Article

Emergency department evaluation of patients with angiotensin converting enzyme inhibitor associated angioedema

a b s t r a c t

Introduction: Angiotensin converting enzyme inhibitor (ACEi) associated angioedema is frequently encountered in the emergency department. Airway management is the primary treatment, but published evidence supporting the decision to intubate patients with this condition is extremely limited.

Method: We performed a retrospective study of all cases of ACEi associated angioedema encountered in a large, urban, tertiary referral emergency department. We classified demographics, duration of symptoms before pre- sentation, Physical exam findings and nasopharyngoscopy findings in patients that did and did not require intu- bation.

Results: We identified a total of 190 separate encounters from 183 unique patients who presented during the 3- year period of the study. Eighteen (9.5%) of these patients required intubation. Patients requiring intubation were more likely to present within 6 h of the onset of angioedema symptoms. Anterior tongue swelling, vocal changes, drooling, and dyspnea were significantly more common in patients requiring intubation. Isolated lip swelling was present in 54% of all patients and was the only finding significantly more common in the group that did not require intubation.

Conclusions: Rapid progression of symptoms within the first 6 h of angioedema onset, anterior tongue swelling, vocal changes, drooling and dyspnea are associated with intubation for ACEi associated angioedema. Isolated lip swelling is significantly more common in patients that do not require intubation. Our data provide risk stratifica- tion guidance for providers treating patients with suspected ACEi associated angioedema in the emergency department.

(C) 2020

  1. Introduction

Angioedema is a frequently encountered and potentially life- threatening condition that impacts patients who present to emergency departments [1,2]. Ten to 30% of all emergency department (ED) pre- sentations for angioedema involve patients who are taking Angiotensin converting enzyme inhibitors (ACEi) [1-4]. ACEi associated angioedema is mediated in part by high bradykinin levels. Typical treatment pro- vided in the ED includes anti-histamine medications and steroids that

* Corresponding author at: Department of Emergency Medicine, Washington University School of Medicine, Campus Box 8072, 660 S. Euclid Ave., St. Louis, MO 63110, United States of America.

E-mail addresses: [email protected] (P.A. Mudd), [email protected] (E.A. Hooker), [email protected] (U. Stolz), [email protected] (K.W. Hart), [email protected] (J.A. Bernstein), [email protected] (J.J. Moellman).

1 Present address: Department of Biostatistics, Vanderbilt University, Nashville, TN, United States of America.

improve histamine-mediated angioedema but do not affect bradykinin-mediated angioedema. Recent studies evaluating the treat- ment of ACEi associated angioedema with bradykinin pathway inhibi- tors have been met with mixed if not overall disappointing results, suggesting that further stratification of patients with this condition may allow more focused treatment that may show increased benefit [5-9]. Observing and securing the airway in patients with severe illness is the only proven effective treatment strategy at the present time. De- termining who has severe illness or who may progress to severe illness is still not well-defined by evidence from the current literature.

Current recommendations for workup and management of patients presenting with ACEi associated angioedema are largely guided by ex- pert opinion and/or classifications developed by subspecialty working groups [10,11]. These recommendations are limited by small sample size of existing data sets and extrapolation of data from otolaryngology literature that may not be applicable to the broader population of pa- tients seen in the ED, such as those with limited lip swelling who are not seen by an otolaryngologist during their initial evaluation.

https://doi.org/10.1016/j.ajem.2019.12.058

0735-6757/(C) 2020

We sought to provide descriptive evidence to assist emergency medicine providers in the management and triage of ACEi associated angioedema patients. Our primary objective was to determine demo- graphic and exam factors in ACEi associated angioedema patients that are associated with need for intubation. Our secondary objective was to evaluate and descriptively report findings in ACEi associated angio- edema patients who underwent nasopharyngoscopy during their ED stay.

  1. Materials and methods
    1. Study design

We completed a retrospective study of all cases of ACEi associated angioedema encountered at a large, urban, tertiary referral center where nasopharyngoscopy, otolaryngology consultation and attending level intensivists are available 24 h a day. The studied ED evaluated and treated an average of 78,462 patients per year during the study in- terval and serves as the main teaching site for a 4-year emergency med- icine residency program. This study was approved by the Institutional Review Board at the study institution. We incorporated the guidelines put forward by Gilbert et al. to improve data collection and reporting in retrospective medical record review studies [12].

