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Acute onset of facial swelling during colonoscopy in a 50-year-old woman
Clinical allergy-immunology rounds
Acute onset of facial swelling during colonoscopy in a 50-year-old woman John D. Mastrovich, MD*; Neill Peters, MD†; and Anju Tripathi, MD*
CHIEF COMPLAINT Acute onset of facial swelling and dyspnea during a colonoscopy. HISTORY OF PRESENT ILLNESS A 50-year-old woman was seen at our institution’s gastrointestinal laboratory for an outpatient colonoscopy and polypectomy. She had not consumed any food or medication, aside from polyethylene glycol (GoLytely; Braintree Laboratories Inc, Braintree, MA), during the previous 14 hours. The patient was given a sodium biphosphate enema before the procedure and intravenous midazolam, 6 mg, and fentanyl, 120 g, in divided doses during the colonoscopy. The colonoscope was advanced to the cecum and a small, hyperplastic polyp was resected. Within minutes of the resection, the patient began to experience facial fullness and mild shortness of breath. Her blood pressure at this time was 94/68 mm Hg, pulse was 99/min, respirations were 14/min, temperature was 37°C, and room air saturations were 98%. The staff feared that the patient might be experiencing an allergic reaction and the procedure was terminated. Although periorbital and facial edema was noticed, no hypotension, tachycardia, arrhythmia, bronchospasm, or rash was documented, and she experienced no pruritus, dysphagia, dysphonia, or light-headedness. The patient was given intravenous diphenhydramine, 50 mg, methylprednisolone, 160 mg, and epinephrine (1 mL of a 1:10,000 preparation) and subsequently given oxygen and transferred to the intensive care unit for observation. Otolaryngology and allergy-immunology consultations were requested. ADDITIONAL MEDICAL HISTORY The patient had a history of allergic rhinitis, psoriasis, gastroesophageal reflux disease, and depression. There was no personal or family history of asthma, angioedema, or food * Division of Allergy-Immunology, Department of Medicine, and the Ernest S. Bazley Asthma and Allergic Diseases Center of Northwestern Memorial Hospital and Northwestern University Medical School, Chicago, Illinois. † Department of Dermatology, Northwestern University Medical School, Chicago, Illinois. Supported by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and Northwestern University Medical School, Chicago, Illinois. Received for publication September 17, 2002. Accepted for publication in revised form July 20, 2003.
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allergies. She had experienced hives after taking a penicillin antibiotic several years ago but otherwise had no episodes of urticaria. She denied any previous reactions on exposure to balloons, condoms, or latex gloves. Notably, the patient had undergone a colonoscopy and esophagogastroduodenoscopy 1 year earlier and was treated with similar analgesics and sedatives without any adverse reactions. Her medications included loratadine, lansoprazole, and fluoxetine for several years without adverse reactions. She did not use any illegal drugs or herbal preparations. PHYSICAL EXAMINATION The patient was an obese woman who appeared to be in no distress when observed in the intensive care unit following the reaction. Vital signs included the following: blood pressure, 125/86 mm Hg; pulse, 125/min; respirations, 12/min; and room air saturations, 97%. Inspection of the face revealed moderate, bilateral periorbital and facial edema (Fig 1). The overlying skin appeared normal in color and texture and palpation of the face was not painful, although a sensation of pressure was noticed. There was no conjunctival erythema or ocular discharge, and findings of an examination of the ears, nose, and oropharynx were unremarkable. The neck appeared to be somewhat edematous on inspection without jugular venous distension. The trachea was palpable at midline. An otolaryngology evaluation found the airway to be patent with no obvious laryngeal edema or irritation. The heart had a regular rate and rhythm with no murmurs to auscultation and no palpable heaves or thrills. The lungs were clear to auscultation throughout with good ventilation and no stridor. The abdomen had active bowel sounds and was soft with no tenderness, masses, or organomegaly to palpation. The extremities were free of edema, cyanosis, or clubbing and were not tender to touch. There were no focal neurologic deficits, and the skin was without urticaria or other rashes. LABORATORY FINDINGS Initial screening laboratory findings were limited and revealed normal electrolytes and a normal blood cell count with differential (no left shift or eosinophils). A telemetry monitor strip recorded no arrhythmias or evidence of ischemia during the reaction in the gastrointestinal laboratory.
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QUESTIONS What additional laboratory data or investigations would be helpful in arriving at a diagnosis in this patient? 1. Test dose challenges to fentanyl and midazolam in a controlled clinical setting. 2. Latex testing. 3. Complement levels for C1q, C3, C4, and CH50. 4. Imaging studies of the head and neck, chest, and/or abdomen. 5. Blood cultures and/or cultures of the oropharynx.
Figure 1. Facial swelling noted in our patient on the day after the colonoscopy.
