Abstract
Introduction:
Systemic toxicity from topical epinephrine is rare because dermal and mucosal absorption is typically limited. However, application to highly vascular mucosa, particularly under occlusion, may result in clinically significant systemic absorption.
Case presentation:
A 42-year-old woman developed severe headache, palpitations, tremor, and marked hypertension shortly after a compounded 2.5% lidocaine with epinephrine (1:2000; 0.5 mg/mL) gel was applied to the labial mucosa under occlusion during a cosmetic procedure. An estimated 0.5 to 1.5 mg of epinephrine was applied. Symptoms began within 10 minutes and persisted until gel removal approximately 25 minutes later. On EMS arrival, heart rate was 145 bpm and blood pressure 210/110 mmHg. In the emergency department, ECG showed sinus tachycardia without ischemic changes; laboratory studies were unremarkable except for mild respiratory alkalosis, and serial high-sensitivity troponin I was negative. Management included prompt removal of the topical agent, supportive care, and cardiac monitoring. Symptoms resolved spontaneously without pharmacologic intervention, and the patient was discharged after 4 hours of observation.
Conclusion:
Topical epinephrine applied to highly vascular mucosal surfaces—especially under occlusion—can rarely cause systemic sympathomimetic toxicity characterized by hypertension, tachycardia, tremor, and anxiety. Although it may resemble local anesthetic systemic toxicity, it is clinically distinct. Careful dosing, avoidance of occlusive dressings, close monitoring, and immediate removal of the agent at the first sign of systemic effects are essential to prevent complications.
Keywords
Introduction
Systemic epinephrine toxicity is a rare complication following inadvertent or excessive administration. Epinephrine is a potent catecholamine commonly added to local anesthetics to prolong anesthesia and limit systemic absorption. Although generally safe, excessive systemic absorption can lead to severe sympathomimetic effects, including tachycardia, hypertension, headache, tremor, and anxiety. Topical preparations of epinephrine are usually well tolerated because intact skin and mucosa limit absorption; however, absorption may be enhanced on highly vascular or injured surfaces.1-5
Topical anesthetic creams – including compounded mixtures of lidocaine, tetracaine, and epinephrine – are widely used in outpatient cosmetic and dermatologic procedures (eg, laser hair removal and tattooing) to minimize pain. 6 These agents are generally considered safe when applied to intact keratinized skin; however, their pharmacokinetic profile and systemic absorption may differ substantially when administered to mucosal surfaces. Mucosa (such as the labial mucosa) lack a keratinized stratum corneum and have a dense capillary network immediately beneath the surface, 7 so drugs applied topically can be absorbed far more rapidly than through ordinary skin. Occlusive dressings (often used to boost anesthetic effect) further enhance percutaneous uptake. 8
Systemic sympathomimetic toxicity from topical epinephrine has been rarely described in cosmetic practice. To our knowledge, 1 prior case of systemic toxicity from a topical anesthetic gel has been documented. Fateha and Willsie described a 33-year-old woman who applied multiple doses of a lidocaine-epinephrine numbing cream for tattoo anesthesia and developed abrupt hypertension, tachycardia, headache, and lactic acidosis. This report highlights that, in rare instances, even topical epinephrine can be absorbed in sufficient quantities to cause systemic effects. Absorption may be especially enhanced on highly vascular or injured surfaces; for example, topical epinephrine applied to burn wounds markedly increased serum epinephrine and lactate levels.1,9 Here, we describe one of the very few reported cases of systemic epinephrine toxicity following mucosal application of an epinephrine-containing anesthetic gel.
Case Presentation
A 42-year-old woman (weight 68 kg) with no significant past medical history was brought to the emergency department by emergency medical services (EMS) after developing sudden palpitations (subjective severity 8/10 on the Numeric Rating Scale [NRS], which correlated with an initial ECG heart rate of 145 bpm) and a headache (9/10 on a 0-10 numeric rating scale). Approximately 30 minutes prior to presentation, the patient underwent a laser hair removal procedure at an outpatient clinic, during which a compounded topical anesthetic gel was applied to the labial mucosa. The gel contained 2.5% lidocaine with epinephrine 1:2000 and was applied as a single application under an occlusive dressing to enhance anesthetic absorption. The estimated volume of anesthetic gel applied was approximately 1 to 3 mL, corresponding to a total epinephrine dose of approximately 0.5 to 1.5 mg.
Approximately 10 minutes after application, while the gel remained in place and before completion of the laser procedure, the patient developed the abrupt onset of a severe, pulsating headache accompanied by intense palpitations, anxiety, and visible tremors in her hands. She denied chest pain, shortness of breath, or perioral numbness. EMS was called approximately 15 minutes later. The gel remained in contact with the mucosa for approximately 25 minutes before being removed by EMS. Upon their arrival, the patient’s vital signs showed sinus tachycardia at 145 bpm and blood pressure of 210/110 mmHg, with an oxygen saturation of 99% on room air. The patient was transported to the emergency department for further evaluation.
