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Management of Anaphylaxis Refractory to Standard First Line Therapy

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Anaphylaxis

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Abstract

Anaphylaxis is a common yet often under-recognized and undertreated phenomenon. Experts have defined the term various ways but all agree that the standard of care is rapid treatment with epinephrine upon diagnosis of anaphylaxis. However, some cases of anaphylaxis are either partially or unresponsive to standard doses of epinephrine, a phenomenon referred to as refractory anaphylaxis. The epidemiology, risk factors, preventative measures, and treatments (both traditionally accepted second-line therapies and more controversial novel therapies) of refractory anaphylaxis are discussed in this chapter.

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References

  1. Simons FE, Ardusso LR, Bilo MB, Cardona V, Ebisawa M, El-Gamal YM, et al. International consensus on (ICON) anaphylaxis. World Allergy Organ J. 2014;7(1):9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Muraro A, Roberts G, Worm M, Bilo MB, Brockow K, Fernandez Rivas M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69(8):1026–45.

    Article  CAS  PubMed  Google Scholar 

  3. Lieberman P, Nicklas RA, Randolph C, Oppenheimer J, Bernstein D, Bernstein J, et al. Anaphylaxis – a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;115(5):341–84.

    Article  PubMed  Google Scholar 

  4. Simons FE, Ardusso LR, Bilo MB, Dimov V, Ebisawa M, El-Gamal YM, et al. 2012 Update: World Allergy Organization Guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol. 2012;12(4):389–99.

    Article  PubMed  Google Scholar 

  5. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report – Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391–7.

    Article  PubMed  Google Scholar 

  6. Francuzik W, Dolle S, Worm M. Risk factors and treatment of refractory anaphylaxis - a review of case reports. Expert Rev Clin Immunol. 2018;14(4):307–14.

    Article  CAS  PubMed  Google Scholar 

  7. Gouel-Cheron A, Harpan A, Mertes PM, Longrois D. Management of anaphylactic shock in the operating room. Presse Med. 2016;45(9):774–83.

    Article  PubMed  Google Scholar 

  8. Tejedor Alonso MA, Moro Moro M, Mugica Garcia MV. Epidemiology of anaphylaxis. Clin Exp Allergy. 2015;45(6):1027–39.

    Article  CAS  PubMed  Google Scholar 

  9. Mullins RJ, Wainstein BK, Barnes EH, Liew WK, Campbell DE. Increases in anaphylaxis fatalities in Australia from 1997 to 2013. Clin Exp Allergy. 2016;46(8):1099–110.

    Article  CAS  PubMed  Google Scholar 

  10. Sclar DA, Lieberman PL. Anaphylaxis: underdiagnosed, underreported, and undertreated. Am J Med. 2014;127(1 Suppl):S1–5.

    Article  PubMed  Google Scholar 

  11. Motosue MS, Bellolio MF, Van Houten HK, Shah ND, Campbell RL. Risk factors for severe anaphylaxis in the United States. Ann Allergy Asthma Immunol. 2017;119(4):356–61. e2

    Article  PubMed  Google Scholar 

  12. Clark S, Wei W, Rudders SA, Camargo CA Jr. Risk factors for severe anaphylaxis in patients receiving anaphylaxis treatment in US emergency departments and hospitals. J Allergy Clin Immunol. 2014;134(5):1125–30.

    Article  PubMed  Google Scholar 

  13. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. 2001;107(1):191–3.

    Article  CAS  PubMed  Google Scholar 

  14. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. 1992;327(6):380–4.

    Article  CAS  PubMed  Google Scholar 

  15. Yunginger JW, Sweeney KG, Sturner WQ, Giannandrea LA, Teigland JD, Bray M, et al. Fatal food-induced anaphylaxis. JAMA. 1988;260(10):1450–2.

    Article  CAS  PubMed  Google Scholar 

  16. Pumphrey RS, Gowland MH. Further fatal allergic reactions to food in the United Kingdom, 1999-2006. J Allergy Clin Immunol. 2007;119(4):1018–9.

