October 23, 2007

Hereditary Angioedema: A Case Study

By Vacca, Vincent M Jr

Abstract: Hereditary angioedema (HAE) is a condition that results from an autosomal dominant trait. It manifests as attacks of swelling involving the extremities, trunk, abdominal viscera, face, neck, or airway. The attacks may occur spontaneously, without any identifiable trigger, or may be the result of a specific trigger, such as a minor tissue trauma. The symptoms of an attack range from abdominal discomfort to a swelling of the upper extremities to a laryngeal edema that can lead to severe airway obstruction. Therapy for HAE can be divided into three distinct phases: treatment for acute attacks, short-term prophylaxis, and long-term prophylaxis. Treatment for an acute attack is largely supportive, including administration of epinephrine and antihistamines to maintain a patent, reliable airway. Shortterm prophylaxis includes fresh frozen plasma and corticosteroids. Long-term prophylaxis includes use of androgens and antifibrinolytics, as well as the avoidance of known triggers. Prior to the advent of such therapies, mortality from an acute attack of HAE was reported as high as 30%. Repeated episodes of unexplained cutaneous edema or abdominal discomfort may be caused by HAE. The nurse's role focuses on prevention of complications and supportive care, as well as education of the patient to minimize risk factors that may cause further episodes. Patient Presentation

Following a minor dental procedure, JW, a 51-year-old right- handed female, developed left-eye proptosis, exophthalmos, and periorbital edema. She was able to open and close her affected eye easily and had full range of ocular movements in both eyes. She did not have scleral injection in her affected eye. The rest of her neurological exam revealed that she was awake, alert, and oriented to person, place, and time. She was able to follow commands, her pupils were equal and reactive to light, and her extraocular movements and blink/corneal reflex were intact. Her face was symmetrical, with tongue midline, and her speech was clear. She moved all her extremities with 5/5 strength without drift, had a positive cough and gag reflex, and denied pain or discomfort. Her lungs were clear and her heart sounds were within normal limits to auscultation. Her abdomen was soft and nontender with adequate bowel sounds. She was able to void spontaneously, and all her laboratory results were within normal limits.

Because her left proptosis was worsening, JW underwent a noncontrast head computed tomography (CT) scan. The CT scan revealed significant thickening of the lateral region of her left orbital bone, extending to the temporal bone and part of the frontal bone, possibly due to fibrous dysplasia. This abnormal and extensive thickening of the bone extended from the sphenoid wing down to the anterior clinoid process with some thickening of the bone around the optic canal. Dramatic enlargement and compression were noted in the lateral orbit; these conditions were causing the proptosis. Despite extensive fibrous dysplasia and proptosis, her visual acuity remained intact.

First Cranial Surgery

JW underwent an operation to resect the thickened bone and remove her sphenoid bone. Prior to surgery, peripheral intravenous (IV) access was started; a right radial arterial catheter was inserted without complication, and because she would receive general anesthesia, JW was intubated for airway protection and management. The frozen section results for bone taken during the operation were negative for either abnormal cells or an infectious process; therefore, fibrous dysplasia was confirmed as the source of JW's symptoms.

JW was transferred to the neuroscience intensive care unit (ICU), where she recovered uneventfully and was successfully weaned from mechanical ventilation and extubated postoperatively. Six hours later, during a routine hourly bedside neurological exam, one of the neuroscience ICU nurses discovered that JWs left pupil had become nonreactive to light. A more detailed exam revealed that JW had a left-lateral-gaze palsy, suggestive of temporal lobe (uncal) herniation. JW's visual acuity had also deteriorated in the same eye. Nursing staff notified the neurosurgeon immediately, and JW was taken for a stat CT scan. The scan was negative for hematoma but did reveal the presence of diffuse cerebral edema.

Second Cranial Surgery

JW was taken back to the operating room for reexploration. The only abnormality discovered was a small epidural hematoma over the frontotemporal lobes; no compression of the optic nerve was noted. The neurosurgeon felt that this finding was not significant enough to account for JW's symptoms and rapid deterioration.

