William W. Muir

The cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in cats.

OBJECTIVE To determine the cardiorespiratory and anesthetic effects of 0, 5, 15, and 50 mg kg(-1) intravenous (IV) alfaxalone in hydroxypropyl beta cyclodextrin (Alfaxan; Jurox Pty Ltd, Rutherford, NSW, Australia) in cats. STUDY DESIGN Four treatments of alfaxalone were administered in sequential order. ANIMALS Eight healthy adult cats (four male; four female) weighing between 3.71 and 5.91 kg. METHODS Cats were instrumented for hemodynamic measurements. Four (0, 5, 15, and 50 mg kg(-1)) IV doses of alfaxalone were administered over one minute, with a 3-hour washout period between doses 0, 5, and 15 mg kg(-1) on Day 0. The 50 mg kg(-1) treatment was administered 24 hours later. Measurements of heart rate, aortic systolic, mean, and diastolic blood pressures, pulmonary arterial and right atrial mean pressures, cardiac output, respiratory rate, tidal and minute volumes, and arterial blood pH and blood gases (PaO(2), PaCO(2)) were performed at pre-determined intervals. Systemic vascular resistance and rate pressure product were calculated. The quality of induction, maintenance, and recovery from anesthesia and the response to noxious stimulation were categorically scored. RESULTS Alfaxalone administration resulted in dose-dependent cardiorespiratory depression. Decreases in arterial blood pressure and increases in heart rate occurred at higher doses. Most variables returned to baseline by 15-30 minutes. Respiratory rate, minute volume, and PaO(2) decreased. Apnea was the most common side effect. Induction and maintenance quality were judged to be good to excellent at all doses and quality of recovery good to excellent at all but the 50 mg kg(-1) dose. The duration of anesthesia and unresponsiveness to noxious stimulation increased with dose. The administration of the 50 mg kg(-1) dose produced marked cardiorespiratory depression and apnea. CONCLUSIONS AND CLINICAL RELEVANCE Alfaxalone produced dose-dependent anesthesia, cardiorespiratory depression and unresponsiveness to noxious stimulation in unpremedicated cats. Hypoventilation and apnea were the most common side effects.

Pain: Mechanisms and Management in Horses

Pain is a multidimensional sensory phenomenon that has evolved as a protective method for maintaining homeostasis and facilitating tissue repair. Both excitatory and inhibitory physiologic and pathologic mechanisms are involved in its generation and maintenance. Untreated pain and nervous system changes (plasticity) that occur during chronic pain make pain much more difficult or impossible to effectively treat. Therapies directed toward the treatment of pain should be mechanism based and preventative whenever possible. Prospective, randomized clinical trials conducted in horses that suffer from naturally occurring pain will help to determine the current best approaches to effective pain therapy.

Evaluation of the analgesic properties of acepromazine maleate, oxymorphone, medetomidine and a combination of acepromazine-oxymorphone.

OBJECTIVE To determine the presence and duration of analgesia after oxymorphone, acepromazine maleate, acepromazine-oxymorphone combination and medetomidine administration in dogs. STUDY DESIGN Blinded, controlled study. ANIMALS Six adult beagle dogs. METHODS Each dog participated in five trials receiving acepromazine maleate (0.2 mg kg-1 IM), oxymorphone (0.2 mg kg-1 IM), acepromazine-oxymorphone drug combination (0.2 mg kg-1 each IM), medetomidine (20 μg kg-1 IM) and sterile saline (control). Two specially designed instruments were used for analgesia determination: a heat device (HD) utilized a linear ramped intensity incandescent bulb and a pressure device (PD) consisted of a pneumatic cylinder that protruded a 2.5-cm bolt. The minimum pressure and heat necessary to produce an avoidance response were determined. Analgesia testing was performed prior to and at 30-minute intervals for six hours after drug administration. RESULTS Oxymorphone, acepromazine-oxymorphone and medetomidine significantly elevated both pressure and heat response thresholds compared to controls and acepromazine. Both medetomidine and acepromazine-oxymorphone provided a significantly longer duration of analgesia than oxymorphone. No adverse effects were observed at any of the thermal or pressure application sites. CONCLUSIONS Oxymorphone, medetomidine and acepromazine-oxymorphone produced significant analgesia with medetomidine and acepromazine-oxymorphone providing the longest duration of analgesia.

