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C1 Esterase Inhibitor Deficiency, Airway Compromise, and Anesthesia

1998; Lippincott Williams & Wilkins; Volume: 87; Issue: 2 Linguagem: Inglês

10.1097/00000539-199808000-00047

1526-7598

Niels F. Jensen, John M. Weiler,

Autoimmune Bullous Skin Diseases

Hereditary angioedema (HAE) is a serious genetic abnormality involving the complement system and characterized by episodic and sometimes life-threatening airway edema. In 1882, von Quincke [1] published the first detailed description, and 3 yr later, Strubing used the term angioedema to describe this disorder. By 1888, Osler [2] had demonstrated the hereditary nature of the clinical presentation. In the early 1960s, HAE was shown to be caused by deficiency of C1 esterase inhibitor, also called "C1 inhibitor" (C1 INH) [3,4]. In 1972, an acquired form of C1 INH deficiency was first reported [5]. Lack of C1 INH leads to uncontrolled activation of the classical pathway of complement and is thought to result in the release of C2 kinin, or perhaps bradykinin [6-10], which then causes increased vascular permeability and edema of the airway, trunk and extremities, and gastrointestinal tract [11,12]. Angioedema (Table 1) describes deep swelling of the dermis associated with a variety of disorders, including HAE, acquired C1 INH deficiency, angiotensin-converting enzyme inhibitor (ACE)-induced disorder, several conditions induced by allergens and drugs releasing histamine, and idiopathic and miscellaneous processes. Although these conditions share this one characteristic (angioedema), only the first two are caused by a complement abnormality.Table 1: Differential Diagnosis of AngioedemaHAE and acquired C1 INH deficiency are especially important to anesthesiologists because patients with these disorders are prone to developing massive swelling of the aerodigestive tract (especially the oral cavity, pharynx, and larynx) and life-threatening airway obstruction. Although angioedema may occur throughout the body, it has a proclivity for the extremities and gastrointestinal tissues, as well as the head and neck [12,13]. Pathophysiology A full understanding of C1 INH deficiency requires a brief review of the complement system (Figure 1) [12,14-16]. This system consists of approximately 20 proteins, many circulating as inactive enzyme precursors, with two pathways for activation: the classical pathway and the alternate pathway. The classical pathway is activated by antigen-antibody complexes, whereas the alternate pathway is activated by naturally occurring substances, such as bacterial cell walls and yeast walls [17,18]. Complement activation by either pathway may result in opsonization [19], lysis [20], anaphylatoxin activity [21,22], chemotactic activity [23], and immune complex clearance [24].Figure 1: The complement system consists of proteins and enzyme precursors. There are two pathways to activation, the classic (shown) and the alternate; activation by either can result in opsonization, lysis, chemotactic activity, and immune complex clearance. Angioedema describes deep swelling of the dermis and has many causes. Hereditary angioedema and acquired C1 esterase inhibitor deficiency specifically involve the complement system.C1, the first component of the classical pathway of complement, exists in serum as a macromolecular complex containing one C1q, two C1r, and two C1s molecules [25]. Activation of this macromolecule leads to cleavage of C1s to produce C1s, also called C1 esterase. C1s may then act on C4 and C2 to produce C4b2a in the fluid phase or on the cell, cleaving C4 and C2. Control proteins limit the amount of complement activation. C1 INH is a single-chain, highly glycosylated alpha2-globulin, serine-protease inhibitor (SERPIN) that contains 478 amino acids and specifically inhibits the spontaneous activation of the first component of complement [3,4,15]. C1 INH binds stoichiometrically (in a 1:1 ratio) to C1r and C1s and less well to their inactivated precursors, C1r and C1s [26-29]. Individuals who lack sufficient C1 INH cannot adequately control the activation of C1, which leads to the consumption of C4 and C2 with subsequent generation of C2 kinin or other biologically active products [8,30]. C2 kinin alone or in conjunction with bradykinin or other substances may then cause increased vascular permeability and subcutaneous and mucosal swelling characteristic of HAE [3,15]. The bradykinin receptor and genotype may have particular relevance to clinical status [31]. C4b2a formation and decay are controlled by complement receptor 1 (CR1, CD35) and C4 binding protein (C4BP), as well as factor I, which prevents C3 levels from decreasing as a result of C1 INH deficiency [14]. Unfortunately, C1 INH is the only known control protein that regulates the consumption of C4 and C2. C1 INH also can inhibit activated Hageman factor (factor XIIa), plasma thromboplastin antecedent (factor XIa), and plasma kallikrein [30]. Activation of the coagulation cascade in C1 INH deficiency has been