The Journal of Allergy and Clinical Immunology
Volume 101, Issue 1 , Pages 33-37, January 1998

Epinephrine absorption in children with a history of anaphylaxis☆☆☆★★★

Winnipeg, Manitoba, Canada

Received 8 July 1997; received in revised form 3 September 1997; accepted 8 September 1997.

Article Outline

Abstract 

Background: Prompt injection of epinephrine is the cornerstone of systemic anaphylaxis treatment. The rate of epinephrine absorption has not been reported previously in allergic children. Objective: Our objective was to study the clinical pharmacology of epinephrine in this population. Methods: We performed a prospective, randomized, blinded, parallel-group study in 17 children with a history of anaphylaxis to food, Hymenoptera venom, or other substances. We injected 0.01 ml/kg epinephrine solution (maximum 0.3 ml [0.3 mg]) subcutaneously, or 0.3 mg epinephrine intramuscularly from an autoinjector. Plasma epinephrine concentrations, heart rate, blood pressure, and adverse effects were monitored. Results: 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. No serious adverse effects were noted in any child. Conclusions: 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. (J Allergy Clin Immunol 1998;101:33-7.)

Keywords:  Epinephrine absorption, subcutaneous/intramuscular injection, children, systemic anaphylaxis, food/venom allergy

Abbreviations:  cAMP , Cyclic adenosine monophosphate

 

Epinephrine injection is the treatment of first choice in systemic anaphylaxis1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11; indeed, failure to inject epinephrine promptly has been identified as the most important factor contributing to death in patients with this disorder.1 In standard textbooks and other references, the subcutaneous route of epinephrine injection,4, 5, 6, 7, 8 or a choice of the subcutaneous route or the intramuscular route,9, 10, 11 are recommended for use in children with anaphylaxis. The intramuscular route is seldom given as the preferred option. There is no published information about the pharmacokinetics of epinephrine or about the rate of epinephrine absorption after injection by either of these routes in this population.

We hypothesized that epinephrine would be absorbed less rapidly after subcutaneous injection than after intramuscular injection.

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METHODS 

We tested this hypothesis in a randomized, single-blind, single-dose, parallel-group pilot study in 17 children who received either a subcutaneous injection of 0.01 ml/kg epinephrine hydrochloride solution (maximum, 0.3 ml [0.3 mg]) or an intramuscular injection of 0.3 ml (0.3 mg) with the EpiPen Auto-Injector (Allerex Laboratory, Ltd., Kanata, Ontario, Canada).

The study was approved by the University of Manitoba Faculty Committee on the Use of Human Subjects in Research. Before entry into the study, assent was obtained from each child, and written informed consent was obtained from the parent of each child.

Subject selection 

Children were eligible to participate if they were 4 to 12 years old, weighed 15 to 40 kg, had a history of severe allergies and systemic anaphylaxis, and carried injectable epinephrine with them at all times in case they inadvertently reencountered the allergen that had previously triggered their anaphylaxis. They were excluded from participation if they did not assent to epinephrine injection and venipuncture, had a recent acute illness, required any oral or injected medication during the month before the study or during the study, or could not discontinue inhaled β 2-adrenergic agents, such as albuterol (Ventolin), for 24 hours before the study or during the study. The only medications permitted on the study day were inhaled glucocorticoids for asthma and intranasal glucocorticoids for allergic rhinitis.

Study outline 

During a preliminary visit, subjects were assessed for their ability to meet the inclusion criteria of the study. Their medical histories were reviewed and physical examinations were performed. They were given the opportunity to discuss the epinephrine injection and the test procedures.

On the study day, they arrived at the Health Sciences Clinical Research Center Allergy Laboratory at 1230 hours. They abstained from ingestion of methylxanthine-containing dietary items (e.g., chocolate, cocoa, or cola) for 24 hours before and during the study. An indwelling venous catheter was inserted after application of EMLA local anesthetic cream (Astra Pharma Inc., Mississauga, Ontario, Canada) to the site of venipuncture. As a safety measure, monitoring of systolic and diastolic blood pressure and heart rate and rhythm was begun (Dinamap Vital Signs Monitor from Critikon, Inc., Johnson & Johnson Company, Tampa, Fla.; and Cardiograph PageWriter XLi (M1700A) from the Hewlett-Packard Company, McMinnville, Ore., respectively).

The children were randomly assigned to receive a single injection of epinephrine subcutaneously or intramuscularly at approximately 1330 hours in a treatment room adjacent to the Allergy Laboratory in which the study took place, administered by a nurse not otherwise involved in the study. The injection site was covered.

