Sherry K. Cox

Effects of intravenous lidocaine, ketamine, and the combination on the minimum alveolar concentration of sevoflurane in dogs

OBJECTIVE To evaluate the effects of intravenous lidocaine (L) and ketamine (K) alone and their combination (LK) on the minimum alveolar concentration (MAC) of sevoflurane (SEVO) in dogs. STUDY DESIGN Prospective randomized, Latin-square experimental study. ANIMALS Six, healthy, adult Beagles, 2 males, 4 females, weighing 7.8 - 12.8 kg. METHODS Anesthesia was induced with SEVO in oxygen delivered by face mask. The tracheas were intubated and the lungs ventilated to maintain normocapnia. Baseline minimum alveolar concentration of SEVO (MAC(B)) was determined in duplicate for each dog using an electrical stimulus and then the treatment was initiated. Each dog received each of the following treatments, intravenously as a loading dose (LD) followed by a constant rate infusion (CRI): lidocaine (LD 2 mg kg(-1), CRI 50 microg kg(-1)minute(-1)), lidocaine (LD 2 mg kg(-1), CRI 100 microg kg(-1) minute(-1)), lidocaine (LD 2 mg kg(-1), CRI 200 microg kg(-1) minute(-1)), ketamine (LD 3 mg kg(-1), CRI 50 microg kg(-1) minute(-1)), ketamine (LD 3 mgkg(-1), CRI 100 microg kg(-1) minute(-1)), or lidocaine (LD 2 mg kg(-1), CRI 100 microg kg(-1) minute(-1)) + ketamine (LD 3 mg kg(-1), CRI 100 microg kg(-1) minute(-1)) in combination. Post-treatment MAC (MAC(T)) determination started 30 minutes after initiation of treatment. RESULTS Least squares mean +/- SEM MAC(B) of all groups was 1.9 +/- 0.2%. Lidocaine infusions of 50, 100, and 200 microg kg(-1) minute(-1) significantly reduced MAC(B) by 22.6%, 29.0%, and 39.6%, respectively. Ketamine infusions of 50 and 100 microg kg(-1) minute(-1) significantly reduced MAC(B) by 40.0% and 44.7%, respectively. The combination of K and L significantly reduced MAC(B) by 62.8%. CONCLUSIONS AND CLINICAL RELEVANCE Lidocaine and K, alone and in combination, decrease SEVO MAC in dogs. Their use, at the doses studied, provides a clinically important reduction in the concentration of SEVO during anesthesia in dogs.

Effects of tramadol on the minimum alveolar concentration of sevoflurane in dogs

OBJECTIVE To evaluate the effect of tramadol on sevoflurane minimum alveolar concentration (MAC(SEVO)) in dogs. It was hypothesized that tramadol would dose-dependently decrease MAC(SEVO). STUDY DESIGN Randomized crossover experimental study. ANIMALS Six healthy, adult female mixed-breed dogs (24.2 +/- 2.6 kg). METHODS Each dog was studied on two occasions with a 7-day washout period. Anesthesia was induced using sevoflurane delivered via a mask. Baseline MAC (MAC(B)) was determined starting 45 minutes after tracheal intubation. A noxious stimulus (50 V, 50 Hz, 10 ms) was applied subcutaneously over the mid-humeral area. If purposeful movement occurred, the end-tidal sevoflurane was increased by 0.1%; otherwise, it was decreased by 0.1%, and the stimulus was re-applied after a 20-minute equilibration. After MAC(B) determination, dogs randomly received a tramadol loading dose of either 1.5 mg kg(-1) followed by a continuous rate infusion (CRI) of 1.3 mg kg(-1 )hour(-1) (T1) or 3 mg kg(-1) followed by a 2.6 mg kg(-1 )hour(-1) CRI (T2). Post-treatment MAC determination (MAC(T)) began 45 minutes after starting the CRI. Data were analyzed using a mixed model anova to determine the effect of treatment on percentage change in baseline MAC(SEVO) (p < 0.05). RESULTS The MAC(B) values were 1.80 +/- 0.3 and 1.75 +/- 0.2 for T1 and T2, respectively, and did not differ significantly. MAC(T) decreased by 26 +/- 8% for T1 and 36 +/- 12% for T2. However, there was no statistically significant difference in the decrease between the two treatments. CONCLUSION AND CLINICAL RELEVANCE Tramadol significantly reduced MAC(SEVO) but this was not dose dependent at the doses studied.