Upon arrival at the ED approximately 20 minutes later, the patient reported that her symptoms were improving but still present. Vital signs at presentation are summarized in Table 1 and demonstrated persistent tachycardia and hypertension. On physical examination, the patient was alert and mildly agitated. On bedside neurologic exam she had a fine postural/action tremor, estimated clinically as Grade 1 to 2 on the Fahn–Tolosa–Marín (FTM) tremor scale (mild–moderate amplitude without functional impairment). No formal tremor grading scale was applied. Her pupils were equal and reactive, and no jugular venous distension was noted. The labial mucosa appeared mildly erythematous, consistent with recent gel application, but without ulceration or necrosis. Cardiopulmonary and abdominal examinations were otherwise unremarkable.
Patient Timeline: Topical Anesthetic Reaction.
An electrocardiogram (ECG) performed in the ED showed sinus tachycardia at 115 bpm, a normal QRS duration of 88 ms, QTc of 420 ms, and no ST-segment or T-wave abnormalities (Figure 1). Laboratory evaluation revealed mild respiratory alkalosis on venous blood gas (pH 7.49, pCO2 28 mmHg, HCO3 24 mEq/L), consistent with hyperventilation. All other laboratory studies, including basic metabolic, renal, hepatic panels, complete blood count, urine drug screen, and serial high-sensitivity troponin I, were within normal limits. Thyroid function tests, including TSH and free T4, were within normal limits. High-sensitivity troponin I was <6 ng/L on arrival and remained undetectable on repeat testing 3 hours later, ruling out myocardial injury.
Representative 12-lead ECG (simulated) showing sinus tachycardia after topical epinephrine–containing anesthetic gel application. Representative 12-lead electrocardiogram (standard calibration 25 mm/s, 10 mm/mV) intended to illustrate the patient’s electrocardiographic findings in the emergency department following topical application of a lidocaine–epinephrine gel to the labial mucosa. The tracing demonstrates sinus tachycardia with a rate of approximately 115 bpm, normal QRS duration (~88 ms), and corrected QT interval (QTc) ≈ 420 ms (Bazett’s correction). There are no ST-segment or T-wave abnormalities, no ectopy, and no conduction delay – findings consistent with transient sympathomimetic effects of systemic epinephrine absorption without evidence of myocardial ischemia or arrhythmia.
The patient was observed in the clinical decision unit for ongoing monitoring due to her initial severe hypertension and tachycardia. No pharmacologic interventions were required, and her symptoms continued to resolve spontaneously. Repeat laboratory analysis showed normalization of all parameters. After approximately 4 hours of observation, the patient reported complete resolution of her headache, palpitations, and tremor. Her vital signs returned to baseline, with a blood pressure of 124/78 mmHg and heart rate of 72 bpm.
Based on the temporal relationship between the application of the topical anesthetic gel and the onset of symptoms, along with the clinical presentation of severe hypertension, tachycardia, tremor, and anxiety that resolved after removal of the gel, the diagnosis of systemic epinephrine toxicity secondary to topical anesthetic absorption was made. The patient was counseled regarding the likely cause of her reaction and discharged home in stable condition after 4 hours of observation, with advice to avoid the use of epinephrine-containing topical agents on mucosal surfaces in the future.
A concise chronological summary is provided in Table 1 and pertinent ED laboratory results are presented in Table 2.
Laboratory Findings (Drawn on ED Arrival, ~45-50 minutes Post-Symptom Onset).
The patient described a sudden and frightening onset of intense headache, palpitations, anxiety, and hand tremors that forced interruption of the procedure. She stated, “I felt my heart racing out of control, and the headache was overwhelming. I thought something was seriously wrong.” She reported gradual improvement after removal of the topical gel and observation in the emergency department and expressed relief upon learning that the symptoms were transient and medication-related, appreciating the explanation and preventive counseling provided.
