Temporary transvenous cardiac pacing in a dog with diltiazem intoxication

Journal of Veterinary Emergency and Critical Care 18(1) 2008, pp 75–80 Temporary transvenous cardiac pacing in a dogwith diltiazem intoxication Rebecca S. Syring, DVM, DACVECC, Merilee F. Costello, DVM, DACVECC and Robert H.
Poppenga, DVM, PhD, DABVT Objective: This case report presents the clinical findings of a dog with diltiazem intoxication and theutilization of temporary transvenous pacing for management of high-grade second-degree atrioventricular(AV) block with associated bradycardia and hypotension.
Case summary: A nine-year-old spayed female Basset Hound, who ingested between 95 and 109 mg/kg ofsustained-release diltiazem exhibited clinical signs of cardiac arrhythmias, bradycardia, hypotension, mentaldepression and gastrointestinal (GI) upset. Bradycardia was present initially, then was followed by high-gradesecond-degree AV block with ventricular escape. Traditional medications to treat calcium channel blocker(CCB) intoxication, including atropine, calcium gluconate, dopamine and glucagon were initially successful inmanaging the cardiac rhythm disturbances and hypotension. Twenty-two hours post-ingestion, however, thedog became refractory to these medications following sedation for GI decontamination and a temporarytransvenous pacemaker was placed. The dog was paced for 19 hours. Transvenous pacing effectivelyincreased heart rate, which increased blood pressure into an acceptable range. The dog was successfullydischarged from the hospital following treatment.
New or unique information provided: The use of a temporary pacemaker should be considered anacceptable treatment for bradycardia, AV block and hypotension associated with CCB intoxication whenconventional medical therapy fails.
(J Vet Emerg Crit Care 2008; 18(1): 75–80) doi: 10.1111/j.1476-4431.2007.00269.x Keywords: AV block, bradycardia, calcium channel antagonist, calcium channel blocker, hypotension, pace-maker contained 300 mg sustained-release diltiazem cap-sules.b The owners estimated that the dog had ingest- ed 7–8 capsules (95–109 mg/kg). The dog had no overt A nine-year-old spayed female Basset Hound, weigh- abnormal clinical signs at that time and she ate a meal ing 22 kg, was referred for treatment following inges- shortly thereafter. One and one-half hours after the tion of the owner’s diltiazem. This dog had been owners noted the ingestion, the dog was let outside into diagnosed with unilateral laryngeal paralysis and the fenced backyard where she was found a few min- pneumonia based upon a positive transtracheal wash utes later, collapsed and unresponsive. She was taken culture one month previously, for which she was immediately to the local emergency veterinary hospital.
receiving oral enrofloxacina therapy.
At presentation to the local veterinarian, she was Four hours before referral, the owners returned home laterally recumbent and bradycardic (heart rate range to find that the dog had chewed open a pill vial that 30–50 b.p.m.). Intravenous (IV) isotonic crystalloidsolution (rate unknown) and atropine (0.01 mg/kg, From the Section of Critical Care, Department of Clinical Studies – IV) were administered. After noting no response to Philadelphia, School of Veterinary Medicine, University of Pennsylvania, the initial dose of atropine, a second dose (0.01 mg/kg, Philadelphia, PA (Syring, Costello) and California Animal Health and FoodSafety Laboratory, School of Veterinary Medicine, University of California IV) of atropine was administered, wherein the heart rate normalized and increased to 100 b.p.m. At that Address correspondence and reprint requests to: time, an electrocardiogram (ECG) revealed second- Dr. Rebecca S. Syring, Room 2066, VHUP, 3900 Delancey Street, Philadel- degree atrioventricular (AV) block with a ventricular phia, PA 19104-6010.