Selection of participants

We identified all patients seen in the studied ED from January 1st 2013 to December 31st 2015 with ACEi associated angioedema. These dates were chosen as a convenience sample to provide a large and re- cent cohort that accurately represents the current practices in the stud- ied emergency department. This sample also provides equal representation for all seasons since seasonal variation in the frequency of ACEi associated angioedema cases has been noted [13]. This study was approved by the institutional review board at the University of Cin- cinnati. We queried the electronic medical record for coded diagnoses relevant to ACEi associated angioedema and corresponding Interna- tional Statistical Classification of Disease and Related Health problems (ICD)-9 and ICD-10 codes including: ‘angioedema’ (ICD-9 code 995.1, ICD-10 code T78.3), ‘anaphylaxis’ (ICD-9 code 995.0, ICD-10 code T78.2), ‘lip swelling’ (ICD-9 code 784.2, ICD-10 code R60.0), ‘oropharyngal and Laryngeal edema‘ (ICD-9 code 782.3, 478.25, ICD-10 code J39.2, J39.3, J38.4), ‘tongue swelling’ (ICD-9 code 529, 529.9, 529.8, ICD-10 code R60.0), ‘Adverse effect of angiotension-converting- enzyme inhibitors’ (ICD-9 code E942.5, ICD-10 code T46.4X5), and Cur- rent Procedural Terminology (CPT) codes for nasopharyngoscopy per- formed in the ED (31575 and 92511).

We defined ACEi associated angioedema as any patient with angio- edema of any severity who was documented to be on an ACEi at the time when they presented to the ED who was not found during their ED or hospital stay to have another documented explanation for their angioedema. We included all ACEi associated angioedema patients within 7 days of the onset of initial symptoms that were found in a search of the medical record for the ICD and CPT codes listed above on the included study dates. We included patients if the treating physician described the patient as having angioedema or if they described edema of the face, lips, tongue, intraoral structures or mucosal airway that was thought to be related to angioedema rather than infection. We included charts if the patient was not experiencing active symptoms but the treating physician described the previous symptoms occurring within the past 7 days as angioedema. Charts from patients who met any of the following criteria were excluded: 1) patients b18 years of age, 2) pa- tients judged by the physician chart reviewers to not have angioedema based upon review of the treating physician documentation in the clin- ical record due to an ICD/CPT coding issue that misclassified the chart,

3) patients found to have angioedema due to trauma or recent invasive procedures, 4) patients with documented known genetic conditions or

other chronic disease processes that result in recurrent angioedema such as Hereditary angioedema, 5) patients thought by the original ED treating team to have angioedema due to a medication other than an ACEi such as tissue plasminogen activator or calcium channel blockers,

6) patients with angioedema that was documented by the original ED treating team to be secondary to other acute causes that are not ACEi as- sociated angioedema, such as anaphylaxis, or 7) patients with angio- edema that the original ED treatment team documented was not related to ACEi medication.

Data collection process

A single emergency physician chart reviewer independently sorted through all of the charts that were pulled from the medical record in the study interval using the ICD-9/-10 and CPT codes listed above and prioritized charts that met the inclusion criteria without any exclusion criteria. We then completed the chart Review process for the study with three independent emergency physician chart reviewers. The three emergency physician chart reviewers all contributed to the design of the study, including the creation of inclusion and exclusion criteria, therefore they were not blinded to the Study objectives. We built an electronic data abstraction instrument in REDCap (Research Electronic Data Capture) that we used to abstract all study variables [14]. We com- pleted training to standardize the use of the electronic data abstraction instrument and together abstracted sample charts from the data set to formalize the abstraction process over a series of two meetings lasting more than three total hours. We created a data dictionary and refined it during the training sessions to clarify any questions that arose. The data dictionary specifically defined all study data variables including the locations to find the data within the medical record.

