to those in this study, was 2.07 ± 0.04. Weighted mean ± SE I(max), and IC(50) estimated by the model were 1.76 ± 0.07%, and 1.05 ± 0.08 ng/mL, respectively. Dexmedetomidine decreased MAC(iso) in a concentration-dependent manner. The lowest MAC(iso) predicted by the model was 0.38 ± 0.08%, illustrating that dexmedetomidine alone is not expected to result in immobility in response to noxious stimulation in cats at any plasma concentration.

Effect of amantadine on oxymorphone-induced thermal antinociception in cats.

This study examined the effect of amantadine, an N-methyl-d-aspartate receptor antagonist, on the thermal antinociceptive effect of oxymorphone in cats. Six adult healthy cats were used. After baseline thermal threshold determinations, oxymorphone was administered intravenously to maintain plasma oxymorphone concentrations of 10, 20, 50, 100, 200, and 400 ng/mL. In addition, amantadine, or an equivalent volume of saline, was administered intravenously to maintain a plasma amantadine concentration of 1100 ng/mL. Thermal threshold and plasma oxymorphone and amantadine concentrations were determined at each target plasma oxymorphone concentration. Effect maximum models were fitted to the oxymorphone concentration-thermal threshold data, after transformation in % maximum response. Oxymorphone increased skin temperature, thermal threshold, and thermal excursion (i.e., the difference between thermal threshold and skin temperature) in a concentration-dependent manner. No significant difference was found between the amantadine and saline treatments. Mean ± SE oxymorphone EC(50) were 14.2 ± 1.2 and 24.2 ± 7.4 ng/mL in the amantadine and saline groups, respectively. These values were not significantly different. Large differences in oxymorphone EC(50) in the saline and amantadine treatment groups were observed in two cats. These results suggest that amantadine may decrease the antinociceptive dose of oxymorphone in some, but not all, cats.

Pharmacokinetics of oxymorphone in cats.

This study reports the pharmacokinetics of oxymorphone in spayed female cats after intravenous administration. Six healthy adult domestic shorthair spayed female cats were used. Oxymorphone (0.1 mg/kg) was administered intravenously as a bolus. Blood samples were collected immediately prior to oxymorphone administration and at various times up to 480 min following administration. Plasma oxymorphone concentrations were determined by liquid chromatography-mass spectrometry, and plasma oxymorphone concentration-time data were fitted to compartmental models. A three-compartment model, with input in and elimination from the central compartment, best described the disposition of oxymorphone following intravenous administration. The apparent volume of distribution of the central compartment and apparent volume of distribution at steady state [mean ± SEM (range)] and the clearance and terminal half-life [harmonic mean ± jackknife pseudo-SD (range)] were 1.1 ± 0.2 (0.4-1.7) L/kg, 2.5 ± 0.4 (2.4-4.4) L/kg, 26 ± 7 (18-38) mL/min.kg, and 96 ± 49 (62-277) min, respectively. The disposition of oxymorphone in cats is characterized by a moderate volume of distribution and a short terminal half-life.

Pharmacokinetics of amantadine in cats.

This study reports the pharmacokinetics of amantadine in cats, after both i.v. and oral administration. Six healthy adult domestic shorthair female cats were used. Amantadine HCl (5 mg/kg, equivalent to 4 mg/kg amantadine base) was administered either intravenously or orally in a crossover randomized design. Blood samples were collected immediately prior to amantadine administration, and at various times up to 1440 min following intravenous, or up to 2880 min following oral administration. Plasma amantadine concentrations were determined by liquid chromatography-mass spectrometry, and plasma amantadine concentration-time data were fitted to compartmental models. A two-compartment model with elimination from the central compartment best described the disposition of amantadine administered intravenously in cats, and a one-compartment model best described the disposition of oral amantadine in cats. After i.v. administration, the apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state [mean ± SEM (range)], and the clearance and terminal half-life [harmonic mean ± jackknife pseudo-SD (range)] were 1.5 ± 0.3 (0.7-2.5) L/kg, 4.3 ± 0.2 (3.7-5.0) L/kg, 8.2 ± 2.1 (5.9-11.4) mL·min/kg, and 348 ± 49 (307-465) min, respectively. Systemic availability [mean ± SEM (range)] and terminal half-life after oral administration [harmonic mean ± jackknife pseudo-SD (range)] were 130 ± 11 (86-160)% and 324 ± 41 (277-381) min, respectively.

Pharmacokinetics of tramadol, and its metabolite O-desmethyl-tramadol, in cats.

Tramadol is an analgesic agent and is used in dogs and cats. Tramadol exerts its action through interactions with opioid, serotonin and adrenergic receptors. The opioid effect of tramadol is believed to be, at least in part, related to its metabolite, O-desmethyl-tramadol. The pharmacokinetics of tramadol and O-desmethyl-tramadol were examined after intravenous (i.v.) and oral administration of tramadol to six cats. A two-compartment model (with first-order absorption in the central compartment for the oral administration) with elimination from the central compartment best described the disposition of tramadol in cats. After i.v. administration, the apparent volume of distribution of the central compartment, the apparent volume of distribution at steady-state, the clearance, and the terminal half-life (mean +/- SEM) were 1553+/-118 mL/kg, 3103+/-132 mL/kg, 20.8+/-3.2 mL/min/kg, and 134+/-18 min, respectively. Systemic availability and terminal half-life after oral administration were 93+/-7% and 204+/-8 min, respectively. O-desmethyl-tramadol rapidly appeared in plasma following tramadol administration and had terminal half-lives of 261+/-28 and 289+/-19 min after i.v. and oral tramadol administration, respectively. The rate of formation of O-desmethyl-tramadol estimated from a model including both tramadol and O-desmethyl-tramadol was 0.014+/-0.003/min and 0.004+/-0.0008/min after i.v. and oral tramadol administration, respectively.

Animal dependence of inhaled anaesthetic requirements in cats.

BACKGROUND: The minimum alveolar concentration (MAC) of an inhaled anaesthetic describes its potency as a general anaesthetic. Individuals vary in their sensitivity to anaesthetics and we sought to determine whether an individual animal's sensitivity to inhaled anaesthetics would be maintained across different agents. METHODS: Six female mongrel cats, age 2 yr (range 1.8-2.3) and mean weight 3.5 (SD 0.3) kg, were studied on three separate occasions over a 12-month period to determine the MAC of isoflurane, sevoflurane and desflurane. Induction of anaesthesia in a chamber was followed by orotracheal intubation and maintenance of anaesthesia with the inhaled agent in oxygen delivered via a non-rebreathing circuit. MAC was determined in triplicate using standard tail-clamp technique. RESULTS: Mean MAC values for isoflurane, sevoflurane and desflurane were 1.90 (SD 0.18), 3.41 (0.65) and 10.27 (1.06)%, respectively. Body temperature, systolic pressure and Sp(O(2)) recorded at the time of MAC determinations for isoflurane, sevoflurane and desflurane were 38.3 (0.3), 38.6 (0.1) and 38.3 (0.3) degrees C; 71.2 (8.3), 74.6 (15.9) and 88.0 (12.0) mmHg; 99.2 (1.1), 99.1 (1.3) and 99.4 (0.8)%, respectively. Both the anaesthetic agent and the individual cat had significant effects on MAC. Correlation coefficients for comparisons between desflurane and isoflurane, desflurane and sevoflurane, and sevoflurane and isoflurane were 0.90, 0.89 and 0.97, respectively. CONCLUSIONS: These findings show that an individual has a consistent degree of sensitivity to a variety of inhaled anaesthetics, suggesting a genetic basis for sensitivity to inhaled anaesthetic effects.