Cardiac Toxicity From Phenylpropanolamine Overdose in a Dog

Introduction

Phenylpropanolamine (PPA) or d, l – norephedrine is a sympathomimetic amine that was once commonly used in appetite suppressants and over-the-counter cough and cold preparations. Its molecular structure is similar to amphetamine, differing by only a single β-carbon hydroxyl group, although it is considerably less potent.¹ The pharmacological activity of PPA may occur from direct α-adrenergic receptor stimulation as well as indirect stimulation of both α- and β-adrenergic receptors by increasing the release of stored norepinephrine from presynaptic sites.¹ Phenylpropanolamine has also been shown to inhibit monoamine oxidase activity at high concentrations (50 mg/kg), which may inhibit the breakdown of endogenous catecholamines.²

Adverse effects associated with PPA include hypertension, cardiac arrhythmias, myocardial infarction, acute renal failure, and neurological abnormalities such as changes in mentation, seizures, and stroke.^3–20 One study demonstrated an association between PPA and hemorrhagic stroke in women.¹⁸ This study, in conjunction with a large number of reported adverse drug reactions, led the Food and Drug Administration to issue both a public health warning and to remove PPA from the human market.²¹ Phenylpropanolamine is still available for veterinary use and is an effective treatment for urinary incontinence from primary urethral sphincter incompetence.^22–24 The purposes of this paper are to report PPA toxicity in a dog and to describe the clinical, physiological, biochemical, and cardiovascular abnormalities that arose after drug exposure.

Case Report

A 5-year-old, 29-kg, intact female Labrador retriever was presented to the referring veterinarian for acute vomiting, diarrhea, lethargy, and anorexia. Injected mucous membranes, dilated pupils with bilaterally absent pupillary light reflexes (PLRs), tachypnea, ataxia, polycythemia, elevated alkaline phosphatase (ALP), elevated alanine aminotransferase (ALT), mild hyperbilirubinemia, elevated blood urea nitrogen (BUN), elevated creatinine, and hypoglobulinemia were also noted. Lactated Ringer’s solution, activated charcoal^a (1.37 mL/kg per os [PO]), and diazepam^b (0.34 mg/kg intravenously [IV]) were administered. No improvement was seen, and the dog was referred for further evaluation and supportive care.

Upon presentation, the dog was hyperthermic (103.8°F), tachypneic (panting), tachycardic (224 to 280 beats per minute), and she had marked pulse deficits. Injected mucous membranes, hyperemic conjunctiva, bilateral fixed and dilated pupils with absent menace responses, bilateral vertical nystagmus (fast phase directed ventrally), and 5% dehydration were also observed. Neurological examination revealed generalized ataxia and hypermetria with mild proprioceptive deficits in all limbs. Spinal reflexes were normal. Differential diagnoses included toxicity or possibly an underlying myocardial disease with central vestibular disease (e.g., vascular, ischemic, hemorrhagic, or inflammatory etiologies). It was later discovered that another dog in the household was being treated for urinary incontinence with PPA,^c and an open bottle had been found with at least 28 tablets (50 mg each) missing. Phenylpropanolamine toxicity was suspected. The missing tablets were equivalent to a dose of 48 mg/kg, if ingested at one time.

Initial diagnostic tests included a complete blood count (CBC), serum biochemical profile, urinalysis, and coagulation profile. The CBC abnormalities were limited to thrombocytopenia, polycythemia, and an elevated hemoglobin concentration [Table 1]. Biochemical abnormalities included hypokalemia, hypoglycemia, and elevations in total carbon dioxide, calcium, BUN, creatinine, ALP, ALT, bilirubin, hemolytic index, and creatinine kinase (CK). The urine was dark brown with a specific gravity of 1.028 and proteinuria (4+). Red blood cell debris and brown-red discoloration of the urine following centrifugation indicated hematuria and either hemoglobinuria or myoglobinuria. Prothrombin time was normal, but activated partial thromboplastin time (PTT) was decreased (7.6 seconds; reference range 8.9 to 18.7 seconds). D-dimer concentrations were positive at 1000 to 2000 ng/mL (reference range 0 to 250 ng/mL). An arterial blood sample indicated alkalosis (pH of 7.49; reference range 7.31 to 7.42), hypocapnia (27.8 mm Hg; reference range 29 to 42 mm Hg), and normal oxygen pressure. A serum sample taken at presentation was submitted for PPA measurement. Pulse deficits initially precluded accurate indirect (Doppler) blood pressure (BP) assessment. Eighteen hours after presentation, indirect systolic BP was normal (150 mm Hg; reference range 100 to 150 mm Hg).^25,26

