Article, Emergency Medicine

Evaluation of myocardial injury through serum troponin I and echocardiography in anaphylaxis

a b s t r a c t

Background: Anaphylaxis is an acute, lethal, multisystem syndrome that results from the sudden release of mast cell– and basophil-derived mediators. Although anaphylaxis can cause Cardiac complications, the incidence of myocardial injury using troponin I (TnI) has not been characterized. In addition, patterns of cardiomyopathy have not been evaluated in patients with elevated TnI. Therefore, we studied the occurrence and patterns of myo- cardial injury with TnI and echocardiography in anaphylaxis.

Methods: We conducted a retrospective review of 300 consecutive anaphylaxis cases that were diagnosed in the emergency department (ED) over 53 months (2011-2015). Myocardial injury was defined as elevation of TnI within 24hrs after arrival at the ED. We investigated systolic function and regional Wall motion abnormality (RWMA) through echocardiography within 5 hours after arrival at the ED in patients with myocardial injury. Results: Among 300 patients (median age, 55 years), 22 patients demonstrated myocardial injury (7.3%). The me- dian TnI was 0.222 ng/mL with a range from 0.057 ng/mL to 19.4 ng/mL. Three patients presented reduced sys- tolic function and 4 patients showed RWMA. One patient showed reverse Takotsubo cardiomyopathy and other 2 patients had RWMA discordant to the distribution of coronary arteries. Another patient showed RWMA (inferior wall) with ST elevation of II, III, and aVF. All 4 patients were discharge after recovery of cardiomyopathy without any specific intervention for cardiomyopathy.

Conclusions: Myocardial injury developed in 7.3% of patients with anaphylaxis. Various cardiomyopathy, includ-

ing Kounis syndrome and Takotsubo cardiomyopathy, has been observed in patients with myocardial injury.

(C) 2015

Introduction

Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into blood circulation [1]. Anaphylaxis frequently results from immunologic reactions to foods, medications, and insect stings, al- though it can also be induced through nonimmunologic mechanisms by any agent capable of producing a sudden, systemic degranulation of mast cells or basophils [2].

Anaphylaxis can cause cardiac complications, which has been associ- ated clinically with myocardial ischemia, as well as conduction defects, including atrial and ventricular arrhythmias and T-wave abnormalities [3]. In 1991, Kounis and colleagues reported the “syndrome of Allergic angina or Kounis syndrome” as the co-incidental occurrence of chest pain and Allergic reactions accompanied by clinical and laboratory find- ings in classic angina pectoris caused by Inflammatory mediators re- leased during allergic reactions [4]. There are also some case reports

* Corresponding author at: Department of Emergency Medicine, Wonju College of Med- icine, Yonsei University, 162 Ilsandong, Wonju, Republic of Korea 220-701. Tel.: +82 33

741 1614; fax: +82 33 742 3030.

E-mail address: [email protected] (H. Kim).

that discuss cardiomyopathy related to anaphylaxis [5-10]. One report described 2 previously healthy patients, without apparent underlying heart disease, who developed profound myocardial depression during anaphylaxis [6]. However, little is known about the occurrence of myo- cardial injury using serum troponin I (TnI), which is expressed in cardio-specific isoforms [11], and patterns of cardiomyopathy through cardiac function evaluation, using echocardiography in patients with elevated TnI.

Therefore, we studied the incidence and patterns of myocardial inju- ry, which was defined as elevated TnI levels when checked within 24 hours after emergency department (ED) arrival, through serum TnI and echocardiography in anaphylaxis.

Methods

Study design and data

This study was retrospectively performed on consecutive adult ED patients with anaphylaxis over 53 months since serum TnI checks were implemented in anaphylaxis (2011 to 2015). Single urban, tertiary-care hospital (Wonju Severance Christian Hospital, in Wonju,

http://dx.doi.org/10.1016/j.ajem.2015.09.038

0735-6757/(C) 2015

Republic of Korea) was used for enrollment with ED that has an annual visit volume in excess of 43,000 and is staffed 24 hours per day with board-certified emergency physicians.

