Third‐Degree Atrioventricular Block in a Horse Secondary to Rattlesnake Envenomation

Abstract

A 4-year-old 400-kg Quarter Horse gelding was referred to the cardiology service at Colorado State University Veterinary Medical Center for evaluation of syncope and collapse 12 days after rattlesnake envenomation. The horse had been bitten on the nostril in a region where prairie (Crotalus viridis viridis) rattlesnakes are known to be endemic. Initial treatment by the referring veterinarian consisted of dexamethasone and furosemide on the day of the incident and procaine penicillin G and flunixin meglumine for 4 days. The horse's clinical signs improved initially, but it developed signs of abdominal pain 5 days after envenomation. The horse was treated with polyionic, isotonic fluids IV and flunixin meglumine for 3 days with no improvement. On day 8 after envenomation, because of worsening clinical signs, including abdominal pain, fever (104°F [40 °C]), persistent tachycardia (62–70 beats per minute [bpm]), and 1 episode of collapse, the horse was referred for further examination. Problems identified on physical examination at admission included tachycardia (52 bpm), dehydration (8%), and hypoperfusion (dark mucous membranes with a 3-second capillary refill time). Laboratory abnormalities included leukocytosis (19.0 × 103/L, reference range, 5.5–10.5 × 103/L), neutrophilia (16.5 × 103/L, reference range, 3.0–7.0 × 103/L), lymphopenia (1.0 × 103/L, reference range, 1.5–4.0 × 103/L), band neutrophilia (0.8 × 103/L, reference range, 0.0–0.1 × 103/L), hyperglycemia (359 mg/dL, reference range, 70–135 mg/dL), hyperlactatemia (8.0 mmol/L, reference range, 1.11–1.78 mmol/L), hypocalcemia (9.9 mg/dL, reference range, 10.5–13.5 mg/dL), hypomagnesemia (0.9 mg/dL, reference range, 1.3–2.5 mg/dL), hypokalemia (2.3 mEq/L, reference range, 2.5–4.6 mEq/L), hypochloremia (84 mEq/L, reference range, 95–108 mEq/L), and hyperphosphatemia (6.5 mg/dL, reference range, 1.9–4.6 mg/dL). Abnormalities in muscle and liver enzyme activities included creatinine kinase (26,852 U/L, reference range, 100–470 U/L), aspartate aminotransferase (2,735 U/L, reference range, 185–375 U/L), γ-glutamyl transferase (23 U/L, reference range, 7–20 U/L), and serum dehydrogenase (24 U/L, reference range, 0–12 U/L). A diagnosis of enteritis/proximal jejunitis was made based on results of abdominal ultrasound, rectal examination, abdominocentesis, and gastric decompression. A base-apex ECG performed by the emergency service was interpreted as ventricular tachycardia with atrioventricular (AV) dissociation. No further cardiac evaluation was performed at that time because the arrhythmia was suspected to be secondary to systemic illness (gastrointestinal disease, electrolyte derangements, or both). Initial treatments consisted of Normosol-R solutiona supplemented with potassium chlorideb (20 mEq/L), 23% calcium gluconatec (5.75 g/L), and magnesium sulfated (2 g/L) administered IV at 2 L/h, flunixin megluminee (0.25 mg/kg IV q8h), potassium penicillin Gf (22,000 U/kg IV q6h), gentamicing (6.6 mg/kg IV q24h), and 2% lidocaine hydrochlorideh administered IV at 0.05 mg/kg/min constant rate of infusion. Nasogastric decompression was performed every 2–4 hours until reflux was not obtained, approximately 36 hours later. The horse's electrolyte status, muscle enzymes, and clinical signs improved over the initial 4 days of treatment. On day 5 of hospitalization (12 days after envenomation), the gelding became acutely ataxic with progression to syncope and collapse. Cardiac auscultation following the collapse revealed an irregular rhythm with intermittent tachycardia (60 bpm). No murmur was ausculted and jugular pulsation was absent. A base-apex ECG revealed 3rd-degree atrioventricular block (AVB), evidenced by a lack of association between the P waves and the QRS complexes and an atrial rate (60 bpm) greater than the ventricular rate (30–38 bpm) (Fig 1). Subsequently, a 24-hour continuous ECG monitor with radiotelemetryi revealed multiple occurrences of ventricular asystole, up to 8.4-second duration, which were caused by