Shortly after admission, sustained ventricular tachycardia (with polymorphic ventricular complexes suggesting at least two foci of origin) and intermittent fusion beats were identified on an electrocardiogram (ECG) [Figure 1]. Chest radiographs demonstrated mild generalized cardiomegaly and decreased size of the caudal vena cava and pulmonary vasculature. The decreased size of the vessels suggested hypovolemia from dehydration or reduced cardiac output. Abdominal radiographs revealed mild to moderate gastric distension. Fluid and a small amount of partially mineralized ingesta were seen in the stomach. Echocardiography showed reduced left ventricular contractility [Table 2]. The dorsal interventricular septal region appeared dyskinetic [Figures 2A, 2B]. Serum cardiac troponin I concentration was markedly elevated [Table 1].

Intravenous lactated Ringer’s solution (with 30 mEq KCl/L and 2.5% dextrose) was started, and famotidine^d (0.5 mg/kg IV q 12 hours) was administered for intermittent vomiting. Serial blood glucose evaluations revealed progressive hypoglycemia to a nadir of 49 mg/dL, necessitating increased dextrose (7.5%) supplementation. The ventricular tachycardia was treated with four intermittent boluses of lidocaine^e (2 mg/kg IV), and temporary conversion to sinus tachycardia followed each bolus. A continuous-rate infusion of lidocaine (80 μg/kg per minute IV) was begun, which decreased the duration and frequency of paroxysmal ventricular tachycardia while maintaining the heart rate ≤ 130 beats per minute. Three supplemental boluses of lidocaine (2 mg/kg IV) were given when episodes of ventricular tachycardia (>200 beats per minute) lasted >2 minutes. Increasing the lidocaine infusion rate (100 μg/kg per minute IV) decreased the frequency and duration of the rapid episodes of ventricular tachycardia.

On the second day of hospitalization, the dog was afebrile and more alert and active. Heart rate was normal except for occasional, short episodes of ventricular tachycardia. The ataxia had improved, and the vertical nystagmus had resolved. The menace response was normal in the left eye and was present but diminished in the right eye. The pupils were no longer dilated, and the PLRs were brisk but incomplete bilaterally. Fundic examination showed a folded bullous region in the right eye, consistent with a previous retinal detachment, and focal decreased tapetal reflectivity in the left eye from subretinal exudation or retinal edema.

Treatment with atenolol^f (0.2 mg/kg PO q 12 hours) and enalapril^g (0.5 mg/kg PO q 12 hours) was begun in an attempt to support myocardial function, because the focal septal dyskinesis suggested myocardial infarction. The lidocaine infusion rate was decreased 36 hours after presentation. The packed cell volume gradually normalized as the dog was rehydrated. A serum biochemical profile on day 2 showed resolution of hypokalemia and azotemia and an improvement in the hemolytic index; however, the liver enzymes and bilirubin values had worsened [Table 1]. A PPA serum analysis using a commercially available enzyme-linked immunosorbent assay (ELISA)^h was 2.3 parts per million, confirming ingestion of PPA.

Over the next 3 days, gradual improvement occurred in the dog’s clinical condition. The ataxia slowly resolved. The dog was weaned from the constant-rate infusion of lidocaine over 36 hours, with only intermittent and brief episodes of ventricular tachycardia that did not alter clinical status. Electrocardiography revealed an increased T wave voltage and inverted polarity compared to the ECG on day 1. The blood glucose remained normal.