Effect of intravenous anesthetics on inward rectifier potassium current in rat and human ventricular myocytes.

Background: Inhibition of the inward rectifying potassium current (IK1) may cause cardiac dysrhythmias by decreasing resting membrane potential or prolonging action potential. Methods: The effects of thiopental, ketamine, and propofol on IK1 conductance were evaluated in rat ventricular myocytes. The effect of thiopental on IK1 conductance was also evaluated in human ventricular myocytes. Currents were recorded using the nystatin‐perforated whole‐cell patch‐clamp technique (holding potential, ‐50 mV; test potentials, ‐140 to ‐40 mV). Pipette solution contained 130 mM KCl, 5 mM MgCl2, 5 mM HEPES, and 5 mM EGTA, pH 7.2. Bath solution (32 [degree sign] Celsius) contained 134 mM NaCl, 4 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 0.3 mM CdCl2, 5 mM HEPES, and 5 mM d‐glucose, pH 7.4. Drug concentrations examined encompassed the range of clinically relevant unbound plasma concentrations. Currents were normalized for cell capacitance. Conductance was calculated as current density/Delta mV from ‐140 to ‐100 mV. Analysis of variance was used to test for changes in conductance as a function of drug concentration. Results: Thiopental reduced IK1 conductance in a concentration‐dependent manner (P < 0.0001). Thiopental‐induced changes in IK1 conductance in rat ventricular myocytes were fit to an inhibitory Emax model, with a median inhibitory concentration of 10.5 micro Meter. The effect of thiopental on IK1 conductance in human ventricular cells was comparable to that observed in rat ventricular myocytes. Neither ketamine nor propofol altered IK1 conductance. Conclusions: Thiopental reduces IK1 conductance in a concentration‐dependent manner at clinically relevant concentrations in both rat and human ventricular myocytes.

Pharmacology and Pharmacokinetics of Drugs Used to Treat Cardiac Disease in Horses

The rational therapy of cardiovascular disease in horses requires a thorough knowledge of the pharmacology and pharmacokinetics of several specific drugs (digitalis, digoxin). Calcium solutions, dopamine, and dobutamine are frequently used to treat congestive heart failure in horses. Quinidine, procainamide, lidocaine, and propranolol are used to treat a variety of supraventricular and ventricular arrhythmias. Furosemide, a highly potent loop diuretic, is used to eliminate edema and promote diuresis. A thorough understanding of the applied pharmacology, dosage recommendations, toxicity, and practical considerations must be attained before these drugs can be used effectively.

Analgesic, hemodynamic and respiratory effects of caudal epidurally administered ropivacaine hydrochloride in mares

