Limited effect of intramuscular epinephrine on cardiovascular parameters during peanut-induced anaphylaxis: An observational cohort study (2020)

Clinical Implications•Intramuscular injection with epinephrine had limited impact in reversing the decrease in stroke volume caused by peanut-induced anaphylaxis. These data question the effectiveness of intramuscular epinephrine alone to treat cardiovascular compromise during anaphylaxis and support the need for guidelines to incorporate effective adjuvant treatments in addition to intramuscular epinephrine in the management of refractory anaphylaxis. •Intramuscular injection with epinephrine had limited impact in reversing the decrease in stroke volume caused by peanut-induced anaphylaxis. These data question the effectiveness of intramuscular epinephrine alone to treat cardiovascular compromise during anaphylaxis and support the need for guidelines to incorporate effective adjuvant treatments in addition to intramuscular epinephrine in the management of refractory anaphylaxis. Acute allergic reactions to peanut are associated with significant cardiovascular changes, with a reproducible decrease in stroke volume (SV), associated with increased peripheral blood flow.1Ruiz-Garcia M. Bartra J. Alvarez O. Lakhani A. Patel S. Tang A. et al.Cardiovascular changes during peanut-induced allergic reactions in human subjects [published online ahead of print July 21, 2020].https://doi.org/10.1016/j.jaci.2020.06.033Google Scholar This may explain why changes in patient positioning during anaphylaxis can trigger decompensation, cardiorespiratory arrest, and death.2Mullins R.J. Wainstein B.K. Barnes E.H. Liew W.K. Campbell D.E. Increases in anaphylaxis fatalities in Australia from 1997 to 2013.Clin Exp Allergy. 2016; 46: 1099-1110Crossref PubMed Scopus (147) Google Scholar In this observational study, we systematically evaluated changes in cardiovascular function after intramuscular (IM) epinephrine administration during peanut-induced anaphylaxis. Peanut-allergic adults (18-45 years) with no known cardiovascular abnormality underwent repeated oral food challenge to peanut, as part of a clinical trial (TRACE Peanut study; ClinicalTrials.gov Identifier: NCT02665793). Detailed methods are described elsewhere.1Ruiz-Garcia M. Bartra J. Alvarez O. Lakhani A. Patel S. Tang A. et al.Cardiovascular changes during peanut-induced allergic reactions in human subjects [published online ahead of print July 21, 2020].https://doi.org/10.1016/j.jaci.2020.06.033Google Scholar Participants were monitored continuously, using a Food and Drug Administration–approved monitor for noninvasive measurement of SV (Cheetah NICOM, Boston, MA). Heart rate (HR) monitoring was undertaken using a 12-lead Holter monitor (GE Healthcare, Chicago, IL). Patients were kept semirecumbent throughout to control for possible movement artifact. Written informed consent was obtained, and the study received ethics approval (NHS Human Research Authority, reference 15/LO/0286). Fifty-seven adults were recruited, of whom 22 (39%) experienced anaphylaxis according to National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria. Consistent with local practice, IM epinephrine (0.5 mg, injected with a 1 mL syringe and 21G needle into the mid-anterolateral thigh) was administered for all reactions presenting with objective respiratory and/or cardiovascular symptoms.3Soar J. Pumphrey R. Cant A. Clarke S. Corbett A. Dawson P. et al.Emergency treatment of anaphylactic reactions—guidelines for healthcare providers.Resuscitation. 