Peripheral α2-adrenoceptor antagonism affects the absorption of intramuscularly coadministered drugs.

OBJECTIVE: We determined the possible effects of a peripherally acting α2-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) coadministered medetomidine, butorphanol and midazolam. STUDY DESIGN: Randomized, experimental, blinded crossover study. ANIMALS: Six healthy Beagle dogs. METHODS: Two IM treatments were administered: 1) medetomidine hydrochloride (20 µg kg-1) + butorphanol (100 µg kg-1) + midazolam (200 µg kg-1; MBM) and 2) MBM + MK-467 hydrochloride (500 µg kg-1; MBM-MK), mixed in a syringe. Heart rate was recorded at regular intervals. Sedation was assessed with visual analog scales (0-100 mm). Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry, with chiral separation of dex- and levomedetomidine. Maximum drug concentrations in plasma (Cmax) and time to Cmax (Tmax) were determined. Paired t-tests, with Bonferroni correction when appropriate, were used for comparisons between the treatments. RESULTS: Data from five dogs were analyzed. Heart rate was significantly higher from 20 to 90 minutes after MBM-MK. The Tmax values for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with coadministration of MK-467, from 23 ± 9 to 11 ± 6 minutes (p = 0.049) for midazolam and from 32 ± 15 to 18 ± 6 minutes for levomedetomidine (p = 0.036), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 accelerated the absorption of IM coadministered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.

Effect of detomidine or romifidine constant rate infusion on plasma lactate concentration and inhalant requirements during isoflurane anaesthesia in horses.

OBJECTIVE: Influence of detomidine or romifidine constant rate infusion (CRI) on plasma lactate concentration and isoflurane requirements in horses undergoing elective surgery. STUDY DESIGN: Prospective, randomised, blinded, clinical trial. ANIMALS: A total of 24 adult healthy horses. METHODS: All horses were administered intramuscular acepromazine (0.02 mg kg-1) and either intravenous detomidine (0.02 mg kg-1) (group D), romifidine (0.08 mg kg-1) (group R) or xylazine (1.0 mg kg-1) (group C) prior to anaesthesia. Group D was administered detomidine CRI (10 µg kg-1 hour-1) in lactated Ringer's solution (LRS), group R romifidine CRI (40 µg kg-1 hour-1) in LRS and group C an equivalent amount of LRS intraoperatively. Anaesthesia was induced with ketamine and diazepam and maintained with isoflurane in oxygen. Plasma lactate samples were taken prior to anaesthesia (baseline), intraoperatively (three samples at 30 minute intervals) and in recovery (at 10 minutes, once standing and 3 hours after end of anaesthesia). End-tidal isoflurane percentage (Fe'Iso) was analysed by allocating values into three periods: Prep (15 minutes after the start anaesthesia-start surgery); Surgery 1 (start surgery-30 minutes later); and Surgery 2 (end Surgery 1-end anaesthesia). A linear mixed model was used to analyse the data. A value of p<0.05 was considered significant. RESULTS: There was a difference in plasma lactate between 'baseline' and 'once standing' in all three groups (p<0.01); values did not differ significantly between groups. In groups D and R, Fe'Iso decreased significantly by 18% (to 1.03%) and by 15% (to 1.07%), respectively, during Surgery 2 compared with group C (1.26%); p<0.006, p<0.02, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Intraoperative detomidine or romifidine CRI in horses did not result in a clinically significant increase in plasma lactate compared with control group. Detomidine and romifidine infusions decreased isoflurane requirements during surgery.

A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.