Discussion
Epinephrine is a sympathomimetic catecholamine that exerts its pharmacologic effects through stimulation of α- and β-adrenergic receptors. 2 Its physiologic actions include contraction of intestinal sphincters, pupillary dilation, and vascular smooth muscle constriction, as well as increased myocardial contractility, heart rate, and renin release. Common routes of administration include intravenous, intramuscular, and transdermal; however, transdermal absorption is typically limited and clinically insignificant in most cases.3,10 When used with local anesthetics (LA), epinephrine increases the depth and duration of the LA while reducing the toxicity and systemic absorption of the vasoconstrictor and LA agent. This extends the duration of anesthetic, reduces toxicity by delaying systemic absorption, increases the LA effect by localizing it to the injection site, and may reduce the overall amount of the LA agent needed. 11
Following topical administration, epinephrine is absorbed into the systemic vasculature in 1 to 2 hours. 10 Topical epinephrine can be systemically absorbed and is associated with measurable systemic effects, including increases in heart rate, serum epinephrine concentrations, and markers suggestive of altered tissue perfusion, particularly in highly vascularized tissue. 9 However, after intravenous administration, epinephrine is quickly dispersed throughout the body, and the pharmacokinetic profile shows that its plasma concentrations drop quickly, with a steady state usually being reached in 10 to 15 minutes when given continuously. Thus, Symptoms of toxicity typically resolve rapidly given epinephrine’s short half-life. 3
Epinephrine’s rapid pharmacokinetics explain the patient’s abrupt symptom course. On richly vascular mucosa, topically applied drugs are absorbed quickly – for example, anesthetics on airway or oral mucosa peak in blood within minutes (often 5-30 minutes). Once epinephrine enters the circulation, it is distributed widely and cleared very rapidly (plasma half-life < 5 minutes). Thus, systemic effects manifest soon after absorption and dissipate quickly after exposure stops. In our case, the patient’s symptoms began ~10 minutes after application (consistent with rapid mucosal uptake) and resolved over the next few hours once the gel was removed, matching epinephrine’s transient hyperadrenergic effect. In other words, the rise and fall of her headache, palpitations, and tremor mirror the expected rise (minutes) and rapid clearance (10-15 minutes to steady state with continuous infusion, even faster as a bolus) of epinephrine. This pharmacokinetic profile distinguishes exogenous epinephrine toxicity from other causes (eg, pheochromocytoma), which often have more prolonged or variable catecholamine elevations.3,8
Common adverse effects of epinephrine include tachycardia, hypertension, chest pain, headache, anxiety, apprehension, palpitations, tremors, diaphoresis, nausea, vomiting, weakness, dyspnea, and decreased renal perfusion. Important laboratory findings include hyperglycemia, hypokalemia, lactic acidosis, and an increase in aspartate transaminase and alanine transaminase. The patient in our case had many of the previously mentioned clinical symptoms upon arrival including a severe throbbing headache, palpitations, tremors, tachycardia, hypertension, tachypnea, agitation, and anxiety. Interestingly, she had none of the laboratory findings except for mild respiratory alkalosis, consistent with her elevated respiratory rate. We hypothesize that this might be due to late blood drawing, which was done a while after the removal of the gel during which the serum markers and electrolytes might have stabilized. Severe epinephrine toxicity can result in ventricular ectopy, coronary vasospasm, tissue ischemia, arrhythmias, and pulmonary edema. Fortunately, none of these complications occurred in our patient.3,9
An important differential diagnosis in this case is local anesthetic systemic toxicity (LAST), a rare but life-threatening condition characterized by central nervous system and cardiovascular manifestations, including seizures, dysrhythmias, circulatory collapse, and methemoglobinemia. Early symptoms of LAST include tinnitus, visual disturbances, lightheadedness, agitation, and perioral or facial paresthesia, while severe toxicity typically produces bradycardia, hypotension, seizures, and cardiac conduction abnormalities. The presence of tachycardia, tachypnea, and transient hypertension in our patient strongly favors epinephrine toxicity over LAST. 12 Other causes of acute catecholamine excess were also considered, including pheochromocytoma and thyrotoxicosis, which may present with palpitations, tremor, hypertension, and anxiety. These diagnoses were considered unlikely given the clear temporal association with topical anesthetic exposure, the absence of prior symptoms suggestive of endocrine disease, and the complete resolution of symptoms without recurrence or targeted therapy. This pattern is most consistent with an exogenous sympathomimetic effect rather than an underlying endocrine disorder. 13 Key differences between these diagnostic considerations are outlined in Table 3.1,14-17
Differential Diagnosis of Systemic Epinephrine Toxicity, LAST, and Pheochromocytoma.