2008; 77: 157-169Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar Fourteen participants received at least 1 dose of IM epinephrine: 11 at the initial challenge and 3 (with non-anaphylaxis to the initial reaction) at the subsequent challenge. Baseline demographics are described in Table E1 (available in this article's Online Repository at www.jaci-inpractice.org). No participant had evidence of hemodynamic instability during reaction. We observed a significant fall in SV (mean decrease: 9.7%, 95% confidence interval [CI]: 3.0 to 16.5; P = .0066) and an increase in HR (mean increase: 10 bpm, 95% CI: 5.0 to 16; P = .0011) and mean arterial blood pressure (MAP) (mean increase: 15.0%, 95% CI: 9.6 to 20.4; P < .0001) at the time of objective clinical reaction (OCR). There was no significant change in cardiac output (CO) at OCR (mean increase: 5.4%, 95% CI: −6.8 to 17.5; P = .36). Administration of 0.5 mg IM epinephrine, although associated with improved symptoms, did not cause a consistent and clinically relevant increase in SV at any single timepoint (Figure 1). Using a composite measure (maximum change in the first 10 minutes after epinephrine), we observed a mean increase in SV of 9.4% (95% CI: 0.3 to 18.6; P = .029). HR also increased (mean: 11.9 bpm, 95% CI: 5.0 to 18.9; P = .0026), with an associated increase in CO (mean: 23%, 95% CI: 10 to 36; P = .0018) but not MAP (mean increase: 0.9%, 95% CI: −3.8 to 5.5; P = .70). Two participants received a second epinephrine dose; interestingly, in these subjects, epinephrine did not result in any further change in SV (Figure E1, available in this article's Online Repository at www.jaci-inpractice.org). Respiratory symptoms with an accompanying change in spirometry were present in 13 reactions. After epinephrine, there was a significant increase in forced expiratory volume in 1 second (mean: 14.1%, 95% CI: 1.3 to 26.9; P = .035) and peak expiratory flow rate (mean: 8.8%; 95% CI: 0.9 to 16.7; P = .033), although these patients also received nebulized salbutamol. Eight subjects had anaphylaxis at a subsequent challenge but did not develop objective respiratory symptoms, and thus epinephrine was not administered. Anaphylaxis was associated with similar changes in HR, SV, and CO at OCR (Figure 2), irrespective of whether epinephrine was subsequently given. Comparing the effect of treatment (or not) with epinephrine in these subjects, epinephrine resulted in a significant increase in HR (compared with no epinephrine) in the first 10 minutes after injection (mean increase: 17 bpm, 95% CI: 4.1 to 29; P = .016) but no significant change in SV (mean increase: 11%, 95% CI: −10 to 32; P = .26) or CO (mean increase: 22%, 95% CI: −4.1 to 49; P = .086). The evidence for IM epinephrine as first-line treatment for anaphylaxis is largely driven by retrospective case series and expert opinion.4Muraro A. Roberts G. Worm M. Bilò M.B. Brockow K. Fernández Rivas M. et al.Anaphylaxis: Guidelines from the European Academy of Allergy and Clinical Immunology.Allergy. 2014; 69: 1026-1045Crossref PubMed Scopus (639) Google Scholar In this first in-human study of IM epinephrine treatment in subjects during food-induced anaphylaxis, epinephrine resulted in limited changes in HR and SV; any change in CO was essentially related to the increase in HR. In the analysis of patients who had anaphylaxis on more than 2 occasions, but only one was treated with epinephrine, a single dose of epinephrine did little to reverse the fall in SV induced by anaphylaxis, that is, there was little evidence of a positive inotropic effect of epinephrine. Although these data are limited by the relatively small sample size and nature of the reactions experienced (with no participant requiring more than 2 doses of IM epinephrine), they are consistent with a canine model of anaphylaxis in which IM epinephrine resulted in a negligible increase in SV.5Bautista E. Simons F.E.R. Simons K.J. Becker A.B. Duke K. Tillett M. et al.Epinephrine fails to hasten hemodynamic recovery in fully developed canine anaphylactic shock.Int Arch Allergy Immunol. 2002; 128: 151-164Crossref PubMed Scopus (81) Google Scholar The majority of food-induced anaphylaxis reactions occurring in a community setting resolve without severe outcomes, whether or not they are treated with epinephrine.6Worm M. Moneret-Vautrin A. Scherer K. Lang R. Fernandez-Rivas M. Cardona V. et al.First European data from the network of severe allergic reactions (NORA).Allergy. 