Epinephrine

What it is

Epinephrine, called adrenaline outside the United States, is a catecholamine the adrenal glands make and which is also manufactured as a medicine. It is sold in many very different products: single-dose auto-injectors of 0.3 mg and 0.15 mg for anaphylaxis, vials and prefilled syringes for hospital use, a nasal spray, an over-the-counter inhaler for asthma symptoms, and as an additive to local anaesthetics for dentistry and surgery. The doses are small and the units matter: an adult auto-injector delivers 0.3 mg, the paediatric one 0.15 mg, while epinephrine in a dental local anaesthetic is present at concentrations of the order of 5 to 10 micrograms per millilitre.

What the research says

For anaphylaxis, the evidence base is almost entirely observational and the sources say so plainly. A Cochrane review looking for randomised or quasi-randomised trials of adrenaline in anaphylaxis found no studies that met its criteria, and still recommended intramuscular adrenaline as first-line on the basis of less than optimal evidence; the FDA label states that because of the lack of randomised controlled trials the true incidence of adverse reactions is difficult to determine. The supporting evidence is pharmacokinetic (intramuscular injection into the thigh reaches peak blood levels in about 8 minutes versus 34 minutes subcutaneously) and epidemiological (delayed administration is a risk factor in fatal food anaphylaxis). In cardiac arrest, by contrast, there are randomised placebo-controlled trials, and they show survival and neurological outcome pulling apart: in PARAMEDIC2, 30-day survival was 3.2% with epinephrine versus 2.4% with placebo, but survival with a favourable neurological outcome was 2.2% versus 1.9% and severe neurological impairment was commoner among the survivors who got epinephrine. The main harms are from the wrong route, the wrong site or the wrong dose rather than from the drug used correctly.

Evidence grade: Limited evidence.

How it works

Drug class: Endogenous catecholamine and sympathomimetic agent; non-selective alpha- and beta-adrenergic receptor agonist

Epinephrine acts on both alpha- and beta-adrenergic receptors. Through the alpha receptors it tightens blood vessels, which counters the vessel widening and leakiness of anaphylaxis and so supports blood pressure; through the beta receptors it relaxes airway muscle and eases wheeze and breathlessness. It also eases itch, hives and swelling and relaxes smooth muscle in the gut and bladder. Given into muscle or under the skin it starts working quickly and wears off quickly. (Source 1)

What it is used for

• Approved and universally recommended, but the direct evidence is not randomised: a Cochrane review found no trials meeting its criteria and the FDA label says the absence of randomised trials makes adverse reaction rates impossible to establish. The supporting evidence is pharmacokinetic, showing intramuscular thigh injection peaks in about 8 minutes against 34 minutes subcutaneously, and epidemiological, with delayed administration a risk factor in fatal food anaphylaxis. The design of that evidence is observational and should not be described as trial-proven. Evidence: limited. (Source 2)
• Here randomised placebo-controlled trials exist and they split the outcome. PARAMEDIC2 in 8014 patients found 30-day survival 3.2% versus 2.4% with placebo, but no significant difference in survival with a favourable neurological outcome (2.2% versus 1.9%), with severe neurological impairment commoner among epinephrine survivors. The earlier Jacobs trial found adrenaline tripled the odds of restarting the heart with no significant survival difference. Whether the drug helps depends on which outcome is counted. Evidence: disputed. (Source 3)
• A Cochrane review of 8 small trials in 225 children found a clinically and statistically significant improvement in croup score 30 minutes after nebulised epinephrine, with the effect gone by two and six hours. The reviewers note the data were limited by very few studies and that none of the trials sought or reported adverse effects. Evidence: limited. (Source 4)
• A Cochrane review of 19 trials in 2256 children under two found fewer admissions on the first day among outpatients (RR 0.67) but no difference by day seven and no difference in length of stay for children already in hospital. The reviewers state there is no evidence of effectiveness for repeated or prolonged use in inpatients. Evidence: limited. (Source 5)
• Clinicians are widely taught to avoid epinephrine in digital blocks because of a necrosis risk. A literature review of 39 relevant articles, including 12 randomised trials, found no reported case of digital necrosis or gangrene attributable to epinephrine across at least 2797 blocks, and concluded the risk may be overstated. Most of those studies excluded people at risk of poor peripheral circulation, so that group remains untested. Evidence: limited. (Source 6)

