Systemic Hypertension and Hypertensive Retinopathy Following PPA Overdose in a Dog

Introduction

Phenylpropanolamine (PPA)^a is a synthetic sympathomimetic amine that acts through direct α-adrenergic stimulation and indirect stimulation of both α- and β-receptors through release of stored norepinephrine.¹ At higher concentrations, PPA can inhibit monoamine oxidase, which may inhibit the metabolism of catecholamines and potentiate their activity.^2,3 PPA was previously widely available in the United States in over-the-counter decongestant and appetite suppressant preparations; however, products containing PPA were recalled by the FDA after reports suggested a significant risk of intracranial hemorrhage and hemorrhagic stroke following ingestion.^4,5 Adverse effects associated with PPA ingestion in humans include dizziness, headaches, hypertension, tachycardia, cardiac arrhythmias, myocardial infarction, and hemorrhagic stroke.^6–9 PPA is used in veterinary medicine to control urinary incontinence in dogs due to urinary sphincter mechanism incompetence.^10–13 At the recommended dose of PPA in dogs with urinary sphincter mechanism incompetence (1.1 mg/kg per os [PO] q 8 hr), the drug effectively controls urinary incontinence with very few documented side effects; however, restlessness, irritability, urine retention, tachycardia, hypertension, and anorexia have been observed.^1,10−14 Although a case of PPA overdose in one dog has been previously reported, severe hypertension with target organ damage was not documented and has not been previously reported.¹⁵ The purpose of this report is to describe the findings in a case of PPA overdose in a dog in which severe hypertension and secondary organ damage were documented.

Case Report

A 4 yr old spayed female Labrador retriever weighing 36 kg presented to the referring veterinarian within 4 hr of ingesting 40–50 tablets (50 mg each) of PPA. The ingested tablets were equivalent to a 56–69 mg/kg dose, which is approximately 14 to 64 times greater than the recommended 1–4 mg/kg per dose. Signs noted by the owner included restlessness and failure to urinate for several hours.

According to the referral information, the patient was agitated but responsive at the time of presentation. Piloerection, hyperemic skin, and injected mucous membranes were noted. The rectal temperature was 40.89°C. The heart rate was 150 beats/min and an irregular heart rhythm was noted during cardiac auscultation. The respiratory rate was 60 breaths/min with no abnormal lung sounds ausculted. Mydriasis and absent pupillary light reflexes were noted oculus uterque (OU). Systolic blood pressure (SBP), measured via the Doppler method, was 180 mm Hg. A lead II electrocardiogram (EKG) showed a normal sinus rhythm with a heart rate of 140 beats/min.

The American Society for the Prevention of Cruelty to Animals Animal Poison Control Center was contacted by the referring veterinarian, and recommendations included the following: induction of emesis; administration of activated charcoal; medical monitoring; and control of any arrhythmias, hypertension, and hyperactivity during hospitalization. An IV catheter was placed, and vomiting was successfully induced with apomorphine^b (0.02 mg/kg IV). PPA tablets were not noted in the vomitus. Activated charcoal^c was administered (1 g/kg PO), and IV fluid therapy was initiated at 240 mL/hr (2.5 × maintenance). The patient became increasingly restless and agitated, necessitating a dose of acepromazine^d (0.02 mg/kg IV) for sedation. Over the next 1 hr, the dog’s rectal temperature normalized to 38.83°C, the heart rate decreased from 150 beats/min to 100 beats/min, and the respiratory rate decreased from 60 breaths/min to 32 breaths/min. The SBP was 160 mm Hg 1 hr after initial measurement. The patient was transferred to the University of Wisconsin Veterinary Medical Teaching Hospital (UW VMTH) for continued care approximately 12 hr after ingestion of the PPA (approximately 8 hr after initial evaluation by the referring veterinarian).