DIFFERENTIAL DIAGNOSIS Based on the history, initial physical examination, and laboratory findings, what is the differential diagnosis for acute facial swelling in this patient? 1. Angioedema from an IgE-mediated, allergic reaction to midazolam. 2. Angioedema from an anaphylactoid, non–IgE-mediated reaction to fentanyl. 3. Angioedema from an IgE-mediated, allergic reaction to latex. 4. Angioedema resulting from a C1 inhibitor deficiency. 5. Acute, idiopathic angioedema. 6. Other process mimicking angioedema of the face: ● bowel wall perforation with air dissection or subcutaneous emphysema ● superior vena cava syndrome ● soft tissue infection (ie, with group A streptococci)
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ADDITIONAL PHYSICAL AND LABORATORY DATA The patient’s facial swelling progressed during the next 24 hours despite the implementation of a latex-free environment and treatment with intravenous diphenhydramine and methylprednisolone. Complement levels were normal: C3, 184 mg/dL (reference range, 79 –165 mg/dL); C4, 32 mg/dL (reference range, 14 – 43 mg/dL); CH50, 156 U (reference range, ⬎145 U); and C1 esterase inhibitor, 19 mg/dL (reference range, 6 –25 mg/ dL). The patient remained afebrile with normal vital signs and no evidence of airway compromise. Subsequent examinations, however, revealed the presence of crepitus along the face, neck, upper shoulders, and anterior aspect of the chest. Throughout the day, the crepitus became more pronounced, involving the upper back, abdomen, and proximal thighs. A chest x-ray examination and acute abdominal series revealed air in the peritoneal cavity, outlining the bowel walls in both upper quadrants, as well as the pericardium, mediastinum, thoracic and abdominal walls, and neck. Computed tomographic (CT) scans of the neck, lungs, pelvis, and retroperitoneum confirmed these findings, and a small, left-sided pneumothorax was also discovered (Figures 2 through 4). Although air was visualized in the retroperitoneum, there was no obvious perforation of the colon or leak of contrast material into the abdominal cavity. The bowel itself, along
Figure 2. Computed tomography overview showing diffuse subcutaneous air (linear, black streaks) in chest wall, neck, and face.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Figure 4. Computed tomogram of the chest visualizing air present in the breasts and chest wall (cw), as well as a pneumothorax (pt), pneumomediastinum (pm), and pneumopericardium (pc).
Figure 3. Computed tomogram of the lower face and jaw area demonstrating subcutaneous air (sca) in the soft tissues.
with the other intra-abdominal organs, appeared to be normal. The surgical service was consulted, and the patient was given intravenous fluid and antibiotics covering typical bowel flora. Use of diphenhydramine and methylprednisolone was discontinued, and the patient slowly improved and was discharged home without additional complications. DISCUSSION Facial swelling may have a number of potential origins. Life-threatening causes include angioedema, superior vena cava syndrome, tension pneumothorax, and soft tissue infection with organisms, such as group A streptococci or Clostridium species. Emergent causes of facial swelling, such as tension pneumothorax or superior vena cava syndrome, were ruled out in the gastrointestinal laboratory and intensive care unit given the patient’s stable vital signs, normal cardiopulmonary examination results, lack of cyanosis, and unremarkable cardiac telemetry readings.
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Facial swelling in this patient was initially attributed to angioedema. Angioedema is a common cause of facial swelling and may result from a number of origins (Table 1). Acute episodes of angioedema (lasting fewer than 6 weeks) are usually the result of a medication, food, or insect sting.1 Although initially suspected, medication exposure as a trigger for angioedema in this patient seemed unlikely. Specifically, the polyethylene glycol (GoLytely) had been consumed more than 14 hours before the acute episode occurred, making it less likely to have caused angioedema. The biphosphate enema also seemed unlikely given its common use and lack of association with angioedema. A narcotic such as fentanyl, however, can directly stimulate mast cell release by a non– IgE-mediated mechanism, resulting predominantly in urticaria and/or angioedema, but her lack of urticaria and prior uneventful exposure to a narcotic agent 1 year previously made fentanyl an unlikely culprit. The only other agent she received was midazolam. Midazolam could have potentially resulted in an allergic, IgE antibody–mediated episode of Table 1. Causes of Angioedema* Idiopathic Non–IgE mediated, drug induced Histamine releasers (narcotics, radiocontrast media) Aspirin or nonsteroidal anti-inflammatory drugs Angiotensin-converting enzyme inhibitors C1 inhibitor deficiency (hereditary or acquired types) Physical stimuli (cold, sunlight, pressure, vibration) Circulating immune complexes (serum sickness, vasculitis, systemic lupus erythematosus) Miscellaneous rare syndromes Cutaneous or systemic mastocytosis Facial angioedema and eosinophilia C3b inactivator deficiency Carboxy peptidase B deficiency Urticaria or angioedema, deafness, and amyloidosis * Adapted with permission from Orfan and Kolski.4
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angioedema, but this would have been unusual given the absence of documented angioedema to this agent.2 In addition, the patient tolerated a similar (or identical) benzodiazepine 1 year earlier with her esophagogastroduodenoscopy. Test dosing to these medications could have been performed in a controlled clinical setting to determine if the patient was sensitive to these agents, but this became unnecessary given her final diagnosis. Latex allergy was another consideration in this patient, and latex precautions were implemented following the reaction. Overall, however, the suspicion for latex allergy was low. Specifically, she had no history of symptoms on exposure to latex products and had no risk factors for developing sensitization to latex aside from allergic rhinitis (no work in the health care field or latex industry, few invasive procedures, and so on).3 Although there initially was a possibility of latex allergy, the patient’s