complete AVB and inadequate ventricular escape (Fig 2). During these periods of asystole the horse showed no signs of altered behavior or decreased cardiac output. An increased serum cardiac troponin-I (cTnI)j concentration measured at admission (25.0 ng/mL; laboratory normal, <0.5 ng/mL; reported equine normal, <0.35 ng/mL1) suggested myocardial damage. Echocardiographic examination revealed neither cardiac abnormalities nor pericardial effusion. Base-apex ECG recorded from a 4-year-old Quarter Horse gelding with 3rd-degree atrioventricular conduction block. Note the lack of association between P waves (arrows) and QRS complexes. The atrial rate = 60 bpm and the ventricular rate = 38 bpm. Paper speed = 25 mm/s. Scale bar = 10 mm (0.4 seconds). bpm, beats per minute. Base-apex ECG from the same horse as in Fig 1 with 3rd-degree atrioventricular block progressing to ventricular asystole (>8.4 second) where identifiable P waves (arrows) are not conducted. Paper speed = 25 mm/s. Scale bar = 10 mm (0.4 seconds). Treatment with dexamethasonek (0.1 mg/kg IV q24h) was initiated, because the most common treatable cause of 3rd-degree AVB is inflammation in or around the AV node.2 Administration of flunixin meglumine, potassium penicillin, and gentamicin was continued as previously described. With the correction of electrolyte abnormalities, intravenous fluids were changed to nonsupplemented Normosol-R administered at 1 L/h. Treatment to address the conduction block included administration of atropine and dopamine. Ten milligrams of atropine sulfatel (0.02 mg/kg IV)3, 4 was initially administered to determine if a decrease in parasympathetic tone would improve conduction through the AV node.2 The rhythm changed from complete (3rd-degree) AVB to 2 : 1 2nd-degree block (Fig 3) and occasional 1st-degree AVB, indicating that atropine enhanced AV nodal conduction. Because of this response, dopamine HClm was subsequently infused at increasing doses (5, 7, and 10 μg/kg/min IV) to augment sympathetic tone. Continuous ECG monitoring showed improved AV conduction with conversion from 2 : 1 2nd-degree AVB to sinus rhythm with intermittent 1st- and 2nd-degree Mobitz Type 1 AVB (Fig 4). The pharmaceutical responses indicated the presence of some functional cells of the AV node and bundle of His. An intravenous constant rate infusion of dopamine was initiated at a rate of 5 μg/kg/min; however, the horse became extremely agitated and developed ventricular tachycardia (>120 bpm). When the dopamine was discontinued the horse became severely bradycardic (<20 bpm). Ultimately, a dopamine infusion of 2.5–3.75 μg/kg/min was used to prevent bradyarrhythmia without causing agitation. Base-apex ECG from the same horse after treatment with atropine sulfate 0.02 mg/kg, IV demonstrating 2 : 1 2nd-degree AVB with a regular P-R interval (0.18 second). Paper speed = 25 mm/s. Scale bar = 10 mm (0.4 seconds). Base-apex ECG from the same horse after treatment with dopamine HCl 10 μg/kg/min. The initial and terminal portions of the ECG strip show Mobitz type I (Wenckebach) 2nd-degree AVB with progressive prolongation of the P-R interval (0.16; 0.36 seconds) followed by nonconducted P waves (asterisk). Ventricular rate = 61 bpm. The intermediate portion of the ECG strip (3rd and 4th QRS complexes) shows 2 : 1 2nd-degree AVB with every other P wave (arrow) conducted. Nonconducted P waves are indicated by the asterisk. Ventricular rate = 40 bpm. Paper speed = 25 mm/s. Scale bar = 10 mm (0.4 seconds). bpm, beats per minute; AVB, atrioventricular block. Fourteen days after envenomation, the horse developed bilateral jugular pulsation. Bradyarrhythmia became increasingly difficult to manage as evidenced by 3rd-degree AVB with asystole and intermittent runs of tachycardia (60–86 bpm) despite titration of the dopamine infusion. The horse had an acute onset of unilateral forelimb lameness. An abbreviated lameness examination was performed, considering the horse's unstable condition, consisting of palpation and flexion of the limb and observation of gait. The examination revealed absence of digital pulsation, negative