We gathered study data variables including patient demographics, patient-reported duration of symptoms prior to presentation when this was reported in the medical record, patient medications, patient al- lergies and patient medical history. We recorded the initial documented ED physical exam with a specific focus on various components of airway swelling. We logged the first vital signs in the medical record, the pres- ence of stridor, vocal changes, drooling, subjective/objective dyspnea, lip swelling, soft palate swelling, floor of mouth swelling, anterior tongue swelling, posterior tongue swelling, posterior oropharyngeal swelling and uvula swelling. We classified certain patients as having iso- lated lip swelling if they had no other documented physical exam find- ings of angioedema in the medical record. Patients with tongue swelling of unspecified location were classified as anterior tongue swelling. We collected reported findings on nasopharyngoscopy when this was com- pleted, including supraglottic swelling, epiglottic swelling, laryngeal swelling, vocal cord swelling and arytenoid swelling. We define airway swelling on nasopharyngoscopy as any airway swelling noted in one or more of the supraglottic, epiglottic, laryngeal, vocal cord or arytenoid areas. All providers performing nasopharyngoscopy in the reviewed charts reported on direct Laryngeal views in addition to upper airway views.

We did not blind the emergency physician chart reviewers to out- comes when abstracting initial patient characteristics at presentation. We divided the data set so that a single emergency physician chart re- viewer abstracted all demographic information and objective chart in- formation including recorded vital signs, dates and times of evaluation and admission or discharge dates and times. We completed dual ab- straction for all critical variables. We measured the Interrater agreement for the documentation of the following critical variables: lip, soft palate, floor of mouth, anterior/posterior tongue, posterior oropharynx, uvula, supraglottic, epiglottic, laryngeal, vocal cord and arytenoid edema. We estimated the percent agreement between two independent reviewers as well as Cohen’s kappa. We then assigned a third emergency physician chart reviewer who had not yet seen or abstracted the patient’s chart to adjudicate a final result for any disparate findings between the first two abstractions for the dual abstracted variables.

Outcomes

We measured the outcome of need for intubation at any point dur- ing the ED or hospital stay. We collected outcome data regarding death within 90 days of the ED ACEi associated angioedema visit, but only one patient evaluated in this study was documented in the medical record to have died within 90 days of the ED ACEi associated angio- edema visit and the death was not related to their encounter for ACEi as- sociated angioedema, therefore that data was not analyzed further.

Analysis

Statistical analyses were conducted using SPSS 24.0 (Statistical Pack- age for Social Sciences, IBM Corporation, Armonk, NY). For all categori- cal comparisons, we used the Chi-Square test or Fisher’s Exact Test, as appropriate. For comparisons of continuous variables, we used Indepen- dent T-Tests. We report 95% confidence intervals and calculated p values. We also report the Bonferroni adjusted p value threshold sepa- rately for each table that accounts for the multiple comparisons that oc- curred in each specific analysis. Bonferroni-adjusted p value thresholds were calculated using a standard alpha of 0.05 divided by the number of separate statistical tests of the data that were performed in the specific analysis.

  1. Results

A total of 190 separate encounters from 183 unique patients with ACEi associated angioedema were identified during the 3-year period of the study. Patient demographics are summarized in Table I. Notably, nearly all patients included in this study were taking Lisinopril, with a much smaller percentage taking Benazepril. Three patients were taking more than one ACEi. Repeat encounters were due to patients taking more than one ACEi and ED providers not recognizing this when discussing discontinuation of their ACEi medications or individual pa- tients simply failing to discontinue taking an ACEi after an episode of ACEi associated angioedema.

No Surgical airways were performed in the studied population. All intubated patients were successfully intubated via the orotracheal or nasotracheal route and did not require rescue with adjunct devices such as an LMA or iGel. All patients during the study interval who

Table I

Patient characteristics.

Characteristic

N

Percent

Total patients

190

100%

Age – mean (SD)

56

(11)

Race

African-American

156

82%

Caucasian

31

16%

Asian/Pacific Islander

1

1%

Other

2

1%

Male

96

51%

Prior angioedema

32

17%

Prior allergic reaction

83

44%

Immunosuppressant use

ACEia

6

3%

Lisinopril

180

95%

Benazepril

7

4%

Ramipril

1

1%

Captopril

1

1%

Enalapril

3

2%

Not documented

1

1%

Diabetes

61

32%

Congestive heart failure

18

9%

Hypertension

182

96%

Renal disease

19

10%

Previous stroke

12

6%

a More than one ACEi taken by some patients.

required intubation were intubated in the ED prior to admission. No pa- tients were admitted to the hospital without a Secure airway.

