1

INTRODUCTION:

Angioedema is a rare, but very serious adverse effect associated with ACEIs, a widely used class of medications used to treat hypertension, congestive heart failure, diabetic nephropathy, and coronary artery disease.ACEIs work by blocking the conversion of angiotensin I to angiotensin II, and also inhibit the breakdown of bradykinin, a potent vasodilator. 1-4 Angioedema is defined as nonpitting, non-pruritic, and asymmetrical deep swelling of the skin and mucous membranes. 5-6Although the incidence of ACEI-induced angioedema is <1%, it is one of the most common adverse reactions seen among hospitalized patients due to the growing number of patients taking this group of medications. 1, 6-8 It is believed to occur more commonly in African Americans, patients older than 65, those who smoke, those who are female, and those who have a history of seasonal allergies or drug rash. 1, 5, 7, 9

The seriousness of ACEI- induced angioedema can vary a great deal between patients. Patients may present to the emergency department and be discharged within hours, while some may experience airway obstruction requiring mechanical ventilation and admission to the intensive care unit. 1,6 Studies examining patients of all acuity found the incidence of ICU admission following ACEI- induced angioedema to range from 2-18%. 5, 11-12 If not identified early and managed properly, severe cases can be a fatal. 2

Despite the increasing incidence and severity of angioedema secondary to ACEI use, there is a lack of literature surrounding the risk factors for mechanical ventilation and effective treatment strategies of severe cases requiring ICU level of care. Treatment of these patients often includes epinephrine, corticosteroids, and histamine antagonists, despite the limited efficacy to support their use and documented adverse effects of corticosteroids. 5, 12-13 The exact mechanism of ACEI-induced angioedema still remains unclear; however it is no longer thought to be an allergic or histamine-mediated angioedema, potentially rendering current treatment regimens ineffective. The purpose of this study was to identify specific predictors of mechanical ventilation in patients suffering from ACEI-induced angioedema and describe current treatment strategies, particularly the role of corticosteroids.

MATERIALS AND METHODS:

Study Population: Adult patients suspected of having ACEI-induced angioedema admitted to the ICU over a four year period were eligible for this study. ACEI-induced angioedema was suspected in patients presenting to the emergency department with documentation of ACEI administration prior to admission and presence of angioedema. This documentation included patient report, family report, or medication reconciliation performed by a pharmacist or pharmacy technician. The final diagnosis of ACEI- induced angioedema was determined by the attending ED physician. Patients were excluded if they were taking corticosteroids and/or histamine antagonists at time of admission, or were transferred from an outside hospital already mechanically ventilated.

Outcomes: The primary outcome of this study was requirement of mechanical ventilation. Predictors of mechanical ventilation analyzed were age, sex, race, comorbidities, tobacco use, number of sites of edema, location of edema, duration and dose of ACEI used, and treatment course in the ED. The dose of ACE inhibitor used was converted to lisinopril equivalents. Secondary outcomes included correlation of corticosteroid dose and duration of use while in the ICU and time to extubation and ICU length of stay.

Statistical Analysis: The two study groups analyzed were patients requiring mechanical ventilation versus those who did not. Patient and hospital characteristics were compared between groups using the chi-square test or Fisher’s Exact test for categorical data as appropriate, and an unpaired t-test or Mann-Whitney test for continuous variables as appropriate. Multivariate analysis to evaluate significant predictors of mechanical ventilation was performed by a stepwise logistic regression using backward elimination. All variables that had a p < 0.15 on univariate analysis were considered for multivariate analysis. Spearman rank correlations were calculated to determine if corticosteroid dose and duration correlated with time to extubation and ICU length of stay. All significant tests were two-sided with a p-value of <0.05 being significant. Statistical analysis was completed using JMP software version 11.1.

RESULTS:

Forty-five patients were admitted to the ICU for ACEI- induced angioedema over a four-year period. Of these patients admitted to the ICU, 22 (49%) required mechanical ventilation. The majority of patients were taking lisinopril (96%) prior to admission, and the dose and duration of ACEI use had no impact on a patient’s need for mechanical ventilation (Table 1). Univariate analysis of baseline demographic parameters and ACEI characteristics revealed that patients were more likely to require mechanical ventilation if they had a past medical history significant for COPD or asthma, were non-Caucasian, or experienced angioedema of the pharynx or soft palate. The univariate analysis showed weak trends (p<0.15) towards mechanical ventilation if patients smoked (Table 1). Multivariate analysis found history of COPD or asthma and angioedema of the pharynx to be independently associated with the need for mechanical ventilation (p <0.02, p<0.009, respectively) (Table 2).