At the time of presentation to the emergency clinician at the UW VMTH, the patient was depressed and vomited a small amount of brown fluid in the examination room. The rectal temperature was 38.56°C, the heart rate was 80 beats/min, and the respiratory rate was 50 beats/min. Mucous membranes were tacky and injected with a capillary refill time of < 2 sec. The cardiac auscultation was normal, and the femoral pulses were strong and synchronous. A brief ophthalmologic examination was performed by the emergency clinician, which revealed mydriasis OU, absent pupillary light reflexes OU, hyphema OU, and absent menace OU. Intraocular pressures were 18 mm Hg oculus dexter (OD) and 19 mm Hg oculus sinister (OS). A single blood pressure measurement was performed using oscillometry and the SBP was 196 mm Hg. A single measurement was repeated 30 min later and the SBP was 188 mm Hg. An EKG was recorded revealing an intermittent, accelerated, idioventricular rhythm and a heart rate of 100 beats/min (Figure 1A). Phenoxybenzamine^e (0.28 mg/kg PO q 12 hr) was prescribed for partial antagonism of the sympathomimetic effects of PPA.

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A complete blood cell count (CBC) and serum biochemical profile were performed. No clinically significant abnormalities were noted on the CBC. The serum biochemical profile showed the following abnormalities: hypoproteinemia (4.6 g/dL; reference range, 5–8.3 g/dL), hypoglobulinemia (1.6 g/dL; reference range, 2.6–4 g/dL), elevated creatine kinase ([CK]; 4,840 U/L; reference range, 50–554 U/L), and elevated aspartate aminotransferase ([AST]; 296 U/L; reference range, 13–81 U/L). Differential diagnoses for the hypoproteinemia included hemorrhage, protein-losing enteropathy, vasculitis, and (less likely), protein-losing nephropathy; however, the specific cause for the hypoglobulinemia was unknown. The combined elevation of CK and AST in the absence of other liver enzyme elevations was suggestive of muscle damage. The most likely cause for the muscle damage given the patient’s recent ingestion of PPA was ischemic myopathy due to vasoconstriction. Other differential diagnoses included either an infectious or immune-mediated myositis and trauma. Additional diagnostic tests were discussed with the owner, including serial monitoring of blood work, a coagulation panel, thoracic radiographs, and abdominal ultrasound; however, testing was postponed until the patient was more stable.

IV lactated Ringer’s solution^f (160 mL/hr) was initiated. Acepromazine (0.02 mg/kg) was again administered IV to provide additional sedation due to recurring agitation. The patient urinated a large amount of brown-colored urine after an unsuccessful attempt to place a urinary catheter. Urinalysis revealed a urine specific gravity of 1.018, a urine pH of 8.5, a large heme reaction, 4+ protein, bilirubinuria, rare finely granular casts, many amorphous crystals, rare red blood cells (RBCs)/high-power field, and neither WBCs or bacteria. The large heme reaction in the absence of a significant number of RBCs in the sediment suggested the presence of either myoglobinuria or hemoglobinuria. Bilirubinuria was present, which suggested hemolysis; however, based on lack of evidence of hemolysis on the CBC and biochemical profile and the presence of an elevated CK and AST, myoglobinuria was more likely and was supportive of muscle damage. The presence of minimally concentrated urine may have been due to the fluid therapy; however, the presence of casts was suggestive of renal tubular damage. Possible differential diagnoses included ischemic damage to the kidneys and pigment nephropathy. The proteinuria may have been due to glomerular damage, severe renal tubular damage, systemic hypertension, systemic inflammation, a paraneoplastic syndrome, or a combination of factors. Although it was discussed with the owners, a urine protein-to-creatinine ratio was not performed at that time. Again, further testing was postponed, and the patient continued to be treated with IV fluid therapy. Overnight, the patient continued to be mildly agitated but her body temperature and heart rate remained normal.

