Myocardial stunning secondary to erroneous administration of intravenous epinephrine

Abstract

Epinephrine is a commonly used medication for emergent conditions, such as anaphylaxis, respiratory distress, and shock. However, its versatility can also lead to iatrogenic errors in dosages, concentrations, and routes of administration. In this case, a 47-year-old female experiencing anaphylaxis received an intravenous dose of 0.3 mg (1:1000) epinephrine formulated for intramuscular injection, resulting in cardiac arrest and acute heart failure due to myocardial stunning, as diagnosed by echocardiography. Management included invasive ventilation and hemodynamic support until cardiac function recovered. This case highlights the potential dangers of epinephrine overdose, and to our knowledge, is the first reported case of iatrogenic epinephrine-induced Takotsubo cardiomyopathy in a rural area. In addition, we review the literature on iatrogenic epinephrine toxicity-associated cardiomyopathy and the epidemiology of epinephrine errors. Safety measures must be considered for improving communication in emergencies, increasing awareness via training, and changing epinephrine’s antiquated packaging design.

Keywords

Takotsubo catecholamine-induced cardiomyopathy epinephrine overdose iatrogenic epinephrine anaphylaxis

Introduction

Epinephrine is the first-line treatment for anaphylaxis, but its various dosages and administration methods can lead to errors with consequent adverse cardiovascular reactions.^1–3 For example, emergency medical carts contain injectable epinephrine for intramuscular (IM) injection (1:1000) and intravenous (IV) administration (1:10,000) for anaphylaxis and cardiac arrest, respectively. We present a case of erroneous epinephrine administration leading to cardiac arrest and acute heart failure due to myocardial stunning, which is the first reported case of iatrogenic epinephrine-induced Takotsubo syndrome (TTS) in a rural area. Rural areas may be at higher risk for epinephrine administration errors during anaphylaxis due to communication challenges, inadequate training, and limited resources. Thus, we also review the literature and the epidemiology on iatrogenic epinephrine toxicity-associated cardiomyopathy in the setting of anaphylaxis.

Case report

A 47-year-old female without prior cardiovascular disease history was struck in the chest by her special-needs student (case timeline in Figure 1). She presented to a local emergency department, where she underwent full-body cross-sectional imaging. Following administration of iodinated contrast, she experienced shortness of breath, raising concern for anaphylaxis. She was erroneously given an IV dose of 0.3 mg (1:1000) epinephrine intended for IM use. Subsequently, she went into cardiac arrest due to ventricular arrhythmia and required 12 min of cardiopulmonary resuscitation with defibrillation until return of spontaneous circulation.

Figure 1.

Case timeline.

She was transferred to the nearest tertiary care hospital on amiodarone, norepinephrine, and vasopressin infusions. Diagnostic tests revealed elevated troponin-T (0.34 ng/mL (normal < 0.01 ng/mL)) and serum lactate (3.0 mmol/L (normal < 2.2 mmol/L)). The electrocardiogram showed normal sinus rhythm with a prolonged QTc interval of 578 ms in the setting of hypokalemia, hypomagnesemia, and hypocalcemia (Table 1). A transthoracic echocardiogram revealed severely reduced left ventricular ejection fraction (LVEF) of 10% with left ventricular (LV) basal-mid wall motion abnormality and apical sparing (Figure 2).

Table 1.

Initial labs.

Initial labs	Values	Reference values
Na	140	136–144 (mEq/L)
K	2.9	3.5–5.1 (mEq/L)
Cl	109	98–107 (mEq/L)
HCO3	21	23–29 (mEq/L)
BUN	11	6–20 (mg/dL)
Cr	0.57	0.6–1.1 (mg/dL)
Mg	0.61	0.75–1.1 (mmol/L)
Ca	6.6	8.6–10.2 (mg/dL)
WBC	11.6	3.8 to 10.4 (×10³/μL)
Hgb	10.3	11.9 to 14.8 (g/dL)
Hct	31.6	35% to 43 (%)
Plt	235	153 to 361 (×10³/μL)
Lactate	3.0	< 2.0 (mmol/L)

BUN: blood urea nitrogen; WBC: white blood cells; Hgb: hemoglobin; Hct: hematocrit; Plt: platelets.

At the time of arrival to Dartmouth–Hitchcock Medical Center.

Figure 2.

Cardiac function over time.