Every patient in the ED received treatment with a corticosteroid, with the majority of patients also receiving a histamine 1 antagonist (91%) and histamine 2 antagonist (62%). Additionally, intramuscular epinephrine was given to 40% of patients. Treatment with these agents in the ED did not alter a patient’s need for mechanical ventilation (Table 3). Upon transfer to the ICU, the majority of patients remained on a corticosteroid (89%) and histamine 1 antagonist(73%). The use of histamine 2 antagonists in the ICU was primarily seen in the mechanical ventilation group (91% vs. 39%, p = 0.01), however use for stress ulcer prophylaxis versus ACE inhibitor induced angioedema could not be distinguished (Table 3).

While in the ICU, there was no correlation between the dose of corticosteroids (mg/day) and a decreased time to extubation (r2 =0.05; p=0.3) or ICU length of stay (r2 = 0.07; p=0.22) (Figure 1 and Figure 3). However, duration of corticosteroid use was correlated withan increased time to extubation (r2 =0.8; p<0.001) and longer ICU length of stay (r2 =0.75; p<0.001)(Figure 2 and 4).Patients in the mechanical ventilation group received an average methylprednisolone dose of 186.8 ± 152.4mg/day for roughly 4.2 days, compared to 174.3 ± 125.2 mg/day for 0.6 days in the non-mechanical ventilation group, with duration of corticosteroid use being statistically longer in the mechanical ventilation group (p =0.002).

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DISCUSSION:

There has been very little data published regarding the characteristics and treatment approaches of severe cases of ACEI- induced angioedema necessitating ICU level of care. The majority of literature surrounding ACEI- induced angioedema has included all patients, with a reported ICU admission rate of 2-18%. 14-17 The lack of literature regarding the proper management of ICU patients has forced practitioners to extrapolate data from all angioedema patients to a small, but high risk subset of patients. This paper is unique because it exclusively enrolled patients admitted to the ICU following this adverse event, and aimed to help identify patients who may be at higher risk for mechanical ventilation. In addition,it examined treatment strategies at a large academic medical center.

If not identified early in the course of patients’ medical care, severe ACEI- induced angioedema necessitating mechanical ventilation can have poor outcomes and may even result in death. 11,18 This study found that history of COPD or asthma and pharyngeal angioedema were independent predictors of mechanical ventilation following ACEI- induced angioedema. Non-Caucasian race and soft palate edema may also be important predictors of mechanical ventilation, however statistical significance was only found on univariate analysis, likely due to small sample size. It is also important to note that having a greater number of sites of angioedema was not an independent risk factor for mechanical ventilation, placing more emphasis on the specific location of edema. Zirkle et al examined all cause head and neck angioedema and also found oropharyngeal swelling to be an independent risk factor for mechanical ventilation. In addition, Grant et al found that Type 3 angioedema (involving larynx or hypopharynx) was associated with higher rates of airway compromise. 11 Roughly half of the patients in this study presented with lip and tongue swelling, making this a common presentation of patients with ACEI- induced angioedema. However, these locations were not associated with an increased risk of mechanical ventilation. Paramedics and emergency room practitioners should have an increased height of awareness when a patient has pharyngeal angioedema secondary to ACEI-induced angioedema, and have a low threshold for intubating these patients. 11, 19-21

Pharmacologic management of ACEI-induced angioedema in the emergency department typically consists of intramuscular epinephrine (IM), histamine 1 and 2 antagonists, and corticosteroids, despite the lack of evidence proving their efficacy. Winters et al attempted to establish a practice guideline regarding the treatment of ACEI-induced angioedema in the ED and offer evidence-based recommendations. They found no randomized, controlled, double-blind trials evaluating the efficacy of these medications in the treatment of patients with ACEI-induced angioedema, but rather retrospective reviews, case series, and case reports primarily from single centers. They concluded that there is currently insufficient evidence to recommend for or against the administration of epinephrine, histamine antagonists, and corticosteroids. 22 The lack of sufficient evidence however does not appear to alter prescribing patterns for these patients while in the ED. This study found that every patient with ACEI-induced angioedema necessitating ICU level of care received a dose of corticosteroids in the ED. In addition, 91% of patients received a histamine 1 antagonist, 62% received a histamine 2 antagonist, and 40% received epinephrine IM (Table 3). The patient’s necessitation for mechanical ventilation was not altered by the treatment regimen they received in the ED, however this was hard to assess given the large number of patients in both groups receiving pharmacologic therapies.

