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  • Confidential - Not for Circulation A case of angioedema from dihydropyridine calcium channel blockers in a child with Burkitt lymphoma Journal: Pediatrics Re Manuscript ID: 2009-3291 Article Type: Case Report Date Submitted by the vi 24-Nov-2009 Author: Complete List of Authors: Pierce, Wesly; University of Mississippi, School of Pharmacy ew Hederman, April; University of Mississippi, Department of Pediatrics, Division of Pediatric Hematology/Oncology Gordon, Catherine; University of Mississippi, Department of Pediatrics, Division of Pediatric Hematology/Oncology Ostrenga, Andrew; University of Mississippi, Department of Pharmacy Co Herrington, Betty; University of Mississippi, Department of Pediatrics, Division of Pediatric Hematology/Oncology Angioedema , Calcium Channel Blockers, Macroglossia, Amlodipine, Keyword/Category: Nicardipine py The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
  • Page 1 of 9 Confidential - Not for Circulation Authors and Affiliations: 1 2 Wesly A. Pierce, B.S.Pharm a 3 April D. Hederman, M.D. b 4 Catherine J. Gordon, M.D. b 5 Andrew R. Ostrenga, Pharm.D. c 6 7 Betty L. Herrington, M.D. b 8 9 a 10 School of Pharmacy, University of Mississippi Medical Center, Jackson, Mississippi b 11 Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Mississippi Medical Center, 12 Jackson, Mississippi c 13 Department of Pharmacy, University of Mississippi Medical Center, Jackson, Mississippi 14 15 Title: 16 17 A case of angioedema from dihydropyridine calcium channel blockers in a child with Burkitt lymphoma. 18 19 20 Abbreviations: 21 Re 22 CCB – Calcium Channel Blocker 23 ACE – Angiotensin Converting Enzyme 24 25 vi 26 Keywords: 27 28 Angioedema, Calcium Channel Blockers, Macroglossia, Amlodipine, Nicardipine ew 29 30 31 Financial Disclosures: None 32 33 Conflicts of Interest: None Co 34 35 36 Corresponding Author: 37 py 38 Betty Herrington, M.D. 39 Assistant Professor, Pediatrics 40 Associate, Pediatric Hematology/Oncology 41 Director, Pediatric Neuro-Oncology 42 University of Mississippi Health Care 43 2500 North State Street 44 45 Jackson, Mississippi 39216 46 (601) 984-5220 (p) 47 (601) 984-2702 (f) 48 bherrington@ped.umsmed.edu 49 50 51 52 53 Abstract Length: 236 words 54 Article Length: 1,594 words 55 56 57 58 59 60 The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
  • Confidential - Not for Circulation Page 2 of 9 Abstract: 1 2 Calcium channel blockers (CCBs) are widely used agents for emergent and non-emergent blood pressure control 3 4 in pediatric patients. Angioedema is a rare, potentially life-threatening phenomenon associated with cutaneous and 5 mucosal swelling, usually involving the face and oropharynx. Multiple etiologies exist for angioedema, however drugs 6 7 are the most common cause, with angiotensin-converting enzyme (ACE) inhibitors being the most recognized offenders. 8 9 Several isolated case reports of angioedema have implicated both dihydropyridine and non-dihydropyridine CCBs, but 10 11 none have involved a pediatric patient. We report a case of angioedema in an eight-year-old boy with Burkitt lymphoma 12 occurring 72 hours after initiation of a nicardipine infusion and prolonged by oral therapy with amlodipine. Resolution 13 14 began 24 hours after cessation of CCB therapy and was complete within one week. Factors contributing to our diagnosis 15 16 were as follows: (1) a strong temporal relationship between the reaction and CCB administration, (2) previous 17 18 documentation of the reaction with CCBs in published case reports, (3) timely resolution of the reaction upon drug 19 withdrawal, and (4) the absence of any other reasonable explanation based on known characteristics of the child’s 20 21 clinical state. The resultant Naranjo probability score indicates a “probable” association between CCBs and angioedema Re 22 23 in our case. We also present a review of the available literature, summarize the diagnostic process, and discuss possible 24 pathophysiologic mechanisms for CCB-induced angioedema. To our knowledge, this is the first reported case of 25 vi 26 angioedema caused by CCB therapy in a child. 