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C1-esterase inhibitor for short-term prophylaxis in a patient with hereditary angioedema with normal C1 inhibitor function
Journal of Clinical Anesthesia (2016) 35, 488–491
Case Report
C1-esterase inhibitor for short-term prophylaxis in a patient with hereditary angioedema with normal C1 inhibitor function☆ Savio K.H. Yu MD (Resident)a , Jeannie Callum MD, FRCPC (Associate Professor)b,c , Asim Alam MD, FRCPC (Assistant Professor)d,⁎ a
Department of Anesthesia, University of Toronto, Toronto, ON M4N 3M5, Canada Department of Clinical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada c Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada d Department of Anesthesia, Trauma, Emergency and Critical Care Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada b
Received 10 December 2015; accepted 14 August 2016
Keywords: Hereditary angioedema; Type III; Normal C1-esterase; HAE-nC1INH; Perioperative; Prophylaxis
Abstract Hereditary angioedema with normal C1-esterase inhibitor (HAE-nC1INH) perioperative is a rare condition which could have potential disastrous ramifications for the anesthesiologist in the perioperative period. However, there is limited evidence and/or guidelines on the optimal way to manage these patients. We present the case of a patient with HAE-nC1INH who was successfully managed in the perioperative period with plasma derived C1-esterase inhibitor (pdC1INH). A 29-year-old woman with a diagnosis of HAEnC1INH presented to the preoperative consultation in preparation for an upcoming total thyroidectomy. She had a 14-year history of ongoing lip and facial edema sometimes necessitating emergency department visitation. Close consultation with her immunologist, transfusion medicine specialists, and anesthesia care providers allowed for a preoperative plan to provide the patient adequate prophylaxis. Both pdC1INH and tranexamic acid were given preoperatively. The patient underwent surgery with no complications. A multidisciplinary team of clinical immunologists, transfusion medicine specialists, and anesthesiologists facilitated the successful perioperative management of a patient with HAE-nC1INH; pdC1INH may a suitable prophylactic perioperative therapy for this rare patient population. © 2016 Elsevier Inc. All rights reserved.
Hereditary angioedema (HAE) is a rare inherited disease that presents as an acute swelling of any or multiple parts of the body. The symptoms of an acute episode can be easily mis-
☆ Conflict of interest/disclosure: The authors (SY, JC, and AA) of this case report have no conflicts of interest to disclose. ⁎ Correspondence: Asim Alam, MD, FRCPC, Department of Anesthesia, Sunnybrook Health Sciences Centre, M3-200, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
http://dx.doi.org/10.1016/j.jclinane.2016.08.042 0952-8180/© 2016 Elsevier Inc. All rights reserved.
taken for an anaphylactic/anaphylactoid reaction, and the diagnosis can be easily overlooked and delayed [1]. While usually self-limiting, attacks involving the oropharynx can lead to insidious airway compromise, asphyxiation, and death in up to 25% to 40% of cases [1,2]. Airway attacks can also be triggered by a slew of stress-related events including infections, angiotensin-converting enzyme inhibitors, nonsteroidal antiinflammatory drugs, menstruation, and minor trauma among other things. Periprocedurally, local anesthetic and endotracheal tube manipulation may precipitate an acute episode [3].