Approximately 22 hr after ingesting the PPA, the patient’s physical examination findings were unchanged except a marked, diffuse ulceration of the gingival mucosa was now visible and frequent premature beats were noted during cardiac auscultation together with pulse deficits noted. A complete ophthalmologic examination, including slit lamp biomicroscopy, indirect ophthalmoscopy with pupillary dilation, and applanation tonometry, showed present, but delayed, pupillary light reflexes OU (prior to pharmacologic dilation with tropicamide^g), an intact menace response OD, and an absent menace response OS. Intraocular pressures were 4 mm Hg OD and 5 mm Hg OS. Aqueous flare, aqueous cell (both 4+), and fibrin strands were noted OU. Episcleral and conjunctival hyperemia (1+ and 4+, respectively) were also noted OU. Diffuse hyphema (RBCs were distributed diffusely throughout the anterior chambers) was also noted. Several small blood clots were in the vitreous of both eyes. An indirect fundic exam was performed after pharmacologic dilation that revealed partial retinal detachment OD in the peripheral aspects of the nasal and dorsotemporal quadrants with associated subretinal hemorrhage. Complete bullous retinal detachment was present OS. Based on the ocular findings, the patient was diagnosed with anterior uveitis and partial retinal detachment OD and complete retinal detachment OS. Prednisone acetate ophthalmic drops (1%)^h were prescribed OU q 4 hr for its anti-inflammatory effects. At that time, an oral lidocaine rinseⁱ was also prescribed to be applied to the oral mucosa q 6 hr for treatment of the oral ulceration.

Approximately 24 hr after ingesting the PPA, the dog’s blood pressure was re-evaluated. The average of five consecutive oscillometric readings (SBP) was 193 mm Hg. Telemetric EKG monitoring was used to monitor heart rate and rhythm. Ventricular bigeminy was noted with a heart rate of 180 beats/min (Figure 1B). Oral sotalol^j (1.7 mg/kg PO q 12 hr) was initiated and the phenoxybenzamine was continued. Nonsustained polymorphous ventricular tachycardia and sinus complexes with ventricular echo complexes were noted within 30 min of initiating the sotalol (Figure 1C). Lidocaine^k (2 mg/kg IV) was administered, but no change in heart rhythm was noted. The patient was then administered a bolus (2 μg/kg IV) followed by a continuous rate infusion of esmolol^l (50 μg/kg/min IV). The heart rhythm normalized, although occasional ventricular premature complexes were noted. When sinus rhythm was restored, the SBP had dramatically increased to 256 mm Hg. Nitroprusside^m was administered (1–5 μg/kg/min IV, titrated to effect) and the patient’s heart rate, heart rhythm, and blood pressure (oscillometric) were measured continuously overnight. The patient was anxious overnight and received a single dose of acepromazine (0.02 mg/kg IV), which provided effective sedation. Telemetry documented a heart rate < 160 beats/min and an accelerated idioventricular rhythm overnight.

Approximately 48 hr after PPA ingestion, the patient had persistent gingival mucosal ulceration, but the cardiac and respiratory auscultation (including heart rate and rhythm) and abdominal palpation were normal. An ophthalmologic examination was repeated, which revealed the patient had regained at least partial vision OU. A fundic examination showed that both retinas were partially reattached and the hyphema was resolving. Prednisone acetate ophthalmic drops (1%) were continued. Telemetric EKG revealed only occasional ventricular premature complexes. Esmolol was discontinued, but the sotalol and phenoxybenzamine were continued. Nitroprusside was discontinued approximately 18 hr after initiating the therapy (42 hr after ingesting the PPA). The blood pressure remained normal during tapering and discontinuation of nitroprusside.

Another serum biochemical profile was performed, which showed persistent hypoproteinemia (4.2 g/dL), hypoalbuminemia (2.5 mg/dL), hypoglobulinemia (1.7 g/dL), elevated CK (> 8,050 U/L), elevated AST (2,471 U/L), and elevated alanine aminotransferase ([ALT]; 395 U/L; reference range, 14–151 U/L). The presence of panhypoproteinemia was attributed to hemorrhage, protein-losing enteropathy, vasculitis, protein-losing nephropathy, or a combination of those conditions. The continued elevation in CK and AST suggested ongoing muscle damage. The mild elevation in ALT could have been attributed to muscle damage, but other causes included hypoxic liver injury, infectious hepatitis, chronic hepatitis, or hepatic neoplasia. At that time, a repeat urinalysis with urine protein-to-creatinine ratio; CBC; coagulation panel; thoracic radiographs; abdominal ultrasound with possible fine-needle aspiration of the liver; and testing for toxoplasmosis, neosporosis, hepatozoonosis, blastomycosis, and histoplasmosis were recommended. All further testing was declined by the owners.