By day 6, the thrombocytopenia had improved. Bilirubin and ALP remained elevated, although ALT had improved [Table 1]. Creatinine kinase and the hemolytic index had normalized. Another echocardiogram indicated improvement in the focal dyskinetic motion of the interventricular septum. The dog was discharged on enalapril and atenolol, with owner instructions to restrict activity.

The dog was reevaluated 11 days later (17 days following PPA exposure). Physical examination indicated complete resolution of all neurological and cardiovascular signs. A CBC, urinalysis, and cardiac troponin I assay were repeated and found to be normal. A serum biochemical profile showed further increases in ALP and ALT, but there was marked reduction in hyperbilirubinemia [Table 1]. An ECG was normal. The T wave polarity had returned to positive, with a much smaller voltage than on day 6. Echocardiography showed improved myocardial function and left ventricular filling [Table 2; Figure 3]. The enalapril dosage was reduced (0.39 mg/kg PO q 12 hours), and the atenolol was discontinued at this time.

Reevaluation in another month was recommended but did not occur. Two months following initial evaluation, the dog was hit by a golf cart and sustained fractures of the left radius and ulna. Preanesthetic CBC and serum biochemical tests showed all blood parameters were normal at that time. Six months following initial presentation, the dog was clinically normal. Echocardiographic evaluation showed no evidence of septal dyskinesis and return of fractional shortening and E-point septal separation to the normal range, although estimated end systolic volume index still suggested mild left ventricular dysfunction.²⁷

Discussion

One of the difficulties associated with PPA administration in people has been the narrow therapeutic index of PPA in relation to its cardiovascular effects. One retrospective study showed that 37% of adverse drug reactions in humans occurred following the ingestion of recommended amounts of PPA.³ The recommended dosage of PPA in humans was 25 mg (immediate-release tablet) q 4 to 6 hours or 75 mg (sustained-release tablet) q 12 to 24 hours. The administration of high doses of PPA have been associated with systolic and diastolic hypertension.^28,29 Lower dosages of PPA have more variable effects on blood pressure and have given rise to the clinical perception of safety despite reports of hypertension.^30–32

The recommended dosage of PPA in dogs suffering from urethral sphincter incontinence is 1.1 mg/kg PO q 8 hours.³³ Doses of 3.1 mg/kg, given via a gastrostomy tube to beagles, have caused elevations in systolic (15.2 mm Hg), diastolic (39 mm Hg), and mean (27 mm Hg) BPs when compared to controls, with maximal effects seen at 30 to 60 minutes and persisting for as long as 300 minutes.⁵ This study concluded that doses of 0.5 to 1 mg/kg PO of PPA were safe, while doses >1 mg/kg could result in dangerous side effects.⁵ Other studies investigating PPA usage in dogs did not reveal any side effects at dosages ranging from 1 to 1.5 mg/kg PO q 8 hours.^22–24 One dog did have lethargy and inappetence after inadvertently receiving 2.5 mg/kg PO q 8 hours.²³ Additional controlled studies are needed to further clarify the therapeutic range and toxic dosages for PPA in dogs. The estimated dosage of PPA ingested by the dog reported here was 48 mg/kg. The absence of hypertension in this dog was not surprising, because PPA ingestion occurred at least 12 hours prior to presentation, and any initial hypertension would have had time to resolve. Additionally, the tachycardia observed in this dog may have masked any hypertension by lowering cardiac output.

Most of the clinical signs and laboratory alterations detected in the dog of this report could be explained by PPA toxicosis and its associated sympathomimetic effects.^34–36 Transient hypertension may have caused the ocular and neurological abnormalities via intracranial hemorrhage, vasculitis, and/or ischemic encephalopathy. The latter has been reported with PPA toxicity in humans.³ Direct neurological toxicity may also have caused the neurological abnormalities identified in this dog. Neurological abnormalities have been attributed to the primary cardiovascular effects of PPA in humans.³ Anxiety, hallucinations, mania, and psychiatric effects have been reported with PPA in people and may have caused some degree of hyperthermia and tachypnea in this dog.³ Additional diagnostic testing, such as magnetic resonance imaging, was not performed because of the dog’s initial critical state and subsequent rapid improvement.