E-mail resyring@vet.upenn.edu escape rhythm. Calcium gluconate (22.7 mg/kg, IV) & Veterinary Emergency and Critical Care Society 2008 was administered over 10–15 minutes. Following this An IV bolus of glucagoni (0.04 mg/kg) was admin- treatment, the heart rate increased to approximately istered. Within five minutes of administration, the car- 160–180 b.p.m., and the dog was referred for ongoing diac rhythm converted to a normal sinus rhythm and the heart rate increased to 130 b.p.m. With this change At presentation to the emergency room, the dog in heart rate and rhythm, the mean arterial blood pres- was mentally dull and recumbent. The heart rate was sure increased to 89 mmHg. As there was a positive bradycardic (50 b.p.m.) with adequate peripheral puls- response to the glucagon bolus, a glucagon CRI es. The mucous membranes were pink with a capillary was initiated at 0.04 mg/kg/hr because glucagon has refill time o2 seconds. The respiratory rate and effort only a 3–6-minute duration of action when given as were normal, with notable inspiratory stridor. Abdom- inal palpation revealed a tense abdomen and elicited An arterial blood gas was obtained that revealed unproductive retching. No other abnormalities were significant hypoxia (PaO2 5 58 mmHg, at an inspired found on the remainder of the physical examination.
oxygen concentration [FiO2] of 0.21). Radiographs Emergency blood screening revealed hemoconcen- revealed marked alveolar infiltrates in the right crani- tration (PCV 60%) but no other significant abnormal- al and middle lung lobes, consistent with aspiration ities. Second-degree AV block with a junctional rhythm pneumonia. Decreased gastric transit time was also and occasional ventricular escape beats persisted on the present since the ingesta, which had been noted on ECG. Arterial blood pressure was not measured at the radiographs 12 hours earlier, was still visible in the time of initial presentation. The only notable finding on stomach. Metoclopramidej (1 mg/kg/day, CRI) and abdominal radiographs was a distended stomach con- ranitidinek (1 mg/kg, IV, q 12 h) were instituted for signs of decreased gastric motility.
An IV balanced electrolyte solutionc was adminis- Gastrointestinal (GI) decontamination (approximate- tered at 4 mL/kg/hr. One dose of prochlorperazined ly 20 hours post-ingestion of diltiazem) was thought (0.2 mg/kg, IM) was administered for persistent to be worthwhile because the ingested drug was a unproductive retching, and enrofloxacina (10 mg/kg, sustained-release formulation, there was evidence of IV, q 24 h) was continued as prescribed previously for delayed gastric emptying, and the dog had not vomited ongoing treatment of bacterial pneumonia.
productively (despite retching). Once the aforemen- Within two hours of presentation, the blood pressure tioned drugs provided a more stable heart rate, rhythm was judged to be inadequate based on subjective palpa- and blood pressure, general anesthesia was induced to tion of arterial pulses. At that time, indirect measure of perform gastric decontamination with a protected air- arterial blood pressure by Dopplere was attempted and way given the dog’s decreased mentation and history was determined to be hypotensive. A constant rate infu- of laryngeal paralysis. General anesthesia was induced sion (CRI) of dopaminef was instituted at 5 mg/kg/min.
with etomidatel (0.3 mg/kg, IV) and midazolamm At this dose, systolic blood pressure increased to (0.5 mg/kg, IV) and maintained with intermittent 50 mmHg. A 500 mL IV bolus of a balanced electrolyte boluses of etomidate (0.2 mg/kg, IV to effect). Gastric solutionc was administered over 30 minutes in an effort lavage was performed and activated charcoaln with to improve perfusion. The dopamine dose was titrated magnesium citrate was administered via a large bore upwards from 5 to 10 mg/kg/min as needed to main- orogastric tube. At that time an endotracheal lavage tain systolic blood pressure as measured by Doppler was performed and ticarcillin/clavulanateo (50 mg/kg, above 100 mmHg. During the following eight hours, the IV, q 6 h) was added to increase the antimicrobial spec- dog’s heart rate ranged from 50 to 100 b.p.m. An ad- trum pending results of culture and sensitivity testing.
