Mohave Rattlesnake Envenomation Causing Allergic Myocardial Infarction (Kounis Syndrome) and Neurotoxic Respiratory Failure

Abstract

Mohave rattlesnakes (Crotalus scutulatus) are known to inhabit the deserts of southwestern United States, with their territory extending into southern Mexico. Envenomation can impart dramatic local and systemic effects on the body, ranging from local skin necrosis to neurotoxicity, depending on the protein complex in the venom. Kounis syndrome, or allergic angina, is an allergic response to a specific insult that results in myocardial injury often in the form of coronary artery vasospasm but can include myocardial infarction and coronary stent thrombosis. To our knowledge, there have not been any reports associating C scutulatus envenomation with Kounis syndrome. We describe a patient who developed Kounis syndrome presenting as an allergic myocardial infarction following envenomation by a Mohave rattlesnake. A second unique feature of this patient's envenomation is that he experienced respiratory failure secondary to right hemidiaphragmatic paralysis. Severe neurotoxicity from Mohave rattlesnake bites in humans has been reported rarely in the literature.

Introduction

The Mohave rattlesnake (Crotalus scutulatus) has a geographic distribution encompassing a large area of southwestern United States, from the Mojave Desert in California through western and southern Arizona and deep into Mexico. The venom from C scutulatis can be broadly classified under the categories of a neurotoxin that is typified by Type A toxin and a cytotoxic or hemorrhagic Type B toxin. ¹ Since the isolation of Mohave toxin in 1975 ² and small-animal studies demonstrating it to be a particularly deadly neurotoxin, ³ medical and public education literature has warned about the risks of death from neurotoxic respiratory failure after Mohave rattlesnake envenomation. However, contemporary studies do not support these warnings for human envenomations, ⁴ and indeed, we were able to find only 1 other case report describing severe neurotoxicity resulting in respiratory failure. ⁵ Although human fatalities in the United States are rare, all envenomation patients should receive urgent medical evaluation and treatment. In 2023, 68.9% of rattlesnake envenomations in Arizona, the state with the most rattlesnake envenomations annually, required critical care admission. ⁶

We present an unusual case of a healthy young patient who was envenomated by a Mohave rattlesnake in rural Arizona and presented with a severe allergic reaction causing an acute myocardial infarction (also known as Kounis syndrome) and delayed neurotoxicity resulting in respiratory failure. We describe the presentation and treatment course of this unique and challenging case.

Case Report

A healthy 39-y-old male was bitten by a rattlesnake on the left posterior calf while doing chores on his rural subsistence farm in west central Arizona. He identified the snake as a Mohave green rattlesnake (C scutulatus) based on his familiarity with the species and described the snake as at least 3 ft long and thick in diameter with a distinctly green color to its skin. Because of the remote location, it took 1 h for emergency services to arrive via air ambulance. On initial evaluation, the patient was diaphoretic, had a pulse of 122 beats/min, and complained of feeling lightheaded. There was a single fang mark posteriorly, adjacent to the Achilles tendon. The surrounding tissue was tender with mild localized swelling and erythema but without necrosis or signs of hemorrhage. During transport, about 2 h after the initial envenomation, the patient experienced sudden onset of chest pain. Electrocardiogram (ECG) demonstrated marked ST elevation concerning for an ST-elevation myocardial infarction. At the same time, the patient’s blood pressure dropped from 160/99 mm Hg down to 70/50 mm Hg. During transport, emergency treatment included a 500-mL intravenous normal saline bolus, norepinephrine infusion at 2 micrograms·kg^–1·min^–1, and 324 mg aspirin. Blood pressure responded well and was maintained above 90/50 mm Hg for the duration of the flight.

