Précis
We present a case of rarely reported paradoxical hypotension after accidental epinephrine overdose for suspected anaphylaxis to raise awareness of the potentially fatal cardiovascular complications of epinephrine toxicity.
Abstract
Epinephrine, the standard treatment for anaphylaxis, is a lifesaving medication that can cause detrimental complications due to wrong-dose or wrong-route errors. Although the known toxicities of epinephrine such as tachycardia, hypertension, and cardiomyopathy are well documented, epinephrine’s paradoxical and prolonged hypotensive effects following overdose are rarely reported. In this case, a 50-year-old man presented to the emergency department with concerns about and symptoms of an allergic reaction. Parenteral epinephrine, antihistamine, and corticosteroid were ordered to manage the suspected anaphylaxis. The patient was inadvertently administered an intravenous push of concentrated epinephrine 1 mg (1 mg/mL) instead of the intended 0.3-mg intramuscular injection, which resulted in clinical manifestations including abnormal electrocardiogram results, elevated cardiac enzymes, and prolonged hypotension that required multiple fluid boluses and continuous infusion to stabilize his blood pressure. Fortunately, the patient responded well to fluid therapy and did not require vasopressors or invasive interventions. Our intention with this case is to add to the limited existing literature on hypotensive effects of epinephrine overdose and increase awareness of the potentially fatal cardiovascular complications. Moreover, we recommend implementing institutional precautionary measures such as stocking epinephrine allergy kits or prefilled epinephrine auto-injectors to help prevent administration errors and ensure patient safety during allergy treatment.
Introduction
Epinephrine is the first-line therapy for anaphylaxis. It works by causing vasoconstriction, increased cardiac output, and bronchodilation via activation of the adrenergic receptors (α1, β1, and β2) to counteract anaphylactic reactions such as hypotensive shock, throat swelling, or difficulty breathing.1 The recommended adult dose for the indication is 0.3 to 0.5 mg via intramuscular (IM) injection, which may be repeated every 5 to 10 minutes if necessary.2 Because limited data are available on epinephrine overdose associated with anaphylaxis management and resultant cardiovascular adverse events, Campbell et al compared rates of epinephrine overdose and cardiovascular complications between routes of epinephrine administration among patients with anaphylaxis in the emergency department (ED) and found numerous instances of iatrogenic overdose of epinephrine—all occurring with intravenous (IV) bolus administration—that resulted in cardiovascular toxicities, including tachycardia, hypertension, and myocardial ischemia.3
To add to the literature on the rarely reported hypotensive effects of epinephrine overdose, we present a case in which a patient with suspected anaphylaxis was accidentally given 1 mg of concentrated epinephrine (1 mg/mL) via IV push instead of the intended 0.3-mg IM injection, resulting in unexpected hypotension, elevated troponins, and abnormal electrocardiogram (ECG) results.
Case Report
A 50-year-old man presented to the ED with concerns about an allergic reaction—reporting an itchy rash and swelling of the arms and legs—that began 10 hours prior and progressively worsened. He also reported episodes of dull, nonradiating chest pain that had resolved before arriving at the hospital and said he was not having difficulty breathing. He reported no recent exposure to new products, such as soaps or detergents, and no changes in dietary intake. The patient had no significant medical history and no known allergies and had not taken any medications before arrival. His initial vital signs at triage were unremarkable: blood pressure (BP), 130/78 mm Hg; heart rate, 78 beats per minute (bpm); respiratory rate, 20 breaths per minute; and oxygen saturation as measured by pulse oximetry (Spo2), 96%. A comprehensive metabolic panel, serial serum cardiac troponin I tests, and an ECG were ordered in triage and came back normal during the patient’s 7-hour stay in the waiting area. This prolonged wait time was due to a high volume of patients in the ED and several hours of electronic health record (EHR) downtime.