eventual diagnosis precluded a need for latex testing. When a patient presents with isolated angioedema without urticaria, angioedema secondary to C1 inhibitor deficiency (hereditary or acquired) must be considered.4 Hereditary angioedema (HAE) stems from a genetic defect that results in either reduced synthesis of C1 inhibitor (HAE type I, approximately 85% of cases) or near-normal levels of dysfunctional C1 inhibitor (HAE type II, approximately 15% of cases). HAE affects between 1 in 10,000 and 1 in 50,000 persons.5 Recently, a new form of HAE (HAE type III) has been discovered, which is clinically indistinguishable from type I or II but occurs only in women. The trait is thought to be inherited by an X-linked dominant mode, and the defining laboratory abnormalities seen in HAE types I and II remain normal in this disorder.6 Acquired C1 inhibitor deficiency results from an approximate 2-fold increased rate of catabolism of C1 inhibitor despite normal synthesis of this functional product.4 These patients are clinically indistinguishable from patients with HAE, but they usually present after the fourth decade of life (often middle-aged or elderly patients) with an absent family history of angioedema.6 Acquired C1 inhibitor deficiency may be associated with malignancies and immune complexes that activate C1 and subsequently consume C1 inhibitor (type I) or with nonmalignant states in
which autoantibody is directed against C1 inhibitor (type II).4 An analysis of the complement profile will distinguish acquired C1 inhibitor deficiency from HAE and can differentiate HAE type I from HAE type II. These particular values remain within normal limits, however, for HAE type III, making the diagnosis difficult (Table 2). Our patient had neither acquired angioedema nor HAE in light of the normal C3, C4, and C1 inhibitor levels (aside from the remote possibility of HAE type III). Furthermore, it would have been unusual for these conditions to present with rapid angioedema for the first time during the colonoscopy. Other causes of facial swelling, such as idiopathic angioedema or infection (group A streptococci or Clostridium species), were not considered to be likely causes. Idiopathic angioedema is usually a chronic disorder, and facial swelling for the first time during colonoscopy would be an atypical presentation for this entity. In addition, idiopathic angioedema generally responds to antihistamines and corticosteroid therapy, whereas our patient’s swelling did not. Finally, infection of the soft tissues of the face was unlikely given the lack of local pain, erythema, fever, and leukocytosis. The presence of crepitus ultimately identified the patient’s facial swelling as subcutaneous emphysema. This was confirmed by both CT and x-ray analysis. Subcutaneous emphysema may initially mimic angioedema, since the deeper, subcutaneous air causes swelling or displacement of the superficial tissues. As the air dissects its way to the surface and infiltrates the dermis or epidermis, the characteristic finding of crepitus (crackling sound and sensation on palpation) becomes apparent. There are many potential causes of subcutaneous emphysema (Table 3). This finding usually results from blunt or penetrating trauma to the airway or any condition that creates a gradient between intra-alveolar and perivascular interstitial pressures.7 Perforation of the gastrointestinal tract, iatrogenic introduction of air into the abdomen or pelvis, or infection (ie, gas gangrene) must also be considered. The cervical soft tissues, mediastinum, and retroperitoneum are associated by a continuum of fascial planes so that air arising in any one of these areas may spread to involve the others.7 Subcutaneous emphysema with involvement of the
Table 2. Differentiating C1 Inhibitor Deficiencies by Complement Analysis* Disorder
C1 q
HAE type I HAE type II
Normal Normal
HAE type III
Normal
Acquired type I
Low
Acquired type II
Low
C1 inhibitor Low quantitative, low functional Normal or high quantitative, low functional Normal quantitative, normal functional Normal or low quantitative, low functional Normal or low quantitative (in 60%–70%), low functional
C3
C4
C2
Normal Normal
Persistently low Persistently low
Acutely low Acutely low
Normal
Normal
Normal
Normal
Persistently low
Acutely low
Normal
Persistently low
Acutely low
Abbreviation: HAE, hereditary angioedema. * Adapted with permission from Orfan and Kolski.4
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ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 3. Origins of Subcutaneous Emphysema* Upper respiratory tract Head or neck infections Fractures or trauma (paranasal sinuses, orbit, mandibles, other facial bones) Mucosal disruption (trauma, surgery, attempted endotracheal intubation) Dental procedures (dental extractions, air turbine drilling) Intrathoracic airways Blunting or penetrating chest trauma Foreign bodies Iatrogenic (bronchoscopy, bronchial brushing, transbronchial biopsy) Neoplasms (invasive) Infection (acute bacterial mediastinitis) Lung parenchyma Direct disruption of alveoli (trauma, surgery, biopsy, needle aspiration) “Spontaneous” alveolar rupture Valsalva maneuver and conscious alterations in breathing (pulmonary function tests) Straining and other involuntary alterations in breathing patterns (vomiting) Local airway obstruction with distal air trapping (asthma, bronchiolitis) Atelectasis of adjacent lung tissue Decompression, gas expansion (SCUBA diving, air travel) Positive intrathoracic pressure of external origin (mechanical ventilation) Intrathoracic airways Penetrating trauma to chest or neck Surgical procedures (tracheotomy, mediastinoscopy, sternotomy, chest tubes) Artificial pneumothorax or pneumomediastinum Gastrointestinal tract Esophageal perforation (carcinoma, nasogastric tube perforation, upper endoscopy) Gastric or intestinal perforation (pneumoperitoneum or pneumoretroperitoneum) Diverticulitis Invasive carcinoma Pneumatosis cystoides intestinalis Endoscopy, sigmoidoscopy or colonoscopy (with or without biopsy) Infection (necrotizing enterocolitis) Abdominal wall disruption Laparoscopic procedures (laparoscopic cholecystectomy, etc) Polyethylene glycol * Adapted with permission from Pierson DJ. Pneumomediastinum. In: Textbook of Respiratory Medicine. Philadelphia, PA: WB Saunders Co; 1994:2251, 2255.