Anaphylaxis was confirmed by emergency physicians in the ED. Di-

agnostic criteria of anaphylaxis included rapid occurrence of 2 or more of the following after exposure to a likely allergen (minutes to several hours): (1) skin and/or mucosal tissue involvement (urticaria, itchiness, flushing, or swelling), (2) respiratory compromise (shortness of breath, wheezes, or stridor), (3) reduced blood pressure or shock (systolic blood pressure b 90 mmHg), (4) persistent Gastrointestinal symptoms (diarrhea, crampy abdominal pain, or vomiting) [1]. All patients complaining of anaphylaxis upon arrival to the ED were done with fluid resuscitation and treated with antihistamine and steroid, and, if needed, epinephrine was used. The study exclusion criteria were: an age less than 18 years, absence of serum TnI level within 24 hrs of arrival at the ED, end-stage renal disease, and cardiac arrest when the patient arrived at the ED, as these can affect serum TnI levels.

Data was collected by retrospectively reviewing electronic medical re- cords. Data collection was conducted by 2 emergency physicians blinded to the Study objectives and hypothesis and if there was inter-observer dis- agreement in the interpretation of clinical data, the 2 emergency physi- cians reviewed the case together to come to a conclusion. Training of abstractors was conducted before data collection to reduce bias. The fol- lowing were obtained from the patients’ medical records: age, gender, causes of anaphylaxis, Cardiovascular risk factors, initial symptoms and signs, initial Glasgow Coma Scale score, initial vital signs including systolic blood pressure (SBP) and pulse rate (PR), use of epinephrine, and mortality. Electrocardiography was performed in the ED and a car- diologist (SOH), who specializes in both emergency medicine and cardiol- ogy, interpreted the ischemic change on the ECG, including ST elevation, ST depression, and T-wave inversion. Ischemic changes were classified as new ST-segment elevation (>= 1 mm) or depression (>= 0.5 mm) or T wave inversion (>=2 mm) in 2 consecutive leads [12]. Serum cardiac bio- chemical markers, including TnI and ?-type natriuretic peptide (BNP), were investigated in the ED. A serum high-sensitivity TnI (hs-TnI) (Sie- mens Healthcare Diagnostics Inc, Newark, DE) was used to determine blood TnI levels (reference range b 0.046 ng/mL). Myocardial injury was defined as elevation of hs-TnI within 24 hours after arrival at the ED be- cause we wanted to minimize the possibility of myocardial injury second- ary to malfunctions of other organs or systems. Echocardiography was investigated in patients with an elevated hs-TnI within 5 hours after arriv- al at the ED to measure Cardiac functions including systolic function and Regional wall motion abnormality (RWMA). Transthoracic echocardiogra- phy was performed with Vivid E9 (General Electrical Medical System, Horton, Norway) using a 2.5-MHz probe. Ejection fraction (EF) was mea- sured using the Modified SImpson’s technique. Normal systolic function was defined as an EF greater than 50%, while an EF of 50% or less was de- fined as reduced systolic function. An experienced cardiologist (SOH) interpreted the echocardiographic findings and was blinded to the pa- tients’ clinical information. This study was approved by the institutional review board of the Wonju College of Medicine, Yonsei University.

Statistical analysis

Categorical variables were presented as frequencies and percent- ages, and continuous variables as medians and interquartile ranges after assessments for normality using the Shapiro-Wilk test. The ?2 test or Fisher exact test was used to compare nominal variables and the Mann-Whitney U test was used to compare continuous variables. P b .05 was considered statistically significant. Statistical analyses were performed using IBM SPSS 20 Ver. (IBM, Aramark, NY).

Results

Characteristics of study subjects

A total 300 consecutive patients older than 18 years were identified with anaphylaxis during study period. The following patients were ex- cluded: cardiac arrest when they arrived at the ED (9 patients), absence of serum hs-TnI levels within 24 hours after arriving at the ED (6 pa- tients), transfer out to other hospital (4 patients), and discharge against medical advice (3 patients) (Figure).

General characteristics are shown in Table 1. One hundred sixty eight of the patients were male (56.0%) and the median age of the study subjects was 55 years. Most frequent causes of anaphylaxis in- cluded food, drug, and insect bite. Hypertension was the most common cardiovascular risk factor. The common symptoms and signs at initial presentation were urticaria (163 patients, 54.5%), dyspnea (158 pa- tients, 52.8%), chest pain (56 patients, 18.8%), and swollen oropharynx (42 patients, 14.0%), respectively. One patient (0.3%) died of multiple organ failure (Table 1).