During the operation, JW developed significant electrolyte abnormalities, including hypocalcemia and hypokalemia. Despite the operative intervention, her left pupil remained nonreactive to light. She also developed significant edema both in her hands and in her upper extremities. In particular, her left hand was extremely tense from edema, and she had Doppler pulses in both upper extremities.

The vascular team was consulted because of concern that JW could develop compartment syndrome, leading to irreversible tissue damage due to ischemia. The vascular team concluded that a combination of careful and frequent evaluation of her circulation, sensation, and movement, along with the elevation of both upper extremities, was sufficient at this time to treat the edema and prevent occurrence of compartment syndrome.

Postoperatively, JW remained intubated for airway protection, control, and management. In the neuroscience ICU, she was awake, alert, and able to follow commands. She was assessed for pain and provided with analgesic medications as needed. In an effort to wean her from mechanical ventilation, sedation was used only as needed. To enable JW to more fully participate in her treatment plan, she was given sedation vacations, so that she could be fully awake for these discussions. She was successfully weaned to pressure support ventilation, set at 5 cm H2O, with the positive end expiratory pressure set at 5 cm H2O and inspired oxygen (FiO^sub 2^), set at 40%. On those settings, the results for arterial blood gases (ABGs) were pH = 7.40, pCO^sub 2^ = 40 mm Hg, and pO^sub 2^ = 95 mm Hg. (These were all within normal parameters.)

JW was evaluated to determine whether she was capable of protecting her airway. She had a rapid shallow breathing index (RSBI) of 67, calculated from her respiratory rate (22) and tidal volume (325 ml). (An RSBI lower than 105 indicates successful weaning). Her lungs were clear to auscultation, her vital signs were stable, and she was euvolemic. Taking all of these clinical indicators into consideration, the decision was made to extubate her.

After the nurses explained the decision and discussed appropriate precautions with the patient and her family, JW was successfully extubated to a humidified 50% FiO^sub 2^. At that time, the nurses noted that during JW's neurological examination, she could open both eyes and had brisk bilateral pupillary responses to light. Her electrolyte derangements had been corrected, and both her left-hand and upper-extremity edema were responding to nursing interventions.

During subsequent neurological examinations, the nurse found that JW was significantly less responsive and had become somnolent and difficult to arouse. The neurosurgeon was notified, and JW was taken for another stat CT scan. This scan revealed further diffuse cerebral edema involving both cerebral hemispheres. The scan also revealed hydrocephalus.

Following the CT scan, JW had an external ventricular drain (EVD) placed. On insertion, the opening intracranial pressure (ICP) was 4 mm Hg. This normal ICP did not explain JW's ongoing somnolence. The nurse kept JW's EVD open at zero as ordered and used specific nursing interventions to maintain her ICP lower than 5 mm Hg. These strategies included

* maximizing rest periods

* maintaining the head of the bed at 30[degrees], with JW's head in neutral position

* assessing for and treating pain or discomfort

* avoiding any pressure on her neck

* avoiding increases in intraabdominal pressure

* avoiding hip flexion

* utilizing the lateral turn technique.

Her oxygenation was maintained by monitoring mixed venous oxyhemoglobin (SvO^sub 2^) and maintaining oxygen saturations at 95% or higher. To ensure a cerebral perfusion pressure (CPP) higher than 70 mm Hg, JW's blood pressure and mean arterial pressure were maintained within ordered parameters. Despite these interventions, JW's somnolence increased, and the neuroscience ICU team was concerned that she would not be able to maintain airway patency. She was therefore intubated for the third time during this hospital admission.

At this time, it was discovered that JW had developed hyponatremia. Her serum sodium level was 131 mEq/L (normal levels are 135-145 mEq/L). Because of the radiographic evidence of cerebral edema on her earlier CT scan and her hyponatremia, she was started on a 3% saline infusion via a central line, with the goal of achieving a serum sodium level lower than 140 mEq/L.