The epinephrine formulation injected subcutaneously in a dose of 0.01 ml/kg (0.01 mg/kg, maximum 0.3 ml [0.3 mg]) was Adrenaline (1 mg/ml ampule; Parke-Davis, Scarborough, Ontario, Canada).12 The epinephrine formulation used for intramuscular injection in a dose of 0.3 mg was the EpiPen Auto-Injector.12

Before injection and at 5, 10, 15, 20, 30, 40, 60, 90, 120, and 180 minutes afterwards, a 3.5 ml blood sample for plasma epinephrine measurement was obtained from the indwelling venous catheter. Before injection and at 30, 60, 120, and 180 minutes afterwards, systolic and diastolic blood pressure and heart rate were monitored, and a rhythm strip was obtained. The children rested quietly for 5 minutes before these measurements were recorded. If heart rate and blood pressure were elevated at the end of the study, they were monitored until they returned to predose baseline values. At the time of blood sampling, any adverse effects observed or reported in response to direct questioning were recorded on the case record forms.

Measurement of plasma epinephrine concentrations 

Blood samples were centrifuged at 4° C. Plasma was transferred into an appropriately labeled polypropylene tube with screw cap, frozen promptly in an upright position, and stored at –20° C until analysis.

After thawing the plasma, solid/liquid-phase extraction was performed, with an efficiency of 75% to 80%. Epinephrine concentrations were measured with a high-performance liquid chromatography (HPLC) reverse-phase system (Waters Corp., Milford, Mass.) with electrochemical detection.13 With modification of this assay, it was possible to detect as little as 5 pg/ml (0.025 nmol/ml) of epinephrine. Calibration curves were linear over the range 25 to 1000 pg/ml (0.125 to 5 nmol/ml) with a coefficient of variation of 3% at 1000 pg and 10% at 25 pg.

Data analysis 

Epinephrine pharmacokinetic parameters were calculated from plasma epinephrine concentration versus time plots by using standard pharmacokinetic equations and the computer program PCNONLIN (Scientific Consulting, Apex, N.C.).

Blood pressure and heart rate versus plasma epinephrine concentrations were evaluated over time after epinephrine administration by using PCSAS computer programs, analysis of variance, analysis of covariance, and linear regression analyses. Differences were considered to be significant at p < 0.05.14

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RESULTS 

All the children participating in this study had a history of systemic anaphylaxis. Each child had an EpiPen available “around-the-clock” in case inadvertent contact with the allergen to which he or she was sensitive triggered another episode of anaphylaxis. The demographics of the two groups of children were similar (Table I).

TABLE I. Demographic data
Epinephrine solution (subcutaneous)EpiPen Auto-injector (intramuscular)
No. of children in group98
Age (mean ± SEM [range])8 ± 1 yr (4-12)8 ± 1 yr (7-11)
Weight (mean ± SEM [range])32 ± 3 kg (19.1-34.5)27 ± 2 kg (18.5-39.3)
History of anaphylaxis to: (no. of subjects)peanut, tree nut, or both (5); fish (1); venom (1); other (2)peanut, tree nut, or both, (4); fish (1); milk (1); venom (1); other (1)
EpiPen available98
History of inhalant allergies, asthma, or rhinitis87

In nine children with preinjection baseline plasma epinephrine concentrations of 285 ± 32 pg/ml (mean ± SEM) who received epinephrine subcutaneously, the mean peak plasma epinephrine concentration was 1802 ± 214 pg/ml. The mean time at which maximum plasma epinephrine concentrations were reached was 34 ± 14 minutes (range, 5 to 120 minutes). Only two of the nine children achieved their maximum plasma epinephrine concentration by 5 minutes. The area under the plasma epinephrine concentration versus time curve from 0 to 3 hours was 67 ± 13 ng/ml/min. After subcutaneous epinephrine injection, absorption was so variable that it was not possible to calculate reliable terminal elimination half-life values, clearance rates, or volumes of distribution (Table II, Fig. 1).

  • View full-size image.
  • FIG. 1. 

    Mean plasma epinephrine concentration versus time plot after injection of epinephrine subcutaneously in nine children and after injection of epinephrine intramuscularly in eight children.

