Roberts, James R. MD
Angiotensin-converting enzyme inhibitors (ACEIs) are one of the most prescribed medications worldwide for hypertension. Many patients with congestive heart failure, renal dysfunction, and diabetes are also taking these medications, and angioedema is a well-recognized and occasionally fatal side effect of all members of this class of medications.
ACEI angioedema occurs in up to almost one percent of treated patients. The edema is a class effect, not an overdose, and symptoms can occur any time after the first dose to up to many years, even after a patient has been well maintained on the medication without this complication. The majority of patients has actually been taking the drug for extended periods, and do not recognize the culprit when the symptoms develop. The pathophysiology is a bit cloudy, but it is thought to be caused by a decreased degradation of bradykinin and up to a 10-fold increase of this potent vasodilator that increases vascular permeability. Oddly, some cases of angioedema recur for weeks and even months after the ACEI has been stopped.
Most emergency physicians are all too familiar with this nefarious complication. Trying to get an airway in advanced cases is a hellish endeavor and not always successful. General empiric treatment guidelines have evolved, but the value of any specific currently used reversal medication is unproven and likely minimal at best.
Emergency Department Management of Patients with ACE Inhibitor Angioedema
Winters M, Rosenbaum S, et al
J Emerg Med
These authors attempted to establish the appropriate ED management of patients with ACEI angioedema. A Medline search yielded 27 appropriate articles that were rigorously reviewed to spawn the recommendations. Unfortunately, attempts to develop a specific treatment protocol based on a high level of evidence were not possible because of limited scientific studies.
Angioedema from ACE inhibitors is characterized by the abrupt onset of nonpitting, nonpruritic swelling involving nondependent areas, usually in an asymmetric distribution. The edema is isolated to the head and neck regions and not accompanied by urticaria. The signs and symptoms include shortness of breath, stridor, hoarseness, drooling, and swelling of the lips, tongue, floor of the mouth, neck and pharyngeal areas, and eyelids. The abdominal viscera can be involved in rare cases, causing intermittent abdominal pain, nausea, and vomiting. These authors recommend that ACEI angioedema be considered in any patient presenting with isolated asymmetric swelling of the areas mentioned.
A variety of anti-allergy medications are generally administered. ACEI edema appears to be an allergic reaction, but it is not mediated by mast cell degranulation; therefore, the efficacy of usually effective anti-allergy drugs such as epinephrine, antihistamines, and corticosteroids is unlikely and remains unproven. No randomized controlled blinded studies have compared these medications, probably because most physicians quickly give all three. The edema generally lasts 24-72 hours and spontaneously subsides if the ACEI is halted. Standard anti-allergy medications have not been noted to be harmful, but no current evidence recommends for or against using any of them to treat ACEI angioedema.
Angioedema of the upper airway and larynx can be life-threatening. It is an ominous finding indicative of a severe process, and often requires ICU admission. The authors suggest the early use of fiber optic examination to determine the presence and extent of laryngeal involvement, and note that no patient with a normal larynx on fiber optic evaluation has progressed to require emergent intubation.
But intubation and cricothyrotomy may be necessary to maintain airway patency. Those presenting with respiratory distress, stridor, drooling, and edema of the floor of the mouth are most likely to require intubation. The literature is varied on the need for admission for patients with minimal and non-progressive edema. Most clinicians consider at least observation for 12-24 hours in any patient with tongue edema. Patients who have edema limited to the face and lips may be observed in the ED or in an observation area, but no recommendations exist for the optimal observation period.
These authors suggest that patients with respiratory distress, edema of the floor of the mouth, stridor, and drooling should be considered for immediate intubation. Those not intubated with the potential for airway compromise should be admitted to the ICU. Patients with angioedema limited to the lips and face may be observed in the ED. Provided there is no progression in four to six hours, discharge home with a discontinuation of the ACE inhibitor can be supported.
These authors conclude that the literature does not support any specific treatment protocol with a high level of evidence. Certain medications may be of minimal benefit, but none has been proven effective. Fiber optic examination of the larynx to determine disposition of patients presenting with this relatively common medical condition is suggested.
Comment: I have personally seen hundreds of cases of ACEI angioedema. (Am J Cardiol 2012;109:774.) It is much more common in African-American women in my experience, and this predilection is supported in studies. The edema is rather characteristic, usually first involving the lips and then the tongue or floor of the mouth. It is certainly true that patients may have been on these medications for many years with no dose increase and then suddenly develop angioedema. The etiology is generally thought to be caused by an accumulation of bradykinin, but the pathophysiology is still somewhat obscure. This looks like an allergy, but it is not.