Perioperative management of a patient with HAE-nC1INH
489
However, traditional treatments for acute anaphylactic/anaphylactoid reactions seem to be ineffective in HAE, further compounding the need for early diagnosis, recognition, and management. The increased risk of airway compromise and hemodynamic instability during the perioperative management of patients with HAE is a major concern for anesthesiologists and other perioperative specialists. Classically, HAE is caused by a mutation in the C1-esterase inhibitor (C1-INH) gene. More than 150 different mutations have been identified, but most patients with HAE have a deficiency (type I) or a functional deficiency of C1-INH (type II) [4]. However, there exists a rare subtype of HAE where patients have normal C1-INH levels. Previously known as HAE type III, it is now referred to as HAE with normal C1INH (HAE-nC1INH). Within this subtype of HAE, there exists one subgroup that has known mutations in the coagulation factor XII (FXII) gene (HAE-FXII) and another subgroup with an unknown genetic etiology (HAE-unknown) [5]. For HAE types I and II, plasma-derived human C1-esterase inhibitors (pdC1INHs) have been approved for treatment and routine prophylaxis of acute abdominal or facial attacks in adolescents and adults in Canada. Consensus guidelines also recommend short-term prophylaxis with the same agents in patients with planned exposure to situations likely to trigger an attack such as substantial dental work and other invasive medical or surgical procedures involving the upper airway [4,6]. However, for patients with HAE-nC1INH, there exists limited evidence regarding the efficacy of any treatments both for short- and long-term prophylaxis and acute attacks, especially in the perioperative period. We present a case of a patient with HAE-nC1INH who was successfully treated with pdC1INH in the perioperative setting.
extraction was uneventful besides having an episode of postoperative nausea and vomiting. Further history revealed that her mother also had similar episodic swelling, but she had declined any further investigation for HAE workup. Our patient was referred to a clinical immunologist for further workup for the diagnosis of HAE. Initial C1 inhibitor levels were found to be 0.42 G/L (performed at McMaster University, Hamilton, ON, Canada; reference range, 0.210.39 G/L). Serum complement factor 4 (C4) levels were 0.24 g/L (performed at St Michael's Hospital, Toronto, ON, Canada; reference, 0.16-0.38 g/L), and C1 inhibitor functional levels were 1.25 U/mL (performed at CHU Sainte-Justine, Montreal, QC, Canada; reference, 0.70-1.30 U/mL). C4 and C1-INH levels during an attack were unfortunately unavailable. Coagulation FXII genetic mutation for HAEnC1INH was completed and no mutation was found in the gene (performed at University Hospital of Wales, Cardiff, UK). Given the clinical features, possible family history, and normal C1-INH levels, a diagnosis of HAE-nC1INH was determined. Her perioperative management was coordinated between her clinical immunologist, a transfusion medicine specialist, and anesthesiologist at our hospital, the Sunnybrook Health Sciences Centre. As a team, we decided to treat the patient prophylactically with 20 U/kg of pdC1INH for a total of 1500 U (Berinert; CSL Behring, Ottawa, ON, Canada). She was also prescribed tranexamic acid 1000 mg orally every 4 hours preoperatively. On the day of surgery, pdC1INH was infused over an hour preoperatively, finishing at the time of induction. Anesthetic induction and endotracheal intubation were performed in the usual fashion, and the operation was uneventful. The intraoperative anesthetic course was uncomplicated. The patient emerged from anesthetic and was extubated without incident. She was discharged home on postoperative day 2 without further complications or concerns. The patient continued to have minor perioral swelling episodes after the surgery not related to specific triggers.
