Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Angioedema of the Head and Neck Angioedema is a sudden onset of a localized nonpitting edema involving the deeper layers of the skin and submucosal tissue, most commonly affecting the lips and face, extremities, and abdominal viscera. In 94% of cases angioedema involves structures in the head and neck including face, lips, palate, and tongue with laryngeal involvement occurring less frequently. This slide is an example of what we can expect to see when consulted in the emergency room. Obviously, the patient has massive tongue swelling and has already had an airway secured. Epidemiology: Ten percent of Americans can expect to have at least one episode of angioedema, specifically seen in the third and fourth decades of life. There is an equal male to female ratio. Attacks are usually self-limiting and resolve within 24 to 48 hours. The principal cause of mortality is airway compromise. The basic pathophysiology of an angioedematous episode is increased vascular permeability in the submucosal, subcutaneous and deep dermal tissues. This is mediated by vasoactive substances including histamine, bradykinin and other products of the complement cascade including C3a and C5a ( anaphylatoxins). There are four main causes of angioedema:
ACE inhibitors account for 25% to 68.5% cases of angioedema. They are included in the top ten most prescribed drugs in the United States and are used for hypertension, congestive heart failure, and diabetic renal insufficiency. Obviously these are very common disease entities in our population, so a fairly large percent of the population are using ACE inhibitors. Angioedema occurs in about 0.1% to 0.7% of patients using the ACEs and episodes can occur anywhere from an hour to two hours after the very first administration of the drug to up to five years after the patient has been taking the drug, with the angioedematous episode occurring, on average, 14 months after starting an ACE inhibitor. The pathophysiology of ACE inhibitor induced angioedema is obviously with reduced function of ACE (angiotensin-converting enzyme). It does two things. It decreases inactivation of bradykinin and also decreases activation of angiotensin II. Bradykinin, being the potent vasodilator, increases the vascular permeability, which will later be shown as a principal mediator hereditary angioedema. Angiotensin II is a potent vasoconstrictor. So we have two different pathophysiologic mechanisms. As far as allergy-induced angioedema, it represents an IgE-mediated hypersensitivity reaction. Inciting agents include medications, food, and environmental allergens, including insect bites. Reaction to the allergen induces release of histamine and other mediators, which eventually lead to vasodilation. Urticaria and hives can be seen on physical exam in these patients and allergy induced angioedema is responsive to antihistamines and corticosteroids. This cartoon illustrates the sensitization phase of the IgE-mediated allergen response.
The third category of angioedema is idiopathic and more specifically nonhistaminergic angioedema. It has similar clinical features to those of C1 inhibitor deficiency. However, it is unresponsive to antihistamines, but it may be mediated by bradykinin-induced vasodilation. Hereditary angioedema only occurs in roughly 1 in 10,000 to 150,000 patients in the population. It is due to deficiency of C1 inhibitor, which is a proteus inhibitor that regulates the activation of the complement and contact immunologic systems. It carries an autosomal dominant inheritance. There are two types of hereditary angioedema:
During asymptomatic periods in patients with hereditary angioedema, plasma C1 inhibitor levels average roughly 30% of normal. During attacks of angioedema, levels further decrease with apparent spontaneous activation of both the complement and the contact systems. Increased vascular permeability in this disease entity results primarily from bradykinin activation. This is a fairly new finding. Inciting events for angioedematous attacks include trauma, infection, febrile illnesses, temperature extremes, and other unknown factors. This is a pathophysiology of hereditary angioedema showing that C1 inhibitors basically control the activation of the complement system, the contact system, and actually the fibrinolytic system. With C1 inhibitor depletion, there is unregulated complement activation resulting in decreases in C4 and C2 levels in the blood. There is also unregulated contact system activation, which produces bradykinin, which again is a main mediator in the increased vascular permeability, resulting in angioedema in these patients. Acquired angioedema is due to an acquired deficiency in circulating levels of C1 inhibitor. It has also been found to be an antibody that it is produced against the inhibitor and is associated with lymphoproliferative disorders, autoimmune, neoplastic, and other infectious diseases, it has similar and almost identical symptoms as the hereditary form. So, how do we manage patients n an emergency setting? First of all, it