Antiarrhythmic and Electrophysiologic Effects of Flecainide on Acutely Induced Atrial Fibrillation in Healthy Horses

Background

Only few pharmacologic compounds have been validated for treatment of atrial fibrillation (AF) in horses. Studies investigating the utility and safety of flecainide to treat AF in horses have produced conflicting results, and the antiarrhythmic mechanisms of flecainide are not fully understood.

Objectives

To study the potential of flecainide to terminate acutely induced AF of short duration (≥15 minutes), to examine flecainide‐induced changes in AF duration and AF vulnerability, and to investigate the in vivo effects of flecainide on right atrial effective refractory period, AF cycle length, and ventricular depolarization and repolarization.

Animals

Nine Standardbred horses. Eight received flecainide, 3 were used as time‐matched controls, 2 of which also received flecainide.

Methods

Prospective study. The antiarrhythmic and electrophysiologic effects of flecainide were based on 5 parameters: ability to terminate acute pacing‐induced AF (≥15 minutes), and drug‐induced changes in atrial effective refractory period, AF duration, AF vulnerability, and ventricular depolarization and repolarization times. Parameters were assessed at baseline and after flecainide by programmed electrical stimulation methods.

Results

Flecainide terminated all acutely induced AF episodes (n = 7); (AF duration, 21 ± 5 minutes) and significantly decreased the AF duration, but neither altered atrial effective refractory period nor AF vulnerability significantly. Ventricular repolarization time was prolonged between 8 and 20 minutes after initiation of flecainide infusion, but no ventricular arrhythmias were detected.

Conclusions and Clinical Importance

Flecainide had clear antiarrhythmic properties in terminating acute pacing‐induced AF, but showed no protective properties against immediate reinduction of AF. Flecainide caused temporary prolongation in the ventricular repolarization, which may be a proarrhythmic effect.     

Feasibility and clinical utility of transvenous intracardiac echocardiography in conscious,sedated horses

Introduction/objectivesIntracardiac echocardiography (ICE) is a method of obtaining echocardiographic images with a steerable ultrasound catheter placed within the heart via a venous or arterial approach. The objectives of this study were to assess the feasibility of a 5–10 MHz, 8 French, 90 cm ICE catheter to evaluate cardiac structures and function in standing, sedated horses, and describe standard views in this species.AnimalsTen apparently healthy horses weighing 458.1–618.2 kg from a university teaching herd.Materials and methodsEach horse had a physical examination, transthoracic echocardiography, and ICE performed through a 10 French introducer percutaneously placed in the right jugular vein in the proximal third of the neck with continuous ECG monitoring using telemetry.ResultsThree intracardiac echocardiography positions (cranial right atrium, mid right atrium, and right ventricle) with seven views were described with the associated 2D, pulse wave Doppler, continuous wave Doppler, color Doppler, and M-mode image acquisition standardized by referencing the intracardiac positions and common landmarks. The positions were confirmed with simultaneous transthoracic echocardiography. The procedure was well tolerated with only mild, occasional ventricular, and supraventricular arrhythmias that resolved with intracardiac echocardiography catheter repositioning.ConclusionsIntracardiac echocardiography is feasible, safe, and allows for the acquisition of diagnostic images in conscious, sedated horses.     

Effects of diltiazem on hemodynamic variables and ventricular function in healthy horses