Myocardial injury

Myocardial injury was observed in 22 patients (7.3%). The median hs-TnI was 0.222 ng/mL with a range from 0.057 ng/mL to 19.4 ng/mL. In the myocardial injury group (n = 22), there were ischemic changes on the ECG in 12 patients. Two patients had ST elevation, 7 pa- tients had ST depression, and 3 patients had T-wave inversion. Echocar- diography was performed on 15 of 22 patients with myocardial injury to analyze cardiac function in the ED. Three patients (case 2, 19, and 22) exhibited reduced systolic function, and 4 patients showed RWMA (cases 2, 9, 19, and 22). One patient (case 2) showed reverse Takotsubo cardiomyopathy and other 2 patients (cases 9 and 19) had RWMA dis- cordant to the distribution of coronary arteries. Another patient (case 22) showed RWMA (inferior wall) with ST elevation of II, III, and aVF. Four patients with cardiomyopathy were discharged after recovery from RWMA and reduced systolic function without any specific inter- vention for cardiomyopathy. Wall motion score index ranged from

1.026 to 2.25 (Tables 2, 3). The case 22 patient was followed up in the cardiology outpatient department after discharge. Echocardiography performed 10 days after discharge revealed that new RWMA, which was hypokinesia in all segments mid LV with EF 54%, had developed.

Figure. Study flow chart.

Table 1

General characteristics of anaphylactic patients

Variables

Total

Non-myocardial injury group

Myocardial injury group

P

N = 300

N = 278 (92.7%)

N = 22 (7.3%)

Age

55 (43-65)?

54 (42-64)?

59 (49-67)?

.149

Male gender

168 (56.0%)

158 (56.8%)

10 (45.5%)

.301

Cause

.165

Drug

91 (30.4%)

84 (30.3%)

7 (31.8%)

Food

90 (30.1%)

87 (31.4%)

3 (13.6%)

Insect bite

71 (23.7%)

64 (23.1%)

7 (31.8%)

Contrast material

13 (4.3%)

13 (4.7%)

0 (0%)

Cardiovascular risk factors

DM

51 (17.0%)

43 (15.5%)

8 (36.4%)

.019

HTN

80 (26.7%)

73 (26.3%)

7 (31.8%)

.570

Hyperlipidemia

18 (6.0%)

18 (6.5%)

0 (0%)

.379

Cardiac disease

25 (8.4%)

22 (7.9%)

3 (13.6%)

.411

Symptoms

Urticaria

163 (54.5%)

157 (56.5%)

6 (28.6%)

.013

Swollen oropharynx

42 (14.0%)

41 (14.7%)

1 (4.8%)

.329

Dyspnea

158 (52.8%)

146 (52.5%)

12 (57.1%)

.682

Chest pain

56 (18.8%)

53 (19.1%)

3 (14.3%)

.775

Diarrhea

12 (4.0%)

12 (4.3%)

0 (0%)

1.000

Initial shock (b90)

90 (30.2%)

82 (29.7%)

8 (36.4%)

.513

SBP (mmHg)

110 (87-137)?

113 (87-137)?

96 (74-119)?

.029

PR (rates/minutes)

89 (76-100)?

88 (76-100)?

89 (77-103)?

.787

GCS

15 (15-15)?

15 (15-15)?

15 (14-15)?

.144

Use of epinephrine

183 (61.0%)

170 (61.2%)

13 (59.1%)

.849

Hs-TnI (ng/mL)

0.015 (0.15-0.015)?

0.015 (0.15-0.015)?

0.222 (0.109-1.445)?

b.001

Mortality

1 (0.3%)

1 (0.4%)

0 (0%)

1.000

DM, diabetes mellitus; HTN, hypertension.

* Median (interquartile range).

Twenty-five days after discharge, although the new RWMA had normal- ized, BNP was 150 pg/mL and mild Dyspnea on exertion (DOE) was ob- served. Therefore, she was administered diuretics. Forty days after discharge, DOE had resolved and diuretic use was stopped. Another 3 patients (cases 2, 9, and 19) were not followed in the outpatient depart- ment, and so we attempted to contact each patient to inquire about their current condition including survival, newly developed symptoms such as dyspnea, chest pain, or chest discomfort, or diagnosis of cardio- pulmonary disease including heart failure or acute coronary syndrome after discharge. All 3 patients were successfully contacted. Each of these patients survived and suffered no further complications.