described in detail [32]. Furthermore, C1 INH inhibits plasmin and tissue plasminogen activator [7] and is encoded by a gene on chromosome 11 [29]. The C1 INH gene consists of eight exons and seven introns and is approximately 1.7 x 104 base pairs in length [30,33]. Androgens may enhance the expression of C1 INH in vivo, whereas gamma-interferon, alpha-interferon, tumor necrosis factor alpha, interleukin-6, and monocyte colony-stimulating factor have been shown to do so in vitro [34-36]. Most C1 INH is synthesized in the liver and blood monocytes [37]. Amino acid composition, physical characteristics, purification, and assays have been described in great detail [30,34,38,39]. In type I HAE, the region of the gene rich in alu repeats often contains the defective gene [33]. In type II HAE, the defect is usually at or near the active site, ARG 444, in exon 8. This explains why patients with type I HAE do not produce normal antigenic levels of C1 INH; their abnormal gene does not allow antigenic C1 INH to be expressed. Patients with type II HAE express nonfunctional protein. Types of C1 INH Deficiency and Laboratory Diagnosis The etiologies of IIAE and acquired C1 INH deficiency are quite different (Table 2). HAE is caused by a defective C1 INH gene that produces either no C1 INH (type I) or dysfunctional C1 INH, which is measurable for antigen but is inactive (type II). In both types of HAE, <50% of normal C1 INH is produced, which is insufficient. In contrast, acquired C1 INH deficiency is caused by the consumption of C1 INH or autoantibodies directed against C1 INH [16]. There are also two types of acquired C1 INH deficiency. Type I is characterized by a malignancy that activates complement or produces idiotype anti-idiotypes or other immune complexes. In contrast, type II is not associated with underlying disorders, except for the presence of an autoantibody that interferes with C1 INH activity.Table 2: Complement Levels in HAE and Acquired C1 INH DeficiencyThe cardinal feature of type I HAE is decreased antigenic and functional levels of C1 INH [12]. Type II HAE is characterized by normal or increased antigenic levels of C1 INH, half of which is dysfunctional [40]. The type II form afflicts approximately 15% of patients with HAE [15]. C1 levels are normal in both types of HAE. A C4 level is a rapid screening test for C1 INH deficiency [15,41-43]. Normal levels during an acute attack tend to exclude the diagnosis, whereas decreased levels of C4 warrant an assay for C1 INH. C4, C2, and C1 INH levels should all remain low between attacks. Low C1 and C1q levels suggest acquired C1 INH deficiency rather than HAE [13,43]. However, C1 INH levels do not necessarily correlate with the level of disease. For example, the C1 INH level may be very low and the patient may be unaffected [40], whereas higher levels may be seen in patients with massive angioedema. Natural History, Manifestations, and Clinical Presentation The importance of recognizing HAE cannot be overemphasized. Frank et al. [13] reported that the interval between onset of symptoms and diagnosis is approximately 20 yr, probably because HAE is an uncommon disorder. In the United States, HAE has a probable incidence of approximately 1:50,000 to 1:150,000, although there are large regional differences related to the presence of afflicted families in certain parts of the country. Acquired C1 INH deficiency is probably less common than HAE, but its prevalence is unknown. Compounding the rarity of the processes is the wide variety of presenting symptoms. Therefore, the natural history and clinical manifestation of C1 INH deficiency deserve careful attention. Most patients with this disorder have a family history [13]. Age of onset is usually not helpful in making the diagnosis, but the disease manifests itself by the age of 30 yr in approximately 98% of patients [44]. Although one half of patients with HAE are symptomatic by the age of 7 yr and two-thirds are symptomatic by the age of 13 yr [45], presentation after the age of 50 yr has been reported [13]. Presenting signs are usually cutaneous edema, abdominal pain, vomiting, and edema of the laryngeal or retropharyngeal area. Attack duration typically ranges from approximately 24 h to several days. Minor or even trivial trauma or emotional upset are the most consistent and frequent precipitators of attack. Trauma may be the trigger of one half of exacerbations [13]. Unlike HAE, acquired C1 INH deficiency is associated with onset at an older age and absence of family history. In addition, acquired C1 INH deficiency may be associated with a lymphoproliferative disorder, such as lymphoma or systemic lupus erythematosis [43,46-48]. HAE and acquired C1 INH deficiency are both characterized by the presence of angioedema and are not clearly distinguishable from each other on this basis [43]. The swelling involves the deep dermis and is nonpruritic, nonerythematous, circumscribed, cutaneous, and asymmetric [3,40,49]. Nearly one fourth of patients with HAE have a nonpruritic rash accompanying