ditional dose of atropineg (0.02 mg/kg, IV) was admin- Initially, the glucagon CRI was effective at maintain- istered; however, the heart rate never exceeded ing a normal heart rate, rhythm and blood pressure, but during general anesthesia, the dog gradually became The following morning the dog was transferred to more refractory to this therapy. First-degree AV block the intensive care unit. She remained mentally dull and returned, which progressed to a high-grade second-de- recumbent. The dog was placed on a continuous gree AV block. At this time the heart rate remained ECG, which revealed persistent high-grade second- between 45 and 50 b.p.m. with a MAP of 55 mmHg.
degree AV block with ventricular escape beats. A 11 in: Repeated bolus doses of atropine (0.02 mg/kg, IV), 10% 22-gauge catheterh was percutaneously placed in a calcium gluconate (9–13.6 mL/kg, IV) and glucagon dorsal pedal artery for continuous direct arterial (0.08 mg/kg, IV) were administered but found to have blood pressure monitoring. Despite 10 mg/kg/min of limited to no effect. Progressive bradycardia and dopamine, she remained hypotensive, with a mean ar- refractory hypotension that persisted approximately one hour beyond the last dose of etomidate were the & Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2007.00269.x Transvenous pacing for diltiazem toxicity primary reasons contributing to the decision to place a increased in parallel with the frequency of their use.3 In human medicine, 9650 cases of CCB ingestion were re- A 6 Fr, 5.5 cm introducerp was inserted percutane- ported in 2003. Of these reported cases, 1481 were ously into the right jugular vein, through which a 6 Fr deemed moderate to severe intoxications, with 57 bipolar pacing wireq was inserted into the right ventri- deaths reported.4 In veterinary medicine, 390 cases of cle. Ventricular capture was successful without the CCB overdose were reported to the American Society need for fluoroscopic guidance. The pacing wire was for the Prevention of Cruelty to Animals National An- attached to an external pulse generatorr and pro- imal Poison Control Center between 1995 and 2000.5 grammed to pace the ventricle at a heart rate of CCBs act at voltage sensitive slow L-type calcium 80 b.p.m. in a ventricular demand mode (VVI). At this channels, inhibiting intracellular influx of calcium.
heart rate, the mean arterial blood pressure was be- Limiting intracellular calcium inhibits both actin–myo- sin cross-linking in blood vessels and excitation–con- Nineteen hours after placement of the pacemaker (41 traction coupling in the myocardium. In addition, hours post-ingestion) the spontaneous heart rate and inhibition of intracellular calcium suppresses automati- rhythm had returned to normal, such that the pace- city at the sinoatrial and AV nodes.6–8 These actions maker was suppressed from firing. The dog was dis- result in varying degrees of vasodilation, negative ino- connected from the external pulse generator and, when tropy, decreased automaticity and suppressed AV con- it was determined that the cardiac rhythm was stable, duction, depending upon the type of CCB used.8 the pacing wire was removed. Throughout the duration Diltiazem, a CCB in the benzothiazepine family, is of pacing and after discontinuation of transvenous pac- used clinically in both human and veterinary medicine.
ing, no additional medical therapy was needed to The benzothiazepine family is reported to have pro- maintain heart rate, rhythm or blood pressure.
found depressant effects on cardiac automaticity and Stored serum samples were submitted for evaluation conduction and moderate effects on vascular tone.6–8 of diltiazem concentrations by high-performance liquid The dog in this report ingested between 95 and chromatography.2 The samples had been collected ap- 109 mg/kg of a sustained-release formulation of diltia- proximately 18 and 48 hours after the latest possible zem. The therapeutic dose published for short-acting exposure to the diltiazem (time 0 being the time when diltiazem in the canine species ranges from 0.5 to the owners found the empty pill vial at home).