The etiology of the gastrointestinal signs in this dog was unknown, although vomiting and nausea have been reported as side effects of PPA in people.⁴ Other possible causes of the vomiting included peripheral vasoconstriction resulting in ischemia of the gastrointestinal tract and liver, and a centrally mediated effect from the neurological toxicosis. The partially mineralized ingesta in this dog’s stomach may also have been a source of focal irritation and contributed to the vomiting. The origin of the mineralized ingesta was unknown. No abnormal-appearing substances or objects were observed in the feces or vomitus during hospitalization.

The polycythemia recognized in this dog was thought to be relative and secondary to dehydration. The hypokalemia and alkalosis likely arose from gastrointestinal fluid losses as a result of the vomiting. The mild alkalosis also may have partially contributed to the hypokalemia. Azotemia was attributed to a combination of dehydration and reduced cardiac output.

Thrombotic disease was suspected based on the thrombocytopenia, shortened PTT, and elevated D-dimer concentration, and it may have occurred secondary to altered hemodynamics and possible transient hypertension. The elevations in liver enzymes and bilirubin may have arisen from transient ischemia from PPA-induced systemic vasoconstriction, possible thrombotic disease resulting in hepatic infarction, and/or hepatic congestion and poor perfusion from the cardiac dysfunction. These alterations could have led to the transient hypoglycemia. Alternatively, the hypoglycemia could have also been caused by decreased intestinal absorption secondary to vomiting.

Hyperbilirubinemia was noted and may have occurred from mild red blood cell lysis, which was supported by hemoglobinemia and by possible hemoglobinuria. The dog had either hemoglobinuria, myoglobinuria, or a combination of both. Presumptive hemolysis supported the presence of hemoglobinuria, although the clinical pathological distinction between hemoglobinuria and myoglobinuria (by either spectrometric tests, serum myoglobin measurement, or CK isoenzyme determination) was not performed. The presence of concurrent myoglobinuria was suspected based on the dramatic elevation in CK and pharmacologically PPA-induced transient muscular ischemia and subsequent rhabdomyolysis. The sources of the hematuria and proteinuria were not readily apparent.

The ventricular tachycardia, focal dyskinesis of the inter-ventricular septum, and transient elevations in CK and cardiac troponin I concentrations were consistent with either myocardial necrosis from infarction or direct catecholamine-induced myocardial toxicity.^9–11,37 Myocardial infarction in dogs has been associated with structural and/or primary cardiovascular abnormalities, endocarditis, and a variety of systemic illnesses (e.g., hypothyroidism, hyper-adrenocorticism, atherosclerosis, pancreatitis, renal disease, immune-mediated hemolytic anemia, neoplasia, and drug administration).^37–47 Unlike humans who typically develop a myocardial infarction from coronary atherosclerosis and coronary thrombosis, dogs usually have nonatheromatous coronary artery disease.⁴⁸ Myocardial ischemia and subsequent myocardial necrosis in this dog may have resulted from coronary artery vasospasm in the absence of preexisting coronary disease.⁴⁹ Intraperitoneal administration of PPA in excess of 8 mg/kg in rats has resulted in myocardial necrosis.⁵⁰