    Article  PubMed  Google Scholar 

  17. Grabenhenrich L, Hompes S, Gough H, Rueff F, Scherer K, Pfohler C, et al. Implementation of anaphylaxis management guidelines: a register-based study. PLoS One. 2012;7(5):e35778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Turner PJ, Jerschow E, Umasunthar T, Lin R, Campbell DE, Boyle RJ. Fatal anaphylaxis: mortality rate and risk factors. J Allergy Clin Immunol Pract. 2017;5(5):1169–78.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Simons KJ, Simons FE. Epinephrine and its use in anaphylaxis: current issues. Curr Opin Allergy Clin Immunol. 2010;10(4):354–61.

    Article  CAS  PubMed  Google Scholar 

  20. Fineman SM, Bowman SH, Campbell RL, Dowling P, O’Rourke D, Russell WS, et al. Addressing barriers to emergency anaphylaxis care: from emergency medical services to emergency department to outpatient follow-up. Ann Allergy Asthma Immunol. 2015;115(4):301–5.

    Article  PubMed  Google Scholar 

  21. Stewart WJ, McSweeney SM, Kellett MA, Faxon DP, Ryan TJ. Increased risk of severe protamine reactions in NPH insulin-dependent diabetics undergoing cardiac catheterization. Circulation. 1984;70(5):788–92.

    Article  CAS  PubMed  Google Scholar 

  22. Dewachter P, Mouton-Faivre C, Hepner DL. Perioperative anaphylaxis: what should be known? Curr Allergy Asthma Rep. 2015;15(5):21.

    Article  PubMed  Google Scholar 

  23. Lieberman JA, Chehade M. Use of omalizumab in the treatment of food allergy and anaphylaxis. Curr Allergy Asthma Rep. 2013;13(1):78–84.

    Article  CAS  PubMed  Google Scholar 

  24. Warrier P, Casale TB. Omalizumab in idiopathic anaphylaxis. Ann Allergy Asthma Immunol. 2009;102(3):257–8.

    Article  PubMed  Google Scholar 

  25. Pitt TJ, Cisneros N, Kalicinsky C, Becker AB. Successful treatment of idiopathic anaphylaxis in an adolescent. J Allergy Clin Immunol. 2010;126(2):415–6. author reply 6

    Article  PubMed  Google Scholar 

  26. Jones JD, Marney SR Jr, Fahrenholz JM. Idiopathic anaphylaxis successfully treated with omalizumab. Ann Allergy Asthma Immunol. 2008;101(5):550–1.

    Article  PubMed  Google Scholar 

  27. Demirturk M, Gelincik A, Colakoglu B, Dal M, Buyukozturk S. Promising option in the prevention of idiopathic anaphylaxis: omalizumab. J Dermatol. 2012;39(6):552–4.

    Article  CAS  PubMed  Google Scholar 

  28. Bell MC, Jackson DJ. Prevention of anaphylaxis related to mast cell activation syndrome with omalizumab. Ann Allergy Asthma Immunol. 2012;108(5):383–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Carter MC, Robyn JA, Bressler PB, Walker JC, Shapiro GG, Metcalfe DD. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol. 2007;119(6):1550–1.

    Article  CAS  PubMed  Google Scholar 

  30. Douglass JA, Carroll K, Voskamp A, Bourke P, Wei A, O'Hehir RE. Omalizumab is effective in treating systemic mastocytosis in a nonatopic patient. Allergy. 2010;65(7):926–7.

    Article  CAS  PubMed  Google Scholar 

  31. Kontou-Fili K, Filis CI, Voulgari C, Panayiotidis PG. Omalizumab monotherapy for bee sting and unprovoked “anaphylaxis” in a patient with systemic mastocytosis and undetectable specific IgE. Ann Allergy Asthma Immunol. 2010;104(6):537–9.

    Article  PubMed  Google Scholar 

  32. Molderings GJ, Raithel M, Kratz F, Azemar M, Haenisch B, Harzer S, et al. Omalizumab treatment of systemic mast cell activation disease: experiences from four cases. Intern Med. 2011;50(6):611–5.

    Article  CAS  PubMed  Google Scholar 

  33. Jagdis A, Vadas P. Omalizumab effectively prevents recurrent refractory anaphylaxis in a patient with monoclonal mast cell activation syndrome. Ann Allergy Asthma Immunol. 2014;113(1):115–6.

    Article  PubMed  Google Scholar 

  34. Choo KJ, Simons FE, Sheikh A. Glucocorticoids for the treatment of anaphylaxis. Cochrane Database Syst Rev. 2012;(4):CD007596.

    Google Scholar 

  35. Sheikh A. Glucocorticosteroids for the treatment and prevention of anaphylaxis. Curr Opin Allergy Clin Immunol. 2013;13(3):263–7.

    Article  CAS  PubMed  Google Scholar 

  36. Alqurashi W, Ellis AK. Do corticosteroids prevent biphasic anaphylaxis? J Allergy Clin Immunol Pract. 2017;5(5):1194–205.

    Article  PubMed  Google Scholar 

  37. Brown AF, McKinnon D, Chu K. Emergency department anaphylaxis: a review of 142 patients in a single year. J Allergy Clin Immunol. 2001;108(5):861–6.

    Article  CAS  PubMed  Google Scholar 

  38. Gaeta TJ, Clark S, Pelletier AJ, Camargo CA. National study of US emergency department visits for acute allergic reactions, 1993 to 2004. Ann Allergy Asthma Immunol. 2007;98(4):360–5.

    Article  PubMed  Google Scholar 

  39. Worm M, Moneret-Vautrin A, Scherer K, Lang R, Fernandez-Rivas M, Cardona V, et al. First European data from the network of severe allergic reactions (NORA). Allergy. 2014;69(10):1397–404.

    Article  CAS  PubMed  Google Scholar 

  40. Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. 2010;126(3):477–80. e1–42.

    Article  PubMed  Google Scholar 

  41. Kemp AM, Kemp SF. Pharmacotherapy in refractory anaphylaxis: when intramuscular epinephrine fails. Curr Opin Allergy Clin Immunol. 2014;14(4):371–8.

    Article  CAS  PubMed  Google Scholar 

  42. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy. 2000;30(8):1144–50.

    Article  CAS  PubMed  Google Scholar 

  43. Macdougall CF, Cant AJ, Colver AF. How dangerous is food allergy in childhood? The incidence of severe and fatal allergic reactions across the UK and Ireland. Arch Dis Child. 2002;86(4):236–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Brown JC. Epinephrine, auto-injectors, and anaphylaxis: challenges of dose, depth, and device. Ann Allergy Asthma Immunol. 2018;121(1):53–60.

    Article  CAS  PubMed  Google Scholar 

  45. Simons FE, Edwards ES, Read EJ Jr, Clark S, Liebelt EL. Voluntarily reported unintentional injections from epinephrine auto-injectors. J Allergy Clin Immunol. 2010;125(2):419–23. e4

    Article  PubMed  Google Scholar 

  46. Wood JP, Traub SJ, Lipinski C. Safety of epinephrine for anaphylaxis in the emergency setting. World J Emerg Med. 2013;4(4):245–51.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Edwards ES, Gunn R, Simons ER, Carr K, Chinchilli VM, Painter G, et al. Bioavailability of epinephrine from Auvi-Q compared with EpiPen. Ann Allergy Asthma Immunol. 2013;111(2):132–7.

    Article  CAS  PubMed  Google Scholar 

  48. Brown SGAKS, Lieberman PL. Anaphylaxis. In: Adkinson Jr NFBB, Burks AW, et al., editors. Middleton's allergy: principles and practice. 2. 8th ed. Philadelphia: Elsevier Saunders; 2014. p. 1237–59.

    Google Scholar 

  49. Brown SG, Blackman KE, Stenlake V, Heddle RJ. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J. 2004;21(2):149–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Campbell RL, Bellolio MF, Knutson BD, Bellamkonda VR, Fedko MG, Nestler DM, et al. Epinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine. J Allergy Clin Immunol Pract. 2015;3(1):76–80.