Quinidine is effective for treatment of atrial fibrillation (AF) in horses, but often accelerates ventricular response rate. Diltiazem effectively controls heart rate response to AF in other species. This investigation determined the effects of diltiazem on cardiac rate and rhythm, left ventricular (LV) function, central hemodynamics, and peripheral blood flow in normal, standing, nonsedated horses. A dose-finding study was performed. Afterward, 8 healthy horses were treated with diltiazem IV every 30 minutes to achieve cumulative dosages of 0 (saline control), 1, 1.5, and 2 mg/kg. Plasma diltiazem concentration, heart rate and rhythm (by electrocardiography), LV function and central hemodynamics (by cardiac catheterization), LV dimensions (by echocardiography), and forelimb blood flow (by Doppler sonography) were determined during each treatment period. Diltiazem plasma concentrations between 390 and 910 ng/mL were achieved, with considerable variation among horses. Cardiac effects of diltiazem included intermittent depression of the sinus and atrioventricular (AV) nodes and mild impairment of systolic and diastolic LV function. Vascular effects of diltiazem included arterial vasodilatation, increased limb blood flow, and decreased systemic vascular resistance. Baroreceptor reflex-mediated sympathetic activation increased sinus node rate and presumably blunted the depressive effects of diltiazem on myocardial and nodal tissues. Two horses developed transient high-grade sinus arrest with severe systemic hypotension. Diltiazem appears relatively safe in healthy horses, but dosage may be limited by hypotension from vasodilatation and direct suppression of sinus node discharge. Because of its inhibitory effects on AV nodal conduction, diltiazem may prove useful for heart rate control in horses with AF.     

Effects of acute gastric distention and recovery on tendency for ventricular arrhythmia in dogs

The gastric distention-volvulus (GDV) syndrome occurs commonly in large-breed dogs and may prove fatal in 15-68% of cases. Approximately 43% of cases with gastric distention (GD) or volvulus develop cardiac arrhythmias that can contribute to mortality. Most of these arrhythmias are ventricular in origin and ventricular fibrillation (VF) may be the cause of death. This study used an iatrogenic model of acute GD to investigate the prevalence of ventricular arrhythmias during acute GD and its recovery, if programmed electrical stimulation (PES) may uncover tendency to VF, if the Q-T interval corrected for heart rate (Q-Tc) of the electrocardiogram (ECG) predicts tendency to VF, and if hemodynamic changes predate VF. Eleven beagles, anesthetized with morphine and alpha-chloralose, and instrumented so that vascular pressures, cardiac output, and PES could be recorded, were used. Five were unperturbed, whereas acute GD to a pressure of 30 mm Hg for 1.5 hours was produced in 6 others. The results were as follows. No dogs with GD developed spontaneously occurring arrhythmias. VF was produced in no dogs by conventional PES, but occurred in all dogs (P < .05) with GD and none of the controls, using accelerated ventricular pacing. The Q-Tc interval of the ECG prolonged minimally in dogs with GD, and shortened (P < .05) in controls. Some hemodynamic changes did predate VF. In conclusion, dogs with acute GD have a tendency for VF, which may be uncovered by accelerated PES. The mechanism for the vulnerability to arrhythmia with GD is unknown.     

Sedative and antinociceptive effects of different combinations of detomidine and methadone in standing horses

Objective

To evaluate intravenous (IV) detomidine with methadone in horses to identify a combination which provides sedation and antinociception without adverse effects.

Thermal,mechanical and electrical stimuli in antinociceptive studies in standing horses: an update

ObjectiveTo perform a literature review of the thermal and mechanical antinociceptive devices used in pharmacological studies in standing horses published after 2011 (2012–2019). To complete a full literature review about electrical stimulation used for evaluation in similar studies.Databases usedPubMed, Google Scholar and Web of Science.ConclusionsA high level of standardization has been reached in antinociceptive studies in standing horses using thermal and mechanical stimuli in most recent years. Commercially available testing devices to deliver thermal, mechanical and electrical stimuli, with observation of aversive responses to these stimuli, are reliable, sensitive and specific. For electrical stimulus testing, there is evidence that the resistance between the electrodes should be measured and should not exceed 3 kΩ to guarantee consistent and reproducible stimuli. The specific analysis of electromyographic activity after an electrical stimulus provides more detailed information about the neurons stimulated.     