Interactions

• Tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine and certain antihistamines (chlorpheniramine, tripelennamine, diphenhydramine) (label): These may potentiate the effects of epinephrine, so the same dose hits harder. The label does not make any of them a contraindication in an acute, life-threatening situation. (Source 7)
• Beta-blockers such as propranolol (label): Beta-blockers antagonise the heart-stimulating and airway-opening effects of epinephrine, which is the part that relieves wheeze in anaphylaxis. (Source 7)
• Cardiac glycosides, diuretics and anti-arrhythmic drugs (label): Taken together with epinephrine these raise the chance of a cardiac arrhythmia, and the label asks for careful observation. (Source 7)
• Sulfites (sodium metabisulfite, the same class of preservative used in foods and wine) (label): The auto-injector contains sodium metabisulfite, a sulfite that in other products can cause allergic-type reactions or asthma in susceptible people. The label is explicit that this should not deter giving the drug in a serious allergic or other emergency, even in a sulfite-sensitive person, because the alternatives may not be satisfactory. (Source 8)
• Ergot alkaloids (label): Ergot alkaloids may reverse the blood-pressure-raising effect of epinephrine, which is the effect being relied on in anaphylactic shock. (Source 7)

Stopping it

• There is no tapering or withdrawal literature for epinephrine, because for anaphylaxis it is a single-dose rescue medicine rather than a daily one. The label's stopping instruction runs the other way: it is emergency supportive therapy, not a substitute for immediate medical care, and more than two sequential doses should only be given under direct medical supervision. (Source 9)
• For nebulised epinephrine in bronchiolitis, the Cochrane reviewers state there is no evidence of effectiveness for repeated dosing or prolonged use in children already admitted to hospital, which is a finding about when to stop rather than how to taper. (Source 5)
• In croup the measured benefit itself stops: the croup score improvement seen at 30 minutes was not significant at two and six hours after treatment. (Source 4)

What goes wrong

The FDA label for the auto-injector states that the absence of randomised controlled trials in anaphylaxis makes the true rate of adverse reactions impossible to establish, and that its adverse reaction list comes from observational trials, case reports and studies. (Source 10)

• Official position, Very low certainty.
• Size: not applicable.
• Who: people given systemic epinephrine.
• How long: not applicable.
• Result: no rates can be given; the label lists reactions without frequencies.
• Funding: regulatory document.

Due to the lack of randomized, controlled clinical trials of epinephrine for the treatment of anaphylaxis, the true incidence of adverse reactions associated with the systemic use of epinephrine is difficult to determine. Adverse reactions reported in observational trials, case reports, and studies are listed below.

In an emergency department cohort, giving epinephrine as an intravenous bolus rather than into muscle carried much higher rates of cardiovascular adverse events and of overdose. (Source 11)

• Cohort study, Low certainty.
• Size: 573 patients meeting anaphylaxis criteria, 301 of whom received epinephrine; 362 doses.
• Who: emergency department patients with anaphylaxis, April 2008 to July 2012.
• How long: the index emergency department visit.
• Result: adverse cardiovascular events 3 of 30 intravenous bolus doses versus 4 of 316 intramuscular doses (10% versus 1.3%; OR 8.7, 95% CI 1.8-40.7, P = .006); overdose 4 of 30 versus 0 of 316 (13.3% versus 0%; OR 61.3, 95% CI 7.5 to infinity, P < .001); all four overdoses occurred with intravenous bolus.
• Funding: not stated in the abstract.

Limit of this finding: The paper says "There were 8 CV adverse events" and then describes 3 of 30 plus 4 of 316, which is 7. That arithmetic slip is the authors' own and the quotation reproduces it. The comparison itself is observational: patients given intravenous bolus adrenaline were not chosen at random and were probably sicker, so the odds ratios show an association with the route, not proof that the route caused the harm.

Adverse CV events were associated with 3 of 30 doses of IV bolus epinephrine compared with 4 of 316 doses of IM epinephrine (10% vs 1.3%; odds ratio 8.7 [95% CI, 1.8-40.7], P = .006). Similarly, overdose occurred with 4 of 30 doses of IV bolus epinephrine compared with 0 of 316 doses of IM epinephrine (13.3% vs 0%; odds ratio 61.3 [95% CI, 7.5 to infinity], P < .001).

A register of fatal anaphylaxis in the UK found adrenaline was given before arrest in only a small minority of fatal reactions, and recorded deaths caused by adrenaline overdose. (Source 12)

• Case series, Very low certainty.
• Size: about 20 fatal reactions recorded each year in the UK register from 1992.
• Who: all fatal anaphylactic reactions traceable from certified cause of death in the UK.
• How long: register established from 1992.
• Result: median time to respiratory or cardiac arrest 30 minutes for foods, 15 minutes for venom, 5 minutes for iatrogenic reactions; adrenaline used in 62% of fatal reactions but before arrest in only 14%; at least three deaths attributed to adrenaline overdose.
• Funding: not stated.