    Article  PubMed  Google Scholar 

  51. Kanwar M, Irvin CB, Frank JJ, Weber K, Rosman H. Confusion about epinephrine dosing leading to iatrogenic overdose: a life-threatening problem with a potential solution. Ann Emerg Med. 2010;55(4):341–4.

    Article  PubMed  Google Scholar 

  52. Khoueiry G, Abi Rafeh N, Azab B, Markman E, Waked A, AbouRjaili G, et al. Reverse Takotsubo cardiomyopathy in the setting of anaphylaxis treated with high-dose intravenous epinephrine. J Emerg Med. 2013;44(1):96–9.

    Article  PubMed  Google Scholar 

  53. Soar J, Perkins GD, Abbas G, Alfonzo A, Barelli A, Bierens JJ, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special circumstances: electrolyte abnormalities, poisoning, drowning, accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electrocution. Resuscitation. 2010;81(10):1400–33.

    Article  PubMed  Google Scholar 

  54. Dhami S, Panesar SS, Roberts G, Muraro A, Worm M, Bilo MB, et al. Management of anaphylaxis: a systematic review. Allergy. 2014;69(2):168–75.

    Article  CAS  PubMed  Google Scholar 

  55. Havel C, Arrich J, Losert H, Gamper G, Mullner M, Herkner H. Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2011;(5):CD003709.

    Google Scholar 

  56. Smith PL, Kagey-Sobotka A, Bleecker ER, Traystman R, Kaplan AP, Gralnick H, et al. Physiologic manifestations of human anaphylaxis. J Clin Invest. 1980;66(5):1072–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hernandez-Cascales J. Does glucagon have a positive inotropic effect in the human heart? Cardiovasc Diabetol. 2018;17(1):148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Javeed N, Javeed H, Javeed S, Moussa G, Wong P, Rezai F. Refractory anaphylactoid shock potentiated by beta-blockers. Catheter Cardiovasc Diagn. 1996;39(4):383–4.

    Article  CAS  Google Scholar 

  59. Thomas M, Crawford I. Best evidence topic report. Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers. Emerg Med J. 2005;22(4):272–3.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zaloga GP, DeLacey W, Holmboe E, Chernow B. Glucagon reversal of hypotension in a case of anaphylactoid shock. Ann Intern Med. 1986;105(1):65–6.

    Article  CAS  PubMed  Google Scholar 

  61. Jang DH, Nelson LS, Hoffman RS. Methylene blue for distributive shock: a potential new use of an old antidote. J Med Toxicol. 2013;9(3):242–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Evora PR, Simon MR. Role of nitric oxide production in anaphylaxis and its relevance for the treatment of anaphylactic hypotension with methylene blue. Ann Allergy Asthma Immunol. 2007;99(4):306–13.

    Article  CAS  PubMed  Google Scholar 

  63. Da Silva PS, Furtado P. Methylene blue to treat refractory latex-induced anaphylactic shock: a case report. A A Pract. 2018;10(3):57–60.

    Article  PubMed  Google Scholar 

  64. Del Duca D, Sheth SS, Clarke AE, Lachapelle KJ, Ergina PL. Use of methylene blue for catecholamine-refractory vasoplegia from protamine and aprotinin. Ann Thorac Surg. 2009;87(2):640–2.

    Article  PubMed  Google Scholar 

  65. Oliveira Neto AM, Duarte NM, Vicente WV, Viaro F, Evora PR. Methylene blue: an effective treatment for contrast medium-induced anaphylaxis. Med Sci Monit. 2003;9(11):CS102–6.

    PubMed  Google Scholar 

  66. Bauer CS, Vadas P, Kelly KJ. Methylene blue for the treatment of refractory anaphylaxis without hypotension. Am J Emerg Med. 2013;31(1):264 e3–5.

    Article  Google Scholar 

  67. Ramin S, Azar FP, Malihe H. Methylene blue as the safest blue dye for sentinel node mapping: emphasis on anaphylaxis reaction. Acta Oncol. 2011;50(5):729–31.