attacks of HAE, described as erythema marginatum [13,50]. Although urticaria (erythematous, pruritic, cutaneous elevations of the skin that blanch with pressure) can occur in patients who have C1 INH deficiency, urticaria that is always associated with angioedema suggests a diagnosis other than HAE [12,51]. HAE characteristically involves the extremities, face, airway, and gastrointestinal tract. In the series reported by Frank et al. [13], 96% had swelling of extremities, 93% had recurrent abdominal pain, 85% had angioedema of the face, and 64% had oropharyngeal involvement. Attacks involving the airway present the greatest threat. Obstruction generally begins slowly with voice change and dysphagia. Often it is preceded by peripheral swelling [13], but facial edema has also been reported as the initial presenting sign [52]. Although the differential diagnosis of airway and extremity swelling is quite extensive (Table 1), sudden airway compromise leading to the death of a relative should raise suspicion of HAE. Because HAE may also cause swelling during head and neck or dental surgery, the diagnosis should be made before these procedures are performed. Abdominal and orthopedic procedures may not trigger an attack unless the patient is also tracheally intubated, whereas dental surgery is more likely to provoke obstructive laryngeal edema in patients with C1 INH deficiency [13,45,53]. Frank et al. [13] reported life-threatening pharyngeal swelling after dental surgery in many patients with untreated HAE. In addition to swelling of the extremities and airway, the gastrointestinal tract is also vulnerable to attacks of HAE. Osler [2] wrote, "Associated with the edema, there is almost invariably gastrointestinal disturbance: colic, nausea, vomiting, and sometimes diarrhea." Unexplained episodic edema in a patient with recurrent abdominal pain or even ascites should raise suspicion of HAE [54]. Unfortunately, as noted above, the diagnosis is often missed, as exemplified by the case of one middle-aged woman who underwent almost 50 extensive evaluations for unexplained abdominal pain occurring almost bimonthly. It was not until HAE was diagnosed in her grandson during a military entrance examination that the etiology of her problem was finally determined [55]. One 52-yr-old man experienced three to four attacks of intermittent abdominal pain per year for 40 yr before HAE was diagnosed. Three exploratory laparotomies for presumed bowel obstruction had been performed during this period [52]. It should be emphasized that recurrent abdominal pain can be the sole manifestation of HAE [56]. Gastrointestinal distress may easily be misinterpreted as representing an acute abdomen, and HAE may be present in patients with a history of multiple negative abdominal operations [52,56,57]. Unexplained abdominal pain has historically led to narcotic use and dependence, as well as psychiatric diagnoses. The traditional name of hereditary angioneurotic edema reflects this presumed psychiatric component. However, major psychiatric illness may not be more frequent in patients with HAE than in the general population [45]. The abdominal pain caused by HAE is best characterized as crampy, colicky, and often excruciating [13,40]. Usually patients have diffuse abdominal tenderness characterized by normal to high-pitched bowel sounds without rigidity and peritoneal signs [12]. The pain may be secondary to intestinal obstruction caused by localized swelling [55], and the radiographic appearance is of stacked coins or a thumbprint [58]. Loss of fluid from the gut wall into the lumen may result in vomiting and copious accompanying watery diarrhea often late in the course of attack [12,45]. Diarrhea can be so severe as to cause hemoconcentration, hypotension, and shock [59]. Significant extraluminal intraperitoneal fluid sequestration can also develop [59]. Leukocytosis may be present [12,57]. Although attacks of HAE during pregnancy are unpredictable, the risk of an attack seems to decrease after the first trimester and during delivery [13]. When attacks occur, however, they are often accompanied by acute abdominal pain mimicking acute appendicitis or peritonitis. HAE should be considered in the differential diagnosis of acute abdominal pain in pregnant patients when no other cause is apparent [45,60]. Pregnancy may worsen symptoms of HAE, but the condition does not seem to adversely affect fetal viability. In one study, of 36 pregnancies, all were carried to term [44]. Most women do not experience improvement at menopause [13,61]. Female patients with HAE may also have cystic ovaries (polycystic or mutifollicular) [62]. Airway Involvement Airway involvement, especially perioral and oropharyngeal, has been the central concern regarding HAE since early reports of this disorder. This is largely because airway obstruction is the most common cause of mortality. Thus, it is important to differentiate C1 INH deficiency from other causes of uvular and pharyngeal swelling, such as localized injection (i.e., Quincke's