Adrenaline (epinephrine) was used in treatment of 62% of fatal reactions but before arrest in only 14%. CONCLUSIONS: Immediate recognition of anaphylaxis, early use of adrenaline, inhaled beta agonists and other measures are crucial for successful treatment. Nevertheless, a few reactions will be fatal whatever treatment is given; optimal management of anaphylaxis is therefore avoidance of the cause whenever this is possible. Predictable cross-reactivity between the cause of the fatal reaction and that of previous reactions had been overlooked. Adrenaline overdose caused at least three deaths and must be avoided.

Measured by ultrasound, the distance from skin to muscle means the approved auto-injector needle lengths would place a large share of injections outside the muscle, and clothing increases that calculated share; no one in the study was injected. (Source 13)

• Survey study, Low certainty.
• Size: 303 children and adolescents and 99 adults measured by ultrasound.
• Who: children, adolescents and adults, with skin-to-muscle and skin-to-bone distances measured.
• How long: not applicable; a measurement study modelling approved needle lengths.
• Result: with winter clothes, risk of subcutaneous rather than intramuscular injection rose from 13% and 0% to 81% and 1% for EpiPen Jr in the youngest children, and from 45% and 17% to 60% and 38% for EpiPen in adults, for the shortest and longest approved needle lengths; risk of intraosseous or periosteal injection fell.
• Funding: not stated.

Limit of this finding: Nobody in this study was injected. The authors measured skin-to-muscle and skin-to-bone distances by ultrasound in 303 children and adolescents and 99 adults, then calculated what proportion of injections a given needle length would place outside the muscle. These are modelled risks, not observed outcomes, and no clinical consequence was measured. The abstract's own Methods text is garbled in the source ("drug delivery fissue depth", "the riof non-intramuscular delivery"), which is why nothing is quoted from it here.

The risk of subcutaneous injection using EpipenJr® in the youngest children increased from 13% and 0% to 81% and 1% with winter clothes, and with Epipen® in adults from 45% and 17% to 60% and 38%.

Where the needle ends up matters because the drug behaves differently by route and site, and the auto-injector label restricts the site to the outer thigh and warns against the buttock, veins, digits, hands and feet. (Source 14)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: anyone using an epinephrine auto-injector.
• How long: at the time of injection.
• Result: no rates; the label names cerebral haemorrhage after accidental intravenous injection, ineffective treatment and Clostridial gas gangrene after buttock injection, and loss of blood flow after injection into digits, hands or feet.
• Funding: regulatory document.

Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration. Do not inject into buttock Injection into the buttock may not provide effective treatment of anaphylaxis. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis. Additionally, injection into the buttock has been associated with Clostridial infections (gas gangrene). Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower this risk.

Lacerations and bent or embedded needles have been reported when auto-injectors were used on young children who moved during the injection. (Source 14)

• Official position, Certainty not rated.
• Size: not applicable; spontaneous reports.
• Who: young children who are uncooperative and kick or move during an injection.
• How long: at the time of injection.
• Result: no rates given.
• Funding: regulatory document.

Lacerations, bent needles, and embedded needles have been reported when EpiPen and EpiPen Jr have been injected into the thigh of young children who are uncooperative and kick or move during an injection. To minimize the risk of injection related injury when administering, hold the child’s leg firmly in place and limit movement prior to and during injection.

Overdose of epinephrine is dangerous in its own right, with very high blood pressure, cerebral haemorrhage, pulmonary oedema and potentially fatal arrhythmias. (Source 15)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: people given too much epinephrine, elderly patients particularly.
• How long: premature ventricular contractions may appear within one minute after injection.
• Result: no rates given; the label describes the sequence of effects.
• Funding: regulatory document.

Epinephrine overdosage can also cause transient bradycardia followed by tachycardia, and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block.

Single-ingredient epinephrine products carry no boxed warning, while at least one combination product containing epinephrine does, and that warning is about the other ingredient rather than about epinephrine. (Source 16)

• Official position, Certainty not rated.
• Size: 13 structured product labels parsed for LOINC 34066-1, with positive and negative controls.
• Who: the labelled product rather than a patient group.
• How long: not applicable.
• Result: no boxed warning found in EpiPen, Auvi-Q, Symjepi, neffy nasal spray, Primatene Mist, plain epinephrine injection vials or lidocaine with epinephrine; a boxed warning found in Sensorcaine, which is bupivacaine with epinephrine, concerning the 0.75% bupivacaine concentration in obstetrical anaesthesia.
• Funding: regulatory documents.