Few reports exist of antemortem diagnosis of myocardial infarction in dogs.^37,40,43,45 The diagnosis of myocardial infarction in dogs may be based on a combination of clinical signs, laboratory parameters, ECG, and echocardiography.^37,43,45 Clinical signs reported with myocardial infarction in dogs and cats include dyspnea, tachypnea, tachycardia, coughing, weakness, collapse, sudden death, and vomiting.^43,45 Laboratory abnormalities associated with myocardial infarction in humans include transient elevations in CK.^9,10 With myocardial infarction caused by PPA toxicity in humans, a rise in CK and CK myocardial band (a specific isoenzyme found primarily in cardiac muscle) peaked at 12 to 14 hours postinfarction and normalized within 34 to 96 hours.⁵¹ The case presented here had a similar rise and fall in CK, with elevated values at presentation (>23,000 IU/L) and normal (156 IU/L) values within 144 hours postpresentation. This transient rise in CK may also have occurred from myocardial necrosis caused by catecholamine-induced damage or ischemia from presumed PPA-induced hypertension. Additionally, this transient elevation may have originated from skeletal muscle ischemia or necrosis. Unfortunately, CK isoenzymes were not analyzed.

The diagnosis of myocardial infarction in humans often requires the measurement of cardiac troponins, which are the most sensitive and specific markers of myocardial necrosis.^52,53 Cardiac troponin I is a protein present in the contractile complex of cardiac muscle.⁵⁴ Cardiac troponin I measurement has been validated in dogs, and the reference range for cardiac troponin I is ≤ 0.07 ng/mL in healthy dogs, which is similar to the range established for humans (0.0 to 0.04 ng/mL).^52,55 Cardiac troponin I measurement has been proven to be a sensitive marker for myocardial infarction in dogs, but it may also be increased with other causes of myocardial necrosis.^54,56 Cardiac troponin I levels peak 1 day postinfarction in dogs and remain elevated for 7 days before gradually returning to baseline approximately 3 weeks later.⁵⁴ The dog reported here had elevated cardiac troponin I levels at presentation (>40 ng/mL), and values were significantly decreased by the 17th day. This transient rise in troponin levels may have been exacerbated by the ventricular tachycardia present at the time of presentation; but whether the arrhythmia was a contributing factor in the rise in cardiac troponin I levels could not be ascertained. Additional studies evaluating cardiac troponin I levels in dogs with various arrhythmias before and after antiarrhythmic therapy are warranted.

Several ECG abnormalities may occur with myocardial infarction in dogs, including ST segment depression, peaked T waves, notched R waves, the development of Q waves, a change in T wave polarity, and the sudden development of atrioventricular block, bundle branch block, atrial fibrillation, or ventricular arrhythmias.^{37,38,43,45,57} The multiform ventricular tachycardia and development of large T waves with inverted polarity that occurred on day 6 of this case and returned to normal on day 11 were consistent with previously reported ECG abnormalities associated with myocardial infarction.^9,57 Echocardiography is used to diagnose myocardial infarction in humans and animals, although there are few reports of antemortem echocardiographic evaluations in dogs with myocardial infarction.^37,43,45 Typical echocardiographic findings of myocardial infarction include regional hypokinesis (reduced contraction), hyperkinesis (increased contraction), akinesis (absent contraction), dyskinesis (asynchronous contraction), regional wall thinning, aneurysms, thrombi in the left heart, and ventricular dysfunction.^37,58 The dog presented here had echocardiographic evidence of myocardial infarction, namely the presence of a thin dyskinetic region within the high-interventricular septum and decreased left ventricular function. Serial echocardiography demonstrated improvement in left ventricular function and resolution of the focal dyskinesis over 6 months.

Conclusion

Accidental PPA overdose in a dog led to cardiac toxicity with multiform ventricular tachycardia and apparent myocardial infarction based on echocardiographic findings, ECG changes, and elevated cardiac troponin I. Other systemic and neurological signs of toxicity were concurrent. Recovery in this dog occurred with supportive therapy. The estimated amount of drug ingested was quite high in this case; however, the therapeutic index of PPA is narrow, and the drug’s potential for cardiac and other toxicity should be recognized.

Acknowledgments

The authors thank Dr. Elizabeth Riedesel for her radiographic and ultrasonographic interpretations and Dr. Thomas Carson for performing the phenylpropanolamine assay. The authors also thank Kathy Hedges, RVT, for her technical assistance with the figures.