We collected patient-reported duration of symptoms when this in- formation was available in the medical record and evaluated for any re- lationship to need for intubation. 90% of patient encounters included this information (Table II). Notably, time of onset was available for 12 of the 18 intubated patients and all 12 intubated patients presented within 6 h of the onset of symptoms.

We next evaluated if any of the history and physical exam items measured were significantly more common in intubated patients. For all of the measured dual abstracted variables related to airway swelling, interrater agreement between chart reviewers was excellent with a me- dian agreement of 95% [interquartile range: 87-96%] and a median kappa of 0.68 [interquartile range: 0.44-0.78] (Supplementary Table I). We found that vocal changes, drooling, dyspnea and anterior tongue swelling were significantly more common in intubated patients compared with patients that did not require intubation (Table III). Pa- tients with isolated lip swelling were significantly less likely to require intubation. The largest effect sizes were observed in patients with vocal changes and anterior tongue swelling where 59% and 61% of intubated patients exhibited these findings, respectively. Patients that required intubation generally had higher systolic and diastolic blood pressure readings at triage, but this finding did not meet criteria for sig- nificance after correcting for multiple comparisons.

70 of 190 encounters included nasopharyngoscopy in the patient

workup (37% of all encounters). Airway swelling was noted in 50 of the 70 patients undergoing nasopharyngoscopy. Nasopharyngoscopy was significantly more likely to be performed on patients that ulti- mately required intubation, highlighting the selection bias of providers to perform nasopharyngoscopy on higher-acuity presentations (Table IV). Despite this limitation, findings of supraglottic or laryngeal edema on nasopharyngoscopy were each significantly more common in patients requiring intubation. Supraglottic swelling demonstrated the largest effect size, with 80% of intubated patients having this finding on nasopharyngoscopy. Finally, patient characteristics did not predict which patients will have findings of airway swelling on nasopharyngoscopy (Table V).

  1. Discussion

Our data point to specific factors that may help risk-stratify ACEi as- sociated angioedema patients with regard to need for intubation. We observed that all intubated patients in our study presented within 6 h of symptom onset. This finding is limited by missing data in one third of the intubated patients, therefore this finding may not be universal. Another study noted a similar trend in severity of outcome with de- creasing time to care initiation [15]. These investigators noted that most patients in their study required advanced airway management within 4 h of symptom onset. Greater than 90% of patients in the other study who ultimately underwent airway intervention experi- enced symptoms for 12 h or less. Differences in the frequency and timing of airway management in these studies may reflect Comfort level of providers at the separate institutions with airway observation prior to intervention. Nevertheless, the large majority of ACEi associated angioedema patients who require airway management have rapid pro- gression of their angioedema early in the disease course, typically within 4-6 h of onset.

Patients with lip swelling, specifically with isolated lip swelling, did well in this cohort and a significant majority of these patients did not re- quire airway intervention. However, 3 patients with only lip swelling documented for their physical exam were intubated. There is difficulty in interpreting whether or not this was true isolated lip swelling since many times in the setting of intubation for angioedema, the complexity of the physical exam documentation in the studied electronic medical record was noted to be low. A large subset of patients with isolated lip swelling presented N12 h after the onset of symptoms. In the absence

Table II

Duration of symptoms by intubation status.

Duration of symptoms Not intubated, n = 172 Intubated, n = 18 Difference (95% CI1) p-Value2,3

n

Percent

n

Percent

b3 h

24

14%

8

44%

30.5% (7.0% to 54.0%)

0.004

3-6 h

47

27%

4

22%

-5.1% (-25.4% to 15.2%)

0.78

6-12 h

47

27%

0

0%

-27.3% (-34.0% to -20.7%)

0.008

N12 h

39

23%

0

0%

-22.7% (-28.9% to -0.2%)

0.027

Not documented

15

9%

6

33%

24.6% (24.3% to 46.8%)

0.007

1 95% confidence interval.

2 Fisher’s Exact test; Bonferroni adjusted p-value threshold = 0.01.

3 Overall test for heterogeneity, p b 0.001.

of rapid progression or significant recent changes in the symptoms of these individuals, discharge without further observation after discontinuing their ACEi medication may be warranted.