27 28 ew 29 30 Introduction: 31 Dihydropyridine calcium channel blockers (CCBs) are the second-most commonly prescribed agents for pediatric 32 33 hypertension behind angiotensin-converting enzyme (ACE) inhibitors.1 Intravenously administered nicardipine is a Co 34 35 rapidly acting dihydropyridine CCB that possesses a short half-life requiring continuous infusion and titration to optimal 36 37 blood pressure.2 It is approved by the United States Food and Drug Administration for the treatment of hypertension py 38 when oral therapy is not feasible or not desirable (i.e. intubation), and has been used safely for severe hypertension and 39 40 hypertensive emergencies in both newborns and children.2,3 Amlodipine is an orally administered dihydropyridine CCB 41 42 with an extended half-life and increased bioavailability allowing for once-daily administration.1,2 It is currently the agent 43 of choice in some institutions for non-emergent blood pressure control in infants and children.2 44 45 Angioedema is a potentially critical condition characterized by swelling of cutaneous and mucosal tissue, usually 46 47 involving areas of loose skin (i.e. the face, neck, and genitalia).4 Maculopapular and pruritic eruptions may accompany 48 49 edema.5-7 Involvement of the upper respiratory and gastrointestinal epithelia can also occur, manifesting as laryngeal 50 edema, macroglossia, abdominal pain, nausea, and diarrhea.4,5 Emergent intervention involving intubation and 51 52 pharmacotherapy with antihistamines and steroids may be necessary to prevent respiratory distress.4 Multiple 53 54 environmental and immune-mediated etiologies exist for developing acute angioedema, but it is most commonly 55 56 iatrogenic in nature, with ACE-inhibitors accounting for the majority of acute cases in emergency hospital departments 57 (17%-38%).4,5 58 59 A PubMed literature search using the search terms “angioedema” and “calcium channel blocker” identified ten 60 published case-reports of angioedema induced by CCBs.6-10 Of these cases, only two cases involved amlodipine9,10 while The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
  • Page 3 of 9 Confidential - Not for Circulation only four involved nicardipine.8,9 None included a pediatric patient. We report a case of angioedema with extensive 1 2 macroglossia in a child with Burkitt lymphoma treated with both nicardipine and amlodipine. 3 4 5 Patient Presentation: 6 7 An eight-year-old white male with no prior medical history presented to the pediatric emergency department 8 9 with complaints of abdominal pain and distention after a history of mild abdominal trauma. Physical exam was 10 11 significant for diffuse abdominal tenderness and distention with a large palpable mass in the right quadrants. Computed 12 tomography revealed a large abdominal mass and biopsy confirmed a diagnosis of Burkitt lymphoma. Metastatic work- 13 14 up was negative. 15 16 Before tumor directed chemotherapy was started, the child developed severe tumor lysis syndrome resulting in 17 18 acute renal failure. He was treated with rasburicase 0.2 mg/kg intravenously and placed on renal dialysis. Initially, he 19 was hypotensive and required pressor support with intubation and mechanical ventilation. While intubated, he was 20 21 sedated with midazolam and fentanyl. Standard chemotherapy for Burkitt lymphoma was subsequently initiated, Re 22 23 resulting in rapid tumor regression. 24 After a period of nine days, the child was successfully extubated, but required re-intubation several days later. 25 vi 26 At this time, he had no physical signs of angioedema. He began having hypertension, which was initially treated with a 27 28 nicardipine infusion at 1 μg/kg/hr. After three days, the child began having facial swelling and significant, protruding ew 29 30 macroglossia [Figure 1]. Eight days after the nicardipine was started, he required a tracheotomy for upper airway 31 obstruction. His nicardipine infusion was discontinued after tracheotomy, and he was titrated to amlodipine 5 mg daily 32 33 for hypertension. Co 34 35 Initially, it was felt that the tongue swelling was due to prolonged intubation or severe mucositis from 36 37 chemotherapy, but the swelling did not improve after tracheotomy or resolution of mucositis. Infection, thrombosis, py 38 and metastatic Burkitt lymphoma were also considered as potential causes of the macroglossia, but these were ruled 39 40 out by cultures, Doppler ultrasound, otolaryngology consult, and radiologic imaging. 