Influence of valvular insufficiency and recurrent airway obstruction on haemodynamics and therapy in warmblood horses with atrial fibrillation

The aim of this study was to investigate the potential haemodynamic effects of valvular insufficiency and recurrent airway obstruction (RAO) in horses with atrial fibrillation (AF). Therefore in ten healthy horses (group 1) and 40 horses with AF a clinical examination, a lung examination, echocardiography and right heart catheterization for measurement of intracardic and pulmonary pressures were performed. According to the clinical findings the horses with AF were subdivided into 4 groups (group 2: AF; group 3: AF/valvular insufficiency; group 4: AF/RAO; group 5: AF/valvular insufficiency/RAO). Most of the horses of group 3 and 5 suffered from two valvular insufficiencies (mitral and tricuspid valve insufficiency: n=11, mitral and aortic valve insufficiency: n=2). The remaining horses showed a single mitral (n=6), tricuspid (n=2) or aortic valve insufficiency (n=1) or more than two valvular insufficiencies (n=4). In group 2 right ventricular mean pressure (RVPm) was higher than in group 1 and 4 (P<0.025); diastolic right ventricular pressure was higher than in group 1; PWP was higher than in group 1 and group 4; PDP was lower compared to group1. Compared to group1 in group 3 left atrial diameter (LA) was greater; the PAPs was higher and the PDP lower (P<0.05). In group 4 RVPm and PWP was lower compared to group 2. In group 5 LA, fractional shortening and diastolic left ventricular diameter were greater, PWP and PAPs were higher and PDP lower compared to group1. Twenty six of the 40 horses with AF (65%) were treated. Successful cardioversion to sinus rhythm occurred in 15 horses (58%). Therapy was successful in 50% of the treated horses of group 2 and 3, in 67% of the treated horses of group 4 and in 63% of the treated horses in group 5. In conclusion the presence of valvular insufficiency or RAO influences the haemodynamics of horses with AF.     

Concentrations of ionized and total magnesium and calcium in healthy horses: effects of age, pregnancy, lactation, pH and sample type

Magnesium (Mg) and calcium (Ca) are the main divalent cations in the body. The free ionized fraction is the physiologically active form of both Mg and Ca. As ion-selective-electrode (ISE) analyzers are becoming widely used in veterinary practice it will be useful to establish reference intervals for horses. In the present study, reference intervals were established for ionized, total and the ratio of the ionized to total Mg and Ca concentrations in four horse groups: adults, neonatal foals, and pregnant and lactating mares, as well as in three sample types, whole blood, plasma and serum, using an ISE-analyzer. Sample pH effect was assessed.Concentration differences in both total and ionized cations were recorded for some measures between horse groups and different sample types. The most significant differences were recorded between neonatal foals and other groups. These results demonstrate the need to use specific reference intervals for horses of different physiologic status and in specific sample types.     

Acute clinical, hematologic, serologic, and polymerase chain reaction findings in horses experimentally infected with a European strain of Anaplasma phagocytophilum

Six horses were experimentally infected by administration of horse blood containing a Swedish strain of Anaplasma phagocytophilum. The polymerase chain reaction (PCR) signal was consistently detected 2-3 days before appearance of clinical signs and persisted 4-9 days beyond abatement of clinical signs, whereas diagnostic inclusion bodies were 1st noted on average 2.6 +/- 1.5 (SD) days after onset of fever. Clinical signs and hematologic changes were largely indistinguishable from those previously reported for diseases caused by A phagocytophilum (formerly Ehrlichia equi--"Californian agent") and the human-derived human granulocytic ehrlichiosis agent. Horses 1st demonstrated antibody response 12-16 days after inoculation, 2 cases of which were still febrile, and serotiters rapidly peaked within 3-7 days of clinical illness. One horse died during the acute stage of disease, but initial clinical signs and hematologic changes were similar to those of other infected horses. This report shows that, despite minor genetic differences, a European equine-derived strain of A. phagocytophilum may be similar in pathogenicity to the Californian agent. The PCR used holds promise to widen the diagnostic window and would also be diagnostic during the initial days of clinical disease when inclusions in neutrophils in blood smears are not yet apparent.     