More complexity exists within the subgroups of patients that have intraoral edema, including lingual, soft palate, uvular and posterior pha- ryngeal edema. Ishoo et al. make the broad assertion from a small, but similar demographically to the current study, group of patients that all patients with Stage III or stage IV angioedema (angioedema involving the tongue or larynx respectively) be admitted to an intensive care unit or undergo advanced airway management [16]. Our data suggest that these patients do require close observation. Furthermore, our data point to anterior tongue swelling as a strong risk factor for intuba- tion. However, many of these anterior tongue swelling patients – 40 in our cohort – could be closely observed without further airway interven- tion. Decisions regarding disposition and potential transfer of these pa- tients must take into account individual provider comfort and institutional resources available to care for patients that may progress in these high-risk groups.

We found that vocal changes, drooling and subjective or objective dyspnea are all significantly more common in patients that required intubation in our study. These symptoms, when present or when they develop, should be closely observed and alert the ED provider of the potential need for intubation. We did not observe any surgical airways in this study, therefore the point at which these symptoms of airway compromise deteriorate into objective stridor may not have been reached in the included patients. Furthermore, the rate at which these symptoms progress into fulminant airway collapse re- quiring a surgical airway cannot be determined based upon our results.

Limited data exist examining the role of nasopharyngoscopy in the evaluation of ACEi associated angioedema, [15,17-19] all of which exists within the otolaryngology or anesthesia literature. Three of these studies [17-19] suggest that all ACEi associated angio- edema patients should undergo nasopharyngoscopy and two [18,19] conclude that evaluation by an otolaryngologist is necessary in all cases of ACEi associated angioedema. However, these options are not always available for emergency medicine providers. The findings from our study emphasize the difficulty in determining which pa- tients may ultimately benefit from nasopharyngoscopy. We were un- able to link specific Vital sign abnormalities, objective demographic factors or specific physical exam findings to the presence or absence of findings on nasopharyngoscopy. Non-significant trends were ob- served with more nasopharnygoscopy findings in patients who re- ported subjective or provider reported objective vocal changes and in posterior oropharyngeal swelling on exam, and fewer findings in patients with isolated lip swelling, however, these findings did not meet criteria for significance even before correcting for multiple comparisons. It is therefore quite difficult to predict which ACEi asso- ciated angioedema patients will have findings upon nasopharyngoscopy. Furthermore, with the bias in our study of only a minority of subjects undergoing nasopharyngoscopy and a significantly higher proportion of patients who required intubation undergoing the procedure, it is difficult to interpret the implications of nasopharyngoscopy findings when they are present and when they are absent. We suggest that the timing of the disease course and the presence or absence of isolated lip swelling should play a larger role than nasopharyngoscopy findings in the ED Disposition decision.

Table III

Physical exam findings and initial vital signs by intubation status.

Not intubated, N = 172 Intubated, N = 18 Difference (95% CI1) p-Value2

n/N (missing)

Percent

n/N (missing)

Percent

Initial vital signs – mean (SD) Respiratory rate

18

(3)

19

(3)

1.2 (-0.4 to 2.8)

0.15

Pulse oximetry reading

98

(2)

97

(3)

-0.2 (-1.3 to 0.8)

0.69

Initial heart rate

89

(17)

93

(19)

3.4 (-5.4 to 12.1)

0.45

Systolic blood pressure

143

(22)

159

(33)

15.2 (3.1 to 27.3)

0.014

Diastolic blood pressure

85

(15)

97

(20)

11.9 (3.9 to 19.8)

0.004

Physical exam findings

Stridor

1/167 (5)

1%

1/17 (1)

6%

5.3% (-6.0% to 16.5%)

0.18

Vocal changes

25/166 (6)

15%

10/17 (1)

59%

43.8% (19.7% to 67.8%)

0.0001

Drooling

5/164 (8)

3%

5/17 (1)

29%

26.4% (4.5% to 48.2%)

0.0008

Dyspnea (subjective or objective)

12/163 (9)

7%

6/17 (1)

35%

27.9% (4.9% to 51.0%)

0.0027

Lip swelling

120/171 (1)