41 42 Eighteen days after the tracheotomy, the child continued to have severe macroglossia of unknown etiology. At 43 this time, a multidisciplinary medical team met together and reviewed the child’s medical course. Clinical pharmacy 44 45 evaluated all medications, including chemotherapy, to determine any possible temporal relationship between 46 47 medication initiation and symptom onset. All medications were temporally unrelated, except for the CCBs. The child 48 49 remained on amlodipine for hypertension at the time of review. Since blood pressures were stable, amlodipine was 50 tapered to discontinuation over a two day period. The next day, the tongue swelling began to improve and was 51 52 completely resolved within one week of amlodipine discontinuation [Figure 2]. 53 54 55 56 Discussion: 57 The earliest isolated case reports of CCB-induced angioedema implicated the non-dihydropyridine CCBs, 58 59 diltiazem and verapamil.6,7 These cases involved male and female patients over the age of 50 and described reactions 60 such as facial and periorbital edema, macroglossia, and maculopapular, pruritic eruptions. More recently, the The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
  • Confidential - Not for Circulation Page 4 of 9 dihydropyridine CCB’s have caused the majority of isolated cases. Suave et al.8 reported 3 cases of classic facial 1 2 angioedema in adult patients, two of which occurred secondary to nicardipine and the third case involved both 3 4 nifedipine and nicardipine. Amlodipine has been recently implicated in two cases of angioedema.9,10 Turcu et al.10 5 reported a 56-year-old woman who developed angioedema of the small intestine, resulting in eight episodes of 6 7 periumbilical, crampy, and intermittent abdominal pain over two years. Each episode lasted 48-72 hours, occurred 8 9 approximately three months apart, and subsequently ceased after amlodipine discontinuation. Therapy re-challenges 10 11 with other dihydropyridine CCBs (nisoldipine and isradipine) resulted in similar reactions. 12 Our case most closely resembles one reported by Southward et al.9 in which a 50 year-old African American 13 14 female developed severe facial edema and protruding macroglossia 24 hours after amlodipine was administered. 15 16 Amlodipine was initiated while a nicardipine infusion was being tapered to discontinuation. Interestingly, the patient’s 17 18 medical history included therapy with verapamil (a non-dihydropyridine CCB), which she tolerated. Similar to our case, 19 her reaction to amlodipine began resolving 24 hours after CCB discontinuation. However in our case, angioedema 20 21 appeared after nicardipine initiation, persisted after nicardipine cessation, and continued throughout amlodipine Re 22 23 therapy. 24 This child’s complicated medical condition and treatment course – which included tumor lysis syndrome, acute 25 vi 26 renal failure, hypotension, hypertension, intensive chemotherapy, and repeated intubation – introduced several 27 28 possible etiologies for the development of macroglossia. Metastatic dissemination of the abdominal tumor was also ew 29 30 considered based on three previous case reports of Burkitt lymphoma involving the base of the tongue.11-13 These cases 31 described adult males who presented with a mass confined to the base of the tongue with no abdominal or other extra- 32 33 abdominal involvement. These potential etiologies were subsequently ruled out by clinical laboratory and medical Co 34 35 imaging. Re-examination of the treatment timeline and medication profile by the clinical pharmacist revealed a strong 36 37 temporal relationship between the administration of nicardipine and the onset of angioedema. This prompted a brief py 38 literature