Hemodynamic support was provided with norepinephrine, vasopressin, and dobutamine. Within 8 h, her cardiogenic shock resolved and she was extubated. Cardiac biomarkers decreased and the QTc interval normalized to 458 ms. Repeat transthoracic echocardiogram showed improved LVEF to 40% with basal-mid segment hypokinesis. She was discharged 3 days later on β-blocker therapy, and additional guideline-directed medical therapy was withheld due to hypotension.

At the 6-month follow-up, her LVEF recovered to 60% and wall motion abnormalities resolved. Though asymptomatic from a cardiac perspective, she experienced post-traumatic stress disorder, depression and anxiety, and mild left-sided neurological deficits secondary to functional disorder versus hypoxemic brain injury.

Discussion

This case describes the erroneous administration of IV epinephrine 0.3 mg (1:1000) formulated for IM administration for anaphylaxis, which resulted in a 30-fold overdose compared to 0.1 mg (1:10,000) IV administration for refractory anaphylaxis.⁴ High levels of epinephrine can cause adverse cardiovascular reactions, such as myocardial ischemia, dysrhythmias, and acute heart failure.^2,5,6 Here, iatrogenic epinephrine toxicity was the suspected cause for myocardial stunning.

Catecholamine- or stress-induced cardiomyopathy, also known as TTS, is a condition whose underlying mechanism is not fully understood. Several hypotheses exist, but none offer a comprehensive explanation. Lyon et al.⁷ discuss the potential role of ischemic and direct myocardial stunning in the development of TTS. Supraphysiological levels of epinephrine are believed to cause alpha-adrenergic receptor-dependent coronary vasospasms and microvascular dysfunction, as well as increased blood pressure and ventricular afterload, resulting in ischemic stunning of the myocardium. Epinephrine can also stimulate beta-adrenergic receptors (βAR) and increase oxidative stress and transient hypercontractility via β1AR-Gs. At higher levels, epinephrine activates negatively inotropic β2AR-Gi receptors, leading to direct myocardial stunning, which is cardioprotective by limiting myocyte necrosis and promoting recovery through anti-apoptotic and phosphoinositide 3-kinase/protein kinase B pathways. The combination of ischemic and direct catecholamine-induced stunning can affect LV intracavity pressure gradients and dynamics. Region differences in sympathetic nerve endings and β1ARs/β2ARs may explain morphological variants of TTS.⁷ Atypical apical-sparing patterns have been reported in almost 50% of TTS patients when triggered by exogenous epinephrine.¹

Epinephrine infusion has demonstrated to induce TTS in animal models.^5,8 In patients, plasma catecholamines were three times higher in TTS compared to those with acute myocardial infarction and post-infarction heart failure.⁷ Litvinov et al.⁶ reported a direct causal role of elevated plasma epinephrine (798 pmol/l (normal: 120–600 pmol/l)) in TTS in a patient who erroneously received high-dose IM epinephrine for anaphylaxis. In addition, patients with TTS often have acute QTc prolongation, as seen in our case. Computational modeling suggests that toxic concentrations of catecholamines in TTS can prolong action potential duration due to increases in late I_Na and decreases I_to, which may increase the risk of ventricular arrhythmias.^2,7

TTS can have severe acute complications, including cardiogenic shock and cardiac arrest, with in-hospital mortality rates of 4%–5%. There is growing recognition that survivors of severe TTS may experience long-term cardiac and noncardiac conditions, with cardiogenic shock being the strongest predictor. A literature review identified 22 other cases of myocardial stunning in the setting of epinephrine administration for anaphylaxis (Table 2), with a mean age of 49 years and 73% being female. Classic TTS with apical ballooning presented in 65% of patients. Erroneous overdose occurred in 64% of cases, while erroneous route of administration occurred in 18% of cases. Normal doses of epinephrine were reported in 18% of cases. 17% of cases were complicated by cardiac arrest, and 38% received hemodynamic support, although the use of vasopressors/inotropes in TTS remains controversial. All cases reported complete recovery.

Table 2.

Epinephrine administration in anaphylaxis complicated by catecholamine-induced cardiomyopathy.