The EHR was back online by the time the patient was roomed. The emergency medicine (EM) nurse then reassessed his vital signs, which were BP, 108/51 mm Hg; heart rate, 73 bpm; respiratory rate, 18 breaths/min; Spo2, 97%; and temperature, 98.1 °F. Next, the EM physician—who suspected acute allergic reactions triggered by an unidentified cause—evaluated the patient; entered orders into the EHR for commonly used treatments for anaphylaxis, including IM epinephrine (0.3 mg), IV dexamethasone (10 mg), and IV diphenhydramine (50 mg); and verbally communicated the orders to the nurse. Because at that time a technical interface issue was causing medication orders to not cross over from the EHR to the automated dispensing cabinet (ADC), all medications were removed from the ADC using the override function, including the epinephrine 1 mg (1 mg/mL) ampule. Medication barcode scanning was done for dexamethasone in the medication administration record (MAR) but not for diphenhydramine or epinephrine. The nurse proceeded to administer all medications based on verbal orders, with no other personnel present in the room.
Shortly after, the patient reported experiencing sudden, sharp, intensifying chest pain that was distinct from the symptoms he had prior to hospital arrival. The nurse immediately recognized the error: All medications had been administered via IV push, including epinephrine 1 mg when 0.3-mg IM was intended. The patient’s BP dropped to 69/41 mm Hg with a mean arterial pressure of 50 mm Hg; his heart rate, respiratory rate, temperature, and Spo2 remained within the normal range. The error was reported to the EM physician and administrators. It was later discovered that epinephrine and diphenhydramine had been mistakenly entered as outpatient-clinic orders instead of inpatient orders, which explained why those medications were not displayed in the MAR for the nurse to confirm the ordered dose and route and to scan the medications.
The patient said he was not having difficulty breathing, throat swelling, dizziness, or any other symptoms besides chest pain. He received boluses of normal saline in response to the acutely developed hypotension (see Table for vital signs, troponin trend, and normal saline fluid treatments during the patient’s hospital stay). Due to suspected cardiovascular toxicity following an epinephrine overdose, the EM physician initiated a comprehensive diagnostic workup, including D-dimer assessment, chest x-ray, computed tomography angiogram (CTA) of the chest, repeat troponin I testing, ECG, and echocardiogram. The chest x-ray showed no abnormalities. A blood test taken 45 minutes after the anaphylaxis treatments revealed an elevated D-dimer level of 2.870 μg/mL, with no baseline for comparison (reference range, < 0.50 μg/mL).4
A subsequent CTA of the chest performed 3 hours later ruled out pulmonary embolism and coronary calcifications. A repeat ECG 4 hours after the medication error showed mild diffuse ST-segment elevation and elevated levels of troponin I (Table). However, a bedside echocardiogram conducted by the cardiologist 5 hours post medication error demonstrated normal ejection fraction and preserved wall motion. An emergent angiocardiography was ordered after the abnormal ECG but canceled after the normal echocardiogram results. The patient’s chest pain resolved after a few hours, and the hives, rashes, and swelling resolved after anaphylaxis treatments. However, the patient was admitted to the cardiac intensive care unit due to the epinephrine overdose and the resultant, persistent hypotension and demand ischemia (ie, when myocardial oxygen demand is greater than myocardial oxygen supply5). Repeat testing of troponin I showed levels peaking at 247.89 ng/L (Table). Because the patient was administered normal saline boluses and given continuous infusion (approximately 5-6 liters over 24 hours), his systolic BP gradually improved to readings in the 80s to 90s mm Hg (Table).
The patient was deemed stable and discharged the next day after normalization of ECG findings, a decline in troponin I levels, and a negative nuclear stress test. He remained asymptomatic at the outpatient cardiology follow-up appointment 3 weeks later.