depends on the etiology of angioedema and the associated symptoms. In general, a shotgun approach is used on initial presentation. Whether the patient is on an ACE-inhibitor or whether an allergy-induced angioedema is suspected, patients should receive IV corticosteroids, H1 and H2 blockers, oxygen, and epinephrine if the airway is severely compromised. H2 blockers are given mostly to prevent stress and steroid-induced gastritis in these patients. Of course, the use of the suspected offending agent, if known, should be discontined. The otolaryngology service is primarily consulted in these situations for airway assessment. Possible airway interventions are oral, nasotracheal intubation, tracheotomy, and cricothyroidotomy . How do we treat acute attacks of hereditary angioedema? First, the typical time course of symptoms: swelling generally increases for 24-36 hours and then decreases for the next 48-72 hours. This happens whether there is treatment or not and this type of angioedema is completely unresponsive to drugs such as corticosteroids and antihistamines. Currently in the United States there is no approved drug to be used in the acute setting for hereditary angioedema. Symptomatic treatment is suggested including oxygen and IV pain mediation. Some of these people have severe small bowel edema and this can be quite painful. There are, however, some experimental therapies used to treat acute attacks of hereditary angioedema. Several studies in Europe have proven a replacement therapy to be efficient. One of the experimental therapies is the antifibrinolytics epsilon-aminocaproic acid or Amicar and tranexamic acid. Other treatments include the anabolic androgens, such as danazol and stanazol. Replacement therapy is basically giving C1 inhibitor directly to the patient. As to the pathophysiology of hereditary angioedema, high molecular weight Aminogen is combined with prekallikrein. Prekallikrein is broken down by factor XIIa to kallikrein and then kallikrein breaks high molecular weight Aminogen to bradykinin. Again, bradykinin is the main mediator of vasopermeability in this disease entity. So, as you can see, C1 inhibitor does two things: it both directly inhibits factor XIIa as well as kallikrein, whereas anabolic androgens stimulate hepatocytes and other cells in the body to increase the serum levels of C1 inhibitor. Tranexamic acid and Amicar are the antifibrinolytics and they block the plasma activation of XII to XIIa. DX 88 is the kallikrein inhibitor and it obviously directly inhibits the kallikrein breakup of high molecular weight Aminogen and producing bradykinin. Finally this drug is the bradykinin-2 receptor antagonist on the endothelial cell. So C1 inhibitor replacement is the only one of these experimental drugs that has been proven in a prospective randomized double-blinded study in Europe to be effective in these acute attacks of hereditary angioedema, with C1 inhibitor concentrate being the most effective. Solvent and detergent wash plasma is another method of giving concentrated C1 inhibitor and FFP (fresh frozen plasma) is yet another way. Theoretically FFP is efficacious in this setting because it provides C1 inhibitor; however, it also provides other substrates in the pathophysiology of hereditary angioedema and thus symptoms can progress. How do we administer prophylaxis to patients with hereditary angioedema? First of all, the person with this disease entity has an average of one episode of swelling a month and the indication for prophylaxis includes having more than one attack every three months. However, it is really the impact on the patient’s life that dictates whether these patients should receive prophylaxis. Drugs that can be used in long-term prophylaxis include anabolic androgens, which are the treatment of choice. Again, danazol or an equivalent dose of stanozol can be given, which increase C1 inhibitor expression in these patients, and the antifibrinolytics, Amicar and tranexamic acid. Remember that in acute attacks, the mechanism was to decrease the plasmin activation of XII to XIIa, but in the long-term prophylactic setting, the mechanism for their efficiency is not known. These patients also require short-term prophylaxis should they be undergoing a planned trauma such as dental or surgical procedure, during which the patient is deemed at high risk of swelling. These patients can receive prophylaxis with high dosed androgens at a slightly higher dose in long-term prophylaxis or the replacement therapy through administration of FFP or the C1 inhibitor concentrate. So why are we talking about this topic at Otolaryngology Grand Rounds as opposed to allergic immunology? the answer is because the otolaryngologist is frequently consulted to assess the airway in these patients and decide whether an intervention is needed, and to decided where these patients should be triaged to - outpatient, in the MICU or on the floor. What part of the clinical history, if any, can be used to assess the need for airway intervention in these patients? Is it the etiology of the angioedema? One study showed the causes