References	Age, gender	Clinical setting	Epinephrine dose	Administration route	Error	Takotsubo pattern	LVEF	Peak Trop	QTC	Cardiac arrest	Hemodynamic support	Outcome
Alyonan et al.⁹	50, F	Anaphylaxis to insect bite, unspecified	1 mg (1:10,000)	IV	Overdose	Apical	35	Trop-I 0.49 ng/mL	Torsades	N	N	Complete recovery
Bhat et al.¹⁰	27, M	Anaphylaxis to brown recluse spider bite	0.3 mg (1:1000)	IV	Erroneous route	Mid-basal	20	Trop-T 4.04 ng/mL	–	N	N	Complete recovery
Cabaton et al.¹¹	54, M	Anaphylaxis to anesthesia	0.1 mg x 3 (1:10,000)	IV	Normal	Apical	30	Trop-T 2.69 ng/mL	–	Y	–	Complete recovery
Dewachter et al.¹²	65, F	Anaphylaxis to anesthesia	Total 6.43 mg (1:10,000)	IV	Overdose	Apical	20	Trop-T 6.18 ng/mL	–	N	Y	Complete recovery
Geppert et al.¹³	70, F	Anaphylaxis to hymenoptera sting	0.3 mg (1:10,000)	IV	Overdose	Apical	42	–	Prolonged	N	N	Complete recovery
Ghanim et al.¹⁴	37, F	Anaphylaxis to hymenoptera sting	0.9 mg (1:10,000)	IV	Overdose	Mid-basal	20	Trop-I 0.0014 ng/mL	–	N	Y	Complete recovery
Han and Yeon¹⁵	41, M	Anaphylaxis to iodine contrast	0.2 mg (1:10,000)	IV	Overdose	Midventricular	30–40	Trop-T 2.09 ng/mL	Normal	N	Y	Complete recovery
Kajander et al.¹⁶	49, F	Exercise-induced anaphylaxis	0.1 mg x 3 (1:10,000)	IV	Normal	Basal	45	Trop-T 2.33 ng/ml	Normal	N	N	Complete recovery
Khoueiry et al.¹⁷	44, F	Anaphylaxis to iodine contrast	1 mg (1:1000)	IV	Erroneous route	Mid-basal	35	Trop-I 3.23 ng/mL	Normal	N	N	Complete recovery
Lainez et al.¹⁸	61, M	Anaphylaxis to anesthesia	High-dose	IV	Overdose	Apical	–	–	–	N	N	Complete recovery
Litvinov et al.⁶	24, F	Anaphylaxis to food	5 mg (1:000)	IM	Overdose	Basal	20	Trop-T 1.06 ng/mL	–	N	N	Complete recovery
Magri et al.¹⁹	26, F	Anaphylaxis to proton-pump inhibitor	0.5 mg (1:1000)	IM	Normal	Apical	42	Trop-I 6.7 ng/mL	Normal	N	N	Complete recovery
Manivannan et al.²⁰	41, M	Anaphylaxis to hymenoptera sting	1 mg (1:10,000)	IV	Overdose	Apical	48	Trop-T 0.49 ng/mL	–	N	N	Complete recovery
Margonato et al.²¹	60, F	Anaphylaxis to plasma expanders	0.5 mg (1:10,000)	IV	Overdose	Apical-mid	47	Trop-T 18 ng/mL	Prolonged	Y	Y	Complete recovery
Nazir et al.²²	37, F	Anaphylaxis to food	0.3 mg (1:1000)	IM	Normal	Apical	35–40	Trop-I 28.21 ng/mL	Normal	N	N	Complete recovery
Patankar et al.²³	44, F	Angioedema to ACE inhibitor	3.3 mg (1:1000)	SC	Overdose	Apical	–	Trop-T 3.97 ng/mL	Normal	N	Y	Complete recovery
Pathangey et al.²⁴	47, F	Anaphylaxis to iodine contrast	0.3 mg (1:1000)	IV	Erroneous route	Mid-basal	10	Trop-T 0.34 ng/mL	Prolonged	Y	Y	Complete recovery
Scheiba et al.²⁵	81, M	Anaphylaxis to hymenoptera sting	0.3 mg	IM	Normal	Apical	–	–	Prolonged	Y	N	Complete recovery
Suk et al.²⁶	32, F	Anaphylaxis to antibiotics	1 mg (1:10,000)	IV	Overdose	Mid-ventricular	50	Trop-T 0.47 ng/mL	Normal	N	Y	Complete recovery
Verdier et al.²⁷	55, F	Anaphylaxis during anesthesia	–	IV	–	Apical	30	–	Prolonged	N	Y	Complete recovery
Winogradow et al.²⁸	70, F	Anaphylaxis to hymenoptera sting	0.3 mg (1:1000)	IV	Erroneous route	Apical	45	Trop-T 0.15 ng/mL	Prolonged	N	N	Complete recovery
Winogradow et al.²⁸	37, F	Anaphylaxis to hymenoptera sting	2 mg (1:10,000)	IV	Overdose	Apical	–	Trop-I 3.35 ng/mL	Prolonged	N	N	Complete recovery
Zubrinich et al.²⁹	76, F	Generalized urticaria and angioedema	0.3 mg (1:1000)	IM	Normal	Apical	–	Trop-T 2.39 ng/mL	–	N	–	Complete recovery

LVEF: left ventricular ejection fraction.

