Epinephrine Pharmacokinetics Research Articles

To the ER? Can Patients Treat Their Anaphylaxis at Home?

To discuss if all patients who use self-injectable epinephrine outside the hospital setting require immediate emergency care. Prior to 2023, anaphylaxis management guidance universally recommended that patients who use self-injectable epinephrine outside of the hospital or clinic setting immediately activate emergency medical services and seek further care. Additional food-induced anaphylaxis management recommendations specified that all patients always carry 2 auto-injector devices and give a second dose of epinephrine if there was not immediate response within 5min of injection. Patients presenting for emergency care after epinephrine are often observed for up to 4-6h afterwards, even when completely asymptomatic. These management steps have lacked evidence for improving outcomes, and universal implementation of these approaches is not cost-effective as guidance for food allergic patients. Epinephrine pharmacokinetics and pharmacodynamics suggest that peak physiologic response is more likely to occur closer to 15min than before 5min, that few patients require a second dose of epinephrine as most stabilize within 15min of use, that 60min of observation after a patient stabilizes after epinephrine use may be adequate as patients infrequently have further sequelae, and that not everyone needs to carry 2 epinephrine auto-injectors on their person at all times. The most recent anaphylaxis practice parameter promotes a contextualized approach to these management questions, outlining the option for watchful waiting to gauge response to epinephrine before seeking emergency care, which has been proven as a more cost-effective management strategy. The recent updated anaphylaxis care guidelines support the evolution of anaphylaxis care, in that universal, immediate activation of emergency services is not required for using self-injectable epinephrine outside the hospital setting.

Pharmacokinetics of epinephrine during cardiac arrest: A pilot study

Aim of the studyEpinephrine has been recommended for several decades for the treatment of cardiac arrest. However, although this potent medicament has a documented impact on the return of spontaneous circulation, it does not improve long-term survival. Decreased cerebral blood flow, one of the side effects of epinephrine, indicates that the use of this drug is a two-edged sword. Despite clinical recommendations, no study has investigated epinephrine pharmacokinetics in a setting of cardiac arrest. Therefore, in a pilot setting, we measured the plasma concentrations of epinephrine following a single administration. MethodsNine patients with cardiac arrest were included in our study. A single dose of 1 mg epinephrine was administered into a peripheral vein. Simultaneously, blood samples were withdrawn every minute from the jugular vein to determine the plasma concentration. A mixed effects model was used to estimate the T1/2 following the peak concentration. ResultsOne patient did not achieve a peak concentration during observation and was hence excluded. The remaining eight patients had 26 measurements suitable for modelling. In a stable model, the decline is estimated to be −0.259 [95 % CI (-0.361, −0.157) (p < 0.001)]. This implies a half-time for epinephrine of 2.6 (1.9, 4.4) minutes. ConclusionOur study indicates that elimination of epinephrine during cardiac arrest is prolonged and that repeated doses of epinephrine may lead to increased plasma levels. Further and larger studies are warranted to determine the optimal plasma concentration during resuscitation.Clinical trial registration: NCT03036202.Institutional protocol number: 2016-00189.

A Single-Period, Single-Dose Study of the Pharmacokinetics of Epinephrine After Administration of Intranasal ARS-1 to Pediatric Subjects with a History of Systemic Allergic Reaction

An epinephrine nasal spray (ARS-1) is being developed as a needle-free alternative to autoinjectors for the emergency treatment of systemic allergic reactions including anaphylaxis in children and adults. This study aims to assess the pharmacokinetics of epinephrine after intranasal (IN) administration of ARS-1 in pediatric atopic allergy subjects.

Randomised trial of epinephrine dose and flush volume in term newborn lambs

ObjectivesNeonatal resuscitation guidelines recommend 0.5–1 mL saline flush following 0.01–0.03 mg/kg of epinephrine via low umbilical venous catheter for persistent bradycardia despite effective positive pressure ventilation (PPV) and chest compressions...