Discussion
Therapeutic dose and route of epinephrine vary depending on the indication. For example, IM administration of 0.3 to 0.5 mg for adults (0.01 mg/kg to 0.5 mg for pediatric patients) is considered safe and effective for treating anaphylaxis, and a 1-mg (1 mg/10 mL) IV push is recommended during cardiac arrest.6 In refractory anaphylaxis, a slow IV push (over 5 minutes) of 0.05 to 0.1 mg (using the 1 mg/10 mL solution further diluted in 10-mL normal saline) may be employed with stringent monitoring until an epinephrine IV infusion (0.01-0.2 mcg/kg/min) is available.6
Epinephrine exerts its effects by stimulating adrenergic receptors, leading to increases in BP and heart rate.1 Thus, the most expected responses from epinephrine overdose are the exaggerated pharmacological effects of epinephrine, such as hypertension and tachycardia. In this case, the patient received 1 mg of epinephrine (1 mg/mL) via IV bolus push, exceeding the dose for refractory anaphylaxis by 10 to 20 times.6 Subsequently, the patient developed chest pain and hypotension, which we suspect were caused by the epinephrine overdose.
Epinephrine at low doses has a greater affinity for β receptors, whereas epinephrine at higher doses activates α receptors.7 Activated β receptors cause increased heart rate, myocardial contractility, and dilation of coronary arteries.7 Stimulated α receptors lead to increased vasoconstriction of cardiac and vascular smooth muscles.7 Yasue et al suggested that severe coronary artery spasms followed by Prinzmetal angina were mediated by activation of α receptors.8 In a case report where a patient developed acute chest pain and an ECG showed widespread ischemia after they accidentally received 2 mg of IV epinephrine instead of naloxone, the author hypothesized that the α effect induced by epinephrine overdose resulted in vasoconstriction of coronary arteries, causing vasospasm and decreased coronary artery perfusion.9 The acute chest pain and ECG change consistent with myocardial ischemia as seen in our patient after epinephrine overdose could be explained by these theories.
Cusumano et al discussed cases of epinephrine-induced hypotension and addressed the risks associated with large-dose, push-dose pressors.10 There is a theory that epinephrine overdose causes a biphasic pattern of BP, where BP significantly declines soon after the expected hypertensive response; it is postulated that α receptors are initially stimulated, causing an increase in BP, and then the more sensitive β receptors continue to respond, resulting in peripheral vasodilation and hypotension.10,11 Krishnamoorthy et al found that in healthy, anesthetized rats, a single IV bolus dose of epinephrine 100 mcg/kg—comparable to 17 mcg/kg in humans (a typical dose used for cardiac arrest)—resulted in a significant systolic BP drop 10 minutes after administration.11 However, it is unclear whether our patient experienced brief hypertension or tachycardia before the development of hypotension because the first recorded vital signs were approximately 20 minutes after the IV bolus push of epinephrine. Although the underlying mechanism is not fully understood, we speculate that our patient’s prolonged hypotension could be the result of myocardial ischemia followed by coronary spasm and peripheral vasodilation from continuously stimulated β receptors after epinephrine overdose. The sequence of activation of various subtypes of adrenergic receptors and the subsequent physiological events in epinephrine overdose merit further study.
In this patient’s case, it is difficult to determine whether the therapeutic dose of IV diphenhydramine that was coadministered with epinephrine further potentiated the hypotension. Although a few case reports document antihistamine-induced hypotension, they do not describe ECG changes or cardiac ischemia like those observed in our patient.2,12
Based on the temporal relationship between the administration of anaphylaxis treatments and the onset of hypotension in this patient, it is probable that the epinephrine overdose caused hypotension and cardiotoxicity.13 It is unlikely that the patient’s acutely developed hypotension was the progression of mild to moderate allergic reaction to severe anaphylactic shock because the patient was hemodynamically stable before treatments.
