OPEN ACCESS Research article 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, , 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 .4 Pediatric nephrologists are often called to assist with these cases and often consider adding a . ACE inhibitors are given once the patient is more stable and can tolerate oral . 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 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 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 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 . 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. 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. ALT and AST peaked on Day 47 at 774 U/L and 314 U/L, respectively, and returned to baseline levels on Day 53. Cotrimoxazole was restarted two weeks later and had no effect on liver transaminases. The transient increase was therefore attributed to cyproheptadine and the authors decided not to re-initiate this therapy. However, it was not entirely certain that the elevated liver enzymes were related to cyproheptadine, since the chemotherapy that the patient received could also have played a role. To test this, a Roussel-Uclaf analysis was performed (a well-known validated tool for assessing the causality of adverse drug reactions) and the results suggested causality (Table 1). Nonetheless, chemotherapy still may have contributed to the elevated liver enzymes. Page 4 of 6 Filler et al. QScience Connect 2014:12

Figure 2. Liver enzymes during and after treatment with cyproheptadine. Cyproheptadine was administered from Day 18 to Day 45 following admission. Following a second intracranial surgery on Day 99 to remove suspected residual medulloblastoma, the child was taken to another institution to undergo high-dose chemotherapy with autologous stem cell rescue. His blood pressure was maintained using atenolol, amlodipine, and clonidine, the last of which was administered at significantly higher doses in order to maintain blood pressure at the 95th percentile.

DISCUSSION Acute or transient intermittent hypertension in children can be caused by the following etiologies: renal, drugs and poisons, central and autonomic nervous system, and miscellaneous conditions. Table 2 lists all of the known conditions. In our case, a patient with a posterior fossa lesion, changes in

Table 1. Roussel-Uclaf Causality Assessment Method (RUCAM). Initial treatment of cyproheptadine leading to hepatocellular type of acute liver injury.

Criteria Description Score Patient’s Score

Time to onset of reaction 5- 90 days of drug start* þ2 þ2 , 5or. 90 days of drug start þ1 # 15 days from drug cessation þ1 Course of reaction after Decrease $50% within 8 days* þ3 þ3 drug cessation (difference Decrease $ 50% within 30 days þ2 between peak ALT and Not application þ1 upper limit of normal) No information/Decrease $ 50% after 30 days 0 Recurrent increase 22 Risk factors Age $ 55 þ1 0 Alcohol use þ1 Concomitant drugs Time to onset incompatible 0 22 Time to onset compatible but unknown reaction 21 Time to onset compatible and known reaction 22 Role proved in this case 23 None or information not available 0 Non-drug related causesa All causes (groups I and II) reasonably ruled out þ2 þ2 6 causes of group I ruled out þ1 5 or 4 causes of group I ruled out 0 Less than 4 causes of group I ruled out 22 Non drug cause highly probable 23 Previous information Reaction unknown 0 þ1 on drugb Reaction published but unlabeled þ1 Reaction labeled in product’s characteristics þ2 Response to Positive þ3 0 readministration Compatible þ1 Negative 22 Not available or Not interpretable 0 a:Group I causes: recent viral infection with hepatitis A or B or C virus, biliary obstruction, alcoholism, acute recent hypotension history Group II causes: complication of underlying disease(s), clinical and/or biological context suggesting CMV, EBV or herpes virus infection b:Cyproheptadine discontinued in Canada since 2003; no monograph available Note: The total score is graded into five categories: i) highly probable (score . 8); ii) probable (6 – 8); iii) possible (3 – 5); iv) unlikely (1 – 2); or excluded (,0) Page 5 of 6 Filler et al. QScience Connect 2014:12