Objective To determine the analgesic, hemodynamic and respiratory effects, sedation and ataxia in mares of caudal epidural administration of ropivacaine hydrochloride solution. Study design Prospective, single-dose trial. Animals Ten healthy mares weighing from 475 to 565 kg. Methods Intravascular catheters and an epidural needle were placed after infiltration of the skin and subcutaneous tissues with 2% lidocaine. Ropivacaine (0.5%, 8 or 9 mL) was then injected epidurally at the fifth sacral or sacrococcygeal vertebrae, respectively. Analgesia was determined by lack of sensory perception to electrical stimulation (> 40 milliamps) and absence of response to needle pricks extending from coccyx to S2 dermatomes. Electrocardiogram, heart and respiratory rates, rectal temperature, arterial blood pressure, arterial acid-base (pH, standard bicarbonate and base excess), gas tensions (PO2, PCO2), PCV, oxyhemoglobin and total solids concentrations, and numerical scores of perineal analgesia, sedation (head drop), and ataxia (position of pelvic limbs) were determined before and during a 5-hour testing period. Analysis of variance (anova) with repeated measures was used to detect significant (p < 0.05) differences of mean values from baseline. Results Epidurally administered ropivacaine induced variable analgesia extending bilaterally from coccyx to S2 (three mares), coccyx to S3 (four mares), and coccyx to S4 (three mares), with minimal sedation, ataxia, and cardiovascular and respiratory disturbances of mares. Perineal analgesia was attained at 10 ± 4 minutes and lasted for 196 ±42 minutes (mean ± SD). Five mares demonstrated inadequate perineal analgesia, probably attributable to deviation of the spinal needle from the midline. They were successfully blocked with ropivacaine on another occasion. Epidural ropivacaine significantly reduced repiratory rates of mares and did not change other variables from baseline. Conclusions and clinical relevance Ropivacaine (0.5%, 8 mL 500 kg-1) can be administered caudal epidurally to produce prolonged (> 2.5 hours) bilateral perineal analgesia with minimal sedation, ataxia, and circulatory and respiratory disturbances in standing mares.

Chapter 23. Calcium Antagonists

Publisher Summary Calcium antagonists can be classified into two groups: calcium entry blockers and intracellular calcium antagonists. In most tissues, calcium is highly compartmentalized with ionic activities across cellular and intracellular membranes often differing by a factor of 1000 or more. The source of calcium for necessary and specific physiological functions cited above is either the extracellular compartments, that is, the basement membrane, the ground substance, or the extracellular fluids or the intracellular calcium storage pools, that is, mitochondria, endoplasmic reticulum, nucleus, inner aspect of the plasma membrane, and possibly secretory vesicles. The extracellular calcium, the intracellular calcium, or both (depending upon the tissue and the stimulus) are involved in initiating the physiological or pharmacological response. Although the inhibition of the slow inward calcium currently is a property common to all calcium entry blockers, most of these agents possess other major pharmacological properties that most assuredly contribute to their mechanisms of action. Thus, local anesthetics block the rapid inward sodium channel. Intracellular calcium antagonists interfere with the physiological functions of calcium by inhibiting the action or mobilization of intracellular calcium, or by enhancing the sequestration of this cation by intracellular organelles or its efflux from the cell. As therapeutic agents, calcium antagonists hold considerable promise particularly for the management of cardiovascular pathologies.

Effect of intravenous administration of lactated Ringer's solution or hetastarch for the treatment of isoflurane-induced hypotension in dogs

OBJECTIVE To determine the effect of IV administration of crystalloid (lactated Ringers solution [LRS]) or colloid (hetastarch) fluid on isoflurane-induced hypotension in dogs. ANIMALS 6 healthy Beagles. PROCEDURES On 3 occasions, each dog was anesthetized with propofol and isoflurane and instrumented with a thermodilution catheter (pulmonary artery). Following baseline assessments of hemodynamic variables, end-tidal isoflurane concentration was increased to achieve systolic arterial blood pressure (SABP) of 80 mm Hg. At that time (0 minutes), 1 of 3 IV treatments (no fluid, LRS [80 mL/kg/h], or hetastarch [80 mL/kg/h]) was initiated. Fluid administration continued until SABP was within 10% of baseline or to a maximum volume of 80 mL/kg (LRS) or 40 mL/kg (hetastarch). Hemodynamic variables were measured at intervals (0 through 120 minutes and additionally at 150 and 180 minutes in LRS- or hetastarch-treated dogs). Several clinicopathologic variables including total protein concentration, PCV, colloid osmotic pressure, and viscosity of blood were assessed at baseline and intervals thereafter (0 through 120 minutes). RESULTS Administration of 80 mL of LRS/kg did not increase SABP in any dog, whereas administration of <or= 40 mL of hetastarch/kg increased SABP in 4 of 6 dogs. Fluid administration increased cardiac index and decreased systemic vascular resistance. Compared with hetastarch treatment, administration of LRS decreased blood viscosity. Treatment with LRS decreased PCV and total protein concentration, whereas treatment with hetastarch increased colloid osmotic pressure. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that IV administration of hetastarch rather than LRS is recommended for the treatment of isoflurane-induced hypotension in dogs.