hoof tester response, no reaction to distal limb palpation, and absence of heat, swelling, or edema of the distal limb. A stiff gait and palpation of firm muscles of the shoulder region led to a presumptive diagnosis of microvascular ischemia of the muscles, but no additional diagnostics were performed. Additional clinical findings on day 14 included ataxia, depression, anorexia, fever (103.6°F [39.7 °C]), and hematuria (3+ blood on urinalysis). These findings prompted additional diagnostics, including an ultrasonographic examination of the abdomen, nasogastric decompression, abdominocentesis, a CBC, and serum biochemistry profile. The presence of increased abdominal fluid, amotile loops of small intestine, and gastric reflux suggested enteritis, potentially caused by ischemia, edema, or both of the intestinal wall. Significant hematologic findings included severe leukocytosis (30 × 103/μL, reference range 5.5–10.5 × 103/μL), mature neutrophilia (28.8 × 103/μL, reference range 3–7 × 103/μL), hypoproteinemia (5.2 g/dL, reference range 5.8–7.8 g/dL), and anemia (27%, reference range, 30–45%). Worsening clinical signs and hematological findings were consistent with myocarditis, severe systemic inflammation, and multi-organ failure. Widespread ischemia of the heart, skeletal muscles, urinary bladder, and gastrointestinal tract was likely, suggesting disseminated intravascular coagulation. Because of the horse's grave prognosis, it was euthanized and a postmortem examination was performed. Gross examination of the heart revealed widespread myocardial necrosis affecting 80% of the left and right ventricular free walls, atria, and the interatrial and interventricular septa. Necrotic regions had mottled areas of pallor alternating with hemorrhage and yellow gelatinous discoloration consistent with edema (5, 6). Multiple foci of hemorrhage extended along the endocardial surface of both ventricles (Fig 5). There was severe cardiac hypertrophy of the pectinate muscles of both atria and the papillary muscles of both ventricles. Approximately 1.5 L of serofibrinous pericardial effusion was present. Noncardiac postmortem findings included transmural petechial hemorrhages of the small and large intestines and the urinary bladder as well as necrosis and fibrosis of the lungs, liver, and kidneys. Cross sections of the right ventricular free wall from the same horse demonstrating myocardial pallor (white arrows) alternating with areas of hemorrhage (asterisk). Image of the left atrial chamber from the same horse illustrating yellow gelatinous discoloration (asterisk) of the myocardium and endocardium alternating with areas of hemorrhage (black arrow). Histologically, myocytes of both ventricles and the right atrium demonstrated varying stages of degeneration and necrosis. There was global and multifocal hemorrhage and necrosis with large aggregates of mixed inflammatory cells, necrotic debris, and fibrin (Fig 7). Necrosis and inflammation extended into and expanded the epicardium of the right ventricle. A thrombus occluded a medium-sized right atrial coronary artery. A systematic histologic examination of myocardium was completed using gross anatomical landmarks to locate the AV node and the bundle of His.5 The AV conduction system was completely effaced and obscured by necrosis and inflammation in the multiple sections examined. Microscopic image of the right ventricle from the same horse illustrating myocardial degeneration and loss with characteristic shrunken, hypereosinophilic, and fragmented myofibers (asterisk). Note replacement of myocardiocytes by abundant numbers of mixed inflammatory cells, fibrin, and necrotic debris (arrows). Hematoxylin and eosin. Scale bar = 200 μm. Pathologic examination indicated extensive, necrotizing, fibrinosuppurative myocarditis. Overall, the lesions in this horse were suggestive of global and extensive vasculitis, disseminated intravascular coagulopathy, and myocarditis secondary to rattlesnake venom toxicity. Multiple organs showed signs of petechial or ecchymotic hemorrhage and fibrosis. The degree of degeneration and necrosis of