Assessment of platelet function in horses: ultrastructure, flow cytometry, and perfusion techniques

We studied equine platelet function and activation using ultrastructural examination, flow cytometry, and perfusion. The main aim of the study was to evaluate hemostatic mechanisms in horses using these techniques. Ultrastructural observations were done on resting and activated platelets. Flow cytometry was used to evaluate binding of antibodies to major platelet glycoproteins (GPIIb-IIIa, GPIV, and GPIb) and activation-dependent antigens (P-selectin and lysosomal integral membrane protein [LIMP]). Perfusion techniques were used to evaluate the interaction between platelets and damaged subendothelium. Aggregation experiments were done to identify the best agonists for flow cytometry. Ultrastructural observations confirmed that equine platelets lack a developed open canalicular system and that release of granule contents occurs by fusion of adjacent granule membranes that ultimately connect with external membranes. Flow cytometry identified a 2-fold increase in binding of antibodies against GPIIb-IIIa and GPIV after activation. Binding of antibodies against P-selectin and LIMP increased from 2.12 and 1.74% to 15.5 and 11.6%, respectively, in response to thrombin and to 21.86 and 10.50%, respectively, in response to collagen. Annexin V binding increased moderately after activation. Perfusion experiments with citrated blood indicated that equine platelets react more strongly to subendothelium than do human platelets. When blood was anticoagulated with low molecular weight heparin, a marked impairment of platelet interactions was observed. In conclusion, although some differences were observed between human and equine platelet function, some techniques currently used to assess human platelet function may be useful to assess equine platelets.     

Hormonal, metabolic and physiological effects of laparoscopic surgery using a detomidine-buprenorphine combination in standing horses

Objective To assess the hormonal, metabolic and physiological effects of laparascopic surgery performed under a sedative analgesic combination of detomidine and buprenorphine in standing horses. Study design Prospective study. Animals Eight healthy adult Dutch Warmblood horses and five healthy adult ponies undergoing laparoscopy were studied. Five healthy adult horses not undergoing laparoscopy were used as a control group. Methods The sedative effect of an initial detomidine and buprenorphine injection was maintained using a continuous infusion of detomidine alone. The heart and respiratory rate, arterial blood pH and arterial oxygen and carbon dioxide tensions were monitored, while blood samples were taken for the measurement of glucose, lactate, cortisol, insulin and nonesterified fatty acids (NEFA). The same variables were monitored in a control group of horses which were sedated, but which did not undergo surgery. At the end of the sedation period the effects of detomidine were antagonized using atipamezole. Results The protocol provided suitable conditions for standing laparoscopy in horses. Laparoscopy induced obvious metabolic and endocrine responses which, with the exception of NEFA values, were not significantly different from changes found in the control group. While atipamezole did not produce detectable adverse effects, it is possible that anatagonism may not be essential. Conclusions The technique described reliably produces adequate sedation and analgesia for laparoscopic procedures. The level of sedation/analgesia was controlled by decreasing or increasing the infusion rate. Antagonism of the effects of detomidine may not be necessary in all cases.     

Anti‐nociceptive and sedative effects of romifidine,tramadol and their combination administered intravenously slowly in ponies

ObjectiveTo evaluate the anti-nociceptive and sedative effects of slow intravenous (IV) injection of tramadol, romifidine, or a combination of both drugs in ponies.Study designWithin-subject blinded.AnimalsTwenty ponies (seven male, 13 female, weighing mean ± SD 268.0 ± 128 kg).MethodsOn separate occasions, each pony received one of the following three treatments IV; romifidine 50 μg kg⁻ (R) tramadol 3 mg kg⁻¹ given over 15 minutes (T) or tramadol 3 mg kg⁻¹followed by romifidine 50 μg kg⁻¹ (RT). Physiologic parameters and caecal borborygmi (CB) were measured and sedation and response to electrical stimulation of the coronary band assessed before and up to 120 minutes following drugs administration. Results were analyzed using the Friedman’s test and 2 way anova as relevant.ResultsWhen compared to baseline, heart (HR, beats minute⁻¹) and respiratory rates (f_R, breaths minute⁻¹) increased with treatment T (highest mean ± SD, HR 43 ± 1; f_R 33 ± 2) and decreased with R (lowest HR 29 ± 1 and f_R 10 ± 4) and RT (lowest HR 32 ± 1 and f_R 9 ± 3). There were no changes in other measured physiological variables. The height of head from the ground was lower following treatments R and TR than T. There was slight ataxia with all three treatments. No excitatory behavioural effects were observed. The response to electrical stimulation was reduced for a prolonged period relative to baseline following all three treatments, the effect being significantly greatest with treatment RT.ConclusionTramadol combined with romifidine at the stated doses proved an effective sedative and anti-nociceptive combination in ponies, with no unacceptable behavioural or physiologic side effects.Clinical relevanceSlow controlled administration of tramadol should reduce the occurrence of adverse behavioural side effects.     