OBJECTIVE: To compare the haemodynamic effects of three premedicant regimens during propofol-induced isoflurane anaesthesia. STUDY DESIGN: Prospective, randomized cross-over study. ANIMALS: Eight healthy purpose-bred beagles aged 4 years and weighing mean 13.6 ± SD 1.9 kg. METHODS: The dogs were instrumented whilst under isoflurane anaesthesia prior to each experiment, then allowed to recover for 60 minutes. Each dog was treated with three different premedications given intravenously (IV): medetomidine 10 µg kg⁻¹ (MED), medetomidine 10 µg kg⁻¹ with MK-467 250 µg kg⁻¹ (MMK), or acepromazine 0.01 mg kg⁻¹ with butorphanol 0.3 mg kg⁻¹ (AB). Anaesthesia was induced 20 minutes later with propofol and maintained with isoflurane in oxygen for 60 minutes. Heart rate (HR), cardiac output, arterial blood pressures (ABP), central venous pressure (CVP), respiratory rate, inspired oxygen fraction, rectal temperature (RT) and bispectral index (BIS) were measured and arterial and venous blood gases analyzed. Cardiac index (CI), systemic vascular resistance index (SVRI), oxygen delivery index (DO2 I), systemic oxygen consumption index (VO2 I) and oxygen extraction (EO2) were calculated. Times to extubation, righting, sternal recumbency and walking were recorded. The differences between treatment groups were evaluated with repeated measures analysis of covariance. RESULTS: HR, CI, DO2 I and BIS were significantly lower with MED than with MMK. ABP, CVP, SVRI, EO2, RT and arterial lactate were significantly higher with MED than with MMK and AB. HR and ABP were significantly higher with MMK than with AB. However, CVP, CI, SVRI, DO2 I, VO2 I, EO2, T, BIS and blood lactate did not differ significantly between MMK and AB. The times to extubation, righting, sternal recumbency and walking were significantly shorter with MMK than with MED and AB. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 attenuates certain cardiovascular effects of medetomidine in dogs anaesthetized with isoflurane. The cardiovascular effects of MMK are very similar to those of AB.

Anaesthetic management and complications of a Humboldt penguin (Spheniscus humboldti) undergoing diagnostic imaging.

BACKGROUND: The presence of a tracheal septum dividing the trachea into two makes intubation one of the main challenges of penguin anaesthesia. Differences in the length and location of the aforementioned tracheal septum have been described in some penguin species. However, to the best of the authors' knowledge, it has not been reported in Humboldt penguins (Spheniscus humboldti). Therefore, one of the aims of this publication is to report the septal position in this Humboldt penguin. Furthermore, this publication describes the anaesthetic protocol and complications encountered and discusses some of the more important features of penguin anaesthesia. It is anticipated that this case report will aid in future procedures requiring anaesthesia of this penguin species. CASE PRESENTATION: A 25-year-old female Humboldt penguin was anaesthetized at the University College Dublin Veterinary Hospital for radiographs and computed tomography (CT) following three weeks of inappetence. After assessing the health status of the penguin from the clinical history and performing a physical examination, an American Society of Anesthesiologists physical status score of II was assigned and a combination of butorphanol 1 mg/kg and midazolam 1 mg/kg was administered intramuscularly to sedate the penguin. Induction of anaesthesia was performed via a face mask using sevoflurane in oxygen. The airway was intubated with a 4.0 mm Cole tube and anaesthesia was maintained with sevoflurane in oxygen during the entire procedure. Anaesthetic monitoring consisted of an electrocardiogram, pulse oximetry, non-invasive blood pressure, capnography, and body temperature. CONCLUSIONS: Tracheal bifurcation was identified as the start of the tracheal septum 4.67 cm from the glottis using CT. Most of the anticipated complications of penguin anaesthesia, such as hyperthermia, hypothermia, regurgitation, hypoventilation, and difficulties in intubation were present in this case. However, no major sequalae occurred following the anaesthetic protocol described.

Morphine in donkeys: Antinociceptive effect and preliminary pharmacokinetics.

BACKGROUND: Morphine is the prototypical µ-opioid receptor agonist used to provide analgesia in veterinary species. Its effects are well-described in horses but not donkeys. OBJECTIVES: To determine the antinociceptive effects of two doses of morphine in donkeys. To describe preliminary pharmacokinetic parameters of morphine in donkeys. STUDY DESIGN: In vivo experiment. METHODS: Eight adult castrated male donkeys were given intravenous (IV) 0.9% saline, morphine 0.1 mg/kg bwt (LDM), or morphine 0.5 mg/kg bwt (HDM) in a randomised order with a minimum 1-week washout period. Mechanical nociceptive thresholds (MNTs) were determined by a blinded investigator pre-injection and 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min post-injection. Venous blood samples were collected pre-injection and 2, 5, 10, 15, 30, 45, 60, 90, and 120 min post-injection. Data were analysed using Friedman's test with Dunn's post hoc test for multiple comparisons. Pharmacokinetic parameters were calculated for the HDM treatment. RESULTS: Baseline MNT was [median (interquartile range)] 8.9 (7.1-10.3) N and did not differ between treatments. Peak MNTs occurred at 60 min for both LDM (16.2 N) and HDM (25.0 N) treatments. MNTs after HDM treatment were higher than saline (p < 0.04) at 15, 60, 90, 120, 150, 180, 240, and 300 min post-injection. MNTs after LDM treatment were higher than baseline (p < 0.05) at 45 and 60 min post-injection. Terminal half-life for HDM was (mean ± SD) 51.0 ± 10.7 min, the volume of distribution at steady-state 2.07 ± 0.33 L/min and clearance 49.2 ± 4.16 ml * min/kg using noncompartmental analysis. The concentration of morphine-3-glucuronide (M3G) was higher than morphine-6-glucuronide (M6G) at all sampled time points. MAIN LIMITATIONS: Short duration of plasma sampling for pharmacokinetic analysis; lack of objective measure of gastrointestinal function. CONCLUSIONS: The HDM treatment provided mechanical antinociception in donkeys with no significant adverse effects.