TABLE II. The pharmacokinetics of epinephrine
Mean ± SEMEpinephrine solution (subcutaneous)EpiPen Auto-injector (intramuscular)
Epinephrine dose (mg) ± SEM0.27 ± 0.04*0.3
C baseline (pg/ml)285 ± 32339 ± 115
C max (pg/ml)1802 ± 2142136 ± 351
t max (min)34 ± 14†8 ± 2†
t 1/2 (min)—43 ± 15
AUC (ng/ml/min)67 ± 13108 ± 18
Cl (ml/min/kg)—147 ± 38
Vd ss (L/kg)—2.0 ± 1.5

C baseline, Baseline plasma concentration; C max, maximum plasma concentration; t max, time at which maximum plasma concentration was achieved; t 1/2, terminal elimination half-life; AUC, area under the plasma concentration versus time curve (t = 0 to 3hr, subcutaneous; t = 0 to infinity, intramuscular); Cl, total body clearance; Vd ss, volume of distribution at steady state.

*Six of 9 children received 0.3 mg; 1 of 9 received 0.20 mg; 1 of 9 received 0.23 mg; and 1 of 9 received 0.24 mg.

†p < 0.05.

In eight children with a preinjection baseline plasma epinephrine concentration of 339 ± 115 pg/ml who received epinephrine intramuscularly, the mean maximum plasma epinephrine concentration was 2136 ± 351 pg/ml. The mean time at which maximum plasma epinephrine concentrations were reached was 8 ± 2 minutes (p < 0.05 compared with the mean time at which maximum plasma epinephrine concentrations were achieved after subcutaneous injection). Six of the eight children achieved their maximum plasma epinephrine concentration by 5 minutes. The area under the plasma epinephrine concentration versus time curve extrapolated to infinity was 108 ± 18 ng/ml/min. The terminal elimination epinephrine half-life was 43 ± 15 minutes, the clearance rate was 147 ± 38 ml/min/kg, and the apparent volume of distribution was 2.0 ± 1.5 L/kg (Table II, Fig. 1).

No serious adverse effects occurred after epinephrine injection in any child. The following transient signs and symptoms were observed or reported: tremor (16 of 17 children), pallor (14 of 17), headache (4 of 17), tingling of the extremities (3 of 17), and nausea (1 of 17). Although an increase in heart rate and diastolic and systolic blood pressure occurred at the time of peak plasma epinephrine concentrations in a few children (Figure 2, A and B), most peak values were within the wide range of normal values,15 and overall no correlations were found between changes in vital signs and epinephrine concentrations.

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  • FIG. 2. 

    A, Systolic and diastolic blood pressure, heart rate, and plasma epinephrine concentration in a child receiving epinephrine subcutaneously. B, Systolic and diastolic blood pressure, heart rate, and plasma epinephrine concentration in a child receiving epinephrine intramuscularly.

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DISCUSSION 

The epinephrine doses and routes of administration selected for testing were based on current published recommendations.3, 4, 5, 6, 7, 8, 9, 10, 11, 12 Ideally, the study would have been conducted in children during an actual episode of systemic anaphylaxis. As frequent timed blood samples are extremely difficult to obtain prospectively during a medical emergency when all efforts are focused on preservation of life, we opted instead to conduct it in highly allergic children at risk for anaphylaxis.

The study had a randomized, single-blind design rather than a double-blind, double-dummy design because it was not considered ethical to administer two injections to young children. It is highly unlikely that the single-blind design affected our findings. The primary outcome measures, plasma epinephrine concentrations, were determined in a laboratory several kilometers away by investigators who, like the nurse and physician monitoring the child, were unaware of the route by which the epinephrine had been injected.

After injection, epinephrine is inactivated in the liver. It is either methylated by catechol-O-methyltransferase to metanephrine; or, alternatively, oxidatively deaminated by monoamine oxidase to 3,4-dihydroxyphenyl glycolaldehyde and then reduced to 3,4-dihydroxyphenyl ethylene glycol or oxidized to 3,4-dihydroxy-mandelic acid.17 The rate of epinephrine elimination has not been reported previously in young subjects with allergic disorders, although epinephrine injections have been the treatment of choice in systemic anaphylaxis for most of the twentieth century and were commonly used for acute asthma treatment until the mid-1980s.16 In this study both endogenous and exogenous plasma epinephrine concentrations were measured with the HPLC assay. The preinjection baseline (presumably endogenous) plasma epinephrine concentrations found (285 ± 32 to 339 ± 115 pg/ml) were higher than those found in 10 healthy adult control subjects studied concurrently in our laboratory, in whom baseline endogenous plasma epinephrine concentrations ranged from 141 ± 22 pg/ml to 173  ± 34 pg/ml on two different study days. On one of these study days, the ten adult control subjects were monitored for 120 minutes without receiving any epinephrine injections, and during that time their endogenous plasma epinephrine concentrations peaked at 237 ± 33 pg/ml.