The patient was airlifted to a tertiary care center with expertise in the management of snake envenomations and arrived in the emergency department ∼3 h after his initial injury. On arrival, his symptoms included retrosternal chest pain, dyspnea, vomiting, and diarrhea. He also complained of throat closing, concerning for a severe allergic reaction. Emergency department blood pressure was 115/62 mm Hg. He was tachycardic with a heartrate of 116 beats/min; respiratory rate was 30 breaths/min; and oxygen saturation was 90% on 2 L of oxygen via nasal cannula. ECG in the emergency room confirmed marked ST elevation in the inferior leads with ST depression in the anterior leads consistent with an ST-elevation myocardial infarction (Figure 1). High-sensitivity troponin T concentration was significantly elevated at 1308 ng·L^–1 (normal, <19 ng·L^–1). Chest x-ray demonstrated no acute cardiopulmonary changes. The remaining laboratory data in the emergency room included a hemoglobin concentration of 18.3 g·dL^–1, a white blood cell count of 24.1×10⁹/L, a platelet count of 429×10⁹/L, a neutrophil count of 16.6×10⁹/L (69%), a blood urea nitrogen concentration of 30 mg·dL^–1, a creatinine concentration of 2.2 mg·dL^–1, an aspartate aminotransferase level of 1116 U·L^–1, an alanine aminotransferase level of 275 U·L^–1, a lactic acid level of 3.3 mmol·L^–1, and creatine kinase level of 33,960 U·L^–1.

Figure 1.

Electrocardiogram (ECG) at presentation, suggestive of inferiolateral ST-elevation myocardial infarction (STEMI) depicted by arrows. Also note the presence of reciprocal ST-segment depressions.

Treatment in the emergency department included norepinephrine infusion started at 5 micrograms·kg^–1·min^–1 titrated to keep systolic blood pressure >90 mm Hg, Ringer's lactate at 150 mL·h^–1 (3 L given in total), 50 mg of diphenhydramine, and 125 mg of methylprednisolone for treatment of the allergic reaction and rhabdomyolysis. Additionally, 10,000 U of unfractionated heparin was administered for treatment of ST-elevation myocardial infarction.

Within 32 min of arriving in the emergency room, the patient was in the cardiac catheterization suite. Left heart catheterization revealed the right coronary artery with no contrast material flow due to intense coronary vasospasm. Intracoronary nitroglycerine was given to relieve the vasospasm with resulting opening of the artery and good blood flow down the right coronary artery. Intravascular ultrasound revealed a minimal lumen area of 6.6 mm² (normal range, 16.2 mm² for males). The remainder of the study showed nonobstructive left anterior descending artery disease (Figure 2a and b). A medical toxicologist accompanied the patient to the catheterization suite, where antivenom was initiated ∼3½ h after envenomation. Initially, 10 vials of crotalidae immune F(ab)2 (equine) antivenom were administered as well as another 50 mg of diphenhydramine and 125 mg of methylprednisolone intravenously. After this combination of medications, hypotension, chest pain, vomiting, and diarrhea resolved. Vital signs recorded 1 h after initiation of antivemon included a blood pressure of 120/80 mm Hg, a heart rate 80 beats/min, and an O₂ saturation of 100% on 2 L of oxygen. At this point, the norepinephrine was discontinued. A 2-dimensional echocardiogram revealed a preserved left ventricular ejection fraction with severe biventricular apical hypokinesis (Figure 3a to c). The ST-elevation myocardial infarction was attributed to Kounis syndrome, or “allergic myocardial infarction” as a reaction to Mohave rattlesnake envenomation.

Figure 2.

a, Coronary artery angiogram (CTA) showing severe proximal right coronary artery (RCA) spasm (white arrow). b, CTA showing nonocclusive middle left anterior descending (LAD) stenosis.

Figure 3.

a, Transthoracic echocardiogram demonstrating left ventricular apical hypokinesis with contrast material (arrow). b, Echocardiogram demonstrating left ventricular apical hypokinesis with contrast material (arrow). c, Echocardiogram demonstrating right ventricular hypokinesis (arrow).