Effects of the α2-adrenoceptor agonist medetomidine on the distribution and clearance of alfaxalone during coadministration by constant rate infusion in dogs.

OBJECTIVE To assess the possible impact of medetomidine on concentrations of alfaxalone in plasma, when coadministered as a constant rate infusion (CRI) to dogs, and to determine the possible impact of medetomidine on the cardiopulmonary effects of alfaxalone during CRI. ANIMALS 8 healthy adult Beagles. PROCEDURES 3 treatments were administered in a randomized crossover design as follows: 1 = saline (0.9% NaCl) solution injection, followed in 10 minutes by induction of anesthesia with alfaxalone (loading dose, 2.4 mg/kg; CRI, 3.6 mg/kg/h, for 60 minutes); 2 = medetomidine premedication (loading dose, 4.0 µg/kg; CRI, 4.0 µg/kg/h), followed by alfaxalone (as in treatment 1); and, 3 = medetomidine (as in treatment 2) and MK-467 (loading dose, 150 µg/kg; CRI, 120 µg/kg/h), followed by alfaxalone (as in treatment 1). The peripherally acting α2-adrenoceptor antagonist MK-467 was used to distinguish between the peripheral and central effects of medetomidine. Drugs were administered IV via cephalic catheters, and there was a minimum of 14 days between treatments. Cardiopulmonary parameters were measured for 70 minutes, and jugular venous blood samples were collected until 130 minutes after premedication. Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry. RESULTS The characteristic cardiovascular effects of medetomidine, such as bradycardia, hypertension, and reduction in cardiac index, were obtunded by MK-467. The concentrations of alfaxalone in plasma were significantly increased in the presence of medetomidine, indicative of impaired drug distribution and clearance. This was counteracted by MK-467. CONCLUSIONS AND CLINICAL RELEVANCE The alteration in alfaxalone clearance when coadministered with medetomidine may be attributed to the systemic vasoconstrictive and bradycardic effects of the α2-adrenoceptor agonist. This could be clinically important because the use of α2-adrenoceptor agonists may increase the risk of adverse effects if standard doses of alfaxalone are used.

Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane.

OBJECTIVE To compare cardiovascular effects of premedication with medetomidine alone and with each of 3 doses of MK-467 or after glycopyrrolate in dogs subsequently anesthetized with isoflurane. ANIMALS 8 healthy purpose-bred 5-year-old Beagles. PROCEDURES In a randomized crossover study, each dog received 5 premedication protocols (medetomidine [10 µg/kg, IV] alone [MED] and in combination with MK-467 at doses of 50 [MMK50], 100 [MMK100], and 150 [MMK150] µg/kg and 15 minutes after glycopyrrolate [10 µg/kg, SC; MGP]), with at least 14 days between treatments. Twenty minutes after medetomidine administration, anesthesia was induced with ketamine (0.5 mg/kg, IV) and midazolam (0.1 mg/kg, IV) increments given to effect and maintained with isoflurane (1.2%) for 50 minutes. Cardiovascular variables were recorded, and blood samples for determination of plasma dexmedetomidine, levomedetomidine, and MK-467 concentrations were collected at predetermined times. Variables were compared among the 5 treatments. RESULTS The mean arterial pressure and systemic vascular resistance index increased following the MED treatment, and those increases were augmented and obtunded following the MGP and MMK150 treatments, respectively. Mean cardiac index for the MMK100 and MMK150 treatments was significantly greater than that for the MGP treatment. The area under the time-concentration curve to the last sampling point for dexmedetomidine for the MMK150 treatment was significantly lower than that for the MED treatment. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated concurrent administration of MK-467 with medetomidine alleviated medetomidine-induced hemodynamic changes in a dose-dependent manner prior to isoflurane anesthesia. Following MK-467 administration to healthy dogs, mean arterial pressure was sustained at acceptable levels during isoflurane anesthesia.

Incidence of tuberculosis and survival after its diagnosis in patients infected with HIV-1 and HIV-2.