The nurse noted that JW's hourly neurological exam responses were inconsistent. At times, JW was able to follow commands but remained somnolent. At other times, she was much less responsive. When trending was done on JW's Glasgow Coma Scale (GSC) scores, they ranged from a best of 10E (E for her endotracheal tube) to a low of 6E. When her scores were at their lowest level, JW would open her eyes only to noxious stimuli and was unable to follow commands. Third Cranial Surgery

Six hours after the EVD was placed and hypertonic saline begun, JW experienced a sudden herniation episode. The worsening cerebral edema resulted in a reduced CPP, and her GCS score dropped to a total score of 3. Her pupils were also fixed and dilated bilaterally. JW was given both an IV of 50 grams of mannitol and a 50 ml bolus of 23.4% hypertonic saline. She was taken first for emergency magnetic resonance imaging (MRI) and then to the operating room for another surgical reexploration. The MRI showed herniation of the left temporal lobe but no evidence of hemorrhagic or ischemic stroke. During this herniation episode, her ICP remained lower than 5 mm Hg, with a functioning, reliable EVD, as evidenced by a normal waveform. The neurosurgeon concluded that the swelling disorder that had affected her upper extremities and hands was related to the diffuse edema now involving her brain tissue. To decompress the brain tissue at risk, the surgeon decided to perform a left fronto- tempo-parietal hemicraniectomy.

Throughout JW's hospitalization, the neuroscience ICU team had already consulted with multiple services, including immunology, allergy, rheumatology, vascular, endocrine, critical care, and human genetics services. Further in-depth interviews with family members conducted by the nursing staff revealed that JW had a family history of idiopathic edema, also known as hereditary angioedema (HAE).


Hereditary Angioedema

Hereditary angioedema is an autosomal dominant condition in which a key inhibitor of the complement system known as C1-INH (C1- inhibitor) is defective or missing (Bork & Barnstedt, 2001). In 1963, Donaldson and Evans discovered the genetic (C1-INH) defect responsible for HAE (Bork & Barnstedt). Either the absence of or a defect in the C1-INH-complement-system inhibitor results in uncontrolled regulation of the complement, kallikrein, and bradykinin systems (Starr, Brasher, Arundhati, & Posey, 2004). C1- INH functions in the body to inactivate or prevent the C1 complement (esterase) from autoactivating the complement cascade. Through the action of the C1 complement (esterase), the complement cascade, once activated, initiates events that generate complement fragments known as membrane attack complexes. Membrane-attack complexes damage cell membranes, and this damage, through the action of specific immunoglobulins, leads to cell lysis. During this process, capillary permeability is increased, causing the cutaneous, abdominal, and respiratory edema seen in an acute episode of HAE (Nzeako, Frigas, & Tremaine, 2001). It is thought that bradykinin is responsible for the edema in HAE.

The signs and symptoms of HAE, which include intense disfiguring and temporary swelling of localized body areas, were first described in 1888 by Osier. Patients may present with skin swelling and abdominal discomfort or with pain caused by the swelling. Upper airway obstruction due to the edema can occur acutely and can be life-threatening. Cutaneous swelling from HAE effects the deeper dermis and subcutaneous tissues and is nonpitting and without pruritus. These two characteristics differentiate the cutaneous swelling of HAE from that of urticaria. Often facial areas are involved as well as the genitals and abdominal viscera.

Although instances of HAE can occur spontaneously, several known precipitating or contributing factors can lead to laryngeal edema in particular. These factors include dental procedures and endotracheal intubation with general anesthesia. Individuals at higher risk to develop potentially lifethreatening acute laryngeal edema include those who are between 11 and 45 years of age and have a history of previous episodes of laryngeal or facial edema (Bork, Hardt, Schicketanz, & Ressel, 2003). JW had experienced previous episodes of facial edema following dental procedures.