Erroneous overdose occurred in 64% of cases, while erroneous route of administration occurred in 18% of cases. Interestingly, normal doses of epinephrine were reported in 18% of cases. Seventeen percent of cases were complicated by cardiac arrest, 38% received hemodynamic support, and all cases had complete recovery.

Limited data are available on the incidence of iatrogenic epinephrine administration in the setting of anaphylaxis, especially in rural areas. Single-center retrospective studies observed a 2.4%–3.3% incidence of potentially life-threatening complications from inappropriate epinephrine administration for anaphylaxis.^3,30 The Pennsylvania Patient Safety Authority (PPSA) reviewed 280 reports from 2004 to 2009 on erroneous epinephrine administration in various scenarios, and 11% (n = 30 of 280) of cases indicated some level of patient harm.³¹ Common errors reported included wrong-route administration, dosing/formulation errors, and erroneous duration of IV infusions. Wrong-route errors accounted for 63.3% of harmful events (n = 19 of 30) reported by the PPSA, while the Institute for Safe Medication Practices (ISMP) Canada database reported wrong-dose errors as most prevalent.^31,32 Interestingly, the observed risk of epinephrine overdose and adverse cardiovascular events was significantly higher with IV administration in comparison to IM administration in anaphylaxis.^9,32

Epinephrine errors have been attributed to communication challenges in emergencies, inadequate training, and outdated packaging. The largest proportion of harmful events (26.8%) occurred in the emergency department.³¹ In a multi-center survey of 253 physicians, no physician provided an ideal response for the correct dose, concentration, and route of epinephrine administration; 17% would have administered an epinephrine overdose, and only 11% knew which concentration of epinephrine was available in their crash cart.³³ In another survey of 150 physicians, 40% were unable to correctly convert doses of epinephrine from a dilution to mass concentration.³⁴ It has been suggested regular training featuring mock scenarios may reduce the risk of such errors.³ In addition, antiquated packaging of IV versus IM epinephrine in emergency carts may partly contribute to confusion. Although the United States Pharmacopeia eliminated ratio expressions in 2016, further modification in design should be considered to decrease the cognitive burden to healthcare personnel during stressful situations.

A single-center emergency department implemented a solution featuring clearly labeled prefilled auto-injectors (containing 0.3 mg of 1:1000 concentration IM dose). No further adverse outcomes were reported for two years after this implementation.³ Other studies report 82% of healthcare workers prefer epinephrine auto-injectors over manually drawn epinephrine, and a contrast-reaction simulation program observed a significant decrease in errors and increased comfort in the autoinjector group versus the manual group.^35,36

Conclusion

Erroneous epinephrine administration can have serious cardiovascular consequences. Further research is needed on the incidence and cardiovascular impact of these errors, particularly in rural areas. Strategies to improve emergency communication, training, and epinephrine design should be considered to reduce the risk of iatrogenic epinephrine overdose.

Supplemental Material

sj-docx-1-sco-10.1177_2050313X231159732 – Supplemental material for Myocardial stunning secondary to erroneous administration of intravenous epinephrine

Supplemental material, sj-docx-1-sco-10.1177_2050313X231159732 for Myocardial stunning secondary to erroneous administration of intravenous epinephrine by Girish Pathangey, Rohitha Moudgal, Christopher Lee and Stanislav Henkin in SAGE Open Medical Case Reports

Footnotes

Acknowledgements

The authors thank the patient for permission to share her medical history for educational purposes and publication.

Authorship

All authors made substantial contributions to the concept or design of the work, or to the acquisition, analysis, or interpretation of data; drafted the article or revised it critically for important intellectual content, and approved the version to be published; and participated sufficiently in the work to take public responsibility for appropriate portions of the content.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics approval

Our institution does not require ethical approval for reporting individual cases or case series.

Informed consent

Patient had decisional capacity to provide written informed consent. Written informed consent was obtained from the patient for their anonymized information to be published in this article.

ORCID iDs

Girish Pathangey

Christopher Lee

Supplemental material

Supplemental material for this article is available online.

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