An echocardiogram and cardiac troponin I (cTnI)ⁿ concentration were assessed approximately 48 hr after PPA ingestion to evaluate the patient for evidence of secondary cardiac injury. The echocardiogram revealed mild mitral regurgitation and mild tricuspid regurgitation, but no evidence suggestive of infarction, ischemia, or hypo- or akinetic ventricular walls was identified. There was some evidence of systolic dysfunction as the fractional shortening was mildly decreased at 10.4% (reference range, 25–40%) and the volumetric ejection fraction was mildly decreased at 33% (reference range, 45–65%). The cTnI concentration was elevated (11.7 ng/mL; reference range, < 0.3 ng/mL). Any reported cTnI concentration > 1.6 ng/mL indicated probable cardiac necrosis (personal communication with UW Health Clinical Laboratories, Madison, WI).

IV fluids were tapered then discontinued 48 hr after PPA ingestion, and the patient started to eat. The oral lidocaine rinse was discontinued at that time as well because the oral ulceration was almost resolved. The patient was monitored until 72 hr after ingesting the PPA, at which time all cardiac parameters, including heart rate, heart rhythm, and blood pressure, remained within normal limits. The patient was discharged approximately 72 hr after PPA ingestion with instructions for the owners to continue to administer sotalol (1.7 mg/kg PO q 12 hr), phenoxybenzamine (0.28 mg/kg PO q 12 hr), and prednisone acetate ophthalmic drops (OU q 4 h) until reexamination.

The patient was re-evaluated 9 days after PPA ingestion. The owner reported that the patient had normal behavior, appetite, and eliminations at home. There was no evidence of impaired vision at home. On physical examination, rectal temperature was 39.06°C, heart rate was 140 beats/min, and the dog was panting. Cardiac auscultation was normal, with an apparent respiratory sinus arrhythmia and strong, synchronous femoral pulses noted. The mucosal ulceration was healed, and mucosal injection had resolved. A complete ophthalmologic examination was performed as described above. Pupillary light reflexes were normal OU, and menace responses were intact OU. Intraocular pressures measured with applanation tonometry were 14 mm Hg OD and 10 mm Hg OS. The aqueous flare had resolved; however, aqueous cell remained (1+ OU). Small blood clots were attached to the posterior lens capsule, extending into the vitreous OU, and a second blood clot was noted in the inferior temporal aspect of the vitreous OD. Those blood clots were thought to represent consolidation of the previously more diffuse vitreal blood. Indirect fundic examination showed that the retinas were attached OU. The examining ophthalmologist commented that the vitreal hemorrhage was expected to resolve over the next several months. SBP (151 mm Hg via oscillometric measurement) was mildly elevated, but did not warrant further therapy. An EKG showed sinus arrhythmia, a heart rate of 100 beats/min, and no abnormal complexes were noted. CTnI concentration was assessed and the result was consistent with normal cardiac health (0.2 ng/mL). A serum biochemical profile was normal, and results of a urinalysis (obtained via cystocentesis) were also unremarkable. Phenoxybenzamine was discontinued, and the sotalol dose was tapered over the next 7 days then discontinued. Prednisone acetate ophthalmic drops were tapered over the next 4 wk then discontinued. At the time the prednisone acetate ophthalmic drops were discontinued, the referring veterinarian reported that the patient’s ophthalmologic exam was normal. There was normal vision OU; pupillary light reflex present OU; menace reflex present OU; normal intraocular pressures (16 mm Hg OD and 15 mm Hg OS); no evidence of hyphema, fibrin strands, or aqueous flare OU; and a normal indirect fundic exam OU, indicating resolution of all signs related to PPA ingestion.

Discussion

The dog described in this case report received a substantial and acute overdose of PPA. Many of the clinical signs, including piloerection, nausea, vomiting, hypertension, restlessness, tachycardia, and urine retention, could conceivably be attributed to exaggerated sympathomimetic effects of PPA. As those symptoms resolved over time, and were not seen prior to the ingestion, it is likely that they were related specifically to the toxin ingestion, rather than a concurrent underlying illness.