Case presentation A 29-year-old woman presented to the anesthesia preoperative clinic for an evaluation before her total thyroidectomy for papillary thyroid carcinoma, diagnosed earlier by fine needle biopsy. Her only significant medical comorbidity was a chronic history of nonpruritic lip and facial swelling thought to be related to possible HAE. The swelling began 14 years ago and was originally thought to be related to the ingestion of ibuprofen. On a number of occasions, episodes continued to occur and were not necessarily temporally related to ingestion of a specific drug or activity. During these episodes, she denied having any respiratory distress, and her swelling improved within a 24-hour period. On a number of occasions, the swelling required her to be admitted to the emergency department for observation. Her only medication included the oral contraceptive pill, but symptoms predated the initial prescription for this medication. General allergy testing proved to be inconclusive. Rotations between different types of oral contraceptive pills also proved to have no effect on the incidence or timing of attacks. A previous general anesthetic for a wisdom tooth
Discussion HAE is most commonly caused by mutations in the C1 inhibitor gene. C1 inhibitor binds irreversibly to the contact, fibrinolytic, and complement pathways and regulates the generation of bradykinin through inhibition of the protease plasma kallikrein. New C1 inhibitor molecules are therefore required to maintain homeostasis once consumed. In HAE, patients have C1 inhibitor activity or levels b50% of normal, and they cannot produce enough C1 inhibitor to offset consumption [7]. The symptoms of an acute HAE episode are thought to be caused by a massive bradykinin release through the contact pathway. Various types and causes of HAE of have been identified, as discussed above. Type I HAE accounts for 85% of cases, whereas type II HAE accounts for almost all
490 of the remainder of cases. A form of the disease where patients have normal C1 inhibitor levels (HAE-nC1INH) is exceedingly rare [6]. HAE-nC1INH typically runs in families and affects mainly women, although male cases have been described. In some cases of HAE-nC1INH, missense mutations (exon 9) on the FXII gene on chromosome 5 ultimately activate the contact pathway to cause the characteristic release of bradykinin (HAE-FXII) [8]. However, a large majority of patients with HAE-nC1INH do not have an identified genetic mutation. In fact, the published frequency of HAE-nC1INH due to the above mutations is approximately 23% in female patients whose symptoms are related to progesterone and have a family history [9]. As a result, many HAE-nC1INH patients have an unknown etiology, and diagnosis is based on a multitude of factors and not simply on the presence or absence of positive laboratory investigations [6]. The role of FXII and exact biochemical mediator in producing edema in patients with HAE-nC1INH is unclear. Coagulation FXII is a part of the kallikrein-kinin system or the “contact activation system” of coagulation. The activation of the contact system ultimately causes a release in bradykinin. It is thought that a mutation in the FXII gene dysregulates this contact system. However, there is conflicting evidence regarding the effect that clinically detected genetic mutations on the FXII gene have on FXII levels or activity [5], and there is no confirmatory evidence for the role of bradykinin in attacks in patients with HAE-nC1INH [6]. There are several features of HAE-nC1INH that distinguish it from HAE types I and II. Although “classic” HAE usually presents in childhood, patients with HAE-nC1INH tend to have clinical symptoms in adulthood. The number of patients under the age of 10 years with symptoms of HAE-nC1INH is low. Clinically, facial swelling and lip swelling are relatively more frequent in HAE-nC1INH. In particular, the tongue is considerably more affected, and recurrent tongue swelling can be considered a cardinal symptom of HAE-nC1INH. As opposed to the generalized subcutaneous and submucosal edema seen in “classic” HAE, HAE-nC1INH patients tend to have edema isolated to the skin and tongue. Abdominal attacks are common but less frequent than in classic HAE. Nevertheless, the clinical presentation of HAE-nC1INH is highly variable [5]. Diagnosis of HAE requires a thorough patient history including a family history in close consultation with a clinical immunologist. Laboratory evaluations of functional and absolute levels of C1-INH and C4 complement levels both during periods of wellness and during acute attacks are key to differentiating between the different types of HAE. FXII genetic testing can be performed to confirm the diagnosis of HAEnC1INH with an abnormal FXII, but there is no laboratory test available to confirm the diagnosis of HAE-nC1INH with an unknown genetic etiology at this point. Idiopathic, acquired (from lymphoproliferative, autoimmune, infectious or neoplastic disease), allergic, or medication-induced angioedema (including from angiotensin-converting enzyme
S.K.H. Yu et al. inhibitors) should be excluded before the diagnosis of HAE can be made [5,10]. The management of HAE includes treatment of acute attacks, short-term prophylaxis to prevent an attack, and longterm prophylaxis to minimize the frequency and severity of recurrent attacks [3]. Most current therapies in HAE are aimed at reducing the production of and/or the biologic effects of bradykinin. Although established treatment guidelines exist in HAE types I and II [6,11], there is insufficient evidence to recommend a specific therapy or management strategy for HAEnC1INH. Nevertheless, given the clinical similarities and suspected common pathogenic molecular pathways between the various forms of HAE, expert opinion suggests that medications proven effective for HAE types I and II may be of benefit for those with HAE-nC1INH as well [6,12]. In HAE types I and II, the latest Canadian guidelines recommend that short-term prophylaxis be considered for all medical, surgical, and dental procedures, as there is a lack of data regarding the specific risk of angioedema associated with a particular procedure. Short-term prophylaxis should also be considered if the patient may be exposed to a known trigger. If a patient does not receive short-term prophylaxis, 2 doses of acute treatment should be immediately available [6]. The agent of choice for short-term prophylaxis is pdC1INH of which 2 brands, Berinert and Cinryze (Shire, Saint-Laurent, QC, Canada), are available in Canada. Both are not approved for short-term prophylaxis in Canada, although, in Europe, Cinryze is licensed to be given 1000 U within 24 hours of the procedure and Berinert 1000 U within 6 hours of the procedure. The optimal dose for periprocedural prophylaxis has not been established, but consensus guidelines recommend 10 to 20 U/kg to be given as close to the procedure as feasible and at least within 6 hours preinduction [6]. A second dose of equal amount should be immediately available at the time of surgery. Postoperatively, daily doses of pdC1INH should be given on an as-needed basis until there is no further risk of angioedema [3,6]. If pdC1INH is not immediately available, 17-α-alkalated anabolic androgen (Danazol 2.5-10 mg/kg/d, maximum dose 600 mg daily for 5 days before the procedure and 2-5 days after) can be used instead. However, attenuated androgen therapy may be less efficacious than pdC1INH and cannot not to be used as treatment for an acute attack. It is also not suitable for use in pregnancy. Other reports suggest that antifibrinolytic agents, such as tranexamic acid, may be efficacious; however, they should only be used if all other therapies are not available [6]. Short- and long-term prophylactic strategies have not been studied in HAE-nC1INH, and to our knowledge, this is the first published case of a successful periprocedural prophylactic course of pdC1INH. However, for acute attacks of HAEnC1INH, treatment has consisted of both C1-INH concentrates or icatibant, a bradykinin receptor blocker, also licensed in Canada (FIRAZYR; Shire, Saint-Laurent, QC, Canada), although the evidence supporting this practice is limited [6].
Perioperative management of a patient with HAE-nC1INH Similarly, other treatments for acute attacks of HAE types I and II have not yet been tested in HAE-nC1INH [6]. We acknowledge that there are specific limitations under which we based our clinical decisions. First, the diagnosis of HAE-nC1INH in this case is extremely difficult to definitively prove, yet in this case, it is based on a strong clinical and laboratory diagnosis. Second, we could not be certain that a general anesthetic and the trauma of surgery would fail to precipitate an acute episode. This is especially true because she had had previous general anesthetic without incident. However, a single episode without an incident does not preclude future episodes from occurring, especially in the face of a particularly stimulating neck surgery such as thyroidectomy. Our team believed that the risk of treatment of pdC1INH was much lower than the risk of having even minor airway swelling in the perioperative period. As a result, we followed a precautionary principle and decided to prophylactically treat our patient. In summary, HAE is a rare, potentially fatal, inherited condition with important perioperative management considerations. HAE may cause severe airway obstruction associated with airway manipulation. We present a case of patient with HAE-nC1INH who was given pdC1INH to prevent any acute symptoms in the perioperative period. Although different perioperative prophylaxis options have recently been approved for HAE types I and II, no established regimens exist for HAE-nC1INH. Ergo, further study is required to establish the safety, effectiveness, and optimal dosing for prophylaxis against acute HAE-nC1INH attacks in the perioperative period.
491
References [1] Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000;356:213-7. [2] Bork K, Barnstedt S-E. Laryngeal edema and death from asphyxiation after tooth extraction in four patients with hereditary angioedema. J Am Dent Assoc 2003;134:1088-94. [3] Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, et al. 2010 international consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010;6:24. [4] Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med 2008;359:1027-36. [5] Bork K. Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor. Allergy Asthma Clin Immunol 2010;6:15. [6] Betschel S, Badiou J, Binkley K, Hébert J, Kanani A, Keith P, et al. Canadian hereditary angioedema guideline. Allergy Asthma Clin Immunol 2014;10:50. [7] Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114:S51-131. [8] Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006;343:1286-9. [9] Vitrat-Hincky V, Gompel A, Dumestre-Perard C, Boccon-Gibod I, Drouet C, Cesbron JY, et al. Type III hereditary angio-oedema: clinical and biological features in a French cohort. Allergy 2010;65:1331-6. [10] Eidelman FJ. Hereditary angioedema: new therapeutic options for a potentially deadly disorder. BMC Blood Disord 2010;10:3. [11] Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy 2014;69:602-16. [12] Riedl MA. Hereditary angioedema with normal C1-INH (HAE type III). J Allergy Clin Immunol Pract 2013;1:427-32.
Case Report
C1-esterase inhibitor for short-term prophylaxis in a patient with hereditary angioedema with normal C1 inhibitor function☆ Savio K.H. Yu MD (Resident)a , Jeannie Callum MD, FRCPC (Associate Professor)b,c , Asim Alam MD, FRCPC (Assistant Professor)d,⁎ a
Department of Anesthesia, University of Toronto, Toronto, ON M4N 3M5, Canada Department of Clinical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada c Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada d Department of Anesthesia, Trauma, Emergency and Critical Care Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada b
Received 10 December 2015; accepted 14 August 2016
Keywords: Hereditary angioedema; Type III; Normal C1-esterase; HAE-nC1INH; Perioperative; Prophylaxis
Abstract Hereditary angioedema with normal C1-esterase inhibitor (HAE-nC1INH) perioperative is a rare condition which could have potential disastrous ramifications for the anesthesiologist in the perioperative period. However, there is limited evidence and/or guidelines on the optimal way to manage these patients. We present the case of a patient with HAE-nC1INH who was successfully managed in the perioperative period with plasma derived C1-esterase inhibitor (pdC1INH). A 29-year-old woman with a diagnosis of HAEnC1INH presented to the preoperative consultation in preparation for an upcoming total thyroidectomy. She had a 14-year history of ongoing lip and facial edema sometimes necessitating emergency department visitation. Close consultation with her immunologist, transfusion medicine specialists, and anesthesia care providers allowed for a preoperative plan to provide the patient adequate prophylaxis. Both pdC1INH and tranexamic acid were given preoperatively. The patient underwent surgery with no complications. A multidisciplinary team of clinical immunologists, transfusion medicine specialists, and anesthesiologists facilitated the successful perioperative management of a patient with HAE-nC1INH; pdC1INH may a suitable prophylactic perioperative therapy for this rare patient population. © 2016 Elsevier Inc. All rights reserved.
Hereditary angioedema (HAE) is a rare inherited disease that presents as an acute swelling of any or multiple parts of the body. The symptoms of an acute episode can be easily mis-
☆ Conflict of interest/disclosure: The authors (SY, JC, and AA) of this case report have no conflicts of interest to disclose. ⁎ Correspondence: Asim Alam, MD, FRCPC, Department of Anesthesia, Sunnybrook Health Sciences Centre, M3-200, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
http://dx.doi.org/10.1016/j.jclinane.2016.08.042 0952-8180/© 2016 Elsevier Inc. All rights reserved.
taken for an anaphylactic/anaphylactoid reaction, and the diagnosis can be easily overlooked and delayed [1]. While usually self-limiting, attacks involving the oropharynx can lead to insidious airway compromise, asphyxiation, and death in up to 25% to 40% of cases [1,2]. Airway attacks can also be triggered by a slew of stress-related events including infections, angiotensin-converting enzyme inhibitors, nonsteroidal antiinflammatory drugs, menstruation, and minor trauma among other things. Periprocedurally, local anesthetic and endotracheal tube manipulation may precipitate an acute episode [3].