the heart and other organs suggests a widespread inflammatory response. Third-degree AVB is an uncommon and pathologic arrhythmia in horses, with few cases reported in the literature.6, 7 Impaired AV conduction is most often associated with inflammation or degeneration of the AV node.4 Slowed conduction can also occur as a result of myocardial or systemic disease, electrolyte abnormalities, drugs, or toxins.8 Third-degree AVB has been recognized transiently in horses after electrical cardioversion for the treatment of atrial fibrillation9 and was suspected as a congenital etiology in a Jerusalem donkey.7 Furthermore, it has been associated with halothane anesthesia in foals4, 10 and duodenitis/proximal jejunitis in adult horses.11 Although cardiotoxicity is a known sequela of rattlesnake envenomation in horses,12, 13 dogs,14 and humans,15, 16 to the authors' knowledge, there is only a single mention in the literature of venom-induced 3rd-degree AVB in equids. In a retrospective analysis of 32 cases, there was an individual horse that developed congestive heart failure and 3rd-degree AVB more than 6 months after envenomation, without further elaboration.13 More common venom-induced cardiac arrhythmias in horses include ventricular and supraventricular tachycardia, 2nd-degree AVB, and atrial fibrillation.13 Complete AVB subsequent to snake envenomation is also uncommon in other domestic species. Thirteen of 31 dogs (42%) with rattlesnake envenomation presented with or developed cardiac arrhythmias following envenomation, including ventricular premature contractions, ventricular tachycardia, or ventricular fibrillation, but not 3rd-degree AVB.14 Tachycardia is the only cardiac arrhythmia that has been reported in New World Camelids following rattlesnake bites.17 In humans, tachycardia, bradycardia, atrial fibrillation, 2nd-degree AVB, and myocardial infarction with sudden death have been recognized in association with rattlesnake envenomation18; however, 3rd-degree AVB is unusual.19 Whereas the mechanism of injury of rattlesnake venom on cardiomyocytes is poorly understood, extrapolation from scorpion and cobra envenomation supports a cardiotoxic effect. The venom of rattlesnakes, cobras, and scorpions is a mixture of proteins, polypeptides, and enzymes that cause necrosis and hemolysis.19 The enzymes function to paralyze the victim and begin tissue breakdown,20 whereas the nonenzymatic proteins include cardiotoxins, neurotoxins, and myotoxins.21 Upon envenomation, toxin-containing venom is injected into the victim, thereby causing both local and systemic effects. Administration of incremental doses of scorpion venom into rats produced all degrees of AVB, with the highest dose inducing 3rd-degree AVB,22 whereas cobra envenomation increased gene expression, including those that regulate the immune response, apoptosis, and ion transport.20 The genes affected were primarily associated with the heart, as compared with various other organs, suggesting that cobra venom is directly cardiotoxic. Furthermore, cobra venom contains cardiotoxic factors that induce the release of calcium ions from cardiac myocyte sarcoplasmic reticulum.23 Given the complex composition of rattlesnake venom, the effect on cardiomyocytes is likely multifactorial and may include massive releases of catecholamines, direct cardiotoxicity, cytokine effects, or a combination of these factors. Pharmacologic intervention can be used to diagnose and treat 3rd-degree AVB. Parasympathetic stimulation decreases the rate of automaticity of the SA node and slows conduction velocity through the AV node, thereby slowing transmission of impulses to the ventricles. Atropine, an anticholinergic agent, can be used to determine if conduction can be improved through inhibition of the parasympathetic tone.24 Another therapeutic approach for the management of AVB is to administer sympathomimetic drugs such as dopamine or dobutamine. Dopamine is a catecholamine that, at moderate doses (3–5 μg/kg/min), exerts positive ionotropy via β1-adrenergic receptors, thereby increasing contractility and cardiac output.4 Because AVB might result from prolonged conduction, high doses of dopamine (≥5 μg/kg/min) may eliminate the block by increasing AV nodal conductivity.4 It is unlikely that the horse described in this report experienced complete destruction of the AV conduction system, because treatment with atropine and dopamine reestablished conduction. In addition to their utility in the diagnosis and prognosis of bradyarrhythmias, catecholamines can be used to sustain a physiologic heart rate until cardiac pacing can be performed. Regardless of the underlying etiology, if complete AV block cannot be treated or eliminated and clinical signs are present as a result of the bradyarrhythmia, cardiac pacemaker implantation is indicated.6, 7 Permanent cardiac pacing has been successfully performed in a Jerusalem donkey7 and in adult horses.6, 25 Because of the overwhelming systemic inflammation and multiorgan failure evidenced in this horse, it was a poor candidate for transvenous pacing. However, this would be a reasonable treatment option for horses whose disease process is either less severe or whose arrhythmia is diagnosed earlier. Thus, clinicians may potentially consider pacemaker placement in horses with 3rd-degree AVB following rattlesnake envenomation for appropriate cases. Although complete AVB has been considered an uncommon sequela to rattlesnake envenomation, it may be that severe pathology is a prerequisite to the development of venom-induced 3rd-degree AVB. The extensive myocardial necrosis and inflammation observed in this horse were sufficient to induce complete AVB. The severity of disease following rattlesnake envenomation is dictated by a combination of factors responsible for the potency of rattlesnake venom. These include the age, species, and size of the rattlesnake; seasonality; time since the snake's last strike; location, depth, and number of bites; and the age, size, and health status of the victim.14, 19 If such widespread, systemic inflammation is a prerequisite for the development of 3rd-degree AVB, then early recognition of this bradyarrhythmia may be a useful negative prognostic indicator. Alternatively, 3rd-degree AVB may simply be an underrecognized consequence of snake envenomation. Potentially, horses that die acutely following a rattlesnake bite may succumb to 3rd-degree AVB without an antemortem diagnosis. Given the delayed onset of 3rd-degree AVB in this horse, it is possible that some horses that initially respond to treatment may later develop undiagnosed complete AVB. Whereas most often signs of cardiac disease are present within hours to days after envenomation, occasionally signs do not develop until several days or months later.13 Horses may be perceived to have recovered, but subsequently die of fatal arrhythmia. It has also been noted that rises in cTnI may be delayed up to 1 week after envenomation in horses (Gilliam, personal communication). Thus, close observation and follow-up evaluations of ECG and cTnI of horses known to be bitten by rattlesnakes, especially those with persistent tachycardia or bradycardia, are advised following the acute phase of envenomation. Furthermore, because it is possible to treat 3rd-degree AVB, early recognition of the arrhythmia may improve our survival rates following envenomation by identifying horses with bradycardia and potentially life-threatening 3rd-degree AVB before congestive heart failure or sudden death occurs. aNormosol-R, Abbott Laboratories, Chicago, IL bPotassium chloride, Abraxis, Schaumburg, IL c23% calcium gluconate, VedCo Inc, St Joseph, MO dMagnesium sulfate, American Regent Inc, Shirley, NY eFlunixin meglumine, Pravail, VetOne, MWI Veterinary Supply, Meridian, ID fPotassium penicillin G, Pfizerpen, Pfizer Inc, New York, NY gGentamicin sulfate, GentaVed 100, VedCo Inc hLidocaine hydrochloride 2%, VedCo Inc iDigital Patient Care Monitoring System, Spacelabs Healthcare, Issaquah, WA jCardiac Troponin I, University of Colorado Clinical Lab, Aurora, CO kDexamethasone, VetOne, Bimeda-MTC Animal Health Inc, Cambridge, ON, Canada lAtropine sulfate, VedCo Inc mDopamine HCl, Hospira Inc, Lake Forest, IL