Effect of 50% and maximal inspired oxygen concentrations on respiratory variables in isoflurane-anesthetized horses

BackgroundThe purpose of this study was to compare the effects of 0.5 fraction of inspired oxygen (FiO2) and >0.95 FiO2 on pulmonary gas exchange, shunt fraction and oxygen delivery (DO2) in dorsally recumbent horses during inhalant anesthesia. The use of 0.5 FiO2 has the potential to reduce absorption atelectasis (compared to maximal FiO2) and augment alveolar oxygen (O2) tensions (compared to ambient air) thereby improving gas exchange and DO2. Our hypothesis was that 0.5 FiO2 would reduce ventilation-perfusion mismatching and increase the fraction of pulmonary blood flow that is oxygenated, thus improving arterial oxygen content and DO2.ResultsArterial partial pressures of O2 were significantly higher than preanesthetic levels at all times during anesthesia in the >0.95 FiO2 group. Arterial partial pressures of O2 did not change from preanesthetic levels in the 0.5 FiO2 group but were significantly lower than in the >0.95 FiO2 group from 15 to 90 min of anesthesia. Alveolar to arterial O2 tension difference was increased significantly in both groups during anesthesia compared to preanesthetic values. The alveolar to arterial O2 tension difference was significantly higher at all times in the >0.95 FiO2 group compared to the 0.5 FiO2 group. Oxygen delivery did not change from preanesthetic values in either group during anesthesia but was significantly lower than preanesthetic values 10 min after anesthesia in the 0.5 FiO2 group. Shunt fraction increased in both groups during anesthesia attaining statistical significance at varying times. Shunt fraction was significantly increased in both groups 10 min after anesthesia but was not different between groups. Alveolar dead space ventilation increased after 3 hr of anesthesia in both groups.ConclusionsReducing FiO2 did not change alveolar dead space ventilation or shunt fraction in dorsally recumbent, mechanically ventilated horses during 3 hr of isoflurane anesthesia. Reducing FiO2 in dorsally recumbent isoflurane anesthetized horses does not improve oxygenation or oxygen delivery.

Cardiorespiratory, gastrointestinal, and analgesic effects of morphine sulfate in conscious healthy horses

OBJECTIVE To compare the cardiorespiratory, gastrointestinal, analgesic, and behavioral effects between IV and IM administration of morphine in conscious horses with no signs of pain. ANIMALS 6 healthy adult horses. PROCEDURES Horses received saline (0.9% NaCl) solution (IM or IV) or morphine sulfate (0.05 and 0.1 mg/kg, IM or IV) in a randomized, masked crossover study design. The following variables were measured before and for 360 minutes after drug administration: heart and respiratory rates; systolic, diastolic, and mean arterial blood pressures; rectal temperature; arterial pH and blood gas variables; intestinal motility; and response to thermal and electrical noxious stimuli. Adverse effects and horse behavior were also recorded. Plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were measured via liquid chromatography-mass spectrometry. RESULTS No significant differences in any variable were evident after saline solution administration. Intravenous and IM administration of morphine resulted in minimal and short-term cardiorespiratory, intestinal motility, and behavioral changes. A decrease in gastrointestinal motility was detected 1 to 2 hours after IM administration of morphine at doses of 0.05 and 0.1 mg/kg and after IV administration of morphine at a dose of 0.1 mg/kg. Morphine administration yielded no change in any horses response to noxious stimuli. Both morphine-3-glucuronide and morphine-6-glucuronide were detected in plasma after IV and IM administration of morphine. CONCLUSIONS AND CLINICAL RELEVANCE Clinically relevant doses of morphine sulfate yielded minimal and short-term behavioral and intestinal motility effects in healthy horses with no signs of pain. Neither dose of morphine affected their response to a noxious stimulus.