Management of epinephrine overdose is primarily supportive. Vasodilators or α-adrenergic blockers may be used to counteract excessive vasoconstriction, while β-adrenergic blockers are reserved for serious arrhythmias or myocardial ischemia. In this case, no pharmacologic intervention was required, as the patient’s symptoms improved spontaneously following gel removal, and laboratory evaluation revealed no concerning abnormalities. 3
A review of the medical literature up to October 2025 identified only 1 prior human case of systemic epinephrine toxicity resulting from a topical epinephrine-containing anesthetic gel. In that report, repeated transcutaneous applications of a lidocaine–epinephrine cream for tattoo anesthesia resulted in abrupt hypertension, tachycardia, lactic acidosis, and myocardial injury. 1 In contrast, our patient developed marked sympathomimetic symptoms after a single application to the labial mucosa, with rapid onset and resolution and without metabolic derangements or cardiac injury. This likely reflects enhanced and more rapid systemic absorption through highly vascular mucosal tissue compared with intact skin, particularly when combined with occlusive application, as well as differences in epinephrine concentration and formulation. This case expands the existing literature by demonstrating that even a single, moderate-dose mucosal application of topical epinephrine can produce clinically significant systemic toxicity and underscores the importance of distinguishing this presentation from local anesthetic systemic toxicity.1,9
Compounded topical anesthetics often lack the stringent quality controls of commercial preparations, leading to wide variability in drug content and pharmacokinetics. 18 This is especially true for epinephrine- containing mixtures: small formulation or storage differences can markedly affect concentration and stability. Epinephrine is known to oxidize and degrade rapidly when exposed to light, oxygen, or heat, so compounded creams may lose potency or become discolored over time. 19 Such variability can alter systemic absorption; excess absorbed epinephrine can cause adrenergic toxicity (eg, tachycardia, hypertension, lactic acidosis) as recently reported after excessive application of a lidocaine–epinephrine topical gel. 1 Conversely, loss of epinephrine’s vasoconstrictive effect could increase uptake of the local anesthetic, raising the risk of LAST. Clinicians should therefore use epinephrine-containing topicals cautiously, following strict compounding and storage protocols (eg, amber vials, refrigeration, short beyond-use dating) or preferably using licensed formulations, and should apply minimal effective doses to minimize unpredictable systemic exposure and toxicity.
To reduce the risk of systemic toxicity from topical epinephrine, clinicians should exercise particular caution when applying epinephrine-containing agents to highly vascular mucosal surfaces. The lowest effective concentration and minimal volume should be used, and the treated surface area should be limited. Occlusive dressings should be avoided on mucosa, as they may enhance systemic absorption. During outpatient cosmetic or dermatologic procedures, careful monitoring of blood pressure and heart rate during and after application is advisable, even when standard dosing is used. The topical agent should be removed promptly at the first sign of systemic sympathomimetic effects, including tachycardia, hypertension, tremor, or anxiety. Although topical epinephrine is generally safe when applied appropriately, higher concentrations, larger volumes, or use on damaged mucosa may increase the risk of clinically significant systemic absorption.5,20
This single-case report has inherent limitations. Its findings cannot be generalized, and causality is inferred from the temporal relationship rather than confirmed by serum epinephrine measurements. The exact volume of gel applied was estimated, and tremor was assessed clinically without use of a formal grading scale. Laboratory testing was performed after removal of the gel, which may have missed transient metabolic or hemodynamic changes. Despite these limitations, the case provides valuable insight into the potential for systemic epinephrine toxicity from topical mucosal application and highlights the need for careful monitoring.
Conclusion
This case underscores that systemic epinephrine toxicity can occur even after topical application on highly vascular mucosal surfaces, particularly when used under occlusive conditions. Although rare, clinicians should be aware of this potential complication, recognize its early signs, and differentiate it from local anesthetic systemic toxicity. Careful dosing, avoidance of occlusive dressings, and vigilant patient monitoring are essential to prevent adverse outcomes. Importantly, systemic adverse effects may occur despite typical dosing and standard administration practices, highlighting the need for caution and close observation when using epinephrine-containing topical anesthetics on mucosal surfaces. Practical preventive measures include using the lowest effective concentration, limiting the application area, and promptly removing topical agents if systemic symptoms appear.
Footnotes
Acknowledgements
None.
Ethical Considerations
Ethical approval was not required for this case report, as it involves a single patient and does not meet the criteria for research requiring institutional review board (IRB) oversight. The use of authorized medications was consistent with clinical practice guidelines, and the management of this individual patient did not require IRB approval.
Consent to Participate
Written informed consent was obtained from the patient prior to publication of this case report and any accompanying images. This consent includes permission for the use of unauthorized, off-label medications as part of the treatment plan. The completed consent form is available to the Editor upon request and will be treated confidentially.
Author Contributions
1. Ziad W. Elmezayen: Conceptualization, Supervision, Study Design, Writing – Review & Editing.
2. Zeina Zakarya Marzouk: Methodology, Data Interpretation, Approval of Final Manuscript, Supervision.
3. Mohammad Adi: Data Curation, Formal Analysis, Writing, Writing - Original Draft , Review and Editing, Contributions to Discussion.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
All data pertinent to this case report have been included in this article. Further inquiries can be directed to the corresponding author.