Postoperative Care in the Neuroscience ICU

Following her third cranial surgery, JW's pupils were bilaterally pinpoint. However, the anesthesiologist determined that this finding was the result of the anesthesia administered during the operation. An electroencephalogram (EEG) ruled out seizure activity. To protect JW's brain, the attending neurosurgeon decided to place her on a pentobarbital infusion, which would reduce cerebral metabolic activity. By decreasing cerebral metabolism, the demand for and consumption of oxygen can be reduced, thereby protecting vulnerable brain tissue from the effects of hypoxia. On the basis of bedside EEG interpretation, the nurse adjusted the pentobarbital dose to achieve the prescribed burst suppression. To further reduce her ICP, JW's EVD was lowered to 10 cm below the tragus.

Over a 2-week period, as JW slowly responded to treatment and showed clinical improvement, the nurses were able to successfully wean her from the pentobarbital. During her entire stay in the neuroscience ICU, JW's fluid status, electrolyte levels, and nutritional requirements were all balanced and maintained. She received a regular and thorough pulmonary toilet, along with the full ventilator nursing care required to minimize the risk of ventilator-associated pneumonia. Because of her extensive hemicraniectomy, the nurses made sure that JW's head was protected at all times, especially during turning and repositioning. Meticulous skin care was provided to avoid breakdown or decubitus ulcer formation.

One month after her admission to the neuroscience ICU, JW became more responsive and was able to open her eyes, follow commands occasionally, and nod her head appropriately. She had positive cough, gag, and corneal reflexes. Because of the sudden onset of her cerebral edema, along with the subsequent uncal herniation syndrome and her stormy postoperative course, the neuroscience ICU team decided to provide JW with a tracheostomy for long-term pulmonary protection and support. She also had a percutaneous endoscopic gastrostomy (PEG) tube placed for long-term nutritional support.

JW's neurological improvement continued, and her EVD was removed. She was fitted with a protective helmet so that nurses could move her safely from the bed to a chair. Getting out of bed to a chair not only benefits the patient physically, but has significant psychological and emotional impact as well. Because of the continuous emotional support of the ICU nurses, JW felt as if she was improving as she transitioned from strict bed rest to transferring to a chair with assistance.

JW was soon able to mouth words. By day 46 after her original craniotomy surgery, she had improved enough to leave the neuroscience ICU. She was transferred to the intermediate neuroscience area, where she continued to receive physical and occupational therapies that resulted in improvements in her strength and conditioning. Her oxygen requirements were easily met with humidified oxygen administered via a tracheostomy collar.

JW was soon able to have her tracheostomy weaned to a Passe Muir valve (PMV). Her cerebral ventricles remained persistently large, however, and the neurosurgeon, JW, and her family decided on placement of a ventriculoperitoneal (VP) shunt. In light of her diagnosis of HAE, extreme caution was used during the placement of the VP shunt to avoid unnecessary brain tissue manipulation that might result in another cerebral edema response. Two days after placement of the VP shunt, JW had her bone flap successfully replaced.

JWs tracheostomy was progressively downsized, and she was able to speak via her PMV. Though she was able to move independently, she remained very deconditioned. Results from a nutritional analysis calculated that she required approximately 1,700 kilocalories per day. Her caloric needs were met with tube feedings via her PEG tube. Based on her daily weight, her renal function measurements, and a laboratory analysis, her fluid volume requirements were met with approximately 700 ml of free water per day. She also received a multivitamin replacement each day, and her serum electrolytes returned to normal levels without the need for further repletion.

Treatment of Postoperative Conditions

JW had developed heparin-induced thrombocytopenia during her acute phase, 10 days after admission. This condition was manifested by a low platelet count; her heparin-induced thrombocytopenia panel was also positive for the condition. The hematology service was consulted for guidance. They recommended argatroban, a direct thrombin inhibitor that does not interact with heparin-induced antibodies; this medication was substituted for heparin where indicated.

While JW was on the pentobarbital drip, which affected her P450 enzyme system, it was difficult to achieve her therapeutic goals for her international normal ratio and activated partial thromboplastin time. The P450 group of enzymes, which is primarily found in the liver and gut, is important in the metabolic management of the pharmacokinetics of many medications. P450 isoenzymes render many medications, including argatroban, more water-soluble for renal excretion (RxList Inc., n.d.). Patients are cautioned not to ingest grapefruit or grapefruit juice while taking medications affected by the P450 enzyme system, because grapefruit is known to inhibit the P450 system, resulting in higher drug concentrations than intended.

Passive range of motion is an essential nursing intervention performed to prevent the occurrence of venous thromboembolism resulting from immobility or venous stasis. JW received frequent range of motion exercises for her extremities. The nurses caring for her routinely exercised JWs extremities to maintain joint, muscular, and vascular tone. Nursing care also included bilateral sequential compression devices. As part of the care plan to prevent both venous thromboembolism and hemorrhage, JWs target coagulation levels while on argatroban were kept within a narrow therapeutic range. All noninvasive scans performed on her edematous extremities were negative for deep venous thrombosis during her hospitalization. The infectious disease service was consulted when JW began showing positive sputum, blood, and urine culture results. She was treated with antibiotics for gram-negative rod bacteremia and Staphylococcus aureus in her sputum and Klebsiella pneumoniae and Candida in her urine. While the EVD was in place, she also received antibiotics as a prophylaxis.

Patient Status at Discharge

Prior to her discharge to a rehabilitation facility, JW was sitting in a chair and speaking, and her strength was 4/5 in her right arm and 3/5 in her right leg. At the time of discharge, she had minimal evidence of edema. She was able to wash her face independently, flip through and read magazines, and write legibly, but she still required moderate assistance with bathing, toileting, and dressing. Her pupils were equal and reactive to light; her face was symmetrical, with her tongue midline. She had positive cough and gag reflexes and no evidence of pronator drift. Her operative sites were healing well with no evidence of infection. On day 100 of her hospitalization, she was transferred to a rehabilitation facility for further reconditioning and training. Following another month in a short-term rehabilitation facility, an independent JW was discharged to home, where she remains to this day.


The incidence of HAE is estimated to be between 1:10,000 and 1:50,000 persons. Often characterized by recurrent episodes of abdominal pain associated with diarrhea, the disorder may go undiagnosed for years (Karim, Griffiths, & Deacock, 2004). Episodes of HAE can be triggered by allergies to foods such as shellfish, by environmental stimuli such as fluctuations in temperature, by adverse reactions to medications such as angiotensin-converting enzyme inhibitors, or by trauma, including minor dental procedures. HAE results from a genetic enzyme deficiency that leads to unregulated stimulation and potentiation of the complement system, resulting in uncontrolled tissue edema. The most lethal feature of HAE is laryngeal edema associated with upper airway obstruction, which can lead to asphyxiation. This response is often unforeseen; therefore, prompt recognition and diagnosis of HAE is essential to prevent death by asphyxiation.

Once diagnosed, individuals can protect themselves from exacerbations of HAE by avoiding injury and alerting all healthcare providers, including dental practitioners, of their diagnosis. Prior to planned procedures, individuals with known HAE, in collaboration with their medical providers, can minimize or even prevent any potential complications. With proper knowledge and planning, individuals diagnosed with HAE can protect themselves and manage this disfiguring and potentially life-threatening disorder.



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Bork, K., Hardt, J., Schicketanz, K., & Ressel, N. (2003). Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Archives of Internal Medicine, 163, 1229-1235.

Karim, Y., Griffiths, H., & Deacock, S. (2004). Normal complement C4 values do not exclude hereditary angioedema. Journal of Clinical Pathology, 57(2), 213-214.

Nzeako, U., Frigas, E., & Tremaine, W. (2001). Hereditary angioedema: A broad review for clinicians. Archives of Internal Medicine, 161, 2417-2429.

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Questions or comments about this article may be directed to Vincent M. Vacca, Jr., MSN RN CCRN, at [email protected] He is a clinical nurse educator in the neuroscience intensive care unit at the Brigham and Women's Hospital, Boston, MA.

Copyright (c) 2007 American Association of Neuroscience Nurses 00472606/07/3905/0311$5.00

Copyright American Association of Neurosurgical Nurses Oct 2007

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