70%

8/17 (1)

47%

-23.1% (-47.8% to 1.6%)

0.06

Soft palate swelling

13/169 (3)

8%

2/16 (2)

13%

4.8% (-11.9% to 21.5%)

0.38

Floor of mouth swelling

10/167 (5)

6%

0/16 (2)

0%

-6.0% (-9.6% to -2.4%)

0.60

Anterior (1/2) of tongue swelling

40/169 (3)

24%

11/18

61%

37.4% (14.0% to 60.9%)

0.0016

Posterior (1/2) of tongue swelling

9/167 (5)

5%

1/17 (1)

6%

0.5% (-11.2% to 12.2%)

1.0

Posterior oropharyngeal swelling

11/169 (3)

7%

2/17 (1)

12%

5.3% (-10.5% to 21.0%)

0.33

Uvula swelling

20/169 (3)

12%

3/15 (3)

20%

8.2% (-12.7% to 29.0%)

0.41

Isolated lip swelling

99/172

58%

3/18 (2)

17%

-40.9% (-59.6% to -22.2%)

0.001

1 95% confidence interval.

2 Fisher’s Exact test; Bonferroni adjusted p-value threshold = 0.003.

Table IV

Nasopharyngoscopy exam findings by intubation status.

Not intubated, N = 172

Intubated, N = 18

Difference (95% CI1)

p-Value2

n/N (missing)

Percent

n/N (missing)

Percent

Nasopharyngoscopy performed

55/172

32%

15/18

83%

51.4% (32.8% to 70.0%)

b0.0001

Any scope finding

35/55

64%

15/15

100%

36.4% (23.7% to 49.1%)

0.004

Supraglottic swelling

18/54 (1)

33%

12/15

80%

46.7% (22.8% to 70.6%)

0.002

Epiglottic swelling

9/55

16%

5/15

33%

17.0% (-8.8% to 42.8%)

0.16

Laryngeal swelling

6/54 (1)

11%

7/15

47%

35.6% (9.0% to 62.2%)

0.005

Vocal cord swelling

3/55

6%

3/15

20%

14.5% (-6.5% to 35.7%)

0.11

Arytenoid swelling

12/54 (1)

22%

8/15

53%

31.1% (3.5% to 58.7%)

0.03

1 95% confidence interval.

2 Fisher’s Exact test; Bonferroni adjusted p-value threshold = 0.007.

Finally, our findings point to factors that can help to risk stratify ACEi associated angioedema patients. Our data support the classification of higher risk presentations that include tongue swelling, vocal changes, drooling, dyspnea and individuals with rapid progression of symptoms over the first 6 h of illness. Lower risk presentations include patients with isolated lip swelling. Nevertheless, the presence or absence of these findings cannot be considered universal and every provider must determine their own tolerance for the possibility of missing an airway-threatening condition in determining need for intubation and the ultimate disposition of these patients.

  1. Limitations

Our study is limited in several ways, most notably by the retrospec- tive observational design. We did perform the broadest inclusion possi- ble to obtain virtually all ACEi associated angioedema cases seen in the studied ED during the three years of the study, but there is always the possibility that cases were missed that should have been included. Inac- curate charting by the original ED providers cannot be excluded as a possibility in some of the reviewed cases. Furthermore, the study chart abstractors were not blinded to the objectives of the study. Only 37% of study subjects underwent nasopharyngoscopy as a part of their ED workup, possibly leading to incomplete data if some lower airway findings were missed. Finally, there were a low number of intubations, even in this relatively large series of ACEi associated angioedema cases.

Ninety-five percent of patients studied were prescribed Lisinopril. We hypothesize that this is related to the high frequency with which this medication is prescribed compared with other ACE inhibitor medi- cations in the catchment area of the studied tertiary care facility. Never- theless, this may serve as a limitation to the generalization of our findings to patients prescribed other ACE inhibitor medications.

The retrospective nature of this study and the dependence of the

outcome of intubation on the comfort level of the individual providers who saw the patient in the ED certainly introduces bias into our find- ings. This bias is most pronounced in our finding that significantly more patients who were ultimately intubated had nasopharyngoscopy performed than patients who did not require intubation. This study did not directly address which specific nasopharyngoscopy findings can be safely observed without further airway management.