1.5 mg/kg, orally, every eight hours.9 There is little Diltiazem was quantified at 1300 ng/mL (1.30 p.p.m.) data regarding the use of sustained-release formula- in the sample 18 hours post-exposure but was unde- tions in dogs and it is important to recognize that dos- tectable in the 48-hour sample. The lower limit of de- ing varies depending on the formulation of the tection for this assay was 250 ng/mL (0.25 p.p.m.).
sustained-release product. For instance, a dosage of The dog remained hospitalized for four days after 1.5–6.0 mg/kg every 12–24 hours has been recommend- discontinuation of transvenous pacing (6 days after the ed in dogs for one extended-release formulation10,t but initial intoxication), primarily for supportive oxygen the dosage recommended for sustained-release prod- therapy and medical management of aspiration pneu- uctu ingested by the dog reported here is 10 mg/kg, monia. Escherichia coli sensitive to cefixime was cultured orally, once daily. Based upon this dose, the dog in this and the dog was discharged on oral cefpodoximes report ingested at least 9.5 times the lower end of the (10 mg/kg, PO, q 12 h). At a follow-up examination therapeutic dose. The lowest reported oral LD50 for two weeks after discharge, the dog was doing well and diltiazem is 50 mg/kg in dogs.11,v In a retrospective there was radiographic resolution of the pneumonia.
human study of CCB intoxication, the mean toxic doseof diltiazem was 2167 mg (approximately 30 mg/kg).
The study did not differentiate short-acting from sus- tained-release formulations when reporting toxic doses; Calcium channel blockers (CCBs) are common medica- however, almost half of the intoxications reported in- tions used to treat both humans and animals with a volved sustained-release formulations.3 Therefore, the variety of cardiac and vascular disorders. There are dose that this dog ingested was substantially higher three different families of CCB and at least 10 different than that reported in the human study.
types of CCB commercially available. The therapeutic Traditional short-acting formulations of diltiazem are effect depends primarily upon the drug family, with rapidly cleared by first-order kinetics following oral some agents (e.g., amlodipine) mostly causing vasodi- administration, with a half-life of 3–5 hours.v However, lation, while others (e.g., verapamil or diltiazem) have sustained-release formulations cause a slow, continual mixed effects on both the systemic vasculature and release of the drug, which prolongs its half-life. The heart. The incidence of human CCB intoxications has product that this dog ingested is reported to reach & Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2007.00269.x detectable plasma concentrations within two hours, insulin administration. Discussion of these therapies with peak concentrations occurring 10–14 hours after is beyond the scope of this report and can be reviewed administration of a therapeutic dose.v Its elimination in detail elsewhere.5,7,19 Treatment with various com- half-life is reported to be 5–8 hours following thera- binations of the aforementioned drugs has failed to peutic dosing.v The pharmacokinetics of sustained-re- yield consistent responses to these therapies in case re- ports of human intoxications.3 In this dog, all these investigated in dogs. However, the product that this agents were used, with the exception of insulin, and dog ingested has been shown to have a terminal half- many were initially successful in maintaining heart rate life of 7.6 hours and 36% bioavailability following once and blood pressure. However, over the course of the daily oral dosing at 10 mg/kg in healthy cats.12 first 24 hours, the dog became refractory to their ad- While the half-lives of short-acting and sustained-re- lease formulations of diltiazem are established for ther- The dose of glucagon that was used in this dog (0.04– 0.08 mg/kg, IV bolus; CRI 0.04 mg/kg/hr) is lower than supratherapeutic doses may differ. One study reports that considered to be appropriate in humans (0.15 mg/kg, half-lives of 5–10 hours following toxic doses of short- IV bolus; CRI 0.05–0.10 mg/kg/hr) for treatment of acting diltiazem, which is longer than reported for CCB overdose.1 However, the dose administered was therapeutic doses.13 Isolated case reports demonstrate higher than doses published (0.05 mg/kg, IV bolus; CRI that the elimination half-life can be dramatically longer 0.6–0.9 mg/kg/hr) for treatment of hypoglycemia in and extremely variable following ingestion of supra- dogs.20 Although the dose of glucagon used in this dog therapeutic doses of diltiazem.14–16 A retrospective was lower than recommended, a positive but transient study of a CCB intoxication in humans reported that therapeutic effect was noted. It is possible that use of a the onset of clinical signs may be delayed by 6–12 hours higher dose may have resulted in longer term efficacy; following ingestion of a toxic dose of sustained-release however, this would have been cost prohibitive if used for as many hours as the dog required pacing.