This is currently the only study to date that has examined the effectiveness of pharmacologic treatment strategies of severe ACEI- induced angioedema cases necessitating ICU level of care, particularly the role of corticosteroids. The paucity of data evaluating the efficacy of pharmacologic treatment of severe cases often results in patients receiving histamine antagonists and corticosteroids for an extended duration of time, even after transfer out of the ICU. Corticosteroids are very high risk medications that should be minimized in the ICU whenever possible. They have been linked to adverse effects such as hyperglycemia, electrolyte abnormalities, gastrointestinal bleeding, infections, and adrenal insufficiency if used long term without a proper taper regimen. 23-27

All patients in this study received high doses of corticosteroids while in the ICU, and in the case of mechanical ventilation, for a long duration of time. The dose of corticosteroids used was not correlated with improved outcomes (Figures 1 and 3). The very low r2 values indicate nearly zero association between dose and a decreased time to extubation (r2 =0.05; p=0.3) or ICU length of stay (r2 = 0.07; p=0.22). In the case of corticosteroid duration, it was actually correlated with an increased time to extubation (r2 =0.8; p<0.001) and increased ICU length of stay (r2 =0.75; p<0.001). (Figures 2 and 4). It is difficult to determine the clinical significance behind this correlation, as physicians may have kept patients on corticosteroids until their symptoms resolved and were able to be extubated. In addition, the exact reasoning behind the prescribing pattern as it relates to aggressive corticosteroid therapy can’t be determined by our study methodology, however the controversy regarding the pathophysiology may be a contributing factor.

ACEI-induced angioedema was once thought to be an allergic or histamine-mediated angioedema, however evolving data has shown treatment with corticosteroids, epinephrine, and histamine antagonists to be ineffective. 13, 22, 28 A potentially more effective approach to managing ACEI-induced angioedema would be the use of medications that directly antagonize the effects of bradykinin, a potent vasodilator that is elevated in patients taking ACEIs.28 Bas et al conducted a randomized, phase 2 trial that examined the effects of icatibant, a selective bradykinin B2 receptor antagonist indicated for use in acute attacks of hereditary angioedema, on median time to complete resolution of symptoms as compared to standard treatment with a corticosteroid and histamine 1 antagonist. They found time to complete resolution of edema to be significantly shorter in the icatibant group (8 vs 27 hours, p=0.002). In addition, more patients who received icatibant had complete resolution of angioedema at 4 hours (5 vs 0, p = 0.02). Although icatibant is expensive(average wholesale cost ranging from $8,000-10,000), its use for ACEI-induced angioedema may be cost beneficial if it is able to prevent ICU admission and mechanical ventilation, and alleviate the cost associated with this level of care. 28

There are several limitations to our study. The retrospective nature of the study was the major limitation, leaving the treatment uncontrolled and at the discretion of the provider. In addition, the sample size was small and it took place at a single center. The incidence of ACEI angioedema is extremely rare, with a small portion of these being severe cases, making research studies difficult to attempt. However, the results of this study indicate a need for prospective data to help determine the clinical effectiveness of current treatment approaches with epinephrine, histamine antagonists, and corticosteroids. Treatment with bradykinin type 2 receptor antagonists over standard therapy approaches may play an important role in the management of these patients. 28

CONCLUSIONS:

Independent predictors of mechanical ventilation following ACEI-induced angioedema included a history of COPD or asthma and pharyngeal angioedema. Non-Caucasian race and soft palate angioedema may also play an important role when determining predictors of mechanical ventilation. Use of corticosteroids, analyzed using both dose and duration, do not appear to improve patient outcomes while in the ICU.

REFERENCES:

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  3. Dunlap ME, Peterson RC. ACE inhibitors vs ARBS: is one class better for heart failure. Cleve Clin J Med 2002; 69: 433-438
  4. Hansson L, Lindhold LH, Ekbom T, et al. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999; 354: 1751-1756
  5. Banerji A, Clark S, Blanda M, et al. Multicenter study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department. Annals of Allergy, Asthma, & Immunology 2008; 100: 327-332.
  6. Lin RY, Shah SN. Increasing hospitalizations due to angioedema in the United States. Ann Allergy Asthma Immunol 2008; 101:185-192
  7. Lin RY, Levine RJ, Lin H. Adverse drug effects and angioedema hospitalizations in the United States from 2000-2009. Allergy Asthma Proc 2013; 34: 65-71
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  9. Hoover T, Lippmann M, Grouzmann E, et al. Angiotensin converting enzyme inhibitor induced angioedema: a review of the pathophysiology and risk factors. Clin Exp Allergy 2010; 40: 50-61
  10. Kyrmizakis DE, Papadakis CE, Liolios AD, et al. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. Arch Otolaryngol Head Neck Surg 2004; 130:1416-1419
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  12. McDowell SE, Coleman JJ, Ferner RE. Systemic review and meta-analysis of ethnic differences in risk and adverse reactions to drugs used in cardiovascular medicine. BMJ 2006; 332: 1177-1181
  13. Bas M, Hoffmann TK, Kojda G. Evaluation and management of angioedema of the head and neck. Curr Opin Otolaryngol Head Neck Surg 2006; 14: 170-175