There have been reports of cardiac arrest with difficult resuscitation or death during use of SENSORCAINE for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management.

Rare but serious skin and soft tissue infections, including necrotising fasciitis and gas gangrene, have been reported at epinephrine injection sites, and alcohol swabbing does not prevent them. (Source 10)

• Case series, Very low certainty.
• Size: not stated; rare reported cases.
• Who: people given epinephrine by subcutaneous or intramuscular injection for anaphylaxis.
• How long: after injection.
• Result: no rates given; described as rare cases.
• Funding: regulatory pharmacovigilance.

Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported following epinephrine injection

What the evidence supports

In children with a history of anaphylaxis, epinephrine injected into the thigh muscle reached peak blood levels about four times faster than the same dose given under the skin. (Source 17)

• Blood level study, Low certainty.
• Size: 17 children (9 subcutaneous, 8 intramuscular)
• Who: children with a history of anaphylaxis to food, Hymenoptera venom or other substances.
• How long: single dose, with plasma concentrations followed over time.
• Result: subcutaneous: mean maximum plasma concentration 1802 +/- 214 pg/ml at a mean 34 +/- 14 minutes (range 5 to 120 minutes), with only 2 of 9 peaking by 5 minutes; intramuscular 0.3 mg: 2136 +/- 351 pg/ml at a mean 8 +/- 2 minutes (p < 0.05), with 6 of 8 peaking by 5 minutes; terminal elimination half-life 43 +/- 15 minutes.
• Funding: Research Support, Non-U.S. Gov't per the PubMed record.

In nine children who received epinephrine subcutaneously, the mean maximum plasma epinephrine concentration (+/- SEM) was 1802 +/- 214 pg/ml, achieved at a mean time of 34 +/- 14 minutes (range, 5 to 120 minutes). Only two of the nine children achieved maximum plasma concentrations by 5 minutes. In eight children who received epinephrine intramuscularly, the mean maximum plasma concentration was 2136 +/- 351 pg/ml, achieved at a mean time of 8 +/- 2 minutes, which was significantly faster than the mean time at which maximum plasma concentrations were achieved after subcutaneous epinephrine injection (p < 0.05). Six of the eight children achieved maximum plasma concentrations by 5 minutes. The terminal elimination half-life was 43 +/- 15 minutes.

A review of fatal anaphylaxis epidemiology names delayed epinephrine administration as a risk factor for fatal food anaphylaxis, while also noting that fatal outcome is rare. (Source 18)

• Expert review, not systematic, Very low certainty.
• Size: not stated; a narrative review of epidemiological series.
• Who: people with food, drug and venom anaphylaxis.
• How long: not applicable.
• Result: fatal anaphylaxis constitutes less than 1% of total mortality risk even for people with known venom or food allergy; delayed epinephrine administration is listed as a risk factor for fatal food anaphylaxis.
• Funding: not stated.

Fatal food anaphylaxis most commonly occurs during the second and third decades. Delayed epinephrine administration is a risk factor; common triggers are nuts, seafood, and in children, milk.

The widely taught rule that epinephrine must never be used in a finger block is not supported: a literature review found no case of digital necrosis attributable to epinephrine in at least 2797 blocks. (Source 6)

• Expert review, not systematic, Low certainty.
• Size: 39 relevant articles including 12 randomised controlled trials and nine reviews; at least 2797 digital nerve blocks with epinephrine.
• Who: mostly healthy patients; most studies excluded people at risk of poor peripheral circulation.
• How long: not applicable.
• Result: no study reported digital necrosis or gangrene attributable to epinephrine; epinephrine at 1:100,000-200,000, that is 5-10 micrograms per millilitre.
• Funding: not stated.

No study reported digital necrosis or gangrene attributable to epinephrine, either in healthy patients or in patients with risk for poor peripheral circulation. In total, at least 2797 digital nerve blocks with epinephrine have been performed without any complications.