Perioperative management of a patient with HAE-nC1INH
489
However, traditional treatments for acute anaphylactic/anaphylactoid reactions seem to be ineffective in HAE, further compounding the need for early diagnosis, recognition, and management. The increased risk of airway compromise and hemodynamic instability during the perioperative management of patients with HAE is a major concern for anesthesiologists and other perioperative specialists. Classically, HAE is caused by a mutation in the C1-esterase inhibitor (C1-INH) gene. More than 150 different mutations have been identified, but most patients with HAE have a deficiency (type I) or a functional deficiency of C1-INH (type II) [4]. However, there exists a rare subtype of HAE where patients have normal C1-INH levels. Previously known as HAE type III, it is now referred to as HAE with normal C1INH (HAE-nC1INH). Within this subtype of HAE, there exists one subgroup that has known mutations in the coagulation factor XII (FXII) gene (HAE-FXII) and another subgroup with an unknown genetic etiology (HAE-unknown) [5]. For HAE types I and II, plasma-derived human C1-esterase inhibitors (pdC1INHs) have been approved for treatment and routine prophylaxis of acute abdominal or facial attacks in adolescents and adults in Canada. Consensus guidelines also recommend short-term prophylaxis with the same agents in patients with planned exposure to situations likely to trigger an attack such as substantial dental work and other invasive medical or surgical procedures involving the upper airway [4,6]. However, for patients with HAE-nC1INH, there exists limited evidence regarding the efficacy of any treatments both for short- and long-term prophylaxis and acute attacks, especially in the perioperative period. We present a case of a patient with HAE-nC1INH who was successfully treated with pdC1INH in the perioperative setting.
extraction was uneventful besides having an episode of postoperative nausea and vomiting. Further history revealed that her mother also had similar episodic swelling, but she had declined any further investigation for HAE workup. Our patient was referred to a clinical immunologist for further workup for the diagnosis of HAE. Initial C1 inhibitor levels were found to be 0.42 G/L (performed at McMaster University, Hamilton, ON, Canada; reference range, 0.210.39 G/L). Serum complement factor 4 (C4) levels were 0.24 g/L (performed at St Michael's Hospital, Toronto, ON, Canada; reference, 0.16-0.38 g/L), and C1 inhibitor functional levels were 1.25 U/mL (performed at CHU Sainte-Justine, Montreal, QC, Canada; reference, 0.70-1.30 U/mL). C4 and C1-INH levels during an attack were unfortunately unavailable. Coagulation FXII genetic mutation for HAEnC1INH was completed and no mutation was found in the gene (performed at University Hospital of Wales, Cardiff, UK). Given the clinical features, possible family history, and normal C1-INH levels, a diagnosis of HAE-nC1INH was determined. Her perioperative management was coordinated between her clinical immunologist, a transfusion medicine specialist, and anesthesiologist at our hospital, the Sunnybrook Health Sciences Centre. As a team, we decided to treat the patient prophylactically with 20 U/kg of pdC1INH for a total of 1500 U (Berinert; CSL Behring, Ottawa, ON, Canada). She was also prescribed tranexamic acid 1000 mg orally every 4 hours preoperatively. On the day of surgery, pdC1INH was infused over an hour preoperatively, finishing at the time of induction. Anesthetic induction and endotracheal intubation were performed in the usual fashion, and the operation was uneventful. The intraoperative anesthetic course was uncomplicated. The patient emerged from anesthetic and was extubated without incident. She was discharged home on postoperative day 2 without further complications or concerns. The patient continued to have minor perioral swelling episodes after the surgery not related to specific triggers.
