Kounis Syndrome after Administration of Ultrasound Enhancing Agent

A 47-year-old man presented with 2 days of chest pressure and was found to have an anteroseptal ST elevation myocardial infarction (STEMI). Emergent coronary angiography demonstrated 100% occlusion of his proximal left anterior descending artery. He received one drug-eluting stent without complications. Afterwards, a transthoracic echocardiogram (TTE) with an ultrasound enhancing agent (UEA) consisting of sulfur hexafluoride lipid-type A microspheres (LUMASON^™; Bracco Diagnostics) was performed which demonstrated a left ventricular ejection fraction (LVEF) of 25–30%. He developed post-STEMI pericarditis and was started on colchicine. He began spironolactone and metoprolol succinate but did not tolerate an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker due to hypotension.

Eleven days after discharge, he presented to the emergency room with recurrent substernal chest discomfort. An electrocardiogram (ECG) was without signs of acute ischemia and a troponin T was 0.4 ng/mL and stable on four-hour repeat. His chest discomfort worsened with sitting upright and improved with supine positioning. He was admitted for workup of suspected pericarditis. A TTE was obtained which demonstrated evidence of remodeling, with reduction in his LVEF to 15% and a newly aneurysmal apex (Video 1). To better assess the aneurysmal apex and rule out apical thrombus, he was administered LUMASON^™ (Figure 1A and 1B, Video 2).

Figure 1:

Echocardiographic Images of the Left Ventricle

(A) Pre-contrast administration

(B) Post-contrast administration

Shown is the left atrium (LA), right atrium (RA), left ventricle (LV), and right ventricle (RV) in an apical 4-chamber view, prior to contrast administration (panel A) and following contrast administration (panel B) at end-diastole (left) and end-systole (right).

Before UEA administration, vital signs were temperature 98.1 degrees Fahrenheit, heart rate 83 beats per minute, blood pressure 90mmHg/ 60mmHg, respiratory rate 18 breaths per minute, and peripheral oxygen saturation of 98% on room air. Immediately after UEA receipt, the patient became diaphoretic and unresponsive. Vital signs were heart rate 66 beats per minute, blood pressure 65mmHg/ 45mmHg, and peripheral oxygen saturation of 95% on room air. Confluent, erythematous, edematous, blanching plaques were noted across his chest and he developed peri-orbital swelling. An ECG was obtained and showed new ST-segment elevations in leads II, III, and aVL (Figure 2A and 2B).

Figure 2:

Electrocardiogram prior to and after administration of a sulfur hexafluoride lipid-type A microsphere ultrasound enhancing agent (LUMASON^™).

(A) Pre-contrast administration

(B) Post-contrast administration

(A) ECG prior to administration of LUMASON^™ shows anterolateral T-wave changes consistent with recent anterolateral infarct. (B) ECG immediately after LUMASON^™ injection shows new inferior ST elevations with reciprocal depressions in the precordial leads.

Peripheral norepinephrine was initiated for hypotension. He had no evidence of airway compromise so intravenous fluids were administered but further treatment for allergic reaction deferred in favor of prompt transfer to the catheterization laboratory. Coronary angiography through right radial access revealed a patent left anterior descending artery stent, normal left circumflex artery and obtuse marginal branches, and diffuse spasm of the right coronary artery when compared to his recent angiogram (Figure 3, Video 3). Right heart catheterization revealed a mean right atrial pressure of 1 mmHg, pulmonary artery pressure of 24mmHg / 8mmHg with a mean of 14 mmHg, and a mean pulmonary capillary wedge pressure of 7 mmHg. His systemic venous oxygen saturation was 70%. By Fick calculation, cardiac output was 5.25 liters per minute and cardiac index was 2.73 liters per minute per meter squared.

Figure 3:

Coronary angiography of the right coronary artery before and after ultrasound enhancing agent injection

Coronary angiography during the patient’s recent STEMI (A) demonstrated mild disease in the right coronary artery. Repeat coronary angiography immediately following LUMASON^™ administration (B) demonstrates diffuse epicardial spasm of the right coronary artery.

Given evidence of distributive shock, intra-arterial nitroglycerin was not administered and his vasospasm improved. Further intravenous fluids were administered and vasopressors were weaned. His periorbital swelling and rash resolved 30 minutes after his initial reaction. A repeat ECG showed resolution of ST segment changes (Figure S1). He tolerated further optimization of guideline-directed medical therapy for his ischemic cardiomyopathy and LUMASON^™ was added to his allergy list.

This patient’s coronary vasospasm in the setting of an allergic reaction is most consistent with Kounis Syndrome (KS). Given the prior exposure to UEA and absence of any other medication administration immediately prior to his reaction, the most likely trigger was UEA receipt. KS is the occurrence of an acute coronary syndrome in the setting of an allergic reaction.¹ Three variants have been identified: type I (coronary vasospasm in the absence of underlying coronary artery disease (CAD)), type II (coronary vasospasm or plaque rupture with known underlying CAD), and type III (stent thrombosis or re-stenosis).¹ This case highlights challenges in distinguishing between type I and type II KS; the patient had mild CAD in his right coronary artery, but had spasm diffusely, even in areas without angiographically apparent disease. A recent review of reported cases of KS² found that type I was the most common type, accounting for 72.6% of cases, followed by type II (22.3%) and then type III (5.1%).

KS is thought to be caused by release of inflammatory mediators in the setting of a Type I hypersensitivity reaction.^1,2 In the case of type I KS, these inflammatory mediators cause spasm of one or more coronary arteries. In the case of type II KS, proteases released during the allergic reaction activate metalloproteinases found in quiescent atheromatous plaques, leading to vasospasm or acute rupture. Finally, type III KS is thought to be due to activation of existing inflammatory cells within previously placed coronary stents, leading to platelet activation and subsequent stent thrombosis. Aspirated clots demonstrate eosinophils and/or mast cells.¹

Typically, type I hypersensitivity reactions are managed with intramuscular epinephrine, intravenous corticosteroids, and anti-histamines. However, epinephrine can worsen coronary vasospasm and increase myocardial demand, worsening ischemia. Therefore, epinephrine is relatively contraindicated in KS. Instead, treatment generally involves fluid resuscitation and intravenous corticosteroids. Given that over 25% of KS cases are thought to be type II or type III, emergency coronary angiography is indicated to evaluate need for percutaneous coronary intervention.²

Overall, UEAs are guideline indicated³ and among the safest of contrast media, with rare adverse events attributed to complement-activation related pseudoallergy (CARPA). CARPA reactions do not involve allergen-specific IgE and therefore do not require prior exposure to the allergen. However, non-CARPA reactions such as KS are rare. Recent reports from individual centers have suggested a recent increase in non-CARPA reactions to UEAs with clinical syndromes of loss of consciousness, loss of pulse, or ST-segment elevation.⁴ While these reports require further confirmation, our case suggests that KS may mechanistically explain a portion of these severe reactions.

In allergic reactions, a high index of suspicion should be maintained for KS if the patient reports chest pain or new ST segment changes are noted on ECG. In this setting, epinephrine is contraindicated as it can worsen coronary vasospasm and infarction. With increasing use of UEAs, KS is likely to be encountered more frequently and thus awareness of this rare entity is critically needed.

Abbreviations:

STEMI

ST elevation myocardial infarction

LVEF

Left ventricular ejection fraction

TTE

Transthoracic echocardiogram

UEA

Ultrasound enhancing agent

ECG

Electrocardiogram

CAD

Coronary artery disease

KS

Kounis Syndrome