What the evidence does not support

A Cochrane review searching for randomised or quasi-randomised trials of adrenaline in anaphylaxis found none, and the reviewers kept the intramuscular recommendation while saying the evidence for it is less than optimal. (Source 19)

• Systematic review, Very low certainty.
• Size: no studies satisfied the inclusion criteria.
• Who: people being treated for anaphylaxis.
• How long: searches to March 2007 across CENTRAL, MEDLINE, EMBASE, CINAHL, BIOSIS, ISI Web of Knowledge and LILACS, plus trial registers and contact with manufacturers and experts.
• Result: no effect estimate exists because no trial was found.
• Funding: not stated.

RESULTS: We found no studies that satisfied the inclusion criteria. CONCLUSIONS: On the basis of this review, we are unable to make any new recommendations on the use of adrenaline for the treatment of anaphylaxis. In the absence of appropriate trials, we recommend, albeit on the basis of less than optimal evidence, that adrenaline administration by intramuscular injection should still be regarded as first-line treatment for the management of anaphylaxis.

The same authors are explicit that the subcutaneous recommendation they tested rested on anecdotal experience rather than measurement. (Source 17)

• Blood level study, Low certainty.
• Size: 17 children.
• Who: children with a history of anaphylaxis.
• How long: single dose.
• Result: no new numbers; the authors' interpretation.
• Funding: Research Support, Non-U.S. Gov't per the PubMed record.

In children, recommendations for subcutaneous epinephrine injection are based on anecdotal experience, and should be reevaluated in view of our finding of delayed epinephrine absorption when this route is used. This delay might have important clinical implications during an episode of systemic anaphylaxis. The intramuscular route of injection is preferable.

The author of that register states that the unpredictability of anaphylaxis and the need for improvised treatment make controlled trials impracticable, which is why the evidence base is what it is. (Source 12)

• Case series, Very low certainty.
• Size: the UK fatal anaphylaxis register.
• Who: people who died of anaphylaxis in the UK.
• How long: from 1992.
• Result: no effect estimate; a statement about study design.
• Funding: not stated.

Immediate recognition of anaphylaxis, early use of adrenaline, inhaled beta agonists and other measures are crucial for successful treatment. Nevertheless, a few reactions will be fatal whatever treatment is given; optimal management of anaphylaxis is therefore avoidance of the cause whenever this is possible.

Where the evidence is mixed

In the largest randomised placebo-controlled trial in out-of-hospital cardiac arrest, epinephrine raised 30-day survival but not survival with a favourable neurological outcome, and more of the survivors were severely impaired. (Source 3)

• Randomized trial, High certainty.
• Size: 8014 patients (4015 epinephrine, 3999 placebo)
• Who: adults with out-of-hospital cardiac arrest attended by five NHS ambulance services in the United Kingdom.
• How long: outcomes at 30 days and at hospital discharge.
• Result: alive at 30 days 130/4015 (3.2%) versus 94/3999 (2.4%), unadjusted OR 1.39 (95% CI 1.06 to 1.82, P=0.02), an absolute difference of 0.8 percentage points; survival to discharge with favourable neurologic outcome 87/4007 (2.2%) versus 74/3994 (1.9%), OR 1.18 (0.86 to 1.61); severe neurologic impairment among survivors 39/126 (31.0%) versus 16/90 (17.8%)
• Funding: UK National Institute for Health Research and others.

At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02). There was no evidence of a significant difference in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (87 of 4007 patients [2.2%] vs. 74 of 3994 patients [1.9%]; unadjusted odds ratio, 1.18; 95% CI, 0.86 to 1.61). At the time of hospital discharge, severe neurologic impairment (a score of 4 or 5 on the modified Rankin scale) had occurred in more of the survivors in the epinephrine group than in the placebo group (39 of 126 patients [31.0%] vs. 16 of 90 patients [17.8%]).

An earlier, smaller randomised placebo-controlled trial in cardiac arrest found adrenaline tripled the odds of restarting the heart but did not significantly improve survival to hospital discharge. (Source 20)

• Randomized trial, Moderate certainty.
• Size: 601 randomised, documentation available for 534 (272 adrenaline, 262 placebo), from 4103 arrests screened.
• Who: out-of-hospital cardiac arrest in Western Australia.
• How long: to hospital discharge.
• Result: return of spontaneous circulation 64/272 (23.5%) versus 22/262 (8.4%), OR 3.4 (95% CI 2.0-5.6); survival to hospital discharge 11 (4.0%) versus 5 (1.9%), OR 2.2 (95% CI 0.7-6.3)
• Funding: Research Support, Non-U.S. Gov't per the PubMed record.