Case presentation A 29-year-old woman presented to the anesthesia preoperative clinic for an evaluation before her total thyroidectomy for papillary thyroid carcinoma, diagnosed earlier by fine needle biopsy. Her only significant medical comorbidity was a chronic history of nonpruritic lip and facial swelling thought to be related to possible HAE. The swelling began 14 years ago and was originally thought to be related to the ingestion of ibuprofen. On a number of occasions, episodes continued to occur and were not necessarily temporally related to ingestion of a specific drug or activity. During these episodes, she denied having any respiratory distress, and her swelling improved within a 24-hour period. On a number of occasions, the swelling required her to be admitted to the emergency department for observation. Her only medication included the oral contraceptive pill, but symptoms predated the initial prescription for this medication. General allergy testing proved to be inconclusive. Rotations between different types of oral contraceptive pills also proved to have no effect on the incidence or timing of attacks. A previous general anesthetic for a wisdom tooth
Discussion HAE is most commonly caused by mutations in the C1 inhibitor gene. C1 inhibitor binds irreversibly to the contact, fibrinolytic, and complement pathways and regulates the generation of bradykinin through inhibition of the protease plasma kallikrein. New C1 inhibitor molecules are therefore required to maintain homeostasis once consumed. In HAE, patients have C1 inhibitor activity or levels b50% of normal, and they cannot produce enough C1 inhibitor to offset consumption [7]. The symptoms of an acute HAE episode are thought to be caused by a massive bradykinin release through the contact pathway. Various types and causes of HAE of have been identified, as discussed above. Type I HAE accounts for 85% of cases, whereas type II HAE accounts for almost all
490 of the remainder of cases. A form of the disease where patients have normal C1 inhibitor levels (HAE-nC1INH) is exceedingly rare [6]. HAE-nC1INH typically runs in families and affects mainly women, although male cases have been described. In some cases of HAE-nC1INH, missense mutations (exon 9) on the FXII gene on chromosome 5 ultimately activate the contact pathway to cause the characteristic release of bradykinin (HAE-FXII) [8]. However, a large majority of patients with HAE-nC1INH do not have an identified genetic mutation. In fact, the published frequency of HAE-nC1INH due to the above mutations is approximately 23% in female patients whose symptoms are related to progesterone and have a family history [9]. As a result, many HAE-nC1INH patients have an unknown etiology, and diagnosis is based on a multitude of factors and not simply on the presence or absence of positive laboratory investigations [6]. The role of FXII and exact biochemical mediator in producing edema in patients with HAE-nC1INH is unclear. Coagulation FXII is a part of the kallikrein-kinin system or the “contact activation system” of coagulation. The activation of the contact system ultimately causes a release in bradykinin. It is thought that a mutation in the FXII gene dysregulates this contact system. However, there is conflicting evidence regarding the effect that clinically detected genetic mutations on the FXII gene have on FXII levels or activity [5], and there is no confirmatory evidence for the role of bradykinin in attacks in patients with HAE-nC1INH [6]. There are several features of HAE-nC1INH that distinguish it from HAE types I and II. Although “classic” HAE usually presents in childhood, patients with HAE-nC1INH tend to have clinical symptoms in adulthood. The number of patients under the age of 10 years with symptoms of HAE-nC1INH is low. Clinically, facial swelling and lip swelling are relatively more frequent in HAE-nC1INH. In particular, the tongue is considerably more affected, and recurrent tongue swelling can be considered a cardinal symptom of HAE-nC1INH. As opposed to the generalized subcutaneous and submucosal edema seen in “classic” HAE, HAE-nC1INH patients tend to have edema isolated to the skin and tongue. Abdominal attacks are common but less frequent than in classic HAE. Nevertheless, the clinical presentation of HAE-nC1INH is highly variable [5]. Diagnosis of HAE requires a thorough patient history including a family history in close consultation with a clinical immunologist. Laboratory evaluations of functional and absolute levels of C1-INH and C4 complement levels both during periods of wellness and during acute attacks are key to differentiating between the different types of HAE. FXII genetic testing can be performed to confirm the diagnosis of HAEnC1INH with an abnormal FXII, but there is no laboratory test available to confirm the diagnosis of HAE-nC1INH with an unknown genetic etiology at this point. Idiopathic, acquired (from lymphoproliferative, autoimmune, infectious or neoplastic disease), allergic, or medication-induced angioedema (including from angiotensin-converting enzyme