Preliminary evaluation of the effects of a 1:1 inspiratory-to-expiratory ratio in anesthetized and ventilated horses

ObjectiveTo describe some cardiorespiratory effects of an inspiratory-to-expiratory (IE) ratio of 1:1 compared with 1:3 in ventilated horses in dorsal recumbency.Study designRandomized crossover experimental study.AnimalsA total of eight anesthetized horses, with 444 (330–485) kg body weight [median (range)].MethodsHorses were ventilated in dorsal recumbency with a tidal volume of 15 mL kg^–1 and a respiratory rate of 8 breaths minute^–1, and IE ratios of 1:1 (IE1:1) and 1:3 (IE1:3) in random order, each for 25 minutes after applying a recruitment maneuver. Spirometry, arterial blood gases and dobutamine requirements were recorded in all horses during each treatment. Electrical impedance tomography (EIT) data were recorded in four horses and used to generate functional EIT variables including regional ventilation delay index (RVD), a measure of speed of lung inflation, and end-expiratory lung impedance (EELI), an indicator of functional residual capacity (FRC). Results were assessed with linear and generalized linear mixed models.ResultsCompared with treatment IE1:3, horses ventilated with treatment IE1:1 had higher mean airway pressures and respiratory system compliance (p < 0.014), while peak, end-inspiratory and driving airway pressures were lower (p < 0.001). No differences in arterial oxygenation or dobutamine requirements were observed. PaCO₂ was lower in treatment IE1:1 (p = 0.039). Treatment IE1:1 resulted in lower RVD (p < 0.002) and higher EELI (p = 0.023) than treatment IE1:3.Conclusions and clinical relevanceThese results suggest that IE1:1 improved respiratory system mechanics and alveolar ventilation compared with IE1:3, whereas oxygenation and dobutamine requirements were unchanged, although differences were small. In the four horses where EIT was evaluated, IE1:1 led to a faster inflation rate of the lung, possibly the result of increased FRC. The clinical relevance of these findings needs to be further investigated.     

The effects of detomidine, romifidine or acepromazine on echocardiographic measurements and cardiac function in normal horses

OBJECTIVE: To evaluate by echo- and electrocardiography the cardiac effects of sedation with detomidine hydrochloride, romifidine hydrochloride or acepromazine maleate in horses. STUDY DESIGN: An experimental study using a cross-over design without randomization. ANIMALS: Eight clinically normal Standardbred trotters. MATERIALS AND METHODS: Echocardiographic examinations (two-dimensional, guided M-mode and colour Doppler) were recorded on five different days. Heart rate (HR) and standard limb lead electrocardiograms were also obtained. Subsequently, horses were sedated with detomidine (0.01 mg kg(-1)), romifidine (0.04 mg kg(-1)) or acepromazine (0.1 mg kg(-1)) administered intravenously and all examinations repeated. RESULTS: Heart rate before treatment with the three drugs did not differ significantly (p = 0.98). Both detomidine and romifidine induced a significant decrease (p < 0.001) in HR during the first 25 minutes after sedation; while acepromazine had a varying effect on HR. For detomidine, there was a significant increase in LVIDd (left ventricular internal diameter in diastole; p = 0.034) and LVIDs (left ventricular internal diameter in systole; p < 0.001). In addition, a significant decrease was found in IVSs (the interventricular septum in systole; p < 0.001), LVFWs (the left ventricular free wall in systole; p = 0.002) and FS% (fractional shortening; p < 0.001). The frequency of pulmonary regurgitation was increased significantly (p < 0.001). Romifidine induced a significant increase in LVIDs (p < 0.001) and a significant decrease in IVSs (p < 0.001) and FS% (p = 0.002). Acepromazine had no significant effect upon any of the measured values. CONCLUSIONS: and clinical relevance The results indicate that sedation of horses with detomidine and to a lesser extent romifidine at the doses given in this study has a significant effect on heart function, echocardiographic measurements of heart dimensions and the occurrence of valvular regurgitation. Although the clinical significance of these results may be minimal, the potential effects of sedative drugs should be taken into account when echocardiographic variables are interpreted in clinical cases.     