ROSC occurred in 22 (8.4%) of patients receiving placebo and 64 (23.5%) who received adrenaline (OR=3.4; 95% CI 2.0-5.6). Survival to hospital discharge occurred in 5 (1.9%) and 11 (4.0%) patients receiving placebo or adrenaline respectively (OR=2.2; 95% CI 0.7-6.3). All but two patients (both in the adrenaline group) had a CPC score of 1-2. CONCLUSION: Patients receiving adrenaline during cardiac arrest had no statistically significant improvement in the primary outcome of survival to hospital discharge although there was a significantly improved likelihood of achieving ROSC.

For croup, a Cochrane review found nebulised epinephrine improved croup scores at 30 minutes but that the effect had gone by two and six hours, and none of the trials sought or reported adverse effects. (Source 4)

• Systematic review, Low certainty.
• Size: 8 studies, 225 participants.
• Who: children, mostly under two, with moderate to severe croup in an emergency department or hospital.
• How long: outcomes at 30 minutes, 2 hours and 6 hours.
• Result: croup score at 30 minutes SMD -0.94 (95% CI -1.37 to -0.51, 3 RCTs, I2 = 0%), not significant at 2 and 6 hours; hospital stay 32.0 hours shorter in one RCT (95% CI -59.1 to -4.9); no difference between racemic and L-epinephrine at 30 minutes.
• Funding: not stated.

Nebulized epinephrine was associated with croup score improvement 30 minutes post-treatment (three RCTs, standardized mean difference (SMD) -0.94; 95% confidence interval (CI) -1.37 to -0.51; I(2) statistic = 0%). This effect was not significant two and six hours post-treatment. Nebulized epinephrine was associated with significantly shorter hospital stay than placebo (one RCT, MD -32.0 hours; 95% CI -59.1 to -4.9). Comparing racemic and L-epinephrine, no difference in croup score was found after 30 minutes (SMD 0.33; 95% CI -0.42 to 1.08). After two hours, L-epinephrine showed significant reduction compared with racemic epinephrine (one RCT, SMD 0.87; 95% CI 0.09 to 1.65). There was no significant difference in croup score between administration of nebulized epinephrine via IPPB versus nebulization alone at 30 minutes (one RCT, SMD -0.14; 95% CI -1.24 to 0.95) or two hours (SMD -0.72; 95% CI -1.86 to 0.42). None of the studies sought or reported data on adverse effects.

For bronchiolitis, a Cochrane review found nebulised epinephrine reduced admissions on the first day for outpatients but not by day seven, and made no difference to length of stay for children already admitted. (Source 5)

• Systematic review, Low certainty.
• Size: 19 studies, 2256 participants.
• Who: children under two with acute viral bronchiolitis.
• How long: admissions at day 1 and day 7; length of stay for inpatients.
• Result: admissions at day 1 RR 0.67 (95% CI 0.50 to 0.89) versus placebo, not significant at day 7; no difference in length of stay for inpatients; versus salbutamol, inpatient length of stay shorter by 0.28 days (95% CI -0.46 to -0.09); no important differences in adverse events.
• Funding: not stated.

Epinephrine versus placebo among outpatients showed a significant reduction in admissions at Day 1 (risk ratio (RR) 0.67; 95% confidence interval (CI) 0.50 to 0.89) but not at Day 7 post-emergency department visit. There was no difference in LOS for inpatients.

The label names groups at greater risk of adverse reactions, including people with heart disease, and states in the same breath that none of those conditions is a contraindication in an acute, life-threatening situation. (Source 21)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: people with cardiac arrhythmias, coronary artery or organic heart disease, hypertension, hyperthyroidism, diabetes, elderly individuals, pregnant women and people with Parkinson's disease.
• How long: at the time of administration.
• Result: no rates given; epinephrine may precipitate or aggravate angina or produce ventricular arrhythmias in these patients.
• Funding: regulatory document.

Some patients may be at greater risk for developing adverse reactions after epinephrine administration. Despite these concerns, it should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation.