disease), trauma, and neoplasms [63,64]. Airway swelling caused by HAE may progress slowly over hours from hoarseness, pooling of secretions, and dysphagia to complete airway obstruction. One should not assume that airway compromise caused by HAE will either resolve or take a slow and deliberate course, because airway compromise can also occur quickly and be deadly. Osler [2] described five generations affected by HAE: "In one instance, possibly two, death resulted from a sudden edema glottidis." Landerman [65] studied 358 cases of HAE in 36 families and found that most deaths occurred from acute laryngeal edema; of 119 deaths, 92 (77%) were secondary to acute laryngeal edema. The average age at death was 35 yr (range 14 mo to 70 yr). In some affected kindred studied by Donaldson [39], the fatality rate from acute airway obstruction was as high as 25%. Ohela [66] reported seven families afflicted with HAE in Finland; six individuals died from acute airway edema, and each had a triad of paroxysmal abdominal pain, peripheral edema, and laryngeal edema. Overall, approximately one half to two thirds of patients with HAE experience an episode of airway compromise, and 14%-33% may die from laryngeal edema [44,45]. There is a similar spectrum of laryngeal symptoms in both hereditary and acquired forms of C1 INH deficiency: fullness in the mouth, dysphagia, facial tightness, hoarseness, stridor, laryngeal edema, and/or laryngospasm [13]. Pruet et al. [67] reported 89 patients with HAE at the National Institutes of Health; 85% had occurrences of head and neck edema. Tracheal intubation was required in only five (6%), although symptoms of airway compromise were present in more than half. Airway obstruction was reported to proceed rapidly. We have also seen airway obstruction progress over 5 min to the brink of respiratory arrest; if resuscitative treatment with C1 inhibitor concentrate (as described below) had been unsuccessful, the patient would likely have died. Neither laryngoscopy and attempted intubation nor tracheostomy are necessarily benign. Airway trauma during intubation may worsen laryngeal edema and necessitate emergent tracheostomy [45]. A patient described in an early case report required at least two tracheotomies for HAE and eventually died from complete airway obstruction [68]. In 7 of the 12 families studied by Donaldson and Rosen [40], one or more member died from acute airway obstruction. In one family, six individuals spanning three generations died as young adults of airway obstruction. One man kept a scalpel in the house for his wife to use should she need to facilitate tracheostomy. Whether the patient eventually died from an attack of HAE is not known. Management of C1 INH Deficiency Drug Therapies to Treat C1 INH Deficiency The anesthesia literature provides only limited guidance regarding the management of patients with C1 INH deficiency [69-78]. Therefore, we describe briefly the major therapies that have been used to treat HAE and how these medications are used under specific circumstances. epsilon-Aminocaproic acid (EACA), an antifibrinolytic drug that inhibits plasminogen activation and plasmin activity, was once thought to be useful in long-term therapy of HAE [13,79,80]. This drug probably acts primarily by limiting the formation of plasmin, which can activate C1. EACA is not often used today because it may cause muscle ache, fatigue, postural hypotension, and thromboembolic events [13,81]. In one recent report, however, long-term use of EACA decreased the frequency and severity of symptoms in two patients with C1 inhibitor deficiency with no apparent side effects or toxicity [82]. Tranexamic acid, another inhibitor of plasminogen activation and of plasmin, has also been used in the prophylaxis of HAE [83,84]. It may limit the activation of C1, but it is rarely used [42,45]. In 1960, Spaulding [85] demonstrated that chronic therapy with methyltestosterone may be useful in the long-term treatment of HAE. Androgens such as methyltestosterone, danazol, and stanozolol act by increasing the synthesis of C1 INH by the liver [42,86]. Attenuated androgens are clearly effective in preventing attacks but may cause serious adverse events including weight gain, headaches, myalgias, menometrorrhagia, amenorrhea, alopecia, acne, altered libido, liver disease, hirsutism, and virilization [45]. These events have limited androgen use, especially use of methyltestosterone. Danazol may also be hazardous in pregnant patients and children secondary to gonadal effects [13]. Currently, stanozolol is the therapeutic mainstay (2 mg [center dot] kg-1 [center dot] d-1 initially and then 0.5-6.0 mg [center dot] kg (-1) [center dot] d-1) as required to control attacks. In general, the final dose of androgen that is selected prevents serious attacks but still allows mild attacks (such as mild swelling of an extremity) to occur occasionally. Patients receiving anabolic steroids should undergo routine liver function testing approximately every 6 mo. Fresh-frozen plasma (FFP) contains C1 INH but