Pharmacokinetics of Intravenous and Oral Tramadol in the Bald Eagle (Haliaeetus leucocephalus)

Abstract Analgesia is becoming increasingly important in veterinary medicine, and little research has been performed that examined pain control in avian species. Tramadol is a relatively new drug that provides analgesia by opioid (μ), serotonin, and norepinephrine pathways, with minimal adverse effects. To determine the pharmacokinetics of tramadol and its major metabolite O-desmethyltramadol (M1) in eagles, 6 bald eagles (Haliaeetus leucocephalus) were each dosed with tramadol administered intravenously (4 mg/kg) and orally (11 mg/kg) in a crossover study. Blood was collected at various time points between 0 and 600 minutes and then analyzed with high-performance liquid chromatography to determine levels of tramadol and M1, the predominate active metabolite. The terminal half-life of tramadol after intravenous dosing was 2.46 hours. The maximum plasma concentration, time of maximum plasma concentration, and terminal half-life for tramadol after oral dosing were 2156.7 ng/ml, 3.75 hours, and 3.14 hours, respectively. In addition, the oral bioavailability was 97.9%. Although plasma concentrations of tramadol and M1 associated with analgesia in any avian species is unknown, based on the obtained data and known therapeutic levels in humans, a dosage of 5 mg/kg PO q12h is recommended for bald eagles. Pharmacodynamic studies are needed to better determine plasma levels of tramadol and M1 associated with analgesia in birds.

Pharmacokinetics of orally administered tramadol in domestic rabbits (Oryctolagus cuniculus)

OBJECTIVE To determine the pharmacokinetics of an orally administered dose of tramadol in domestic rabbits (Oryctolagus cuniculus). ANIMALS 6 healthy adult sexually intact female New Zealand White rabbits. PROCEDURES Physical examinations and plasma biochemical analyses were performed to ensure rabbits were healthy prior to the experiment. Rabbits were anesthetized with isoflurane, and IV catheters were placed in a medial saphenous or jugular vein for collection of blood samples. One blood sample was collected before treatment with tramadol. Rabbits were allowed to recover from anesthesia a minimum of 1 hour before treatment. Then, tramadol (11 mg/kg, PO) was administered once, and blood samples were collected at various time points up to 360 minutes after administration. Blood samples were analyzed with high-performance liquid chromatography to determine plasma concentrations of tramadol and its major metabolite (O-desmethyltramadol). RESULTS No adverse effects were detected after oral administration of tramadol to rabbits. Mean +/- SD half-life of tramadol after administration was 145.4 +/- 81.0 minutes; mean +/- SD maximum plasma concentration was 135.3 +/- 89.1 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE Although the dose of tramadol required to provide analgesia in rabbits is unknown, the dose administered in the study reported here did not reach a plasma concentration of tramadol or O-desmethyltramadol that would provide sufficient analgesia in humans for clinically acceptable periods. Many factors may influence absorption of orally administered tramadol in rabbits.

Antinociceptive effects after oral administration of tramadol hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis)

OBJECTIVE To evaluate antinociceptive effects on thermal thresholds after oral administration of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). Animals-15 healthy adult Hispaniolan Amazon parrots. PROCEDURES 2 crossover experiments were conducted. In the first experiment, 15 parrots received 3 treatments (tramadol at 2 doses [10 and 20 mg/kg] and a control suspension) administered orally. In the second experiment, 11 parrots received 2 treatments (tramadol hydrochloride [30 mg/kg] and a control suspension) administered orally. Baseline thermal foot withdrawal threshold was measured 1 hour before drug or control suspension administration; thermal foot withdrawal threshold was measured after administration at 0.5, 1.5, 3, and 6 hours (both experiments) and also at 9 hours (second experiment only). RESULTS For the first experiment, there were no overall effects of treatment, hour, period, or any interactions. For the second experiment, there was an overall effect of treatment, with a significant difference between tramadol hydrochloride and control suspension (mean change from baseline, 2.00° and -0.09°C, respectively). There also was a significant change from baseline for tramadol hydrochloride at 0.5, 1.5, and 6 hours after administration but not at 3 or 9 hours after administration. CONCLUSIONS AND CLINICAL RELEVANCE Tramadol at a dose of 30 mg/kg, PO, induced thermal antinociception in Hispaniolan Amazon parrots. This dose was necessary for induction of significant and sustained analgesic effects, with duration of action up to 6 hours. Further studies with other types of noxious stimulation, dosages, and intervals are needed to fully evaluate the analgesic effects of tramadol hydrochloride in psittacines.

Pharmacokinetics of Tramadol Hydrochloride and its Metabolite O-Desmethyltramadol in Peafowl (Pavo cristatus)

Abstract Tramadol is a centrally acting opiate analgesic that has not been well studied in avian species. Tramadol and its metabolites exert their effects at multiple sites, including opiate (μ, κ, and δ), adrenergic (α-2), and serotonin (5HT) receptors. This multi-receptor mode of action is advantageous for avian patients because the mechanisms for analgesia have not been fully elucidated in all species. The objective of this study was to document the pharmacokinetics of tramadol and its active metabolite O-desmethyltramadol (M1) in common peafowl (Pavo cristatus). Based on results from a pilot animal, six adult peafowl (three male, three female) judged to be clinically healthy based on physical exam and routine bloodwork were selected for this study. Each bird was anesthetized for placement of a jugular catheter, and 7.5 mg/kg tramadol was administered orally via gavage tube. Blood samples were collected just prior to drug administration; at 30 min; and at 1, 2, 3, 4, 6, 8, 10, 12, 24, and 34 hr. Plasma levels of tramadol and M1 were measured and the pharmacokinetics for each drug was calculated. Although tramadol was quickly metabolized, plasma levels of M1 remained at or near human analgesic levels for 12–24 hr. Based on these data, tramadol may be a practical option as an orally administered analgesic agent in avian patients. Further studies, including antinociceptive studies, are needed.