Rapidly administering the first-line therapy of IM epinephrine is vital for effective anaphylaxis management. It is not recommended to delay epinephrine until breathing difficulty worsens or shock occurs.2 Clinicians should be aware that antihistamines and corticosteroids are not first-line therapies because they do not adequately address severe symptoms associated with anaphylaxis.2 These medications are used for mild allergic reactions or as adjuncts to epinephrine for supportive symptom relief, so these therapies should be considered after reassessing the effects of IM epinephrine and should not be ordered emergently or simultaneously with epinephrine.2 This approach also reduces nurses’ cognitive burden (ie, managing multiple parenteral routes) and decreases the risk of potential administration errors.14
In our patient’s case, however, epinephrine should have been deemed unnecessary because the patient did not exhibit anaphylactic symptoms during his long wait times in the ED. The patient’s cutaneous allergic symptoms could have been effectively managed by corticosteroids and antihistamines. Clinicians must be mindful that epinephrine—a lifesaving yet high-risk medication—can cause severe, unintended harm when used incorrectly.3 Moreover, toxic doses and clinical toxic effects of epinephrine can vary significantly from case to case, and there are no standardized guidelines for treating epinephrine overdose. For instance, a 51-year-old man died after receiving a 3-mg dose of epinephrine (presumed via IM route) for an allergic reaction.15 Conversely, another case involved the accidental IV administration of an extremely high (5-mg) dose of epinephrine, intended for nebulization, which did not result in cardiac arrest or death but did require intensive monitoring and treatment.16
About the Authors
Kwang Yoon, PharmD, BCPS, BCEMP, is the emergency medicine clinical pharmacist at Endeavor Health Swedish Hospital in Chicago, Illinois.
Stephanie Mojumdar, PharmD, is a clinical staff pharmacist at Pali Momi Medical Center in Aiea, Hawaii. At the time of writing, she was a PGY-1 pharmacy resident at Endeavor Health Swedish Hospital in Chicago.
Rodney Fullmer, DO, MBS, FACEP, FACOEP, is the emergency medicine residency associate program director at Endeavor Health Swedish Hospital in Chicago.
Kimberly McCarthy, MS, BSN, RN, is a director of nursing at Endeavor Health Swedish Hospital in Chicago.
Many institutions have comprehensive safety medication systems, such as computerized provider order entry, ADC, and barcode medication administration. However, human errors or technology issues are ineliminable. Continued systemic institutional efforts should be made to prevent errors in epinephrine administration. These efforts include promoting error reporting to facilitate learning from mistakes, providing regular education on the various indications and dosages of epinephrine, and addressing potential risks associated with its incorrect use. Additionally, the use of institutionally prepacked epinephrine allergy kits, commercially prepacked epinephrine convenience kits, or prefilled epinephrine auto-injectors can reduce the risk of inadvertent epinephrine overdose and prevent costs associated with medication error.17,18 After this patient, Endeavor Health Swedish Hospital implemented a modification in which concentrated epinephrine ampules were replaced with pharmacy-prepared epinephrine allergy kits in ADCs in both ED and inpatient units. Each kit contains an epinephrine ampule, a filter needle, IM needles, and a slip-tip 1-mL syringe with clear dosing and route instructions (Figure). Since this change was implemented approximately 2 years ago, no errors related to IV push of concentrated epinephrine or incorrect dosing in allergy treatments have been reported.
Conclusion
Epinephrine overdose can trigger various and potentially fatal cardiovascular reactions, yet there is no standardized approach to managing epinephrine toxicity. We aim for this case to raise awareness of the paradoxical hypotensive effects of inadvertent IV epinephrine administration and add to the limited existing literature. Although in this patient the hypotension was resolved with only fluid resuscitation and effective management of transient cardiotoxicity, clinicians need to be aware of the potentially life-threatening consequences of epinephrine when erroneously administered. Implementing institutional precautionary measures is an essential step in mitigating errors involving this high-alert medication and improving patient safety.
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Disclosures
The authors have no conflicts of interest to disclose.
No data were used to support this study.
The authors received no financial support for the research, authorship, and/or publication of this article.