also contains the kinins and substrates (including uncleaved C2 and C4) that may fuel complement activation (see below). FFP therapy also presents a risk of infection by blood borne pathogens. Although anabolic steroids and FFP are currently the chief therapies for C1 INH deficiency, purified C1 INH concentrate is one of the most promising therapies for the future. C1 INH has been available commercially only in Europe since the 1980s (C1-Inactivator HS; Behring, Marburg, Germany). From its use there, we know that lyophilized C1 INH concentrate can effect partial resolution of symptoms within 1 h and complete resolution within 24 h. C1 INH is obtained from pooled human plasma, and the usual dose is 25 U/kg. Appropriate administration can increase C1 INH levels by 50% in adults over 15 min [80]. C1 INH concentrate offers specific rapid therapy and can be used to treat acute attacks. It may also be used for acute prophylaxis for which the efficacy of other treatments is more problematic. Disadvantages include lack of availability in the United States, expense, the need for IV administration, and concern about transmission of hepatitis or human immunodeficiency virus. Regarding the latter concern, C1 INH concentrate must be tested to assure that it does not transmit a virus. Currently, C1 INH concentrate has not been approved by the Food and Drug Administration for use in the United States and is only available on an investigational basis [78]. After infusion, C1 INH concentrate can be effective within 15 min and may be protective for approximately 2 days [80], or perhaps longer. Its efficacy during the induction of labor and for tonsillectomy have also been described [76,78]. Chronic Prophylaxis Prophylactic therapy is given to prevent airway obstruction or when the frequency of attacks is greater than once or twice per month and is severe enough to require treatment [80]. Danazol and stanozolol maintenance therapy have clearly been shown to prevent attacks. A typical oral adult dose is 2 mg/d stanozolol or 600 mg/d danazol. Patients with acquired C1 INH deficiency may need much larger doses than those given to patients with HAE. Prophylaxis Before Elective Surgical Procedures Before elective surgical procedures, patients with HAE may be given stanozolol [78], FFP [13,72,87] or C1 INH concentrate [78,88,89]. Stanozolol has been used alone or in combination with other therapies [78]. Stanozolol is typically given 4 mg four times a day for 5-7 days before scheduled surgery. FFP may be given several hours or the evening before dental procedures when C1 INH concentrate is not available. In one report, dental procedures precipitated serious or life-threatening swelling in five of six untreated patients, but when prophylaxis with 2 U of FFP was undertaken 1 day before dental extraction, no swelling was observed immediately postoperatively [13]. FFP causes only a transient increase in C1 INH serum levels. C1 INH levels decrease to subnormal levels within days. FFP obviously presents risks of infection and should be reserved for situations in which stanozolol has not been effective and C1 INH concentrate is not available. Given its cost, when C1 INH concentrate is approved for use in the United States, it will probably be reserved for cases in which stanozolol is ineffective or contraindicated. Prophylaxis Before Emergency Procedures The best option for prophylaxis before an emergency surgical procedure is C1 INH concentrate, although this is an investigational drug in the United States. Alternatively, 2 U of FFP may be given before an emergency procedure [13]. However, when FFP is given in this setting, a mild attack may worsen, perhaps because FFP contains C2 and C4. Glucocorticoids, antifibrinolytic drugs, epinephrine, and antihistamines have not been shown to be efficacious when given before an emergency procedure [13,90]. Treatment of Acute Attacks Acute attacks do not respond to treatment with anabolic steroids, glucocorticoids, antifibrinolytic drugs, epinephrine, or antihistamines. Treatment options in this setting are limited, but it is important to be prepared for possible tracheal intubation [42]. The most effective therapy seems to be C1 INH concentrate [91-93]. In situations in which C1 INH concentrate is not available, FFP may be considered. New and Experimental Therapies Until C1 INH concentrate is licensed for use in the United States, patients with HAE must be treated with supportive care to minimize the risk from an attack. Patients with a history of severe disease (previous airway obstruction) should be enrolled in a protocol study so that C1 INH concentrate can be used to treat life-threatening attacks. Other therapies are also being evaluated. Since the 1920s, we have known that heparin can inhibit complement in vitro, acting on both the classical and alternative pathways of complement [94]. More recently, heparin has been shown to augment the activity of C1 INH in vitro [95] and, perhaps, in vivo [96,97]. Studies are continuing to determine the safety and efficacy of