Gingival mucosal ulceration was noted approximately 24 hr after ingestion of PPA and resolved within 1 wk of ingestion. Gingival mucosal ulceration has not been reported with PPA ingestion, and the cause for the ulceration was unknown. PPA is not a caustic substance but given its sympathomimetic effects, it is possible that ulceration was due to ischemia secondary to severe vasoconstriction of the blood vessels supplying the gingival mucosa. Severe vasoconstriction of the gingival mucosal vessels should result in blanching of the gums (rather than the injection that was noted when the patient was initially examined at the UW VMTH); however, it is possible that the mucosal “injection” noted initially may have been erythema related to initial erosion of the mucosa, leading to more apparent ulceration with reevaluation. A recent study demonstrated variable vasoconstrictive effects of IV PPA on murine tail veins and mesenteric veins, depending on the proportion of α₁ and α₂ receptors present.¹⁶ The proportion of α₁ and α₂ receptors in the gingival mucosal vessels in dogs is unknown, but differences in proportions, if present, might explain ischemic effects of a specific area of the body.

Multiple indicators of muscle injury were present in this case. Progressive and severe CK elevation in conjunction with AST elevation suggests a component of ongoing muscle damage. An elevation in ALT was also documented in this patient, which has been reported in conditions with severe muscle damage.¹⁷ Pigmenturia was also noted approximately 12 hr after the dog ingested the PPA. Given the elevations in CK and AST during hospitalization, the pigmenturia was likely due to myoglobinuria because there was no evidence of hemolysis based on the CBC. The elevated serum cTnI concentration was consistent with myocardial necrosis, which has also been documented in a previous report of PPA toxicity in a dog.^15,18–22 Taken together, the above-described findings suggest acute, transient muscle damage in this patient.

Cardiac abnormalities noted in this patient are similar to findings in a previous report of PPA toxicity.¹⁵ Several different types of cardiac arrhythmias were noted, including an accelerated idioventricular rhythm, ventricular premature complexes, ventricular bigeminy, and ventricular tachycardia. The ventricular tachycardia was not responsive to lidocaine; however, resolution of this arrhythmia was noted after initiation of esmolol, a β-receptor antagonist. The patient’s autonomic nervous system was under the influence of various pharmacologic agents, including PPA, phenoxybenzamine, sotalol, and esmolol, so it is difficult to determine what medications may have been most influential in resolving the arrhythmias. Within 10 days of the PPA overdose, no arrhythmias were noted, suggesting that the arrhythmias were transient and likely associated with the effects of PPA ingestion.

Echocardiographic changes noted 72 hr after PPA ingestion showed no obvious structural damage, but evidence of systolic dysfunction was noted. Interpretation of those findings was confounded by concurrent treatment with sotalol; however, when an echocardiogram was repeated approximately 1 wk later (while treatment with sotalol continued), both the fractional shortening and ejection fraction had normalized, suggesting that the initial decrease in systolic function may have been associated with the PPA overdose. Similar findings were noted in another report of PPA toxicity, although cardiovascular abnormalities were more severe in that report.¹⁵ In the case described herein, the elevated cTnI concentration indicated probable acute myocardial necrosis despite the lack of structural evidence on the echocardiogram.

The current case report documents severe and prolonged hypertension, which is in contrast to a recent report of PPA toxicity in a dog where hypertension was not noted despite ocular and neurologic changes in the patient that might otherwise be attributed to hypertension.¹⁵ In the current case, hypertension was documented 24 hr after ingestion of PPA, was associated with target organ damage, and required continuous IV antihypertensive therapy until 42 hr after ingestion of PPA. It is not possible to rule out the possibility that the patient described herein may have been hypertensive before ingesting the PPA; however, the patient’s blood pressure was only mildly increased initially after ingestion, followed by a severe elevation of blood pressure then resolution of hypertension over time. This pattern suggests that the hypertension was associated with the PPA ingestion.