Of cardiovascular risk factors, diabetes mellitus was significantly higher in the myocardial injury group (P = .019). Patients with cardiac diseases including coronary artery disease (18 patients), valvular heart

disease (1 patient), heart failure (2 patient), and atrial fibrillation (4 pa- tient) were 25 patients (8.4%). However, there was no significant differ- ence in terms of cardiac disease between 2 groups. Urticaria as an initial symptom was significantly more common in the nonmyocardial injury group (P = .013). Although SBP was higher in the myocardial injury group than in the nonmyocardial injury group (P = .029), there was no difference in terms of initial shock between 2 groups. There was no difference in terms of age, cause, and use of epinephrine. There was no mortality in the myocardial injury group (Table 1).

Discussion

Myocardial injury and anaphylaxis-induced cardiomyopathy in ana- phylaxis have been discussed primarily in case reports. This study

Table 2

Characteristics of patients with myocardial injury

Patients number

Age

Gender

Cause

Initial shock

Use of epinephrine

Chest pain

ECG

hs-TnI (ng/mL)

1

61

F

Hairdye

No

No

Yes

0.059

2

33

F

Drug

No

No

No

ST depression

8.883

3

52

F

Insect bite

Yes

Yes

No

0.130

4

52

M

Insect bite

No

No

No

0.277

5

60

F

Insect bite

No

No

No

ST depression

0.062

6

51

F

Bite

No

No

No

0.063

7

63

M

Insect bite

No

No

No

T wave inversion

0.170

8

58

F

Drug

Yes

Yes

No

T wave inversion

0.456

9

71

F

Drug

No

No

No

0.146

10

70

F

Drug

Yes

Yes

No

ST depression

7.50

11

72

M

Unknown

Yes

No

No

T wave inversion

0.105

12

80

F

Drug

Yes

Yes

No

ST depression

2.80

13

49

F

Food

No

Yes

No

2.03

14

83

M

Drug

Yes

Yes

No

0.212

15

66

M

Insect bite

No

No

No

0.110

16

56

M

Insect bite

Yes

Yes

No

0.231

17

60

M

Snake bite

No

Yes

No

ST depression

0.116

18

49

M

Insect bite

No

Yes

No

ST depression

0.057

19

36

M

Unknown

No

Yes

No

ST elevation

0.477

20

66

F

Food

Yes

Yes

Yes

ST depression

0.459

21

47

F

Drug

Yes

No

No

1.25

22

46

F

Food

Yes

No

No

ST elevation

19.4

Table 3

Features of patients with anaphylaxis induced cardiomyopathy

Case

Systolic function

BNP (pg/mL)

CAG

wall motion abnormalities

2

Reduced

25.71

Akinesis of basal all segments and mid anterior and anteroseptum

9

Normal

59.75

Hypokinesis of apicoseptum

19

Reduced

5.00

Hypokinesis of basal anterior and anteroseptum

22

Reduced

5.45

Normal

Akinesis of inferior wall from base to apex

included 2 types of myocardial injury, only elevated TnI and cardiac dys- function with elevated TnI. To our knowledge, this is the first study to investigate the incidence of myocardial injury using hs-TnI and anaphylaxis-induced cardiomyopathy using echocardiography.

In this study, the incidence of myocardial injury that developed within 24 hours after arrival at the ED in anaphylactic patients was higher as 7.3% (22 patients of a total of 300 patients). The median hs-TnI level (0.222 ng/mL) was relatively low compared to the levels associated with other myocardial injuries, such as myocardial infarction and myocarditis [13]. However, case 22 showed high elevation of TnI (19.4 ng/mL). In this study, there was no difference in terms of use of epinephrine or initial shock between 2 groups. Therefore, we could not explain that exogenous epinephrine or initial shock mainly cause early myocardial injury (Tables 1, 2).