In the children in this study receiving epinephrine subcutaneously, compared with those receiving it intramuscularly, epinephrine absorption was delayed. This was evidenced by a significant increase in the time at which the mean maximal plasma epinephrine concentrations were reached. Epinephrine is a potent vasopressor with direct α-adrenergic actions on the vasculature, chiefly on the precapillary arterioles and small venules. Our documentation, for the first time, of delayed epinephrine absorption after subcutaneous injection in allergic children is not surprising in view of its known vasoconstrictor action in the skin and marked ability to decrease cutaneous blood flow.17

The epinephrine clearance rate of 147 ± 38 ml/min/kg (range, 56 to 347 ml/min/kg) found in our study was faster than the clearance rate of 34 ± 9 ml/min/kg (range, 20 to 79 ml/min/kg) reported in the only other published study of epinephrine pharmacokinetics in children. The pediatric population investigated and the route of epinephrine injection differ considerably in the two studies. The previous study was conducted in an intensive care unit with six critically ill, comatose, hypotensive children over a wide age range (7 months to 16 years) who were receiving steady-state epinephrine infusions of 0.03 to 0.2 μg/kg/min for the purpose of maintaining blood pressure and cardiac output.18

In anaphylaxis, the vasopressive effects of epinephrine, along with its effects in preventing and relieving laryngeal edema and bronchoconstriction, may be life-saving.17 The ability of epinephrine to suppress release of chemical mediators of inflammation from mast cells and basophils is also of considerable importance.19, 20 In vitro, inhibition of mediator release through activation of membrane-bound adenylate cyclase and elevation of cyclic adenosine monophosphate (cAMP) are concentration-dependent and bidirectional (i.e., inhibited by high concentrations of cAMP and enhanced by low concentrations of cAMP).19 Although plasma and tissue epinephrine concentrations required for symptom relief and inhibition of release of chemical mediators have not been determined in vivo in humans with anaphylaxis, achieving high epinephrine concentrations rapidly is thought to be crucial to survival.1

No serious adverse effects were observed or reported after epinephrine injection in the children in this study; indeed, adverse effects were less frequently noted than in our previous study of epinephrine in children with asthma.16 Their absence is important because concerns are often raised about children weighing 15 to 30 kg receiving the same maximum epinephrine dose (0.3 ml [0.3 mg]) as larger children and adults, and thus receiving a relatively higher dose on a milligram per kilogram basis than older children and adults. The transient adverse effects noted immediately after injection, and the high preinjection baseline endogenous plasma epinephrine concentrations, may have been caused by the childrens' anxiety about receiving an injection and a venipuncture.

Our finding of delayed epinephrine absorption after subcutaneous injection might have important clinical implications during life-threatening episodes of anaphylaxis. Although failure to administer epinephrine promptly has been identified as the most important factor contributing to death in children and adolescents with anaphylaxis,1 even when epinephrine is injected promptly, it is not always effective.1, 2, 3 This is believed to occur because some anaphylactic reactions progress extremely rapidly. Another disturbing possibility raised by the results of this study is that in some patients with anaphylaxis, subcutaneously injected epinephrine may not be absorbed rapidly enough to prevent and relieve symptoms. Recommendations for subcutaneous epinephrine injection are based on anecdotal experience and should be reevaluated. The intramuscular route of injection is preferable in children. Additional prospective studies of epinephrine pharmacokinetics and pharmacodynamics are required in children with systemic anaphylaxis.

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Acknowledgements 

We thank Mrs. Diane Dilay, RN, and Mrs. Cathy Gillespie, RN, for their expertise.

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References 

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☆ From athe Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, Faculty of Medicine and bthe Division of Pharmaceutical Sciences, Faculty of Pharmacy, University of Manitoba, Winnipeg.

☆☆ Supported by the Children's Hospital Research Foundation.

★ Reprint requests: F. Estelle R. Simons, MD, FRCPC, Children's Hospital of Winnipeg, 820 Sherbrook Street, Winnipeg, Manitoba, Canada, R3A 1R9.

★★ 1/1/85986

PII: S0091-6749(98)70190-3

The Journal of Allergy and Clinical Immunology
Volume 101, Issue 1 , Pages 33-37, January 1998

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