Epinephrine delivery via EpiPen\xae Auto-Injector or manual syringe across participants with a wide range of skin-to-muscle distances

BackgroundIntramuscular (IM) injection of epinephrine (adrenaline) at the mid-anterolateral (AL) thigh is the international standard therapy for acute anaphylaxis. Concerns exist regarding implications of epinephrine auto-injector needles not penetrating the muscle in patients with greater skin-to-muscle-distances (STMD).MethodsThis open-label, randomized, crossover study investigated pharmacokinetics and pharmacodynamics following injection of epinephrine in healthy volunteers. Individuals were stratified by maximally compressed STMD (low, < 15 mm; moderate, 15–20 mm; high, > 20 mm). Participants received epinephrine injections via EpiPen® Auto-Injector (EpiPen; 0.3 mg/0.3 mL) or IM syringe (0.3 mg/0.3 mL) at mid-AL thigh or received saline by IM syringe in a randomized order. Eligible participants received a fourth treatment (EpiPen [0.3 mg/0.3 mL] at distal-AL thigh). Model-independent pharmacokinetic parameters and pharmacodynamics were assessed.ResultsThere were numerical trends toward higher peak epinephrine concentrations (0.52 vs 0.35 ng/mL; geometric mean ratio, 1.40; 90% CI 117.6–164.6%) and more rapid exposure (time to peak concentration, 20 vs 50 min) for EpiPen vs IM syringe at mid-AL thigh across STMD groups. Absorption was faster over the first 30 min for EpiPen vs IM syringe (partial area under curve [AUC] over first 30 min: geometric mean ratio, 2.13; 90% CI 159.0–285.0%). Overall exposure based on AUC to the last measurable concentration was similar for EpiPen vs IM syringe (geometric mean ratio, 1.13; 90% CI 98.8–129.8%). Epinephrine pharmacokinetics after EpiPen injection were similar across STMD groups. Treatments were well tolerated.ConclusionsEpinephrine delivery via EpiPen resulted in greater early systemic exposure to epinephrine vs IM syringe as assessed by epinephrine plasma levels. Delivery via EpiPen was consistent across participants with a wide range of STMD, even when the needle may not have penetrated the muscle.Trial registrationsThis trial was registered with the German Clinical Trials Register (DRKS-ID: DRKS00011263; secondary ID, EudraCT 2016-000104-29) on 23 March 2017.

Tibial Intraosseous Administration of Epinephrine Is Effective in Restoring Return of Spontaneous Circulation in a Pediatric Normovolemic But Not Hypovolemic Cardiac Arrest Model.

We compared the efficacy of tibial intraosseous (TIO) administration of epinephrine in a pediatric normovolemic versus hypovolemic cardiac arrest model to determine the incidence of return of spontaneous circulation (ROSC) and plasma epinephrine concentrations over time. This experimental study evaluated the pharmacokinetics of epinephrine and/or incidence of ROSC after TIO administration in either a normovolemic or hypovolemic pediatric swine model. All subjects in the TIO normovolemia cardiac arrest group experienced ROSC after TIO administration of epinephrine. In contrast, subjects experiencing hypovolemia and cardiac arrest were significantly less likely to experience ROSC when epinephrine was administered TIO versus intravenous (TIO hypovolemia: 14% [1/7] vs IV hypovolemia: 71% [5/7]; P = 0.031). The TIO hypovolemia group exhibited significantly lower plasma epinephrine concentrations versus IV hypovolemia at 60, 90, 120, and 150 seconds (P < 0.05). Although the maximum concentration of plasma epinephrine was similar, the TIO hypovolemia group exhibited significantly slower time to maximum concentration times versus TIO normovolemia subjects (P = 0.004). Tibial intraosseous administration of epinephrine reliably facilitated ROSC among normovolemic cardiac arrest pediatric patients, which is consistent with published reports. However, TIO administration of epinephrine was ineffective in restoring ROSC among subjects experiencing hypovolemia and cardiac arrest. Tibial intraosseous-administered epinephrine during hypovolemia and cardiac arrest may have resulted in a potential sequestration of epinephrine in the tibia. Central or peripheral intravascular access attempts should not be abandoned after successful TIO placement in the resuscitation of patients experiencing concurrent hypovolemia and cardiac arrest.