mediastinum, pericardium, and/or retroperitoneum has been linked, for example, with dental extractions and dental surgery,8 –10 use of high-speed air-turbine dental drills,11 temporomandibular joint surgery,12 labor and delivery,13,14 foreign body aspiration,15,16 dermatomyositis or interstitial pneumonitis,17,18 perforation in ulcerative colitis,19,20 and routine measurements of maximal expiratory pressures.21 There-
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fore, whenever subcutaneous emphysema is detected, the physician should evaluate all of these interconnected areas to identify the source of the problem. Our patient’s subcutaneous emphysema most likely resulted from a retroperitoneal bowel perforation that occurred during colonoscopy, possibly at the time of polyp resection. Although gross perforation was not detected on CT imaging, air was visualized in the retroperitoneum, and a microperforation probably occurred as a result of elevated intraluminal bowel pressures at the polypectomy site. The resection could have compromised bowel wall integrity, providing a channel for air dissection into the retroperitoneum. The air subsequently traveled through the continuum of fascial planes to involve the mediastinum, pericardium, chest and abdominal walls, proximal extremities, and cervical tissues of the neck and face. This explanation is plausible because subcutaneous emphysema is a known complication of intra-abdominal procedures. Indeed, episodes of subcutaneous emphysema with associated pneumomediastinum, pneumopericardium, pneumoretroperitoneum, or pneumothorax have been reported with laparoscopy,22–24 upper gastrointestinal tract endoscopy,25 polyethylene glycol tube placement,26 colonoscopy,27,28 endoscopic polypectomy,29 and sigmoidoscopy.30 The incidence of perforation with colonoscopy has been estimated to be approximately 0.1%, and plain x-ray films may be more helpful than contrast studies in distinguishing intraperitoneal from retroperitoneal perforations.27 Treatment for retroperitoneal perforations is usually supportive, whereas intraperitoneal perforations often require surgical exploration and correction.27 In most instances, subcutaneous emphysema can be managed with supportive measures only, and the routine use of chest tubes, tracheostomy, and mediastinal drains is not recommended.7 CONCLUSION This case reveals that physicians should maintain a broad differential diagnosis when assessing a patient with facial swelling. Although angioedema is one of the most common causes of facial swelling, angioedema is not responsible for all cases and other possibilities should be considered. REFERENCES 1. Kaplan AP. Urticaria and angioedema. In: Middleton E, Reed CE, editors. Allergy: Principles and Practice. St. Louis, MO: Mosby Inc; 1998:1104. 2. Physicians’ Desk Reference. Montvale, NJ: Thomson PDR; 2003;54:862. 3. Yunginger JW. Natural rubber latex allergy. In: Middleton E, Reed CE, editors. Allergy: Principles and Practice. St. Louis, MO: Mosby Inc; 1998:1073–1077. 4. Orfan NA, Kolski GB. Angioedema and C1 inhibitor deficiency. Ann Allergy. 1992;69:167–172. 5. Bork K, Siedlecki K, Bosch S, et al. Asphyxiation by laryngeal edema in patients with hereditary angioedema. Mayo Clin Proc. 2000;75:349 –354.
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6. Bork K, Sven-Erik B, Koch P, et al. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet. 2000;356: 213–217. 7. Maunder RJ, Pierson DJ, Hudson LD. Subcutaneous and mediastinal emphysema: pathophysiology, diagnosis and management. Arch Intern Med. 1984;144:1447–1453. 8. Sandler CM, Libshitz HI, Marks G. Pneumoperitoneum, pneumomediastinum and pneumopericardium following dental extraction. Radiology. 1975;115:539 –540. 9. Chen SC, Lin FY, Chang KJ. Subcutaneous emphysema and pneumomediastinum after dental extraction. Am J Emerg Med. 1999;17:678 – 680. 10. Shackelford D, Casani JAP. Diffuse subcutaneous emphysema, pneumomediastinum and pneumothorax after dental extraction. Ann Emerg Med. 1993;22:248 –250. 11. Trummer MJ, Fosburg RG. Medistinal emphysema following the use of a high-speed air-turbine drill. Am Thorac Surg. 1970;9:378 –381. 12. Chuong R, Boland TJ, Piper MA. Pneumomediastinum and subcutaneous emphysema associated with temporomandibular joint surgery. Oral Surg Oral Med Oral Pathol. 1992;74:2– 6. 13. Demetroulakos J, Morris MS, Waldhorn R. Postpartum subcutaneous emphysema with pneumomediastinum. Ear Nose Throat J. 1990;69:752–755. 14. Sparacino ML, Mackay PE. Subcutaneous emphysema and pneumomediastinum complicating labor in a twin pregnancy. J Am Osteopath Assoc. 1989;89:185–187. 15. Yaniv E, Weinberg J. Pneumomediastinum with subcutaneous emphysema as a complication of foreign body in the bronchus. Int J Pediatr Otorhinolaryngol. 1984;7:75–77. 16. Saoji R, Ramchandra C, D’Cruz AJ. Subcutaneous emphysema: an unusual presentation of foreign body in the airway. J Pediatr Surg. 1995;30:860 – 862. 17. Jang KA, Kim SH, Choi JH, et al. Subcutaneous emphysema with spontaneous pneumomediastinum and pneumothorax in adult dermatomyositis. J Dermatol. 1999;26:125–127. 18. Nagai Y, Ishikawa O, Miyachi Y. Pneumomediastinum and subcutaneous emphysema associated with fatal interstitial pneumonia in dermatomyositis. J Dermatol. 1997;24:482– 484. 19. Alvares JF, Dhawan PS, Tibrewala S, et al. Retroperitoneal perforation in ulcerative colitis with mediastinal and subcutaneous emphysema. J Clin Gastroenterol. 1997;25:453– 455. 20. Cohen ME, Kleinman MS. Pneumomediastinum during relapse of ulcerative colitis. Am J Gastroenterol. 1997;92:2306 –2307. 21. Manco JC, Terra-Filho J, Silva GA. Pneumomediastinum, pneu-
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22. 23. 24. 25. 26. 27. 28. 29.
30.
mothorax and subcutaneous emphysema following the measurement of maximal expiratory pressure in a normal subject. Chest. 1990;98:1530 –1532. Kalhan SB, Reaney JA, Collins RL. Pneumomediastinum and subcutaneous emphysema during laparoscopy. Cleve Clin J Med. 1990;57:639 – 642. Santana A, Crausman RS, Dubin HG. Late onset of subcutaneous emphysema and hypercarbia following laparoscopic cholecystectomy. Chest. 1999;115:1468 –1471. Kent RB. Subcutaneous emphysema and hypercarbia following laparoscopic cholecystectomy. Arch Surg. 1991;126: 1154 –1156. Girardi A, Piazza I, Giunta G, et al. Retroperitoneal, mediastinal and subcutaneous emphysema as a complication of routine upper gastrointestinal endoscopy. Endoscopy. 1990;22:83– 84. Stathopoulos G, Rudberg MA, Harig JM. Subcutaneous emphysema following PEG. Gastrointest Endosc. 1991;37:374 –376. Humphreys F, Hewetson KA, Dellipiani AW. Massive subcutaneous emphysema following colonoscopy. Endoscopy. 1984; 16:160 –161. Schmidt G, Borsch G, Wegener M. Subcutaneous emphysema and pneumothorax complicating diagnostic colonoscopy. Dis Colon Rectum. 1986;29:136 –138. Ho HC, Burchell S, Morris P, et al. Colon perforation, bilateral pneumothoraces, pneumopericardium, pneumomediastinum, and subcutaneous emphysema complicating endoscopic polypectomy: anatomic and management considerations. Am Surg. 1996;62:770 –774. Mccarthy JH, Laurence BH. Subcutaneous emphysema: a rare complication of fiberoptic sigmoidoscopy. Aust NZ J Med. 1985;15:47– 49.
Requests for reprints should be addressed to: Anju Tripathi, MD Northwestern University Medical School Department of Medicine Division of Allergy and Immunology Tarry Building 3–711 Mail Code S207 303 E Chicago Ave Chicago, IL 60611 E-mail: [email protected]
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Acute onset of facial swelling during colonoscopy in a 50-year-old woman John D. Mastrovich, MD*; Neill Peters, MD†; and Anju Tripathi, MD*
CHIEF COMPLAINT Acute onset of facial swelling and dyspnea during a colonoscopy. HISTORY OF PRESENT ILLNESS A 50-year-old woman was seen at our institution’s gastrointestinal laboratory for an outpatient colonoscopy and polypectomy. She had not consumed any food or medication, aside from polyethylene glycol (GoLytely; Braintree Laboratories Inc, Braintree, MA), during the previous 14 hours. The patient was given a sodium biphosphate enema before the procedure and intravenous midazolam, 6 mg, and fentanyl, 120 g, in divided doses during the colonoscopy. The colonoscope was advanced to the cecum and a small, hyperplastic polyp was resected. Within minutes of the resection, the patient began to experience facial fullness and mild shortness of breath. Her blood pressure at this time was 94/68 mm Hg, pulse was 99/min, respirations were 14/min, temperature was 37°C, and room air saturations were 98%. The staff feared that the patient might be experiencing an allergic reaction and the procedure was terminated. Although periorbital and facial edema was noticed, no hypotension, tachycardia, arrhythmia, bronchospasm, or rash was documented, and she experienced no pruritus, dysphagia, dysphonia, or light-headedness. The patient was given intravenous diphenhydramine, 50 mg, methylprednisolone, 160 mg, and epinephrine (1 mL of a 1:10,000 preparation) and subsequently given oxygen and transferred to the intensive care unit for observation. Otolaryngology and allergy-immunology consultations were requested. ADDITIONAL MEDICAL HISTORY The patient had a history of allergic rhinitis, psoriasis, gastroesophageal reflux disease, and depression. There was no personal or family history of asthma, angioedema, or food * Division of Allergy-Immunology, Department of Medicine, and the Ernest S. Bazley Asthma and Allergic Diseases Center of Northwestern Memorial Hospital and Northwestern University Medical School, Chicago, Illinois. † Department of Dermatology, Northwestern University Medical School, Chicago, Illinois. Supported by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and Northwestern University Medical School, Chicago, Illinois. Received for publication September 17, 2002. Accepted for publication in revised form July 20, 2003.
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allergies. She had experienced hives after taking a penicillin antibiotic several years ago but otherwise had no episodes of urticaria. She denied any previous reactions on exposure to balloons, condoms, or latex gloves. Notably, the patient had undergone a colonoscopy and esophagogastroduodenoscopy 1 year earlier and was treated with similar analgesics and sedatives without any adverse reactions. Her medications included loratadine, lansoprazole, and fluoxetine for several years without adverse reactions. She did not use any illegal drugs or herbal preparations. PHYSICAL EXAMINATION The patient was an obese woman who appeared to be in no distress when observed in the intensive care unit following the reaction. Vital signs included the following: blood pressure, 125/86 mm Hg; pulse, 125/min; respirations, 12/min; and room air saturations, 97%. Inspection of the face revealed moderate, bilateral periorbital and facial edema (Fig 1). The overlying skin appeared normal in color and texture and palpation of the face was not painful, although a sensation of pressure was noticed. There was no conjunctival erythema or ocular discharge, and findings of an examination of the ears, nose, and oropharynx were unremarkable. The neck appeared to be somewhat edematous on inspection without jugular venous distension. The trachea was palpable at midline. An otolaryngology evaluation found the airway to be patent with no obvious laryngeal edema or irritation. The heart had a regular rate and rhythm with no murmurs to auscultation and no palpable heaves or thrills. The lungs were clear to auscultation throughout with good ventilation and no stridor. The abdomen had active bowel sounds and was soft with no tenderness, masses, or organomegaly to palpation. The extremities were free of edema, cyanosis, or clubbing and were not tender to touch. There were no focal neurologic deficits, and the skin was without urticaria or other rashes. LABORATORY FINDINGS Initial screening laboratory findings were limited and revealed normal electrolytes and a normal blood cell count with differential (no left shift or eosinophils). A telemetry monitor strip recorded no arrhythmias or evidence of ischemia during the reaction in the gastrointestinal laboratory.
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QUESTIONS What additional laboratory data or investigations would be helpful in arriving at a diagnosis in this patient? 1. Test dose challenges to fentanyl and midazolam in a controlled clinical setting. 2. Latex testing. 3. Complement levels for C1q, C3, C4, and CH50. 4. Imaging studies of the head and neck, chest, and/or abdomen. 5. Blood cultures and/or cultures of the oropharynx.
Figure 1. Facial swelling noted in our patient on the day after the colonoscopy.
DIFFERENTIAL DIAGNOSIS Based on the history, initial physical examination, and laboratory findings, what is the differential diagnosis for acute facial swelling in this patient? 1. Angioedema from an IgE-mediated, allergic reaction to midazolam. 2. Angioedema from an anaphylactoid, non–IgE-mediated reaction to fentanyl. 3. Angioedema from an IgE-mediated, allergic reaction to latex. 4. Angioedema resulting from a C1 inhibitor deficiency. 5. Acute, idiopathic angioedema. 6. Other process mimicking angioedema of the face: ● bowel wall perforation with air dissection or subcutaneous emphysema ● superior vena cava syndrome ● soft tissue infection (ie, with group A streptococci)
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ADDITIONAL PHYSICAL AND LABORATORY DATA The patient’s facial swelling progressed during the next 24 hours despite the implementation of a latex-free environment and treatment with intravenous diphenhydramine and methylprednisolone. Complement levels were normal: C3, 184 mg/dL (reference range, 79 –165 mg/dL); C4, 32 mg/dL (reference range, 14 – 43 mg/dL); CH50, 156 U (reference range, ⬎145 U); and C1 esterase inhibitor, 19 mg/dL (reference range, 6 –25 mg/ dL). The patient remained afebrile with normal vital signs and no evidence of airway compromise. Subsequent examinations, however, revealed the presence of crepitus along the face, neck, upper shoulders, and anterior aspect of the chest. Throughout the day, the crepitus became more pronounced, involving the upper back, abdomen, and proximal thighs. A chest x-ray examination and acute abdominal series revealed air in the peritoneal cavity, outlining the bowel walls in both upper quadrants, as well as the pericardium, mediastinum, thoracic and abdominal walls, and neck. Computed tomographic (CT) scans of the neck, lungs, pelvis, and retroperitoneum confirmed these findings, and a small, left-sided pneumothorax was also discovered (Figures 2 through 4). Although air was visualized in the retroperitoneum, there was no obvious perforation of the colon or leak of contrast material into the abdominal cavity. The bowel itself, along
Figure 2. Computed tomography overview showing diffuse subcutaneous air (linear, black streaks) in chest wall, neck, and face.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Figure 4. Computed tomogram of the chest visualizing air present in the breasts and chest wall (cw), as well as a pneumothorax (pt), pneumomediastinum (pm), and pneumopericardium (pc).
Figure 3. Computed tomogram of the lower face and jaw area demonstrating subcutaneous air (sca) in the soft tissues.
with the other intra-abdominal organs, appeared to be normal. The surgical service was consulted, and the patient was given intravenous fluid and antibiotics covering typical bowel flora. Use of diphenhydramine and methylprednisolone was discontinued, and the patient slowly improved and was discharged home without additional complications. DISCUSSION Facial swelling may have a number of potential origins. Life-threatening causes include angioedema, superior vena cava syndrome, tension pneumothorax, and soft tissue infection with organisms, such as group A streptococci or Clostridium species. Emergent causes of facial swelling, such as tension pneumothorax or superior vena cava syndrome, were ruled out in the gastrointestinal laboratory and intensive care unit given the patient’s stable vital signs, normal cardiopulmonary examination results, lack of cyanosis, and unremarkable cardiac telemetry readings.
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Facial swelling in this patient was initially attributed to angioedema. Angioedema is a common cause of facial swelling and may result from a number of origins (Table 1). Acute episodes of angioedema (lasting fewer than 6 weeks) are usually the result of a medication, food, or insect sting.1 Although initially suspected, medication exposure as a trigger for angioedema in this patient seemed unlikely. Specifically, the polyethylene glycol (GoLytely) had been consumed more than 14 hours before the acute episode occurred, making it less likely to have caused angioedema. The biphosphate enema also seemed unlikely given its common use and lack of association with angioedema. A narcotic such as fentanyl, however, can directly stimulate mast cell release by a non– IgE-mediated mechanism, resulting predominantly in urticaria and/or angioedema, but her lack of urticaria and prior uneventful exposure to a narcotic agent 1 year previously made fentanyl an unlikely culprit. The only other agent she received was midazolam. Midazolam could have potentially resulted in an allergic, IgE antibody–mediated episode of Table 1. Causes of Angioedema* Idiopathic Non–IgE mediated, drug induced Histamine releasers (narcotics, radiocontrast media) Aspirin or nonsteroidal anti-inflammatory drugs Angiotensin-converting enzyme inhibitors C1 inhibitor deficiency (hereditary or acquired types) Physical stimuli (cold, sunlight, pressure, vibration) Circulating immune complexes (serum sickness, vasculitis, systemic lupus erythematosus) Miscellaneous rare syndromes Cutaneous or systemic mastocytosis Facial angioedema and eosinophilia C3b inactivator deficiency Carboxy peptidase B deficiency Urticaria or angioedema, deafness, and amyloidosis * Adapted with permission from Orfan and Kolski.4
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angioedema, but this would have been unusual given the absence of documented angioedema to this agent.2 In addition, the patient tolerated a similar (or identical) benzodiazepine 1 year earlier with her esophagogastroduodenoscopy. Test dosing to these medications could have been performed in a controlled clinical setting to determine if the patient was sensitive to these agents, but this became unnecessary given her final diagnosis. Latex allergy was another consideration in this patient, and latex precautions were implemented following the reaction. Overall, however, the suspicion for latex allergy was low. Specifically, she had no history of symptoms on exposure to latex products and had no risk factors for developing sensitization to latex aside from allergic rhinitis (no work in the health care field or latex industry, few invasive procedures, and so on).3 Although there initially was a possibility of latex allergy, the patient’s