Where the research disagrees

Whether epinephrine-containing products carry a boxed warning. Parsing the boxed warning section (LOINC 34066-1) across the single-ingredient epinephrine labels - EpiPen and EpiPen Jr, Auvi-Q, Symjepi, neffy nasal spray, the Primatene Mist over-the-counter inhaler and plain epinephrine injection - returned no boxed warning section in any of them, while a combination product containing epinephrine does carry one, for a risk belonging to its other ingredient

• Single-ingredient epinephrine products (EpiPen and EpiPen Jr auto-injector, Auvi-Q, Symjepi, neffy nasal spray, Primatene Mist OTC inhaler, plain epinephrine injection), position: Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. (Source 14)
• Sensorcaine, a combination of bupivacaine hydrochloride and epinephrine bitartrate, position: WARNING: RISK OF CARDIAC ARREST WITH USE OF SENSORCAINE IN OBSTETRICAL ANESTHESIA There have been reports of cardiac arrest with difficult resuscitation or death during use of SENSORCAINE for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of SENSORCAINE is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary (Source 16)

Whether epinephrine improves outcome in cardiac arrest

• Perkins and colleagues, PARAMEDIC2, rct: In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group. (Source 3)
• Jacobs and colleagues, Western Australia randomised trial, rct: Patients receiving adrenaline during cardiac arrest had no statistically significant improvement in the primary outcome of survival to hospital discharge (Source 20)

What should be concluded when no randomised trial of adrenaline in anaphylaxis exists

• Sheikh and colleagues, Cochrane review, systematic-review: In the absence of appropriate trials, we recommend, albeit on the basis of less than optimal evidence, that adrenaline administration by intramuscular injection should still be regarded as first-line treatment for the management of anaphylaxis. (Source 19)
• Pumphrey, UK fatal anaphylaxis register, case-series: Nevertheless, a few reactions will be fatal whatever treatment is given; optimal management of anaphylaxis is therefore avoidance of the cause whenever this is possible. (Source 12)

How much

• Reference intake: Dosing is set by the prescriber and by the product. As a position, the FDA auto-injector label gives 0.3 mg for patients weighing 30 kg or more and 0.15 mg for patients of 15 kg to 30 kg, injected intramuscularly or subcutaneously into the anterolateral thigh. (Source 9)
• Upper limit: The label sets no numerical maximum dose; instead it states that more than two sequential doses should only be given under direct medical supervision. For patients needing less than 0.15 mg, it directs the prescriber to other forms of injectable epinephrine, because the auto-injector dose is fixed. The practical ceiling is set by harm: the label describes cerebral haemorrhage after accidental intravenous injection or large doses. (Source 9)
• Studied: The paediatric pharmacokinetic study gave 0.01 ml/kg of epinephrine solution subcutaneously to a maximum of 0.3 ml (0.3 mg), or 0.3 mg intramuscularly from an auto-injector. (Source 17)
• Studied: PARAMEDIC2 gave parenteral epinephrine or saline placebo to 8014 adults in out-of-hospital cardiac arrest alongside standard care; the Jacobs trial gave 1 ml aliquots of adrenaline 1:1000 or saline placebo according to advanced life support guidelines. (Source 20)
• Studied: The digital block literature used epinephrine at 1:100,000 to 1:200,000, which the review states is 5 to 10 micrograms per millilitre, mixed with local anaesthetic. (Source 6)

A common belief, and what the research shows

The belief: Epinephrine must never be injected into a finger or toe, because it will cause the digit to die.

What the research shows: A review of the literature on digital nerve blocks found the opposite of a documented harm: "No study reported digital necrosis or gangrene attributable to epinephrine, either in healthy patients or in patients with risk for poor peripheral circulation." and "A lack of reported complications suggests that the risk of epinephrine-induced vasoconstriction to digits may be overstated." Two things keep this from being a general all-clear. Most of those studies excluded people at risk of poor peripheral circulation. And the concentrations are not comparable: a digital block uses 5-10 micrograms per millilitre mixed with local anaesthetic, whereas an accidental auto-injector discharge delivers a whole 0.3 mg dose into the finger, which the FDA label warns may cause loss of blood flow to the affected area.

Questions and answers

What is it?

Epinephrine, also called adrenaline, is a catecholamine your adrenal glands produce and which is also made as a medicine. It comes in very different products: single-dose auto-injectors of 0.3 mg or 0.15 mg for anaphylaxis, vials for hospital use, a nasal spray, an over-the-counter inhaler, and as an additive in local anaesthetics. The amounts are small and the units matter: an adult auto-injector holds 0.3 mg of epinephrine in 0.3 mL of solution. (Source 9)

What does it do in the body?

It acts on both alpha- and beta-adrenergic receptors. Through the alpha receptors it tightens blood vessels, countering the widening and leaking that drops blood pressure in anaphylaxis. Through the beta receptors it relaxes airway muscle, easing wheeze and breathlessness. It also eases itch, hives and swelling. Given into muscle or under the skin it starts quickly and wears off quickly, which is why a second dose can be needed. (Source 1)

Is it good or bad for you?