Caudal epidural co-administration of methadone and morphine in horses: An evaluation of analgesic properties and effects on locomotor function,mentation and physical examination parameters

Caudal epidural analgesia is a well-established therapeutic modality for pain alleviation in horses. Additionally, epidural analgesia could potentially be a complementary diagnostic tool for confirmation of pain-related conditions in horses presenting with nonspecific signs of poor performance or rideability issues. To use the epidural as a diagnostic tool, the administered medications should provide efficient analgesia without accompanying adverse effects. Therefore, the objectives of the current study were to evaluate the analgesic properties and effects on locomotor function, mentation and physical examination parameters of caudal epidural co-administration of methadone and morphine in horses. Five mares received a caudal epidural injection of 0.1 mg/kg bwt methadone and 0.1 mg/kg bwt morphine diluted to a total volume of 4.4 mL/100 kg. Before and several times thereafter, horses were subjected to mechanical nociceptive threshold evaluation, physical examination, assessment of mentation and locomotor function examination. Horses were assigned ataxia scores (0–4) by a group of inexperienced raters (three senior-year veterinary students) and a group of experienced raters (two board-certified internal medicine specialists) that assessed the locomotor examinations either live or video-based. The epidural co-administration of methadone and morphine resulted in clinically relevant and statistically significant increases of horses’ tolerance to mechanical noxious stimuli at the coccygeal, perineal, sacral, lumbar and thoracic regions. Analgesia was evident after 4.4 h and lasted at least 5 h. Regional differences in the onset of analgesia reflected a cranial spread of the analgesic solution. No horses showed signs of gait disturbances; the overall median ataxia score was 0 at all times; and the average difference in scores between two randomly selected raters for a random horse at a random time point was 0.377 indicating high inter-rater agreement. There were no adverse changes of mentation and physical examination parameters. Observed side effects included signs of decreased frequency of defaecation, generalised sweating, and pruritus.     

Equine castration: review of anatomy, approaches, techniques and complications in normal, cryptorchid and monorchid horses

Complications associated with equine castration are the most common cause of malpractice claims against equine practitioners in North America. An understanding of the embryological development and surgical anatomy is essential to differentiate abnormal from normal structures and to minimise complications. Castration of the normal horse can be performed using sedation and regional anaesthesia while the horse is standing, or under general anaesthesia when it is recumbent. Castration of cryptorchid horses is best performed under general anaesthesia at a surgical facility. Techniques for castration include open, closed and half-closed techniques. Failure of left and right testicles to descend occurs with nearly equal frequency, however, the left testicle is found in the abdomen in 75% of cryptorchid horses compared to 42% of right testicles. Bilateral cryptorchid and monorchid horses are uncommon. Surgical approaches described for the castration of cryptorchid horses include an inguinal approach with or without retrieval of the scrotal ligament, a parainguinal approach, or less commonly a suprapubic paramedian or flank approach. Laparoscopic castration of cryptorchid horses has recently been described but the technique has limited application in practice at this time. A definitive diagnosis of monorchidism can only be made after surgical exploration of the abdomen, removal of the normal testis and hormonal testing. Hormonal assays reported to be useful include analysis of basal plasma or serum testosterone or oestrone sulphate concentrations, testosterone concentrations following hCG stimulation, and faecal oestrone sulphate concentrations. Reported complications of castration include postoperative swelling, excessive haemorrhage, eventration, funiculitis, peritonitis, hydrocele, penile damage and continued stallion-like behaviour.