search for previous cases of angioedema induced by CCBs. Amlodipine removal was then attempted, followed 39 40 by complete resolution of protruding macroglossia. Although the child was never re-challenged with a CCB to confirm 41 42 causality, use of the Naranjo probability scale revealed a “probable” relationship between CCB therapy and 43 angioedema.14 Contributing factors included a strong temporal relationship, previous documentation of the reaction 44 45 with CCBs, timely resolution upon withdrawal, and the absence of any other reasonable explanation based on known 46 47 characteristics of the child’s clinical state. 48 49 ACE-inhibitors induce angioedema by reducing angiotensin II-mediated vasoconstriction and antagonizing ACE- 50 mediated catabolism of bradykinin, a highly vasoactive peptide that increases vascular permeability in the skin.4,15 51 52 Bradykinin accumulation along with decreased angiotensin II production results in vasodilation and subcutaneous 53 54 edema.15 While this pathophysiologic mechanism is well understood for ACE-inhibitors, CCB-induced angioedema has no 55 56 substantiated mechanism.10 CCBs inherently cause arteriolar vasodilation, but this action alone cannot fully explain the 57 relative rarity of angioedema with these agents. It has been postulated that amlodipine has pleiotropic effects 58 59 independent of its action on L-type calcium channels, such as the stimulation of kinin and vascular nitrous oxide 60 production.9,16 This may potentiate the inherent action of amlodipine and precipitate angioedema in some patients. The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
  • Page 5 of 9 Confidential - Not for Circulation However, stimulation of kinin activity and nitrous oxide production by amlodipine has been observed primarily in canine 1 2 and primate models and requires further corroboration in human clinical trials.17,18 To our knowledge, this effect has not 3 4 been documented for nicardipine. It should be noted that nicardipine is a potent inhibitor of the CYP3A4 enzyme, of 5 which amlodipine is a substrate.9,19 In our case, providing amlodipine after the administration of a nicardipine infusion 6 7 may have resulted in a supra-therapeutic bioavailability for amlodipine, intensifying and prolonging the patient’s initial 8 9 reaction to nicardipine until amlodipine was removed. 10 11 Due to the established mechanism, angioedema from ACE-inhibitors is considered a class effect.20 Interestingly 12 enough, the anecdotal evidence suggests CCB-induced angioedema may not be a class effect in all patients. Turcu et 13 14 al.10 demonstrated that CCB-induced angioedema in their patient was a class effect for dihydropyridine CCBs because 15 16 therapy re-challenges with two other dihydropyridine CCBs yielded the same reaction. Similarly, angioedema seems to 17 18 be a dihydropyridine class effect for our patient, as the reaction was first noted after nicardipine initiation and persisted 19 through amlodipine therapy. In contrast, Southward et al.9 reported a patient who seemed to develop angioedema only 20 21 after amlodipine administration despite her previous toleration to verapamil and nicardipine. These reports, albeit small Re 22 23 in number, suggest that cross-reactivity among CCBs may vary from patient to patient. Further clinical trials, 24 immunologic studies, and biochemical investigations would be needed to substantiate and explain this unique finding. 25 vi 26 To conclude, we believe this is the first reported case of CCB-induced angioedema in a pediatric patient. 27 28 Angioedema is rare phenomenon most strongly associated with ACE-inhibitors, however, CCBs were the offending agent ew 29 30 in this case. The association between CCBs and angioedema is supported by a small number of similar case reports in 31 adults, which collectively suggest that angioedema may not be a CCB class effect in all patients. Several mechanisms 32 33 have been suggested for CCB-induced angioedema, but none have been substantiated. Because of the widespread use Co 34 35 of these drugs in children and potential criticality of angioedema, pediatric clinicians everywhere should be cognizant of 36 37 this association so that future occurrences are diagnosed and treated in a timely manner. py 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