For anaphylaxis, the whole field treats it as the first-line treatment, while being open that no randomised trial supports that. For cardiac arrest, randomised trials show it restarts more hearts and buys a small survival gain, but no gain in survival with good neurological function, and more severely impaired survivors. The harms recorded in the literature come mostly from the wrong route, the wrong site or the wrong dose, including deaths from overdose and a much higher adverse event rate when given as an intravenous bolus instead of into muscle. (Source 11)

How do you get more of it?

There is no food or supplement route to therapeutic epinephrine; your own adrenal glands make the body's supply. An auto-injector is obtained on prescription and the dose is fixed by the device at 0.3 mg or 0.15 mg, chosen by body weight. What the literature says you can influence is whether a dose that is given actually lands in muscle: ultrasound studies show auto-injector needle lengths often miss muscle, and injecting through winter clothing increases the chance the drug goes into fat instead. (Source 13)

If it is harmful, what reduces it?

You cannot speed up clearance, and you would rarely want to: the terminal elimination half-life measured in children was about 43 minutes. When too much has been given, the label describes treating the consequences rather than removing the drug, with rapidly acting vasodilators or alpha-blocking drugs and respiratory support for the blood pressure effects, and a beta-blocker such as propranolol for arrhythmias. (Source 15)

Why might someone be low in it or missing it?

This is not a nutrient you can be low in. The question that matters in practice is why someone at risk of anaphylaxis does not have a working dose available when they need it. The UK fatal anaphylaxis register found adrenaline was used in 62% of fatal reactions but given before arrest in only 14%, and the author reported that self-treatment kits had proved unhelpful for a variety of reasons, depending on the right medication being chosen, the device being easy to use, and good training. (Source 12)

Which whole foods contain it or feed it?

No whole food contains therapeutic epinephrine. The food connection in the literature runs two other ways. Foods are the commonest triggers of the fatal anaphylaxis the drug treats, with nuts, seafood and, in children, milk named in the epidemiology. And the preservative in the auto-injector is a sulfite of the same class used in foods and wine, which the label addresses directly. (Source 18)

What happens if you do not have it?

For someone having anaphylaxis with no epinephrine available, the observational evidence is that delay is a risk factor for a fatal outcome, though fatal anaphylaxis is rare even among people with known food or venom allergy, at under 1% of total mortality risk. The timings matter: in the UK register the median time to respiratory or cardiac arrest was 30 minutes for food reactions, 15 minutes for venom and 5 minutes for reactions to medicines. None of this comes from a randomised trial. (Source 12)

How can you test for it?

There is no test for whether you need epinephrine or whether a dose worked; the decision is clinical, on the pattern of symptoms the label describes. Plasma epinephrine concentrations can be measured, and that is how the route comparison was done, but it is a research measurement, not a clinical one. Ultrasound can measure skin-to-muscle distance, which is how the needle-length studies showed that approved auto-injector needles often do not reach muscle, and that is the closest thing to a test of whether a device suits a particular person. (Source 2)

References

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2. DailyMed / Viatris Specialty LLC, labeler of record for SPL version 37 (published 12 February 2025); the label's own How Supplied text still reads "Manufactured for Mylan Specialty L.P.". EPIPEN and EPIPEN Jr (epinephrine injection, auto-injector) - FDA label, 1 INDICATIONS AND USAGE. 2025. Read the source
3. The New England journal of medicine. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.. 2018. PMID 30021076, DOI 10.1056/NEJMoa1806842. Read the source
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8. DailyMed / Viatris Specialty LLC, labeler of record for SPL version 37 (published 12 February 2025); the label's own How Supplied text still reads "Manufactured for Mylan Specialty L.P.". EPIPEN and EPIPEN Jr (epinephrine injection, auto-injector) - FDA label, 5.4 Allergic Reactions Associated with Sulfite. 2025. Read the source
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13. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. Epinephrine auto-injector needle length: The impact of winter clothing.. 2020. PMID 32322286, DOI 10.1186/s13223-020-00422-4. Read the source
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17. The Journal of allergy and clinical immunology. Epinephrine absorption in children with a history of anaphylaxis.. 1998. PMID 9449498, DOI 10.1016/S0091-6749(98)70190-3. Read the source
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21. DailyMed / Viatris Specialty LLC, labeler of record for SPL version 37 (published 12 February 2025); the label's own How Supplied text still reads "Manufactured for Mylan Specialty L.P.". EPIPEN and EPIPEN Jr (epinephrine injection, auto-injector) - FDA label, 5.5 Disease Interactions. 2025. Read the source