S.K.H. Yu et al. inhibitors) should be excluded before the diagnosis of HAE can be made [5,10]. The management of HAE includes treatment of acute attacks, short-term prophylaxis to prevent an attack, and longterm prophylaxis to minimize the frequency and severity of recurrent attacks [3]. Most current therapies in HAE are aimed at reducing the production of and/or the biologic effects of bradykinin. Although established treatment guidelines exist in HAE types I and II [6,11], there is insufficient evidence to recommend a specific therapy or management strategy for HAEnC1INH. Nevertheless, given the clinical similarities and suspected common pathogenic molecular pathways between the various forms of HAE, expert opinion suggests that medications proven effective for HAE types I and II may be of benefit for those with HAE-nC1INH as well [6,12]. In HAE types I and II, the latest Canadian guidelines recommend that short-term prophylaxis be considered for all medical, surgical, and dental procedures, as there is a lack of data regarding the specific risk of angioedema associated with a particular procedure. Short-term prophylaxis should also be considered if the patient may be exposed to a known trigger. If a patient does not receive short-term prophylaxis, 2 doses of acute treatment should be immediately available [6]. The agent of choice for short-term prophylaxis is pdC1INH of which 2 brands, Berinert and Cinryze (Shire, Saint-Laurent, QC, Canada), are available in Canada. Both are not approved for short-term prophylaxis in Canada, although, in Europe, Cinryze is licensed to be given 1000 U within 24 hours of the procedure and Berinert 1000 U within 6 hours of the procedure. The optimal dose for periprocedural prophylaxis has not been established, but consensus guidelines recommend 10 to 20 U/kg to be given as close to the procedure as feasible and at least within 6 hours preinduction [6]. A second dose of equal amount should be immediately available at the time of surgery. Postoperatively, daily doses of pdC1INH should be given on an as-needed basis until there is no further risk of angioedema [3,6]. If pdC1INH is not immediately available, 17-α-alkalated anabolic androgen (Danazol 2.5-10 mg/kg/d, maximum dose 600 mg daily for 5 days before the procedure and 2-5 days after) can be used instead. However, attenuated androgen therapy may be less efficacious than pdC1INH and cannot not to be used as treatment for an acute attack. It is also not suitable for use in pregnancy. Other reports suggest that antifibrinolytic agents, such as tranexamic acid, may be efficacious; however, they should only be used if all other therapies are not available [6]. Short- and long-term prophylactic strategies have not been studied in HAE-nC1INH, and to our knowledge, this is the first published case of a successful periprocedural prophylactic course of pdC1INH. However, for acute attacks of HAEnC1INH, treatment has consisted of both C1-INH concentrates or icatibant, a bradykinin receptor blocker, also licensed in Canada (FIRAZYR; Shire, Saint-Laurent, QC, Canada), although the evidence supporting this practice is limited [6].
Perioperative management of a patient with HAE-nC1INH Similarly, other treatments for acute attacks of HAE types I and II have not yet been tested in HAE-nC1INH [6]. We acknowledge that there are specific limitations under which we based our clinical decisions. First, the diagnosis of HAE-nC1INH in this case is extremely difficult to definitively prove, yet in this case, it is based on a strong clinical and laboratory diagnosis. Second, we could not be certain that a general anesthetic and the trauma of surgery would fail to precipitate an acute episode. This is especially true because she had had previous general anesthetic without incident. However, a single episode without an incident does not preclude future episodes from occurring, especially in the face of a particularly stimulating neck surgery such as thyroidectomy. Our team believed that the risk of treatment of pdC1INH was much lower than the risk of having even minor airway swelling in the perioperative period. As a result, we followed a precautionary principle and decided to prophylactically treat our patient. In summary, HAE is a rare, potentially fatal, inherited condition with important perioperative management considerations. HAE may cause severe airway obstruction associated with airway manipulation. We present a case of patient with HAE-nC1INH who was given pdC1INH to prevent any acute symptoms in the perioperative period. Although different perioperative prophylaxis options have recently been approved for HAE types I and II, no established regimens exist for HAE-nC1INH. Ergo, further study is required to establish the safety, effectiveness, and optimal dosing for prophylaxis against acute HAE-nC1INH attacks in the perioperative period.
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