Intranasal epinephrine effects on epinephrine pharmacokinetics and heart rate in a nasal congestion canine model

BackgroundHistamine release and vasodilation during an allergic reaction can alter the pharmacokinetics of drugs administered via the intranasal (IN) route. The current study evaluated the effects of histamine-induced nasal congestion on epinephrine pharmacokinetics and heart rate changes after IN epinephrine.MethodsDogs received 5% histamine or saline IN followed by 4 mg epinephrine IN. Nasal restriction pressure, epinephrine concentration, and heart rate were assessed. Maximum concentration (Cmax), area under plasma concentration-time curve from 1 to 90 min (AUC1–90), and time to reach Cmax (Tmax) were measured. Clinical observations were documented.ResultsIn the 12 dogs in this study, nasal congestion occurred at 5–10 min after IN histamine administration versus no nasal congestion after IN saline. After administration of IN epinephrine, IN histamine-mediated nasal congestion was significantly reduced to baseline levels at 60, 80, and 100 min. There were no significant differences in Cmax and AUC1–90 between histamine and saline groups after IN epinephrine delivery (3.5 vs 1.7 ng/mL, p = 0.06, and 117 vs 59 ng/mL*minutes, p = 0.09, respectively). After receiving IN epinephrine, the histamine group had a significantly lower Tmax versus the saline group (6 vs 70 min, respectively; p = 0.02). Following IN epinephrine administration, the histamine group showed rapidly increased heart rate at 5 min, while there was a delayed increase in heart rate (occurring 30–60 min after administration) in the saline group. Clinical observations included salivation and emesis.ConclusionIN histamine led to more rapid epinephrine absorption and immediately increased heart rate compared with IN saline. IN epinephrine decreased histamine-induced nasal congestion.

Epinephrine in the Management of Anaphylaxis

Epinephrine is life-saving and the only first-line medication in the management of anaphylaxis. At therapeutic doses, it acts rapidly to reverse nearly all symptoms of anaphylaxis, and stabilize mast cells. The standard approved doses administered intramuscularly in the lateral thigh have a long track record for safe and effective use, but more information is needed on epinephrine pharmacokinetics and pharmacodynamics to ensure that current dosing strategies are optimal. Epinephrine should be administered promptly once anaphylaxis is suspected, to minimize morbidity and mortality. Providers on the front-line for managing patients with life-threatening allergic reactions need clear parameters and tools to guide the appropriate use of epinephrine, which take into account the potential evolution of symptoms and signs over time. All patients at risk for anaphylaxis should carry 2 epinephrine autoinjectors and be taught and able to demonstrate how to use them. Epinephrine autoinjectors need to be affordable, readily available, and easy for patients with allergies to carry and use. Furthermore, these devices should be available to meet the needs of all patients, from small infants through large or obese adults. The ideal means for storing and delivering epinephrine in prehospital and hospital environments warrants further study, to determine how to best balance efficiency, safety, and costs.

Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status

IntroductionIn septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock.MethodsThirty-eight consecutive adult patients with septic shock were prospectively recruited immediately before epinephrine infusion. A baseline blood sample (C0) was taken to assess endogenous epinephrine, norepinephrine, renin, aldosterone, and plasma cortisol levels before epinephrine infusion. At a fixed cumulative epinephrine dose adjusted to body weight and under steady-state infusion, a second blood sample (C1) was taken to assess epinephrine and norepinephrine concentrations. Data were analyzed using the nonlinear mixed effect modeling software program NONMEM.ResultsPlasma epinephrine concentrations ranged from 4.4 to 540 nmol/L at steady-state infusion (range 0.1 to 7 mg/hr; 0.026 to 1.67 μg/kg/min). A one-compartment model adequately described the data. Only body weight (BW) and New Simplified Acute Physiologic Score (SAPSII) at intensive care unit admission significantly influenced epinephrine clearance: CL (L/hr) = 127 × (BW/70)0.60 × (SAPS II/50)-0.67. The corresponding half-life was 3.5 minutes. Endogenous norepinephrine plasma concentration significantly decreased during epinephrine infusion (median (range) 8.8 (1 – 56.7) at C0 vs. 4.5 (0.3 – 38.9) nmol/L at C1, P < 0.001).ConclusionsEpinephrine pharmacokinetics is linear in septic shock patients, without any saturation at high doses. Basal neurohormonal status does not influence epinephrine pharmacokinetics. Exogenous epinephrine may alter the endogenous norepinephrine metabolism in septic patients.

Pharmacokinetics and safety of epinephrine use in liposuction.