inhaled and subcutaneously administered heparin in preventing attacks of HAE. Special Anesthetic Considerations Anesthesiologists must be prepared to manage the airway of patients with HAE in three settings: electively, when the airway is not compromised; urgently, when mild or moderate airway edema is present; and emergently, when airway swelling is life-threatening. In the elective surgical setting, monitored, regional, or general anesthesia can be performed safely [69]. The presence of angioedema does not influence drug choices for the induction of either general or regional anesthesia or the use of muscle relaxants, including succinylcholine [69]. There are no known constraints regarding the use of any of the volatile anesthetics. It is important to avoid manipulation of the airway as much as possible by relying on regional or inhalation techniques. These obviate the need for the pressure and traction resulting from laryngoscopy and eliminate one important trigger for an attack. Abada and Owens [71] reported the successful use of spinal anesthesia for a urologic procedure, and Schar [73] reported a mask inhalation technique using no form of artificial airway. Regional and mask inhalation techniques are certainly safe and offer some theoretical advantage. However, endotracheal intubation is not necessarily contraindicated or, under proper circumstances, hazardous [69]. The role of the laryngeal mask airway in the these patients is not completely clear, but it is reasonable to assume that its larger surface contact area may lead to worsened airway edema. When intubation is necessary, so is heightened awareness; perhaps some form of prophylaxis should also be given. There are no universally accepted guidelines, but the administration of anabolic steroids for 5-7 days before surgery, as described above, and C1 INH concentrate (or FFP if concentrate is not available) immediately before surgery are most often used. These treatments make intubation generally safe, but they may not be completely protective. This was suggested by a report of a mild generalized flare of angioedema in a 15-yr-old male patient with HAE after tonsillectomy who had been treated prophylactically the week before surgery with stanozolol (4 mg four times daily) and then IV C1 INH concentrate just before surgery. Patients with HAE can usually be tracheally intubated safely, but they require close observation even after prophylactic premedication with stanozolol and C1 INH concentrate [78]. Unless the surgical procedure dictates surgical intensive care, this is not generally necessary [69]. Patients with HAE who are hemodiluted and undergo cardiopulmonary bypass (CPB) require extra diligence. One case report describes a patient with acquired C1 INH deficiency with a preoperative C1 INH level of 30% of normal who underwent CPB. Apparently, hemodilution during surgery reduced these levels even further, and the patient died intraoperatively of symptoms related to uncontrolled complement activation [74]. In contrast, in another similar case, the C1 INH level increased to approximately 75% of normal after stanozolol therapy preoperatively, and the patient underwent uneventful CPB with a membrane oxygenator [75]. The acceptable lower preoperative limit for C1 INH is not clear, but 50% of normal has been suggested [98]. When HAE attacks involve the airway, the anesthesiologist may be called on to render emergency care. In cases of mild airway edema, symptoms can resolve without further treatment, usually within a few days. Patients should be carefully observed in the hospital. Oxygen therapy may be provided, and oxygenation should be monitored using pulse oximetry. In extreme distress, ventilation via a mask followed by immediate tracheal intubation is warranted. The use of muscle relaxants is inadvisable if the patient demonstrates the ability to maintain even marginal oxygenation. When performing emergency laryngoscopy and intubation, the attendance of an otolaryngologist is mandatory should a tracheostomy be necessary. The laryngeal mask airway has no established or demonstrated role in this setting and, given the potential for laryngeal distortion secondary to edema, would probably be ineffective in most cases. The presence of severe airway swelling and the demand for acute intervention can greatly limit the effectiveness of fiberoptic intubation. Instrumentation of the airway is best performed in the operating room, in which full resuscitative measures can most readily be undertaken. This may not always be possible, and the risk of transport from the emergency room to the operating room certainly must be assessed on the basis of the rapidity of progression of airway compromise. If this risk is deemed unacceptable, an emergency tracheostomy should be performed without delay. Airway swelling may become so severe that even tracheostomy may be ineffective in providing a patent airway. Swelling may extend into the airway to such an extent that death is inevitable in the absence of specific therapy (C1 INH replacement).