  • Confidential - Not for Circulation Page 6 of 9 1 References: 2 3 4 5 1. Robinson RF, Nahata MC, Batisky DL, Mahan JD. Pharmacologic treatment of chronic pediatric hypertension. 6 7 Pediatr Drugs. 2005;7(1):27-40 8 2. Sahney S. A review of calcium channel antagonists in the treatment of pediatric hypertension. Pediatr Drugs. 9 10 2006;8(6):357-373 11 12 3. Cardene® [package insert]. Bedminster, NJ: EKR Therapeutics, Inc., 2007 13 14 4. Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol. 2005;53(3):373-388 15 5. Temino VM, Peebles RS. The spectrum of treatment of angioedema. Am J Med. 2008;121(4):282-286 16 17 6. Sadick NS, Katz AS, Schreiber TL. Angioedema from calcium-channel blockers. J Am Acad Dermatol. 18 19 1989;21(1):132-133 20 7. Romano A, Pietrantonio F, Garcovich A, et al. Delayed hypersensitivity to diltiazem in two patients. Ann Allergy. 21 Re 22 1992;69(1):31-32 23 24 8. Sauve L, Gras-Champel V, Decocq G, Masson H, Andrejak M. Angioedema associated with the use of 25 vi 26 dihydopyridines [in French]. Therapie. 1999;54(1):64-65 27 9. Southward J, Irvine E, Rabinovich M. Probable amlodipine-induced angioedema. Ann Pharmacother. 28 ew 29 2009;43(4):772-776 30 31 10. Turcu AF, White JA, Kulaga ME, Skluth M, Gruss CB. Calcium channel blocker-associated small bowel 32 33 angioedema. J Clin Gastroenterol. 2009;43(4):338-341 Co 34 11. Manolopoulos L, Nikolopoulos TP, Yiotakis J, Karapatsas J, Maris A, Ferekidis E. Burkitt’s lymphoma at the base 35 36 of the tongue: differential diagnosis and management. ORL J Otorhinolaryngol Relat Spec. 2003;65(4):226-229 37 py 38 12. Yoskovitch A, Hier MP, Begin LR, et al. Dorsal tongue mass. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 39 2000;90:5-8 40 41 13. Feinberg SM, Ou SHI, Gu M, Shibuya TY. Burkitt’s lymphoma of the base of the tongue: a case report and 42 43 review of the literature. Ear Nose Throat J. 2007;86(6):356-360 44 45 14. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin 46 Pharmacol Ther. 1981;30(2):239-245 47 48 15. Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-oedema. 49 50 Lancet. 1998;351(9117):1693-1697 51 52 16. Mason RP, Marche P, Hintze TH. Novel vascular biology of third-generation L-type calcium channel antagonists: 53 Ancillary actions of amlodipine. Arterioscler Thromb Vasc Biol. 2003:23(12);2155-2163 54 55 17. Zhang X, Recchia FA, Bernstein R, Xu X, Nasjletti A, Hintze TH. Kinin-mediated coronary nitric oxide production 56 57 contributes to the therapeutic action of angiotensin-converting enzyme and neutral endopeptidase inhibitors 58 and amlodipine in the treatment of heart failure. J Pharmacol Exp Ther. 1999;288(2):742-751 59 60 The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
  • Page 7 of 9 Confidential - Not for Circulation 18. Forfia PR, Zhang X, Knight DR, et al. NO modulates myocardial O2 consumption in the nonhuman primate: an 1 2 additional mechanism of action of amlodipine. Am J Physiol. 1999; 276(6 pt. 2): H2069–H2075 3 4 19. Nakamura K, Ariyoshi N, Iwatsubo T, et al. Inhibitory effects of nicardipine to cytochrome P450 (CYP) in human 5 liver microsomes. Biol Pharm Bull. 2005;28(5):882-885 6 7 20. Vleeming W, van Amsterdam JG, Stricker BH, de Wildt DJ. ACE inhibitor-induced angioedema: incidence, 8 9 prevention and management. Drug Saf. 1998;18(3):171–188 10 11 12 13 14 15 16 17 18 19 20 21 Re 22 23 24 25 vi 26 27 28 ew 29 30 31 32 33 Co 34 35 36 37 py 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
  • Confidential - Not for Circulation Page 8 of 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Re 22 23 24 25 vi 26 27 28 ew 29 30 31 32 33 Co 53x40mm (400 x 400 DPI) 34 35 36 37 py 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
  • Page 9 of 9 Confidential - Not for Circulation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Re 22 23 24 25 vi 26 27 28 ew 29 30 31 32 33 Co 34 35 190x146mm (96 x 96 DPI) 36 37 py 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007