Serum concentrations of diltiazem were quantified at Because the dog in this case report had been retching, 1300 ng/mL (1.3 p.p.m.) 18 hours post-intoxication in GI decontamination was not initially attempted. Gastric this dog and below the range of detection 48 hours lavage and administration of activated charcoal was not post-intoxication. Therapeutic serum concentrations of performed until approximately 20 hours after ingestion.
diltiazem in humans are reported to range from 50 to Optimally, GI decontamination should have been per- 200 ng/mL (0.05–0.20 p.p.m.).v Therapeutic serum con- formed within four hours of intoxication. However, in centrations of diltiazem are not published for dogs, but massive overdoses, sustained-release formulations can should approximate those concentrations recommend- form concretions within the GI tract that can persist for ed for humans.17 The serum concentration measured 18 days.21 Therefore, based upon radiographic evidence of hours post-ingestion represents a value 6.5 times above ingesta persisting within the stomach the following day the high end of the therapeutic range. Because serum and the progression of the dog’s clinical signs, we felt concentrations were not obtained more frequently dur- that the dog would benefit from GI decontamination ing the first two days following intoxication, it is diffi- even 20 hours post-intoxication. Although repeated cult to predict the peak serum concentration for this doses of charcoal have not proven effective in cases of dog. However, it is likely that the concentration ob- short-acting diltiazem intoxication,13 repeated or de- tained 18 hours post-ingestion was lower than the peak layed administration of activated charcoal may help serum concentration. A serum concentration as high as limit further systemic absorption of sustained-release 6090 ng/mL has been documented in a human who formulations.21 Extracorporeal removal, such as hemo- survived acute intoxication with short-acting diltia- dialysis, might enhance drug elimination, but such in- zem.15,17 Reports of sustained-release intoxication are terventions are unlikely to alter clinical outcome and less prevalent in the literature, however a serum con- centration as high as 3171 ng/mL was reported in a A temporary transvenous pacemaker was inserted in person who survived intoxication.14 In humans, plasma this dog because of persistent bradycardia, AV block concentrations of CCB do not appear to correlate with and hypotension despite standard medical therapy.
A temporary pacemaker was selected because thearrhythmia was expected to be transient in nature, Treatments for toxicity and novel information negating the need for long-term pacing. Alternative There are numerous reported treatments for CCB in- routes of temporary pacing include transesophageal toxication including calcium supplementation, para- and transthoracic, although the use of transesophageal sympatholytic agents, vasopressors, glucagon and pacing has only recently been described in veterinary & Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2007.00269.x Transvenous pacing for diltiazem toxicity medicine.w Transthoracic pacing was not used in this pacing seems to be more common with overdoses of patient because heavy sedation or general anesthesia is verapamil,26–30 while most positive responses to pacing often required to minimize skeletal muscle activity and involve diltiazem overdoses.3,7,15,16,31–36 Verapamil, alleviate pain.22 If the transvenous pacemaker could not which is in a different family of CCB, is known to be placed with ease, the dog could have been paced exert more profound effects on vasomotor tone, ino- externally with transthoracic paddles under anesthesia tropy and cardiac conduction compared to diltiazem.21 while a transvenous pacemaker could be placed.
Thus, it is possible that ventricular pacing to a higher The diltiazem overdose likely decreased cardiac out- heart rate is less likely to compensate for the more put in this dog by altering both heart rate and stroke profound vasodilation and impairment in contractility volume. A decreased heart rate was noted secondary to AV blockade. While not directly measured by invasive The fact that diltiazem was undetectable in this dog’s cardiac output monitoring, stroke volume may also serum 48 hours post-ingestion corresponds with the have been decreased in this dog given the negative clinical signs. The need for pacemaker support until 41 inotropic properties of diltiazem. By pacing the dog’s hours post-intoxication corresponds with the metabo- ventricle to a higher heart rate, cardiac output was in- creased, which subsequently increased systemic bloodpressure, despite having no effect on inotropy or vaso-motor tone.