BACKGROUND: In sub-Saharan Africa, tuberculosis (TB) is the most frequently diagnosed opportunistic infection and cause of death among HIV-infected patients. HIV-2 has been associated with less immune suppression, slower disease progression and longer survival. OBJECTIVE: To examine whether the incidence of TB and survival after TB are associated with CD4 cell count rather than HIV type. METHODS: Clinical and immunological data were retrospectively evaluated among an open clinic-based cohort of HIV-1- and HIV-2-infected patients to determine incidence of TB (first diagnosis > 28 days after HIV diagnosis) and subsequent mortality. Patients were grouped by CD4 cell count into those with < 200, 200-500 and > 500 x 10 cells/l. RESULTS: Incident TB was diagnosed among 159 of 2012 patients, with 4973 person-years of observation time. In 105/159 (66.0%), the diagnosis was confirmed by direct microscopy or culture. Incidence of TB was highest in the group with < 200 x 10 cells/l (9.1/100 and 8.8/100 person-years in HIV-1 and HIV-2, respectively). Adjusted for CD4 cell count, there was no significant difference in incidence or mortality following TB between HIV-1- and HIV-2-infected patients. Mortality rate was higher in those with incident TB and HIV infection, most markedly in the group with the highest CD4 cell count (hazard ratio, 10.0; 95% confidence interval, 5.1-19.7). CONCLUSION: Adjusted for CD4 cell count, incidence of TB was similar among HIV-1- and HIV-2-infected patients. Mortality rates after TB diagnosis were similar in both groups and high compared with those without TB.

Influence of morphine sulfate on the halothane sparing effect of xylazine hydrochloride in horses.

OBJECTIVE: To quantitate the dose and time-related effects of morphine sulfate on the anesthetic sparing effect of xylazine hydrochloride in halothane-anesthetized horses and determine the associated plasma xylazine and morphine concentration-time profiles. ANIMALS: 6 healthy adult horses. PROCEDURE: Horses were anesthetized 3 times to determine the minimum alveolar concentration (MAC) of halothane in O2 and characterize the anesthetic sparing effect (ie, decrease in MAC of halothane) by xylazine (0.5 mg/kg, i.v.) administration followed immediately by i.v. administration of saline (0.9% NaCI) solution, low-dose morphine (0.1 mg/kg), or high-dose morphine (0.2 mg/kg). Selected parameters of cardiopulmonary function were also determined over time to verify consistency of conditions. RESULTS: Mean (+/- SEM) MAC of halothane was 1.05 +/- 0.02% and was decreased by 20.1 +/- 6.6% at 49 +/- 2 minutes following xylazine administration. The amount of MAC reduction in response to xylazine was time dependent. Addition of morphine to xylazine administration did not contribute further to the xylazine-induced decrease in MAC (reductions of 21.9 +/- 1.2 and 20.7 +/- 1.5% at 43 +/- 4 and 40 +/- 4 minutes following xylazine-morphine treatments for low- and high-dose morphine, respectively). Overall, cardiovascular and respiratory values varied little among treatments. Kinetic parameters describing plasma concentration-time curves for xylazine were not altered by the concurrent administration of morphine. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of xylazine decreases the anesthetic requirement for halothane in horses. Concurrent morphine administration to anesthetized horses does not alter the anesthetic sparing effect of xylazine or its plasma concentration-time profile.

Use of opioids for pain and anesthetic management in horses.

REGIONAL ADMINISTRATION: There is limited, but convincing, evidence that epidural administration of morphine and some other mu-agonist opioids consistently relieves regional pain in horses. In addition, this effect is not accompanied by notable undesirable effects. On the other hand, a clinically important analgesic action has not been demonstrated for similarly administered kappa-agonist opioids. There has been little objective data presented to support the analgesic effectiveness of intra-articularly administered opioids in horses. However, the evidence of local opioid receptors legitimately encourages work to substantiate the value of intra-articular opioid administration to relieve joint-associated pain in horses. SYSTEMIC ADMINISTRATION: So far, study results do not provide convincing, objective evidence to support the opinion that systemically administered opioids consistently and effectively relieve pain in horses. Given this lack of evidence, and considering that opioids stimulate locomotor and other forms of unwanted excitant behavior, reduce propulsive gastrointestinal motility, decrease alveolar ventilation (especially in association with general anesthesia), and require regulatory and practical considerations for abuse potential in both humans and horses, we conclude that routine, indiscriminate administration of opioids for pain relief in horses is not justified. Identification and focused, objective study of selective beneficial opioid actions to provide guidance for appropriate clinical use is long overdue.