eventual diagnosis precluded a need for latex testing. When a patient presents with isolated angioedema without urticaria, angioedema secondary to C1 inhibitor deficiency (hereditary or acquired) must be considered.4 Hereditary angioedema (HAE) stems from a genetic defect that results in either reduced synthesis of C1 inhibitor (HAE type I, approximately 85% of cases) or near-normal levels of dysfunctional C1 inhibitor (HAE type II, approximately 15% of cases). HAE affects between 1 in 10,000 and 1 in 50,000 persons.5 Recently, a new form of HAE (HAE type III) has been discovered, which is clinically indistinguishable from type I or II but occurs only in women. The trait is thought to be inherited by an X-linked dominant mode, and the defining laboratory abnormalities seen in HAE types I and II remain normal in this disorder.6 Acquired C1 inhibitor deficiency results from an approximate 2-fold increased rate of catabolism of C1 inhibitor despite normal synthesis of this functional product.4 These patients are clinically indistinguishable from patients with HAE, but they usually present after the fourth decade of life (often middle-aged or elderly patients) with an absent family history of angioedema.6 Acquired C1 inhibitor deficiency may be associated with malignancies and immune complexes that activate C1 and subsequently consume C1 inhibitor (type I) or with nonmalignant states in
which autoantibody is directed against C1 inhibitor (type II).4 An analysis of the complement profile will distinguish acquired C1 inhibitor deficiency from HAE and can differentiate HAE type I from HAE type II. These particular values remain within normal limits, however, for HAE type III, making the diagnosis difficult (Table 2). Our patient had neither acquired angioedema nor HAE in light of the normal C3, C4, and C1 inhibitor levels (aside from the remote possibility of HAE type III). Furthermore, it would have been unusual for these conditions to present with rapid angioedema for the first time during the colonoscopy. Other causes of facial swelling, such as idiopathic angioedema or infection (group A streptococci or Clostridium species), were not considered to be likely causes. Idiopathic angioedema is usually a chronic disorder, and facial swelling for the first time during colonoscopy would be an atypical presentation for this entity. In addition, idiopathic angioedema generally responds to antihistamines and corticosteroid therapy, whereas our patient’s swelling did not. Finally, infection of the soft tissues of the face was unlikely given the lack of local pain, erythema, fever, and leukocytosis. The presence of crepitus ultimately identified the patient’s facial swelling as subcutaneous emphysema. This was confirmed by both CT and x-ray analysis. Subcutaneous emphysema may initially mimic angioedema, since the deeper, subcutaneous air causes swelling or displacement of the superficial tissues. As the air dissects its way to the surface and infiltrates the dermis or epidermis, the characteristic finding of crepitus (crackling sound and sensation on palpation) becomes apparent. There are many potential causes of subcutaneous emphysema (Table 3). This finding usually results from blunt or penetrating trauma to the airway or any condition that creates a gradient between intra-alveolar and perivascular interstitial pressures.7 Perforation of the gastrointestinal tract, iatrogenic introduction of air into the abdomen or pelvis, or infection (ie, gas gangrene) must also be considered. The cervical soft tissues, mediastinum, and retroperitoneum are associated by a continuum of fascial planes so that air arising in any one of these areas may spread to involve the others.7 Subcutaneous emphysema with involvement of the
Table 2. Differentiating C1 Inhibitor Deficiencies by Complement Analysis* Disorder
C1 q
HAE type I HAE type II
Normal Normal
HAE type III
Normal
Acquired type I
Low
Acquired type II
Low
C1 inhibitor Low quantitative, low functional Normal or high quantitative, low functional Normal quantitative, normal functional Normal or low quantitative, low functional Normal or low quantitative (in 60%–70%), low functional
C3
C4
C2
Normal Normal
Persistently low Persistently low
Acutely low Acutely low
Normal
Normal
Normal
Normal
Persistently low
Acutely low
Normal
Persistently low
Acutely low
Abbreviation: HAE, hereditary angioedema. * Adapted with permission from Orfan and Kolski.4
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ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 3. Origins of Subcutaneous Emphysema* Upper respiratory tract Head or neck infections Fractures or trauma (paranasal sinuses, orbit, mandibles, other facial bones) Mucosal disruption (trauma, surgery, attempted endotracheal intubation) Dental procedures (dental extractions, air turbine drilling) Intrathoracic airways Blunting or penetrating chest trauma Foreign bodies Iatrogenic (bronchoscopy, bronchial brushing, transbronchial biopsy) Neoplasms (invasive) Infection (acute bacterial mediastinitis) Lung parenchyma Direct disruption of alveoli (trauma, surgery, biopsy, needle aspiration) “Spontaneous” alveolar rupture Valsalva maneuver and conscious alterations in breathing (pulmonary function tests) Straining and other involuntary alterations in breathing patterns (vomiting) Local airway obstruction with distal air trapping (asthma, bronchiolitis) Atelectasis of adjacent lung tissue Decompression, gas expansion (SCUBA diving, air travel) Positive intrathoracic pressure of external origin (mechanical ventilation) Intrathoracic airways Penetrating trauma to chest or neck Surgical procedures (tracheotomy, mediastinoscopy, sternotomy, chest tubes) Artificial pneumothorax or pneumomediastinum Gastrointestinal tract Esophageal perforation (carcinoma, nasogastric tube perforation, upper endoscopy) Gastric or intestinal perforation (pneumoperitoneum or pneumoretroperitoneum) Diverticulitis Invasive carcinoma Pneumatosis cystoides intestinalis Endoscopy, sigmoidoscopy or colonoscopy (with or without biopsy) Infection (necrotizing enterocolitis) Abdominal wall disruption Laparoscopic procedures (laparoscopic cholecystectomy, etc) Polyethylene glycol * Adapted with permission from Pierson DJ. Pneumomediastinum. In: Textbook of Respiratory Medicine. Philadelphia, PA: WB Saunders Co; 1994:2251, 2255.