    Article  CAS  PubMed  Google Scholar 

  68. Li PH, Wagner A, York M, Rutkowski R, Haque R, Rutkowski K. Blue dye allergy: pitfalls in diagnosis and how to avoid them. J Allergy Clin Immunol Pract. 2018;6(1):272–3.

    Article  PubMed  Google Scholar 

  69. Mertes PM, Demoly P, Alperovitch A, Bazin A, Bienvenu J, Caldani C, et al. Methylene blue-treated plasma: an increased allergy risk? J Allergy Clin Immunol. 2012;130(3):808–12.

    Article  PubMed  Google Scholar 

  70. Clifton J 2nd, Leikin JB. Methylene blue. Am J Ther. 2003;10(4):289–91.

    Article  PubMed  Google Scholar 

  71. Takazawa T, Mitsuhata H, Mertes PM. Sugammadex and rocuronium-induced anaphylaxis. J Anesth. 2016;30(2):290–7.

    Article  PubMed  Google Scholar 

  72. Ue KL, Kasternow B, Wagner A, Rutkowski R, Rutkowski K. Sugammadex: an emerging trigger of intraoperative anaphylaxis. Ann Allergy Asthma Immunol. 2016;117(6):714–6.

    Article  PubMed  Google Scholar 

  73. Nakanishi T, Ishida K, Utada K, Yamaguchi M, Matsumoto M. Anaphylaxis to sugammadex diagnosed by skin prick testing using both sugammadex and a sugammadex-rocuronium mixture. Anaesth Intensive Care. 2016;44(1):122–4.

    CAS  PubMed  Google Scholar 

  74. Barthel F, Stojeba N, Lyons G, Biermann C, Diemunsch P. Sugammadex in rocuronium anaphylaxis: dose matters. Br J Anaesth. 2012;109(4):646–7.

    Article  CAS  PubMed  Google Scholar 

  75. McDonnell NJ, Pavy TJ, Green LK, Platt PR. Sugammadex in the management of rocuronium-induced anaphylaxis. Br J Anaesth. 2011;106(2):199–201.

    Article  CAS  PubMed  Google Scholar 

  76. Platt PR, Clarke RC, Johnson GH, Sadleir PH. Efficacy of sugammadex in rocuronium-induced or antibiotic-induced anaphylaxis. A case-control study. Anaesthesia. 2015;70(11):1264–7.

    Article  CAS  PubMed  Google Scholar 

  77. Whitehead A. Sugammadex in anaphylaxis. A case-control study? Anaesthesia. 2016;71(2):236–7.

    Article  CAS  PubMed  Google Scholar 

  78. Pumphrey R. Anaphylaxis: can we tell who is at risk of a fatal reaction? Curr Opin Allergy Clin Immunol. 2004;4(4):285–90.

    Article  PubMed  Google Scholar 

  79. De Souza RL, Short T, Warman GR, Maclennan N, Young Y. Anaphylaxis with associated fibrinolysis, reversed with tranexamic acid and demonstrated by thrombelastography. Anaesth Intensive Care. 2004;32(4):580–7.

    Article  PubMed  Google Scholar 

  80. Bansal RA, Nicholas A, Bansal AS. Tranexamic acid: an exceedingly rare cause of anaphylaxis during anaesthesia. Case Rep Immunol. 2016;2016:7828351.

    CAS  Google Scholar 

  81. Li PH, Trigg C, Rutkowski R, Rutkowski K. Anaphylaxis to tranexamic acid-a rare reaction to a common drug. J Allergy Clin Immunol Pract. 2017;5(3):839–41.

    Article  PubMed  Google Scholar 

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  1. Department of Pediatrics, Allergy/Immunology, University of Tennessee Health Science Center, Memphis, TN, USA

    Catherine Hammond & Jay Lieberman

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Correspondence to Jay Lieberman .

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  1. Queen’s University, Kingston, ON, Canada

    Anne K. Ellis

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Hammond, C., Lieberman, J. (2020). Management of Anaphylaxis Refractory to Standard First Line Therapy. In: Ellis, A. (eds) Anaphylaxis. Springer, Cham. https://doi.org/10.1007/978-3-030-43205-8_3

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