Anaphylaxis-induced cardiomyopathy was also observed in 4 pa- tients (cases 2, 9, 19, and 22) of a total of 300 patients (1.3%). Three pa- tients (cases 2, 19, and 22) showed a decreased ejection fraction on transthoracic echocardiography, and 4 patients (case 2, 9, 19, and 22) showed RWMA. One patient (case 2) showed reverse Takotsubo cardio- myopathy and another patient (case 22) showed akinesis of inferior wall from base to apex with ST elevation of II, III, and aVF (Table 3). This study confirmed that anaphylaxis may cause RWMA as well as global dysfunction, based on the results and comparison with other case reports [5,8-10]. Four patients were discharge after recovery of RWMA and reduced systolic function without any specific intervention for cardiomyopathy. After discharge, one patient (case 22) developed a new RWMA, but it resolved and DOE disappeared with short-term use of diuretics. The development of another transient type of cardiomyopathy after recovery from acute cardiomyopathy is possible; thus, if a patient ex- Declaration of interest“>periences new dyspnea after discharge, further echocardiography and BNP may be needed.

The pathophysiology of myocardial injury and cardiomyopathy can vary in anaphylaxis. The proposed pathophysiology is as follows. First, anaphylaxis can trigger myocardial ischemia, called Kounis syndrome [14,15]. Degranulation of the mast cells is the primary mechanism and most mast cells are localized in the lungs and heart. Mast cells then release histamine, prostaglandin D2, thromboxane, and cysteinyl leukotriens. Histamine is a potent vasoconstrictor that causes vaso- spasms. Release of these inflammatory mediators induces coronary artery spasm and/or atheromatous plaque erosion or rupture. Epinephrine that is used to treat anaphylaxis may aggravate platelet aggregation [16,17]. Case 22 showed ST elevation in ECG and highly elevated TnI (19.4 ng/mL). Therefore, the Coronary angiography was done immedi- ately and result of CAG was normal coronary artery and possible suspicion of vasospasm. Kounis syndrome by vasospasm was developed in case 22. Although RWMA including inferior wall was disappeared after the CAG, the echocardiography at 3 days after the admission showed mid- ventricular variant of Takotsubo cardiomyopathy. Second, Takotsubo car- diomyopathy may develop in anaphylaxis, which has been reported in several cases [8-10]. It has been suggested that the systemic catechol- amine increase, with excessive activation of cardiac catecholamine recep- tors in the left ventricle, plays a major role in the pathophysiology of stress-induced cardiomyopathy [18,19]. In anaphylaxis, compensatory catecholamine is released by the Renin-angiotensin-aldosterone system, and histamine stimulates the release of catecholamine by direct action on the adrenal medullary cells [20,21]. In addition, administration of a cat- echolamine, such as epinephrine and norepinephrine, for hemodynamic

support in anaphylactic shock also increases the plasma catecholamine levels. It is possible that the increased catecholamine levels during ana- phylaxis may provoke Takotsubo cardiomyopathy. In this study, case 2 was found to have reverse Takotsubo cardiomyopathy, which is a vari- ant of Takotsubo cardiomyopathy. Although we did not check serum catecholamine level, we did not use epinephrine to case 2. Therefore, we thought that reverse Takotsubo cardiomyopathy of case 2 could be caused by endogenous catecholamine. Third, hypersensitivity myocar- ditis is also possible, and finally, myocardial injury may be caused by profound shock. In this study, there was no difference in terms of initial shock between 2 groups.

There were some limitations to this study. First, the study was con- ducted using a retrospective design at a single hospital. As a result, not all relevant assessment parameters were included. We did not investi- gate an echocardiography in all patients with myocardial injury. Second, although there was no mortality in myocardial injury group, there were 9 patients that were admitted to the ED for cardiac arrest and they were not included in this study. We were unable to determine their cardiac status and cause of arrest because we did not perform an autopsy. Third, a bias might be caused by exclusions. Therefore, we propose that further prospective studies are required to investigate serum cate- cholamine, serial TnI, echocardiography and prognosis of cardiac injury in patients with anaphylaxis.

Conclusions

Myocardial injury developed in 7.3% of patients with anaphylaxis. Various cardiomyopathy, including Kounis syndrome and Takotsubo cardiomyopathy, has been observed in patients with myocardial injury.

Declaration of interest

The authors have no potential conflict of interest to declare.

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