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  1. Toh S, Reichman ME, Houstoun M, et al. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med 2012; 172:1582-1592
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  3. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004; 17:103-111
  4. Vleeming W, van Amsterdam JG, Stricker BH, et al. ACE inhibitor induced angioedema: incidence, prevention and management. Drug Saf 1998; 18:171-188
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TABLES:

Table I. Patient Parameters
Variable / All ICU Patients (n=45) / Mechanical Ventilation (n=22) / No Mechanical Ventilation (n=23) / p Value
Age, years / 60.2 ± 13.7 / 59.8 ± 15 / 62.5 ± 11.7 / 0.24
Female gender / 24 (53) / 10 (45) / 14 (61) / 0.18
Race/ethnicity other than white / 18 (40) / 13 (73) / 5 (22) / 0.01
Tobacco Use / 16 (36) / 11 (45) / 6 (26%) / 0.07
ACEI
  • Lisinopril
  • Ramipril
  • Benazepril
/ 43 (96)
1 (2)
1 (2) / 21 (95)
1 (5)
0 / 22 (96)
0
1 (4) / 0.97
1
1
ACEI Characteristics
  • Lisinopril dose, mg
  • Duration of use prior to ADR, months
/ 19.2 ± 11.2
23.5 ±17.1 / 20.9 ± 15
18.9 ± 18.2 / 17.9 ± 19.2
30.5 ± 33 / 0.38
0.58
Comorbid conditions
  • HTN
  • Diabetes Mellitus
  • COPD/Asthma
/ 42 (93)
11 (24)
12 (27) / 21 (95)
7 (32)
11 (50) / 21 (91)
4 (17)
1(4) / 0.99
0.26
0.005
 2 sites of edema / 27 (60) / 15 (77) / 12 (52) / 0.27
Sites of Angioedema
  • Lips
  • Face
  • Tongue
  • Pharynx
  • Soft Palate
/ 22 (49)
10 (22)
23 (51)
10 (22)
5 (11) / 9 (41)
3 (14)
13 (59)
9 (41)
5 (23) / 13 (57)
7 (30)
10 (43)
1 (4)
0 / 0.38
0.26
0.38
0.004
0.02
ICU Length of Stay, hrs / 68.9 ± 83.5 / 120.5 ± 95.5 / 19.6± 5.5 / 0.04
Time to Extubation, hrs / 90 ± 81 / 90 ± 81 / 0 / 1
Data are presented as mean +/- STD or No. (%)
Table II. Multivariate Predictors of Endotracheal Mechanical Ventilation at Admission
Variable / Multivariate Regression Analysis
(Overall Model Fit: p<0.0001)
OR [95% CI] / p-value
Tobacco Use / 1.7 [0.17– 12.4] / 0.63
Race / 3.8 [0.63 – 25.9 / 0.1
COPD/Asthma / 11.6 [1.9 – 357] / 0.02
Sites of Angioedema
  • Pharynx
  • Soft Palate
/ 15.2 [2.45 – 297.6]
2.7 [0.3 – 21.2] / 0.009
0.16
Table III. Treatment in the Emergency Department and Intensive Care Unit
Treatment / All ICU Patients (n=45) / Mechanical Ventilation (n=22) / No Mechanical Ventilation (n=23) / p Value
Emergency Department
Corticosteroid
  • Methylprednisolone, mg
/ 45 (100)
111.9 ± 31.2 / 22 (100)
116.5 ± 27.9 / 23 (100)
107.5 ± 34.1 / 1
0.34
Histamine 1 antagonist
  • Diphenhydramine 25 mg IV
  • Diphenhydramine 50 mg IV
/ 41 (91)
15 (33)
26 (58) / 20 (91)
9 (41)
11 (50) / 21 (91)
6 (26)
15 (65) / 0.96
0.35
0.37
Histamine 2 antagonist
  • Famotidine 20 mg IV
/ 28 (62)
28 (62) / 16 (73)
16 (73) / 12 (52)
12 (52) / 0.22
0.22
Epinephrine IM / 18 (40) / 11 (50) / 7 (30) / 0.23
Intensive Care Unit
Corticosteroids
  • Methylprednisolone, mg/day
  • Duration, days
/ 40 (89)
180.9 ± 138.7
2.3 ±3.4 / 21 (96)
186.8 ± 152.4
4.2 ± 4.2 / 19 (82)
174.3 ±125.2
0.62 ± 0.61 / 1
0.68
0.002
Histamine 1 antagonist / 33 (73) / 18 (82) / 15 (65) / 0.96
Histamine 2 antagonist / 29 (64) / 20 (91) / 9 (39) / 0.01
Data are presented as mean +/- STD or No. (%)

FIGURES: