Cyproheptadine for Central Hypertension?
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OPEN ACCESS Research article Cyproheptadine for central hypertension? Guido Filler1,2,*, Lara Hart1, April Chan3, Elizabeth Cairney4, Asuri N Prasad5 1Department of Paediatrics, Division of Paediatric Nephrology, Schulich School ABSTRACT of Medicine & Dentistry, London, ON, Background: Approximately one-fifth of paediatric intracranial tumors result in hypertension. Canada N6A 5W9 2Department of Pathology and The condition is difficult to treat in this population, particularly if it is refractory, since there is little Laboratory Medicine, Schulich School of guidance on patient management beyond first-line therapy with IV labetalol. Medicine & Dentistry, University of Western Ontario, London, Ontario, Methods: A 20-month-old patient was hospitalized with cerebral herniation-induced loss of Canada N5A 5A5 consciousness and a posterior fossa mass was found. Although several first-line treatments including 3 School of Pharmacy, University of IV labetalol, furosemide, amlodipine, clonidine, and atenolol were administered, the patient’s Western Ontario, London, ON, Canada 5A 5A5 hypertension persisted. With few options left, positive findings from previously published case reports 4Department of Paediatrics, Division of led the team to administer cyproheptadine. Hematology/Oncology, Schulich School of Medicine & Dentistry, London, ON, Results: Cyproheptadine resulted in improved blood pressure and allowed for a dose reduction in Canada N6A 5W9 other antihypertensives, but elevated liver transaminases and suspected hepatotoxicity several weeks 5 Department of Paediatrics, Division of later resulted in the discontinuation of this treatment. Neurology, Schulich School of Medicine & Dentistry, London, ON, Canada N6A Conclusions: Despite the safety concerns associated with using cyproheptadine to treat paediatric 5W9 central hypertension, this treatment holds promise for persistent refractory hypertension as a last-line *Email: [email protected] agent when all other treatment options are exhausted. Clinical use of this agent should be investigated in future studies, under careful supervision. Keywords: cyproheptadine, hypertension, sympathetic nervous system, anti-hypertensive agents http://dx.doi.org/ 10.5339/connect.2014.12 Submitted: 5 March 2014 Accepted: 8 April 2014 ª 2014 Filler, Hart, Chan, Cairney, Prasad, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. Cite this article as: Filler G, Hart L, Chan A, Cairney E, Prasad AN. Cyproheptadine for central hypertension?, QScience Connect 2014:12 http://dx.doi.org/10.5339/connect.2014.12 Page 2 of 6 Filler et al. QScience Connect 2014:12 BACKGROUND It has been reported that approximately one-fifth of children with intracranial tumors suffer from hypertension,1 a comorbidity that is challenging to treat in this paediatric population. Although the mechanisms surrounding the underlying pathophysiology of this condition are not yet entirely clear, over-activity of the sympathetic nervous system appears to play an important role.2 This condition differs from neurogenic hypertension, which is associated with tumors of a neural origin that produce epinephrine and norepinephrine. There is a lack of case reports, case series, and trials relating to this condition. Treatment should be based on the disease mechanism, targeting three systems: sodium/volume, renin-angiotensin system (RAS), and the sympathetic nervous system (SNS).3 First-line therapy for small children experiencing a hypertensive crisis is intravenous (IV) labetalol, followed by diuretics.4 Pediatric nephrologists are often called to assist with these cases and often consider adding a calcium channel blocker. ACE inhibitors are given once the patient is more stable and can tolerate oral medications. It is unclear how physicians should manage patients with hypertension who are resistant to these treatments, which is why it is important to identify other treatment options. Here we describe a patient who exhibited refractory hypertension after receiving IV and oral beta-blockers, calcium channel blockers, central alpha-blockers, and diuretics, and who finally responded favorably to cyproheptadine, a medication that acts on the SNS. CASE REPORT A previously healthy 20-month-old boy was admitted to the critical care unit after a cerebral herniation- induced loss of consciousness (Day 1). The patient’s height was 90.5 cm and his weight was 12 kg. His initial blood pressure was 132/57 mm Hg and his heart rate was 82 beats/min, which was inappropriately low for a hemoglobin count of 69 g/L. His breathing was also irregular and his pupils were unequal. The patient was given nifedipine (0.125 mg/kg) with little effect. Upon further examination, a significant hydrocephalus and a posterior fossa mass were discovered. Since his intracranial pressure was 40 cm H2O, an external ventricular drain was inserted and the tumor was debulked. Eventually it was confirmed that the mass was a medulloblastoma. He was not treated with chemotherapy until the 19th day post-surgery because of a delay in obtaining the histological results. Following neurosurgery on Day 1 after admission to remove the medulloblastoma, the patient developed severe hypertension. In the first 24 hours post-op, he received 3 doses of dexamethasone 2 mg, followed by a rapid taper, which may have contributed to the high blood pressure. His blood pressure was tested using random sampling, and the 50th,95th, and 99th percentiles were 93/44 mm Hg, 110/63 mm Hg, and 118/71 mm Hg, respectively. He was treated with IV labetalol (increasing doses of up to 0.3 mg/kg/dose, followed by a continuous infusion of 0.5 mg/kg/hour), which did not adequately control his blood pressure (Fig. 1) He was also given a fentanyl infusion (2 mg/kg/hour) and a midazolam infusion (2 mg/kg/min). Tylenol and ibuprofen were given for additional pain control. Continuing treatment with IV furosemide (up to 3.5 mg/kg/day) and a single oral dose of 10 mgof clonidine were ineffective and led to intravascular volume contraction, necessitating their discontinuation. Increased doses of amlodipine (up to 0.33 and later 0.5 mg/kg/day, maximum dose 0.2–0.5 mg/kg/day)5 and clonidine (0.02 mg/kg/day, maximum dose 0.01–0.025 mg/kg/day)6 failed to lower his blood pressure to below the 95th percentile. The route of administration of labetalol was changed from IV to oral and the dosage was increased (up to 11.6 mg/kg/day, maximum dose 12 mg/kg/day)7, then replaced with atenolol, at a dose of up to 1.54 mg/kg/day (maximum dose 2 mg/kg/day)8. The patient’s blood pressure climbed to 157/102 mm Hg. An additional workup was performed to further elucidate the etiology of the hypertension. Cystatin C eGFR was normal at 137 mL/min/1.73 m2.13 Twenty-four hour hydroxyindole acetic acid in urine was normal at 37 mmol/d [normal ,43 mmol/d], vanillylmandelic acid was normal at 9.1 mmol/d [normal ,14.0 mmol/d], and homovanillic acid was 6.7 mmol/mmol creatinine [normal ,14.0 mmol/mmol creatinine]. Chemotherapy with IV vincristine, etoposide and cyclophosphamide was not started until the 19th day post-surgery because of a delay in obtaining the histology of the posterior fossa tumor. Blood pressure control remained poor during this time, and most options for antihypertensive therapy had been exhausted. We considered other options: vasodilators were not given as IV formulations of direct vasodilators such as minoxidil (licensed for children) are unavailable.14 Agents from the other classes of antihypertensives were already being given at maximum doses, and combining agents of the same class is not recommended. We did not consider an ACE inhibitor targeting the RAS to treat this Page 3 of 6 Filler et al. QScience Connect 2014:12 Figure 1. Systolic and diastolic blood pressure in a patient with neurogenic hypertension in relationship to the blood pressure medications used. The increase above the tic on the right y-axis reflects the increase to the maximum dose recommended for each drug. Cyproheptadine was administered from Day 18 to Day 45 following admission. condition, as we preferred to use an approach that would target the potential underlying mechanism and it was unlikely that aldosterone was responsible.12 Consequently, making use of a different agent in treating this child, namely cyproheptadine,9 was a feasible alternative (Fig. 1). The recommended dose for cyproheptadine is 2 mg every 12 hours for children 2–6 years old, with no recommendations for children under 2. A starting dose of 1 mg was administered, which significantly improved the patient’s blood pressure. The median systolic pressure dropped from 128 Hg (143 measurements, interquartile range (IQR) 113 to 141 mm Hg) to 118 Hg (177 measurements, IQR 108 to 130 mm Hg), which was statistically significant ( p , 0.0001, Mann-Whitney test). This improvement was sustained even though doses of other antihypertensive medications were reduced (Fig. 1). Moreover, there was a marked reduction in the patient’s diurnal variability. Unfortunately, the patient developed elevated liver enzymes one month after being hospitalized (Fig. 2): liver transaminases were measured on Day 31, with alanine aminotransferase (ALT) at 93 U/L and aspartate aminotransferase (AST) at 21 U/L. On Day 45, his ALT and AST escalated to 486 U/L and 236 U/L, respectively. Total bilirubin and alkaline phosphatase were unaffected. Testing did not reveal a viral cause for liver injury and results from an abdominal ultrasound were normal. Drugs given to the patient with the potential to induce hepatic injury included sulfamethoxazole/trimethoprim (cotrimoxazole), prophylactic therapy for Pneumocystis jirevocii pneumonia started on Day 31 (5 mg/kg/day of trimethoprim component), and cyproheptadine (0.04 mg/kg/dose q12h) initiated on Day 18.10,11 Both drugs were discontinued on Day 46.