The following day, ∼30 h after envenomation, the patient became restless and complained of progressive shortness of breath. A repeat ECG was unremarkable. Serum biomarkers were unchanged, and a repeat echocardiogram demonstrated normal systolic function with no new wall motion abnormalities and some improvement in the prior inferior wall motion. Vital signs showed a heart rate of 99 beats/min, blood pressure of 150/70 mm Hg, respiration rate of 26 breaths/min, and O₂ saturation of 90% on 3 L of oxygen via nasal canula. The lungs were clear to auscultation with reduced breath sounds in the lower third of the right lung base. Progressive dyspnea and hypoxia ensued rapidly requiring high-flow nasal oxygen to keep the O₂ saturation at 90%. Intravenous steroid and diphenhyramine were administered, but the patient’s symptoms continued to progress. He denied chest pain but was extremely agitated and restless and insisted on standing at the bedside complaining that he could not breath while lying in bed. Repeat chest x-ray demonstrated no pulmonary edema but now showed elevation of the right hemidiaphragm (Figure 4a).

Figure 4.

a, Chest x-ray showing right hemidiaphragm elevation. b, Repeat chest x-ray showing resolution of diaphragm elevation.

Over the next several hours, the patient continued to complain of dyspnea with a respiratory rate of 28 to 33 breaths/min, and O₂ saturation dropped to 89% on 30 L of oxygen via high-flow nasal cannula at 70% FiO₂. The patient was then switched to bilevel positive airway pressure with improvement of symptoms and oxygenation. The clinical conclusion was that the Mohave toxin caused neurotoxicity of the phrenic nerve resulting in diaphragmatic muscle paralysis. Six additional vials of antivenom were administered, as recommended by toxicology. Over the next 12-h period, respiratory symptoms improved. Bilevel positive airway pressure was discontinued, oxygen was deescalated slowly, and the patient was more restful. Approximately 2 d after onset of dyspnea, supplementary oxygen was discontinued. A subsequent chest x-ray (Figure 4b) showed resolution of the elevated right hemidiaphragm. Clinical exam revealed improved breath sounds in the right basal segments. Vital signs had returned to baseline with a blood pressure of 134/75 mm Hg, heart rate of 86 beats/min, respiratory rate of 16 breaths/min, and O₂ saturation of 93% on room air.

In all, the patient spent 4 d in the ICU and was discharged on Day 10. At discharge, he was asymptomatic, and all laboratory tests and the ECG had returned to normal.

Discussion

One of the most distinctive features of the Mohave rattlesnake is that it is known to produce 2 different venom types in different populations of snakes that are morphologically indistinguishable but are separated geographically. ¹ Type A venom contains Mohave toxin, a phospholipase toxin complex with neurotoxic activity. Type B venom contains proteolytic peptides that cause cell and tissue injury but lack Mohave toxin. Snakes possessing the Mohave toxin, specifically type A Mohave rattlesnakes, show lower rates of local myonecrosis or tissue necrosis effects but have the potential for neurotoxicity, ⁷ which manifested as right hemidiaphragmatic paralysis in our case. Patients with Type B Mohave rattlesnake envenomation are more likely to exhibit hemorrhagic and local tissue necrosis, which we did not see in our patient. There is a third, small population in an area of intergradation that exhibits a combination of venom Type A plus Type B.^1,8 The geographic area where our patient was bitten is known to be inhibited by snakes producing Type A venom.

Mohave rattlesnake envenomation causing a severe allergic reaction with acute ST-elevation myocardial infarction (Kounis syndrome) is extremely rare and has not been described previously, to our knowledge. Kounis syndrome was first described by Nicholas Kounis in 1991 and is defined as an allergic response of the coronary arteries causing vasospasm secondary to a hypersensitivity reaction. ⁹ The syndrome occurs as a result of massive mast cell activation. ¹⁰ During a hypersensitivity reaction, numerous different inflammatory pathways are activated that can significantly impact the cardiovascular system. Degranulation of mast cells activates histamine, which has been shown to induce coronary artery vasoconstriction. This inflammatory pathway also can activate platelets and matrix metalloproteinases, causing degradation of the collagen cap and plaque rupture. ¹¹ Inciting agents for Kounis syndrome include various medications, ¹² contrast dye, ¹³ poison ivy, bee stings, and shellfish. ⁹ Mohave rattlesnake (C scutulatis) venom now can be added to the list of offending agents.