Patients are routinely exposed to high-dose epinephrine infiltration during large-volume liposuction. Because of the serious cardiovascular side-effect profile of catecholamine overdose, the authors examined the safety of larger-volume liposuction by assessing epinephrine pharmacokinetics. Five female volunteers with American Society of Anesthesiologists physical status of I or II, aged 29 to 40 years and weighing 75.9 to 95 kg, underwent liposuction. The wetting solution contained 7.3 mg (SEM, 0.7 mg) of epinephrine, corresponding to 0.09 mg/kg (0.04 mg/kg). Total plasma epinephrine and norepinephrine concentrations were assessed by high-performance liquid chromatography. Approximate exogenous epinephrine absorption was calculated after correction for estimated endogenous epinephrine production. Pharmacokinetic assessments were performed using standard equations. The total plasma epinephrine peak occurred at the final intraoperative reading (5 hours after induction) and was 323 pg/ml (24.8 pg/ml), three to four times maximum baseline resting levels. The norepinephrine level was slightly elevated throughout the study period, with a reversal of the normal epinephrine/norepinephrine ratio (<0.5:1) demonstrated intraoperatively (>5:1). Estimated time to peak exogenous epinephrine level ranged from 1 to 4 hours from the start of infiltration. Area under the plasma concentration versus time curve was approximately 2089 to 2610 pg x hour/ml. Peak exogenous epinephrine concentration was estimated to be 286 to 335 pg/ml. Clearance was 764,508 ml/hour and volume of distribution was 0.4 liter/kg (0.006 liter/kg). Total absorbed epinephrine was estimated, 1.8 mg to 2.2 mg, equivalent to 25 to 32 percent of the infiltrated dose. The reversal of the normal epinephrine/norepinephrine ratio and the fact that norepinephrine levels were within normal range implied that the majority of plasma epinephrine measured was exogenously infiltrated and not endogenously synthesized. On the basis of these observations, pharmacokinetic analyses were performed. Although unequivocal toxic epinephrine levels were not demonstrated, epinephrine peaks were three to four times the maximum observed in normal resting patients. Peak levels were comparable to those observed during major physiologic stresses, such as exercising to exhaustion, open abdominal surgery, or cross-clamping the aorta during surgical repair. Furthermore, epinephrine has been associated with myocardial infarction, arrhythmias, and fatal asystole in susceptible patients at these levels. Patients should be carefully screened for clinical evidence of hemodynamic and cardiac pathology before larger-volume liposuction is undertaken, as it may result in unnecessary high risk for patients who have preexisting cardiovascular disorders. Healthy American Society of Anesthesiologists physical status I or II patients should have sufficient cardiac reserve to tolerate these catecholamine levels.

Epinephrine Absorption in Children With a History of Anaphylaxis

Simons FER, Roberts JR, Gu A, Simons KJJ Allergy Clin Immunol.10119983337To study the clinical pharmacology of epinephrine in allergic children with a history of anaphylaxis.A total of 17 children, ages 4 to 12 years old, with a history of severe allergies and systemic anaphylaxis.This was a randomized, single-blind, single-dose, parallel-group study. Subjects received either a subcutaneous injection of 0.01 mL/kg (maximum 0.3 ml [0.3 mg]) epinephrine solution or an intramuscular injection of 0.3 mL (0.3 mg) of epinephrine via an EpiPen Auto-Injector (Dey; Napa, CA). Before injection and at timepoints up to 180 minutes afterwards, blood samples were collected for plasma epinephrine measurement. Heart rate, blood pressure, and rhythm strip monitoring were also performed during the same intervals. Plasma epinephrine concentrations were measured with a high-performance chromatography (HPLC) reverse-phase system with electrochemical detection.Nine subjects were randomized to the subcutaneous epinephrine group (epinephrine solution) and 8 to the intramuscular injection group (EpiPen Auto-Injector). The mean peak plasma epinephrine concentration in the subcutaneous group was 1802 ± 214 pg/mL. The mean time to reach maximum plasma concentrations was 34 ± 14 minutes in this group, with only 2 subjects achieving maximum concentration by 5 minutes. In contrast, the mean peak maximum plasma epinephrine concentration in the intramuscular group was 2136 ± 351 pg/mL. The mean time to reach maximum plasma concentration was 8 ± 2 minutes (P < .05, compared to subcutaneous group), with 6 achieving the peak concentration by 5 minutes. No serious adverse effects were reported in either group.Epinephrine has a delayed absorption when given via the subcutaneous route compared with the intramuscular route in children.Although a small sample size, this study of the pharmacologic dynamics of epinephrine delivery in children has great implications. Epinephrine remains the drug of choice for the treatment of acute systemic anaphylaxis, yet epinephrine dosing in children is currently recommended on the basis of findings in adult populations and anecdotal reports. This study is the first to demonstrate the pharmacokinetics of epinephrine in children. The authors clearly demonstrate delayed absorption and lower peak plasma concentrations when epinephrine is given via the subcutaneous route compared with the intramuscular route. These findings have important clinical implications for use of epinephrine in all settings of systemic anaphylaxis, indicating that intramuscular delivery of epinephrine may be preferable.