  1. Conclusions

Our exploratory and hypothesis-generating data suggest that ACEi associated angioedema patients do not frequently require intubation when they present N6 h after the onset of symptoms. Patients with tongue swelling, vocal changes, drooling or dyspnea are more likely to require intubation. Patients with isolated lip swelling are usually lower-risk with regards to need for intubation, however these individ- uals can occasionally require airway management so evaluating other

Table V

Physical exam findings by presence of airway swelling on nasopharyngoscopy.

No swelling, N = 20 Swelling, N = 50 Difference (95% CI1) p-Value2

n

Percent

n

Percent

Age – mean (SD)

56

(10)

57

(10)

0.3 (-5.2 to 5.7)

0.927

Male

12

60%

27

54%

-6.0% (-32% to 20.0%)

0.648

African American

14

70%

39

78%

8.0% (-15.0% to 31.0%)

0.262

Initial vital signs – mean (SD)

Respiratory rate

19

(2)

18

(4)

-0.1 (-2.1 to 1.9)

0.915

Pulse oximetry reading

98

(2)

97

(3)

-0.5 (-1.8 to 0.9)

0.488

Initial heart rate

89

(12)

92

(17)

2.4 (-6.1 to 10.9)

0.574

Systolic blood pressure

146

(21)

150

(28)

3.1 (-11.1 to 17.2)

0.665

Diastolic blood pressure

84

(13)

89

(18)

5.2 (-3.8 to 14.2)

0.251

Physical exam findings

Stridor

0

0%

1

2%

2.0% (-1.9% to 5.9%)

1.000

Vocal changes

4

20%

23

47%

26.9% (3.7% to 48.3%)

0.056

Drooling

2

10%

7

14%

4.0% (-12.3% to 20.3%)

1.000

Dyspnea (subjective or objective)

1

5%

9

18%

13.0% (-1.3% to 27.3%)

0.261

Isolated lip swelling

5

25%

6

12%

-13.0% (-34.0% to 8.0%)

0.274

Lip swelling

7

35%

20

41%

4.8% (-19.9% to 29.9%)

0.653

Soft palate swelling

4

20%

11

23%

2.9% (-19.0% to 23.0%)

1.000

Floor of mouth swelling

3

15%

3

6.4%

-8.6% (-26.0% to 8.0%)

0.353

Isolated anterior (1/2) of tongue swelling

1

5%

2

4.0%

-1.0% (-12.0% to 10.0%)

1.000

Anterior (1/2) of tongue swelling

11

55%

21

42.0%

-13.0% (-38.7% to 12.7%)

0.324

Posterior (1/2) of tongue swelling

2

11%

6

12%

1.7% (-13.9% to 17.9%)

1.000

Posterior oropharyngeal swelling

1

5%

10

21%

15.8% (0.4% to 29.6%)

0.155

Uvula swelling

5

26%

13

28%

1.3% (-21.5% to 23.5%)

1.000

1 95% confidence interval.

2 Fisher’s Exact test; Bonferroni adjusted p-value threshold = 0.003.

aspects of the presentation including rapid symptom progression may be warranted.

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2019.12.058.

Presentations

None.

Financial support

The REDCap program used in the collection of data for this project was supported by an Institutional Clinical and Translational Science Award, National Center for Research Resources of the National Institutes of Heath, United States, Grant Number 8UL1-TR000077. This funding source had no role in the study design; the collection, analysis or inter- pretation of data; the writing of the report; or the decision to submit the article for publication.

Author contributions

JJM conceived the study; PAM, EAH, KWH, JAB and JJM assisted with study design; PAM, EAH and JJM performed the chart review and ac- quired the data; US and KWH provided statistical expertise and per- formed data analysis; PAM, EAH, US, KWH, JAB and JJM interpreted the data; PAM drafted the manuscript and EAH, US, KWH, JAB and JJM performed critical revision of the manuscript for important intellectual content.

Declaration of competing interest

JAB is an investigator, consultant, speaker for Shire/Takeda, CSL Beh- ring and Pharming; investigator and consultant for Bicryst, Kalvista and IONIS. The following authors declare no conflicts of interest relevant to this study: PAM, EAH, US, KWH, JJM.

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