Because the angioedema appears like an allergy, almost all physicians reflexively treat with epinephrine, antihistamines, and corticosteroids. Epinephrine does not seem to be harmful with regard to hypertension, and the Physicians' Desk Reference specifically suggests using epinephrine as well as securing the airway in patients with significant symptoms.
Most patients who have anything more than lip or facial swelling should be admitted to the hospital for further observation. That means admitting them to a floor where they will actually be observed because decompensation can be rapid. Fiber optic intubation is probably the best technique, but I have also used nasotracheal intubation.
Patients with ACEI angioedema usually get intubated either too early or too late. It is tempting to wait this out with careful observation, but securing the airway while the tongue is still passable with your laryngoscope is probably the best tactic. Many patients will be intubated unnecessarily with an aggressive empiric approach. Once they are intubated, however, the emergency is over. Most physicians will give standard allergy medications, but they are of no proven value. It's still difficult to eschew their use. The following articles will offer some potential life-saving interventions for this unusual process.
Fresh Frozen Plasma in the Treatment of Resistant Angiotensin-Converting Enzyme Inhibitor Angioedema
Warrier M, Copilevita CA, et al
Ann Allergy Asthma Immunol
This 10-year-old article was one of the first to suggest fresh frozen plasma (Icatibant) for treating ACEI angioedema. Another article before this letter was published similarly espoused the use of FFP. (J Allergy Clin Immunol 2002;109:370.) The authors note that the inhibition of angiotensin-converting enzyme by ACE inhibitors results in diminished production of angiotensin II. This is the effect on the blood pressure and kidney function that is sought by treatment. Unfortunately, this mechanism also inhibits the degradation of bradykinin, and this accumulation is largely responsible for the adverse effects.
The patient in this report was taking ramipril for hypertension. She had an initial episode of angioedema of the lips and fingers that resolved with antihistamines, corticosteroids, and epinephrine, and the dose of ramipril was lowered. She did well for four months and then developed severe edema of the tongue and lips that was recalcitrant to any conventional therapy, including multiple doses of subcutaneous epinephrine. She received antileukotrienes, cyclosporine, and intravenous immune globulin without benefits. Her complement level was normal, as was her total C1 inhibitor level. After four days of failure to resolve, she had a complete resolution of symptoms within two to four hours of the infusion of two units of FFP. It was postulated that administration of FFP leads to the breakdown of accumulated bradykinin with subsequent resolution of the angioedema.
Comment: The use of FFP is supported by a variety of case reports, and most people believe it is beneficial, but it's rarely used. Recently, Hassen et al reported on seven patients refractory to current interventions who demonstrated a temporal resolution of ACEI angioedema. (J Emerg Med 2013;44:764.) The rationale for FFP is that it provides ACE, also known as kininase II, and this catalyzes the degradation of excessive bradykinin.
One problem is that it takes a while to obtain FFP, and by that time patients are either getting better or have been intubated. Once they are intubated, there seems little benefit in exposing them to blood products. No studies or reports support using epinephrine, antihistamines, or corticosteroids, though a number of case reports support using FFP, and I believe it reasonable to administer FFP as soon as possible in patients who have more than minimal swelling. Certainly those who are borderline and likely will require intubation, should receive FFP if it can be given before intubation is performed. Given the lack of rapidity of obtaining FFP and the little known use for this indication, it is likely that FFP will be infrequently administered. Some patients are also resistant to receiving blood products.
Therapeutic Efficacy of Icatibant in Angioedema Induced by Angiotensin-Converting Enzyme Inhibitors: A Case Series
Bas M, Greve J, et al
Ann Emerg Med
This article from Germany includes a case series of eight patients with acute ACEI angioedema who were treated with a single subcutaneous injection of icatibant. ACEI angioedema resembles the pathophysiology behind hereditary angioedema, specifically mediated by bradykinin-induced activation of vascular bradykinin B II receptors. Icatibant is a synthetic bradykinin II receptor antagonist used to treat hereditary angioedema, and these authors speculated that icatibant would be effective therapy for ACEI angioedema. Icatibant is stable and not degraded by bradykinin-cleaving enzymes such as ACE inhibitors.
These investigators treated eight patients with acute ACEI angioedema with a single 30 mg dose of subcutaneous icatibant. All patients had angioedema for fewer than 10 hours, and were taking an ACE inhibitor. Following the injection of icatibant, patients had hourly fiber optic transnasal laryngoscopy to assess resolution. Four patients had angioedema of the tongue and four of the laryngeal area. The most common offending drugs were enalapril and ramipril. Following icatibant, the first symptom improvement was noted after 50 minutes, and the mean time for complete resolution was 4.4 hours. No patient required intubation or retreatment, and no additional medications were used. All patients did develop local reactions at the injection site. Compared with previous patients treated with corticosteroids, the results of this intervention were markedly better, particularly that no patient required intubation.
The authors concluded that the subcutaneous injection of the specific bradykinin B II receptor antagonist icatibant resulted in rapid symptom improvement and prompt complete recovery from ACEI angioedema. Most subjects were discharged within 24 hours. The scientific rationale for using bradykinin B II receptor blocker is that it blocked excessive bradykinin stimulation. The authors note that their observations should be confirmed in a prospective randomized controlled trial, but their results were impressive.
Comment: Icatibant is currently available in the United States for about $8000 per 30 mg dose. It has been reported by other authors to be effective in ACEI angioedema. This drug was developed for treating hereditary angioedema, but its use for ACEI angioedema is exciting. Another drug developed for hereditary angioedema, ecallantide, decreases bradykinin production, and was thought to be potentially useful for ACEI angioedema, but it was found to be ineffective. Trials were stopped when the lack of clinical effect was demonstrated.
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Dr. Roberts: We read with great interest your column, “Think Twice Before Routinely Administering Oxygen.” (2013;35:12; http://bit.ly/1mGWOEM.) He has addressed an important issue concerning oxygen administration and hyperoxia in emergency situations. We cannot agree more about the problems with extreme hyperoxia. Many studies, including the ones reviewed, have found that long-term exposure to high oxygen (>300mm Hg) leads to pulmonary toxicity and poor outcomes. (Crit Care Med 2014;42:387; JAMA 2010;303:2165.) Calzia et al (Crit Care Med 2010;38[10 Suppl]:S559) and others, however, hypothesize that hyperoxia during the acute phase could be beneficial. It is also likely that oxygen, like any other drug, may have its own therapeutic dose range, and no uniform range may apply to all ages or all clinical situations.
Traditional recommendations targets a PaO2 of 55-80 mm Hg in acutely ill pediatric patients on mechanical ventilation. (N Engl J Med 2000;342:1301; Intensive Care Med 2008;34:17.) The definitions of hyperoxia could also be different in the pediatric age group. In fact, hyperoxia (PaO2 > 300 mm Hg) as defined by the studies above were not commonly seen in children from our PICU (0.006% of a total of 3041 PaO2 records).
We have examined the association between hyperoxia and outcomes in acutely ill children in our PICU (manuscript under peer review for publication), and performed a retrospective analysis of prospectively collected data from 246 mechanically ventilated children. Partial pressure of oxygen in 1785 arterial blood gas samples during the first 72 hours of mechanical ventilation was analyzed. The mean and maximum PaO2 values were used to create receiver-operator characteristics (ROC) curves for determining PaO2 cutoffs that could predict survival. (Figure 1.)
Mean PaO2 of 100 had 75% sensitivity and 60% specificity for predicting survival on ROC curves and a maximum PaO2 of 150 had 72% sensitivity and 61% specificity for survival. Based on these cutoffs of mean and maximum PaO2 values, we created four groups (Group I: PaO2 55-100 mm Hg, Group II: 101-150, Group III: 151-200, Group IV: 201-300; Table 1). Patients in groups II, III, and IV showed better survival compared with the traditional normoxemic group I.
A multivariate logistic regression analysis revealed PRISM III score and mean PaO2 group to be independent predictors of survival after adjustment for age, sex, length of mechanical ventilation and incidence of nosocomial infections. We also compared PaO2 values from 594 children (3041 records) and found that max PaO2 range of 200-300 mm Hg appeared to be associated with a higher incidence of culture-positive nosocomial infections.
Our data suggest that mild hyperoxia (PaO2 of 100-200 mm Hg) during the first 72 hours of mechanical ventilation in children may be associated with higher survival and lower culture-positive nosocomial infections. Further studies should address optimal PaO2 levels for acutely ill mechanically ventilated children. — L. G. Saptharishi, MD, & Sunit Singhi, MD, Chandigarh, India
Dr. Roberts responds: Many thanks to Drs. Saptharishi and Singhi for their comments. Providing high levels of inspired oxygen is a universal reflex action in critically ill patients, but like any other intervention, it may have downsides. The detrimental effects of prolonged hyperoxia are not well defined, difficult to prove when multiple treatments are simultaneously instituted, and not often addressed in the literature. The work of these physicians adds significantly to our knowledge.
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Dr. Roberts has disclosed that the U.S. Food and Drug Administration has not approved the use of icatibant and ecallantide for treating ACEI angioedema as discussed in this article. Please consult the products' labeling for approved information.
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