Epinephrine pharmacokinetics and pharmacodynamics following endotracheal administration in dogs: the role of volume of diluent

Objective: to define the optimal volume of dilution for endotracheal (ET) administration of epinephrine (EPI). Design: prospective, randomized, laboratory comparison of four different volumes of dilution of endotracheal epinephrine (1, 2, 5, and 10 ml of normal saline). Setting: large animal research facility of a university medical center. Subjects and interventions: epinephrine (0.02 mg/kg) diluted with four different volumes (1, 2, 5, and 10 ml) of normal saline was injected into the ET tube of five anesthetized dogs. Each dog served as its own control and received all four volumes in different sequences at least 1 week apart. Arterial blood samples for plasma epinephrine concentration and blood gases were collected before and 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30 and 60 min after drug administration. Heart rate and arterial blood pressure were continuously monitored with a polygraph recorder. Measurements and main results: higher volumes of diluent (5 and 10 ml) caused a significant decrease of PaO 2, from 147±8 to 106±10 torr, compared with the lower volumes of diluent (1 and 2 ml), from 136±10 to 135±7 torr ( P<0.05). These effects persisted for over 30 min. Mean plasma epinephrine concentrations significantly increased within 15 s following administration for all the volumes of diluent. Mean plasma epinephrine concentrations, maximal epinephrine concentration ( C max) and the coefficient of absorption ( K a) were higher in the 5 and 10 ml groups. The time interval to reach maximal concentration ( T max) was shorter in the 5 and 10 ml groups. Yet these results were not significantly different. Heart rate, systolic and diastolic blood pressures did not differ significantly between the groups throughout the study. Conclusions: Dilution of endotracheal epinephrine into a 5 ml volume with saline optimizes drug uptake and delivery without adversely affecting oxygenation and ventilation.

Pharmacokinetics of cardiovascular drugs in children. Inotropes and vasopressors.

Infants and children with congenital or acquired heart disease and children with systemic disease often require pharmacological support of their failing circulation. Catecholamines may serve as inotropic (enhance myocardial contractility) or vasopressor (elevate systemic vascular resistance) agents. Noncatecholamine inotropic agents, such as the cardiac glycosides or the bipyridines, may be used in place of, or in addition to, catecholamines. Developmental changes in neonates, infants and children will affect the response to inotropic or pressor therapy. Maturation of the gastrointestinal tract, liver and kidneys alters absorption, metabolism and elimination of drugs, although there are few clear examples of this among the vasoactive drugs considered in this review. Changes in body composition affect the volume of distribution (Vd) and clearance (CL) of drugs. Developmentally based pharmacodynamic differences also affect the responses to both therapeutic and toxic effects of inotropes. These pharmacodynamic differences are based in part upon developmental changes in myocardial structure, cardiac innervation and adrenergic receptor function. For example, the immature myocardium has fewer contractile elements and therefore a decreased ability to increase contractility; it also responds poorly to standard techniques of manipulating preload. Available data suggest that dopamine and dobutamine pharmacokinetics are similar to those in adults. Wide interindividual variability has been noted. A consistent relationship between CL and age has not been demonstrated, although one investigator demonstrated an almost 2-fold increase in the CL of dopamine in children under the age of 2 years. The CL of dopamine appears to be reduced in children with renal and hepatic failure. Fewer data are available regarding the pharmacokinetics of epinephrine (adrenaline), norepinephrine (noradrenaline) and isoprenaline (isoproterenol). Digoxin pharmacokinetics have been extensively evaluated in infants and children. The Vd for digoxin is increased in infants and children. Children beyond the neonatal period display increased CL of digoxin, approaching adult values during puberty. Although it was previously thought that children both needed and tolerated higher serum concentrations of digoxin than adults, more recent studies indicate that adequate clinical response can be achieved with serum concentrations similar to those aimed for in adults, with decreased toxicity. Evaluation of studies of digoxin pharmacokinetics is complicated by the presence of an endogenous substance with digoxin-like activity on radioimmunoassay. Limited studies of amrinone pharmacokinetics in infants and children indicate a dramatically larger Vd, and a decreased elimination half-life in older infants and children, compared with values observed in adults.