It is important to note that the dog became resistant This report outlines the use of temporary transvenous to medical therapy during general anesthesia. Anes- pacing as an adjunct to conventional medical therapy in thesia may have played a role in this dog’s clinical de- a case of severe diltiazem intoxication in a dog. When terioration by directly altering cardiac function and traditional therapies, such as atropine, calcium, gluc- vasomotor tone or by blunting the physiologic response agon and other vasopressors fail to maintain blood to such changes. Etomidate and midalozam, the only pressure and perfusion, temporary pacing should be anesthetics used, are reported to have minimal effects considered as a means to improve cardiac output.
on the cardiovascular system and are preferred in car-diovascular instability.23,24 Additionally, the doses ofetomidate used to maintain anesthesia in this dog (0.2 mg/kg) were much lower than published doses for The authors graciously thank Margie Cummings in the Laboratory of Large Animal Pathology and Toxicology The use of prochlorperazine as an antiemetic early in at the University of Pennsylvania for her assistance in the course of this intoxication was contraindicated.
determining serum diltiazem concentrations.
Prochlorperazine acts primarily by a-2 antagonism,which can impair vasoconstriction, adding to thehypotensive effects seen with diltiazem. In addition it has mild anticholinergic effects which could contribute Baytril, Bayer Health Care LLC, Shawnee Mission, KA.
Cardizem-CD, Biovail Pharmaceuticals Incorporated, Morrisville, NC.
The pacemaker was placed in a ventricular demand Normosol-R, Hospira Inc., Lake Forest, IL.
Compazine, GlaxoSmithKline, Research Triangle Park, NC.
mode. In this mode, if the spontaneous rate of the heart Ultrasonic Doppler Flow Detector, Model 811-BL, Parks Medical is slower than the set rate of the pacemaker, the pace- Dopamine HCl, American Regent Inc., Shirley, NY.
maker will discharge and trigger a depolarization.
Atropine SA, The Butler Company, Columbus, OH.
However, if the spontaneous rate exceeds that set for BD Insyte, Becton Dickinson, Sandy, UT.
the pacemaker, the pacemaker will sense this depolar- Glucagon, Bedford Laboratories, Bedford, OH.
Reglan, SICOR Pharmaceuticals Inc., Irvine, CA.
ization and be temporarily suppressed. This is a supe- rior mode of ventricular pacing, because it prevents Amidate, Itospira Inc., Lake Forest, IL.
Midazolam, Baxter Healthcare Corp., Deerfield, IL.
depolarization of the ventricle during repolarization, Actidose, Paddock Laboratories, Minneapolis, MN.
which could predispose to fibrillation.25 Performing brief pacemaker cessation trials may have been helpful Avanti1, Cordis Corporation, Miami, FL.
in this dog to determine if the pacemaker could have Temporary pacemaker placement is occasionally Dilacor XR, Watson Pharmaceuticals Inc., Corona, CA.
used in human CCB intoxication. Similar to other rec- North American Companion Animal Formulary, Sixth Edition, 2004, ommended therapeutic interventions, the clinical re- published online at http://www.vin.com/Members/Drug/NACA.plx?ID=257.
sponse to pacing is variable. The lack of response to Product monograph, Cardizem CD, Biovail Laboratories Incorporated.
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28. Goenen M, Col J, Compere A, et al. Treatment of severe verapamil 9. Miller M, Tilley L. Disorders of cardiac rhythm, In: Birchard S, poisoning with combined amrinone-isoproterenol therapy. Am J Sherding R. eds. Saunders Manual of Small Animal Practice. Phil- adelphia: W.B. Saunders Company; 1994, pp. 421–435.
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