of angioedema as: 50% were idiopathic, 33% were ACE inhibitor induced, and the remainder were caused by allergy and hereditary. Two different studies found that there was no difference in the presentation or the prognosis in the ACE inhibitor induced angioedema compared to and among the other causes. Moreover, the time from onset of symptoms to the clinical presentation of these patients also did not correlate with the need for intervention. This is somewhat surprising since some of these patients come in 30 to 40 minutes after an attack and are deemed to be in extremis; but other patients can present up to the 8 to 12 hours after an attack and still need airway intervention. Gender and previous history of an angioedema attack are also factors that did not correlate with the need for airway intervention. So what did correlate with the need for airway intervention in terms of the clinical history? Increasing age was found to correlate positively with the need for airway intervention in the Zirkle study and symptoms of the patient were also found to be predictive. In particular, stridor, hoarseness, and dyspnea were found in two different studies to positively correlate with the need for airway intervention and/or ICU management. These are some graphs from those two studies. Statistically, voice change, dyspnea, hoarseness, and stridor were found to correlate positively with the ICU placement and/or airway intervention. What aspects of the physical exam, if any, can be used to help decide whether these patients need airway intervention? In the Zirkle study, only oral cavity and oropharyngeal involvement were found to positively correlate with the need for airway intervention. Interestingly, laryngeal and hypopharyngeal involvement were found not to correlate with the need for airway intervention. The reason for this is that the decision to intervene in these patients is often made by the physicians in the emergency room, often without examination of hypopharynx or larynx. So, when a patient presents, a decision is made to perform an airway intervention and otolaryngology is not consulted and the hypopharynx and larynx are not seen. This is an admitted problem with a retrospective chart review. Ishoo developed the staging of angioedema to help predict the need for airway intervention. Stage I is a facial rash edema or lip edema. Stage II is soft palate edema. Stage III is tongue edema. Stage IV is laryngeal edema. With tongue edema, a difference is not made between anterior or posterior tongue edema, which obviously has fairly dramatic clinical implications. Stage I and stage II are mostly treated as outpatients or on the floor for observation, whereas stage III and stage IV have a higher percentage of airway intervention and/or ICU monitoring. Bentsiznov et al looked particularly at findings on fiberoptic endoscopy for these patients and found that laryngeal edema, particularly when coupled with pharyngeal edema, had a very high correlation with the need for airway intervention and/or ICU management; whereas patients with no edema or just simply pharyngeal edema were found to be able to be seen or followed on the floor without the need for airway intervention. In these studies, the following findings were not found to correlate with the disease severity. Tongue enlargement, but again, this is a controversial area. The Zirkle study shows that oral cavity involvement was a predictor of airway intervention whereas this study, although it did not distinguish between anterior and posterior tongue edema, found it not to be significant. Lips and facial swelling did not correlate and nor did intraoral sites, including the floor of the mouth, buccal mucosa, oral palate, or uvula. So, how should we proceed when consulted in the ER to manage one of these patients. First of all, we should obviously focus on the location of the edema and perform a flexible scope exam. The basic shotgun approach of oxygen, antihistamines, steroids and plus or minus epinephrine (depending on the severity of the problem) should be used in all of these patients. Again, the decision for intervention and appropriate triage to be used should be decided by the otolaryngologist in conjunction with the other members of the medical team. This is a breakdown of the different types of airway intervention in the Zirkle study. Awake fiberoptic nasotracheal intervention was the procedure of choice followed by orotracheal intervention, tracheotomy, and finally cricothyroidotomy, depending on the extremis of the patient. What kind of algorithm should be followed when confronted with this issue? This is my own algorithm based on the research that I did for this presentation. First, perform a head and neck exam. Should this exam find the swelling to be limited only to the face with anterior tongue, give a trial of medical management. Two things could happen after this. Either the patient does not respond, at which time they should be admitted to the floor with continued steroids and antihistamines, or the patient shows improvement, at which time they can be discharged home on a prednisone taper. However, if the head and neck exam finds signs or symptoms of more extensive involvement in the face, lip, and anterior tongue, or stage I edema, we should go ahead and perform our scope exam. Signs indicating more extensive involvement with the edema or symptoms were those that we talked about before: stridor, voice change, or dyspnea. If our scope exam shows a significant oropharyngeal or hypopharyngeal involvement and obvious laryngeal swelling, the patient should be considered for an airway intervention, and at the least followed in the ICU. However, if the scope exam does not find more extensive involvement and just has soft palate or floor of the mouth swelling or state II swelling, the patient can be followed either on the floor or in ICU depending on the hospital setting. In summary of the initial management of angioedema attacks, airway intervention is needed in up to 20% of cases, and these are cases that otolaryngologists will see. Airway intervention is ultimately based on the patient’s stability. All patients receive the shotgun approach of medical management, and it is important to ascertain the etiology of the event for preventative purposes. Again, whether these patients are on ACE inhibitors or whether you suspect an allergy-induced angioedematous attack, all patients receive the same medical management and preventative measures, meaning that patients should be counseled on stopping the ACE inhibitor or not coming into contact with any allergy that might be suspected. The next clip is an actual angioedema episode, and there are three important points that I would like for you to see. One, this is a type I hypersensitivity reaction. It is IgE mediated and is via a contact allergen. Also, he has fairly impressive voice change, which by itself should alert the physician that this patient might need an airway intervention. Again, IgE mediated to the contact allergen. Our patient presents for the third time in five weeks with similar history; however, he has got only oral cavity and some floor of the mouth swelling and he was noted to have taken Motrin one day prior for a fall that he had at his house. Exam was significant only for floor of the mouth swelling and anterior tongue swelling, which can be considered type I/type II angioedema. He received the typical medical management in the emergency room and was then admitted to the floor and discharged the next day. He also received an allergy/immunology follow-up after being discharged on a prednisone taper and although they could not identify any allergies to food or medications and his C1 inhibitor levels were found to be within normal limits, they prescribed an EpiPen to be used in case of future attacks and also the H1 and H2 blockers to be used for a period of six weeks. The EpiPen delivers 0.3 mg of epinephrine to a patient should an attack occur. Ffinally, some pearls from this presentation. There are four basic causes of angioedema: idiopathic, allergic reactions, ACE inhibitor allergy and hereditary or acquired C1 inhibitor deficiency. Medical management on initial presentation should be fairly consistent and the decision for airway intervention and the appropriate triage should be made by the otolaryngologist in consult with the other healthcare professionals. Case Presentation: G.M. is a 71-year-old male who presented to the VAMC ER on October 5, 2005, complaining of swelling in his mouth and face, with increasing “tightening” of his throat. These symptoms had been progressing for a period of 24 hours. He denied changing or starting new medication recently, and there was no history of medication or food allergy. He had never experienced these symptoms before. Past Medical History: Hypertension, DM, COPD, Hypercholesterolemia, BPH, and low back pain. Past Surgical History was negative. Social History: 40 years of smoking tobacco, negative for alcohol consumption. Currently his medications are: Lisinoptil, Hydrochlorothiazide, aspirin, Simvastatin, Iboprofen, Metfomin, Terazosin, Atenolol, Albuterol inhaler and Omeprazole. He has no allergies. Upon physical examination he complained of dyspnea, but no strider or voice change. OC/OP: edema of lips, tongue. Posterior pharyngeal wall not visualized. Flexible larngoscopy: unilateral base of tongue, lateral hypopharyngeal wall edema with inability to visualize hemilarynx. Assessment and Plan: IV Solumedrol, Benadryl, given in the ER. Patient was taken to the OR for fiberoptic nasotracheal intubation. He was admitted to the MICU for medical management, including continued steroids, H1 and H2 blockers, and mechanical ventilation. He was transferred to floor after extubation and discharged home 5 days later. Bentsianov BL, Parhiscar A, Azer M, Har-El G. The role of fiberoptic nasopharyngoscopy in the management of the acute airway in angioneurotic edema. Laryngoscope 2000;110:2016-2019. 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Clin Immunol 2005;114:10-16. Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2006 Baylor College of Medicine
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