mediastinum, pericardium, and/or retroperitoneum has been linked, for example, with dental extractions and dental surgery,8 –10 use of high-speed air-turbine dental drills,11 temporomandibular joint surgery,12 labor and delivery,13,14 foreign body aspiration,15,16 dermatomyositis or interstitial pneumonitis,17,18 perforation in ulcerative colitis,19,20 and routine measurements of maximal expiratory pressures.21 There-
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fore, whenever subcutaneous emphysema is detected, the physician should evaluate all of these interconnected areas to identify the source of the problem. Our patient’s subcutaneous emphysema most likely resulted from a retroperitoneal bowel perforation that occurred during colonoscopy, possibly at the time of polyp resection. Although gross perforation was not detected on CT imaging, air was visualized in the retroperitoneum, and a microperforation probably occurred as a result of elevated intraluminal bowel pressures at the polypectomy site. The resection could have compromised bowel wall integrity, providing a channel for air dissection into the retroperitoneum. The air subsequently traveled through the continuum of fascial planes to involve the mediastinum, pericardium, chest and abdominal walls, proximal extremities, and cervical tissues of the neck and face. This explanation is plausible because subcutaneous emphysema is a known complication of intra-abdominal procedures. Indeed, episodes of subcutaneous emphysema with associated pneumomediastinum, pneumopericardium, pneumoretroperitoneum, or pneumothorax have been reported with laparoscopy,22–24 upper gastrointestinal tract endoscopy,25 polyethylene glycol tube placement,26 colonoscopy,27,28 endoscopic polypectomy,29 and sigmoidoscopy.30 The incidence of perforation with colonoscopy has been estimated to be approximately 0.1%, and plain x-ray films may be more helpful than contrast studies in distinguishing intraperitoneal from retroperitoneal perforations.27 Treatment for retroperitoneal perforations is usually supportive, whereas intraperitoneal perforations often require surgical exploration and correction.27 In most instances, subcutaneous emphysema can be managed with supportive measures only, and the routine use of chest tubes, tracheostomy, and mediastinal drains is not recommended.7 CONCLUSION This case reveals that physicians should maintain a broad differential diagnosis when assessing a patient with facial swelling. Although angioedema is one of the most common causes of facial swelling, angioedema is not responsible for all cases and other possibilities should be considered. REFERENCES 1. Kaplan AP. Urticaria and angioedema. In: Middleton E, Reed CE, editors. Allergy: Principles and Practice. St. Louis, MO: Mosby Inc; 1998:1104. 2. Physicians’ Desk Reference. Montvale, NJ: Thomson PDR; 2003;54:862. 3. Yunginger JW. Natural rubber latex allergy. In: Middleton E, Reed CE, editors. Allergy: Principles and Practice. St. Louis, MO: Mosby Inc; 1998:1073–1077. 4. Orfan NA, Kolski GB. Angioedema and C1 inhibitor deficiency. Ann Allergy. 1992;69:167–172. 5. Bork K, Siedlecki K, Bosch S, et al. Asphyxiation by laryngeal edema in patients with hereditary angioedema. Mayo Clin Proc. 2000;75:349 –354.
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6. Bork K, Sven-Erik B, Koch P, et al. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet. 2000;356: 213–217. 7. Maunder RJ, Pierson DJ, Hudson LD. Subcutaneous and mediastinal emphysema: pathophysiology, diagnosis and management. Arch Intern Med. 1984;144:1447–1453. 8. Sandler CM, Libshitz HI, Marks G. Pneumoperitoneum, pneumomediastinum and pneumopericardium following dental extraction. Radiology. 1975;115:539 –540. 9. Chen SC, Lin FY, Chang KJ. Subcutaneous emphysema and pneumomediastinum after dental extraction. Am J Emerg Med. 1999;17:678 – 680. 10. Shackelford D, Casani JAP. Diffuse subcutaneous emphysema, pneumomediastinum and pneumothorax after dental extraction. Ann Emerg Med. 1993;22:248 –250. 11. Trummer MJ, Fosburg RG. Medistinal emphysema following the use of a high-speed air-turbine drill. Am Thorac Surg. 1970;9:378 –381. 12. Chuong R, Boland TJ, Piper MA. Pneumomediastinum and subcutaneous emphysema associated with temporomandibular joint surgery. Oral Surg Oral Med Oral Pathol. 1992;74:2– 6. 13. Demetroulakos J, Morris MS, Waldhorn R. Postpartum subcutaneous emphysema with pneumomediastinum. Ear Nose Throat J. 1990;69:752–755. 14. Sparacino ML, Mackay PE. Subcutaneous emphysema and pneumomediastinum complicating labor in a twin pregnancy. J Am Osteopath Assoc. 1989;89:185–187. 15. Yaniv E, Weinberg J. Pneumomediastinum with subcutaneous emphysema as a complication of foreign body in the bronchus. Int J Pediatr Otorhinolaryngol. 1984;7:75–77. 16. Saoji R, Ramchandra C, D’Cruz AJ. Subcutaneous emphysema: an unusual presentation of foreign body in the airway. J Pediatr Surg. 1995;30:860 – 862. 17. Jang KA, Kim SH, Choi JH, et al. Subcutaneous emphysema with spontaneous pneumomediastinum and pneumothorax in adult dermatomyositis. J Dermatol. 1999;26:125–127. 18. Nagai Y, Ishikawa O, Miyachi Y. Pneumomediastinum and subcutaneous emphysema associated with fatal interstitial pneumonia in dermatomyositis. J Dermatol. 1997;24:482– 484. 19. Alvares JF, Dhawan PS, Tibrewala S, et al. Retroperitoneal perforation in ulcerative colitis with mediastinal and subcutaneous emphysema. J Clin Gastroenterol. 1997;25:453– 455. 20. Cohen ME, Kleinman MS. Pneumomediastinum during relapse of ulcerative colitis. Am J Gastroenterol. 1997;92:2306 –2307. 21. Manco JC, Terra-Filho J, Silva GA. Pneumomediastinum, pneu-
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Requests for reprints should be addressed to: Anju Tripathi, MD Northwestern University Medical School Department of Medicine Division of Allergy and Immunology Tarry Building 3–711 Mail Code S207 303 E Chicago Ave Chicago, IL 60611 E-mail: [email protected]
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