Three variants of Kounis syndrome have been described in the literature. The Type I variant (allergic angina) induces coronary artery vasospasm in normal or near-normal arteries without elevation in cardiac enzymes or progression to acute myocardial infarction. Type II variant (allergic myocardial infarction) occurs in patients with preexisting (subclinical, as in this patient) coronary plaque. With this variant, coronary artery spasm can occur with or without elevation in troponins and cardiac enzymes and can be associated with plaque erosion or rupture resulting in an acute myocardial infarction. The Type III variant (stent thrombosis with occluding thrombus) involves thrombosis in a preexisting coronary artery stent. In treating Kounis syndrome, both the allergic reaction and cardiac symptoms must be addressed concurrently. ⁹ The presentation of shock caused by a severe allergic reaction required prompt identification and treatment with high-dose intravenous steroids, norepinephrine, diphenhydramine, and inotropic agents. Coronary artery spasm was managed with intracoronary nitroglycerine, and after the patient's blood pressure stabilized, guideline-directed medical therapy was initiated with diltiazem, a rate-lowering calcium-channel blocker. Beta blockers were avoided because they can risk blunting the sympathetic response and worsen an anaphylactic reaction. ¹⁴ Treating chest pain with opioids in Kounis syndrome should be avoided as well because they can worsen an allergic reaction by inducing further mast cell degranulation. ¹⁵

The second unusual feature of this case is neurotoxicity presenting as hemidiaphragm paralysis. Historically, Mohave rattlesnake toxin was thought to present a significant risk for respiratory failure. However, a large retrospective review of 3440 suspected rattlesnake envenomations in Arizona occurring between 1990 and 2020 revealed no cases of neurotoxic respiratory weakness, leading the authors to conclude that it was indeed extraordinarily rare in this region. ⁴ A further literature search revealed only 1 other case report of respiratory failure, published in 1992, describing an 11-y-old female who suffered neurotoxicity and respiratory failure after a Mohave rattlesnake bite. ⁵ The onset of neurologic symptoms was reported to occur at ∼12 h after envenomation. Initially, the patient complained of paresthesias that progressed to facial nerve weakness, bilateral ptosis, difficulty swallowing and clearing secretions, and dyspnea. Approximately 30 h after envenomation, the patient required intubation. The timing of respiratory failure was very similar to our case. The patient also responded to supportive care and additional antivenom.

Limitations

Limitations of this case report include that there is no definitive identification of the species of rattlesnake. Although the patient was confident in his ability to identify the rattlesnake as a Mohave green, the ability of nonexperts to identify snakes has been shown to be imperfect at best. ¹⁶ The other limitation is that we were not able to obtain a diaphragmatic muscle biopsy or indirect testing to prove neurotoxicity and diaphragmatic paralysis. In this case, there was evidence of a newly elevated hemidiaphragm on chest x-ray along with the clinical course as described, which is consistent with transient diaphragmatic paralysis. In this case, the most likely cause was rattlesnake envenomation, presumptively Mohave toxin Type A.

Conclusion

We report a case of myocardial infarction due to an allergic reaction also known as Kounis syndrome secondary to a rattlesnake envenomation. Furthermore, this patient also experienced presumptive neurotoxicity from Type A venom, manifesting as dyspnea, tachypnea, oxygen desaturation, and the need for respiratory support. Based on our experience and the previous report, ⁵ patients may benefit from careful monitoring of respiratory status in the first 48 h after a suspected Type A toxin envenomation. Both of these reactions are atypical in human rattlesnake envenomations and were life threatening without expedited medical intervention.