Tramadol Use in Zoologic Medicine

Numerous analgesics are available for use in animals, but only a few have been used or studied in zoologic species. Tramadol is a relatively new analgesic that is available in an inexpensive, oral form, and is not controlled. Studies examining the effect of tramadol in zoologic species suggest that significant differences exist in pharmacokinetics parameters as well as analgesic dynamics. This article reviews the current literature on the use of tramadol in humans, domestic animals, and zoologic species.

Evaluation of Oral Itraconazole Administration in Captive Humboldt Penguins ( Spheniscus humboldti )

Abstract Aspergillus spp. fungal infections are the most common cause of morbidity and mortality in captive penguins. Itraconazole has been the drug of choice for both therapeutic and prophylactic treatment; however, the pharmacokinetic and pharmacodynamic parameters can be highly variable in different species, and it has not been evaluated in penguins. In this study, four preliminary steady-state trials were performed to compare two oral formulations of itraconazole (commercial capsules compared with generic bulk compounded powder) at two different dosages (6 or 12 mg/kg once a day) administered in fish to small groups of captive Humboldt penguins (Spheniscus humboldti). Building on this data, a final steady-state trial was performed with the use of a 7 mg/kg oral dosage twice a day of commercial capsules given in fish to a group of 15 penguins. With sparse sampling, blood was drawn for testing from small subsets of each treatment group at 4–7 time points in the 24-hr period after the final dose of itraconazole on day 14. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole, the major metabolite, were determined by reverse phase high-performance liquid chromatography with fluorescence detection. Treatment with the generic bulk compounded product resulted in plasma levels of itraconazole that were undetectable for 26 out of 30 blood samples, compared with seven out of 20 blood samples for the commercial product at the same dosage. On the basis of study results, an estimated oral dosage of either 8.5 mg/kg twice a day or 20 mg/kg once a day of the commercial itraconazole capsules given in fish would produce adequate steady-state therapeutic blood levels in Humboldt penguins.

Microassay for determination of itraconazole and hydroxyitraconazole in plasma and tissue biopsies

A simple, rapid and sensitive method for the extraction and HPLC analysis of itraconazole and hydroxyitraconazole in tissue and plasma or serum is described. Tissue (5-100 mg) and plasma (0.1 ml) underwent a simple extraction into methanol. Chromatography was performed on a Novapak C18 column using a mobile phase of water-acetonitrile-diethylamine (42:58:0.05, v/v), pH 2.45, with a flow-rate of 1.5 ml/min. Fluorescence was measured at excitation 260 nm and emission 365 nm. The procedure produced a linear curve for the concentration range 10-1000 ng/ml. The development of the assay produced accurate, rapid repeatable results for both tissue and plasma or serum.

Pharmacokinetics after oral and intravenous administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis)

OBJECTIVE To determine pharmacokinetics after IV and oral administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS 9 healthy adult Hispaniolan Amazon parrots (3 males, 5 females, and 1 of unknown sex). PROCEDURES Tramadol (5 mg/kg, IV) was administered to the parrots. Blood samples were collected from -5 to 720 minutes after administration. After a 3-week washout period, tramadol (10 and 30 mg/kg) was orally administered to parrots. Blood samples were collected from -5 to 1,440 minutes after administration. Three formulations of oral suspension (crushed tablets in a commercially available suspension agent, crushed tablets in sterile water, and chemical-grade powder in sterile water) were evaluated. Plasma concentrations of tramadol and its major metabolites were measured via high-performance liquid chromatography. RESULTS Mean plasma tramadol concentrations were > 100 ng/mL for approximately 2 to 4 hours after IV administration of tramadol. Plasma concentrations after oral administration of tramadol at a dose of 10 mg/kg were < 40 ng/mL for the entire time period, but oral administration at a dose of 30 mg/kg resulted in mean plasma concentrations > 100 ng/mL for approximately 6 hours after administration. Oral administration of the suspension consisting of the chemical-grade powder resulted in higher plasma tramadol concentrations than concentrations obtained after oral administration of the other 2 formulations; however, concentrations differed significantly only at 120 and 240 minutes after administration. CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of tramadol at a dose of 30 mg/kg resulted in plasma concentrations (> 100 ng/mL) that have been associated with analgesia in Hispaniolan Amazon parrots.