Hypertension secondary to PPA ingestion has been documented in humans.^7–9,23 Increased risk for hypertension and hemorrhagic stroke has been reported in multiple studies.^4,9,23 A recent meta-analysis of the impact of oral PPA on blood pressure in humans also showed that across studies, a significant increase in systolic, diastolic, and mean arterial pressures was associated with PPA ingestion.²³ Effects of PPA on blood pressure have also been evaluated in dogs. A study comparing PPA and ephedrine for control of urinary incontinence in dogs showed a significant increase in diastolic and mean arterial pressure during treatment with either medication.¹⁴ When PPA was compared with pseudoephedrine, both medications effectively controlled urinary incontinence, and there was no significant change in blood pressure noted during treatment with either medication.¹¹ In healthy beagles given 3.1 mg/kg PPA, significant increases in systolic, diastolic, and mean blood pressures were reported. The maximal increase occurred at 30–60 min, and a persistent elevation was noted for as long as 5 hr.²⁴ The effect of PPA on blood pressure in a clinical population of dogs remains unknown; however, administration of PPA is noted as a possible cause of systemic hypertension in a recent American College of Veterinary Internal Medicine consensus statement.²⁵

To the authors’ knowledge, this is the first report of documented target organ damage associated with systemic hypertension in a dog secondary to PPA ingestion. A recent consensus statement on the diagnosis and therapy of systemic hypertension states that the goal of antihypertensive therapy is to prevent injury to tissues secondary to hypertension.²⁵ Retinal detachment and hyphema, consistent with hypertensive retinopathy, were noted in this patient, and each of those conditions has been reported secondary to hypertension in dogs.^26–30 The consensus recommendation, when either the SBP or diastolic blood pressure is severely elevated (i.e., ≥ 180 mm Hg and ≥ 120 mm Hg, respectively) or when a patient has hypertension with evidence of target organ damage, is for immediate intervention to minimize risk of either new or additional organ damage.²⁵ In the case of hypertensive retinopathy, immediate intervention is aimed at maximizing the possibility for reversal of the changes. In the patient described in this report, rapid intervention with IV nitroprusside and control of severe hypertension was associated with resolution of both the hyphema and retinal detachment. Ideally, direct arterial blood pressure monitoring would have been performed, particularly for monitoring response to nitroprusside therapy, because that is the most accurate way to assess blood pressure. In the current case, blood pressure was monitored with noninvasive (indirect) techniques because placement of an arterial catheter was not possible at the time of presentation due to the agitation of the patient. In addition, the authors felt that the consistent and severe elevation in blood pressure obtained indirectly, in combination with a recent history of PPA overdose and signs of target organ damage, warranted immediate therapy.

Causes of hyphema and retinal detachment in dogs include hypertension, coagulopathies, vasculitis, uveitis, and neoplastic syndromes.³¹ The retinal detachment was not confirmed with ultrasound; however, the ophthalmic exam findings (elevated retina, slow pupillary light reflex, loss of menace response OS), were consistent with retinal detachment. It was not felt that an ocular ultrasound was warranted given the gravity of the dog’s other systemic signs. Given the other systemic findings and response to therapy, hypertension was the most likely cause of the ophthalmic changes found in this case.

Acepromazine was initially effective for control of anxiety in this patient, which is consistent with a previous report.¹⁵ The antihypertensive effects and the anxiolytic effects of acepromazine may also have contributed to the gradual decrease in blood pressure noted, but significant antihypertensive effects of acepromazine are most frequently documented at dosages > 0.05 mg/kg IV.^32–35 The effect of dosages similar to those administered to the dog described in this case does not appear available. Regardless, any antihypertensive effect of acepromazine would conceivably last only as long as the duration of action of the drug.

Conclusion

This is a case of persistent severe hypertension and hypertensive retinopathy in a dog that ingested > 50 times the recommended dose of PPA. With aggressive management of the hypertension and supportive ocular care, the ocular changes were reversed and the patient’s vision was restored. Based on this case, the authors recommend thorough monitoring, including frequent blood pressure measurement and screening for evidence of target organ damage in cases of PPA overdose in dogs. If either hypertension or target organ damage is documented, immediate and aggressive antihypertensive therapy is recommended to minimize organ damage.