Table 2. Conditions associated with transient or intermittent hypertension in children (adapted from Nelson, Textbook of Pediatrics, Kliegman, Behrman, Jenson and Stanton eds., 18th edition, Saunders, 2007:1989). Renal Drugs and Toxins Acute postinfectious glomerulonephritis Cocaine Anaphylactoid purpura with nephritis Oral Contraceptives Hemolytic uremic syndrome Sympathomimetic Agents Acute tubular necrosis Amphetamines After renal transplant Phencyclidine After blood transfusion in a patient with azotemia and adrenocorticoid Hypervolemia Calcineurin inhibitors after transplantation After surgical procedures in the genitourinary tract Liquorice Pyelonephritis Heavy metals Renal trauma Antihypertensive withdrawal Leukemic infiltrates of the kidney Vitamin D intoxication Obstructive uropathy associated with Crohn’s disease Central and autonomic nervous system Miscellaneous Increased intracranial pressure Preeclampsia Guillain Barre Syndrome Fractures of long bones Burns Hypercalcemia Familial dysautonomia After Coarctation repair Stevens Johnson Syndrome White cell transfusion Posterior fossa lesions (our patient) Extracorporeal membrane oxygenation Porphyuria Chronic upper airway obstruction Poliomyelitis Encephalitis the dopamine or serotonin system may play a key role. Despite treatment using three agents, with both labetalol and clonidine targeting the sympathetic blockade, the patient’s blood pressure remained well above the 99th percentile for his age, signaling resistant hypertension and suggesting that serotonin may have been playing a part in the patient’s symptoms.12 We hypothesized that central hypertension, independent of catecholamines, may have played a role. While there is no test to directly diagnose central hypertension, the appearance of a number of clinical signs, such as labile and unexplained severe hypertension refractory to drug combinations targeting the RAS and sodium/volume systems, with the absence of a clinical picture of volume excess,3 adds to mounting evidence and increases suspicion of this condition. These clinical cues, along with the substantial fluctuations in his blood pressure that suggested autonomic deregulation, led us to suspect that he had central hypertension (Fig. 1). Cyproheptadine is a serotonin antagonist, competing with histamine for H1-receptor sites on effector cells in the gastrointestinal tract, respiratory tract, and blood vessels. It is primarily used as an and prophylactically to treat headaches. It is also an (used in nervosa) and used for managing spasticity associated with spinal cord damage.15 Side effects include hypotension, sedation, hepatitis–and in rare cases–central anticholinergic syndrome.15 Though the role of serotonin in fluctuating blood pressure is not yet entirely clear, there have been published cases suggesting that cyproheptadine can be used to control hypertension induced by a carcinoid tumor’s release of this vasoactive neurotransmitter, through its anti-serotonin mechanism of action.16 Similarly, cyproheptadine has also been found to be effective in treating both “autonomic storms” present in cases of traumatic brain injury and acute baclofen withdrawal17 and Cushing syndrome, the latter by evening out the diurnal blood pressure variations associated with this condition.9 Our patient did receive but not while on cyproheptadine, and it is not entirely clear whether there was autonomic dysregulation. Our treatment rationale was based on the preceding evidence and our patient was given cyproheptadine for his refractory hypertension. He responded well and his systolic blood pressure decreased, a change that was statistically significant. The results of this case demonstrate the favorable efficacy profile of cyproheptadine when used to treat refractory hypertension in a 20-month-old child. Unfortunately, however, its safety profile in this situation is questionable. The cyproheptadine was discontinued when the patient developed “transaminitis”, thought to be a drug-induced liver injury (DILI). DILI is known to cause a spectrum of reactions, from mild biochemical changes to acute liver failure. The severity of these secondary effects can be unpredictable and unrelated to dose, and they can emerge after a latency period (usually 5-90 days). The injury can either be predominantly hepatocellular or cholestatic, or a mix of both.11 Previous case reports18,19 have Page 6 of 6 Filler et al. QScience Connect 2014:12

directly linked cyproheptadine to liver injury, albeit this is a very rare . This correlation is supported by the patient’s lack of a history of liver disease, the normal biliary tract ultrasound findings, and the reversal of “transaminitis” after the drug was discontinued.19 The Roussel-Uclaf causality assessment20 was used to expand the investigation into the cause of liver injury, and cyproheptadine received a score of 6, or ‘probable’ (Table 1). Concomitant chemotherapy and drug interactions with amlodipine, clonidine and atenolol may have also confounded this rare side effect. As with most cases of DILI, the effect of cyproheptadine was reversed once the agent was discontinued.10,11 Although the DILI was reversed once the cyproheptadine was discontinued, his blood pressure became elevated once again, suggesting that the treatment with cyproheptadine targeted an important pathophysiological mechanism. We feel that cyproheptadine may be a suitable alternative for the management of refractory central hypertension.

CONCLUSION Cyproheptadine therapy significantly improved systolic and diastolic blood pressure and reduced the diurnal variability in a paediatric patient with resistant central hypertension. It is unfortunate that this treatment was hepatotoxic and had to be discontinued for this reason. Elevated liver enzymes are a rare side effect and causality is not certain. We conclude that cyproheptadine’s efficacy in treating this condition may be promising and future clinical use of this agent (if carefully monitored for hepatotoxicity) should be considered.

AUTHORS’ CONTRIBUTIONS: GF and AP developed the therapeutic idea and designed the data acquisition, data analysis and interpretation of the data. GF drafted the study, together with LH. GF performed the analyses and generated the figures. AC collected all medication data and entered all data into a spreadsheet, necessary for the creation of the graphs. EC contributed to the conception and design of the study. All authors revised the manuscript critically for content, read and approved the final manuscript.

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