2014; 69: 1397-1404Crossref PubMed Scopus (180) Google Scholar Although food-induced anaphylaxis is considered to be predominantly a respiratory event,6Worm M. Moneret-Vautrin A. Scherer K. Lang R. Fernandez-Rivas M. Cardona V. et al.First European data from the network of severe allergic reactions (NORA).Allergy. 2014; 69: 1397-1404Crossref PubMed Scopus (180) Google Scholar cardiovascular changes are common, even in clinically mild reactions1Ruiz-Garcia M. Bartra J. Alvarez O. Lakhani A. Patel S. Tang A. et al.Cardiovascular changes during peanut-induced allergic reactions in human subjects [published online ahead of print July 21, 2020].https://doi.org/10.1016/j.jaci.2020.06.033Google Scholar; this might explain reports of fatal food anaphylaxis related to the postural change in young people without obvious severe symptoms.2Mullins R.J. Wainstein B.K. Barnes E.H. Liew W.K. Campbell D.E. Increases in anaphylaxis fatalities in Australia from 1997 to 2013.Clin Exp Allergy. 2016; 46: 1099-1110Crossref PubMed Scopus (147) Google Scholar Severe reactions are often refractory to bolus epinephrine, but respond to a combination of low-dose intravenous epinephrine infusion in conjunction with fluid boluses.7Brown S.G.A. Blackman K.E. Stenlake V. Heddle R.J. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous epinephrine and volume resuscitation.Emerg Med J. 2004; 21: 149-154Crossref PubMed Scopus (151) Google Scholar In this context, the limited impact of IM epinephrine on SV is concerning. Indeed, we reported a 5-fold greater sustained increase in SV after administration of intravenous fluids in the same series of patients, compared with that seen with IM epinephrine injection in this study.1Ruiz-Garcia M. Bartra J. Alvarez O. Lakhani A. Patel S. Tang A. et al.Cardiovascular changes during peanut-induced allergic reactions in human subjects [published online ahead of print July 21, 2020].https://doi.org/10.1016/j.jaci.2020.06.033Google Scholar This does not negate the value of IM epinephrine in the management of anaphylaxis: we observed a clear beneficial impact on symptoms as well as lung function. Epinephrine causes vasoconstriction and reduces vascular leak, counteracting many of the adverse consequences of anaphylaxis. This is likely to explain why epinephrine administration in hemodynamically stable anaphylaxis patients is associated with a reduced risk of developing hypotension.8Ko B.S. Kim J.Y. Seo D. Kim W.Y. Lee J.H. Sheikh A. et al.Should epinephrine be used in patients with hemodynamically stable anaphylaxis? Incident case control study nested within a retrospective cohort study.Sci Rep. 2016; 6: 20168Crossref PubMed Scopus (10) Google Scholar Rather, our data emphasize the need for adjunctive treatments in addition to further IM epinephrine in those patients in whom initial epinephrine has only a limited effect. Further work is needed to identify determinants of a prompt physiological response to epinephrine during anaphylaxis. Around 10% of food-induced anaphylaxis reactions fail to respond to a single dose of IM epinephrine.9Ierodiakonou D. Patel N. Chong K.W. Yip A.G. Bartra J. Boyle R.J. et al.Need for more than one dose of epinephrine to treat anaphylaxis: a systematic review and meta-analysis [abstract].Allergy. 2020; 75: 49Google Scholar Current guidelines tend not to recommend intravenous fluids in the absence of hemodynamic instability,3Soar J. Pumphrey R. Cant A. Clarke S. Corbett A. Dawson P. et al.Emergency treatment of anaphylactic reactions—guidelines for healthcare providers.Resuscitation. 2008; 77: 157-169Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar,4Muraro A. Roberts G. Worm M. Bilò M.B. Brockow K. Fernández Rivas M. et al.Anaphylaxis: Guidelines from the European Academy of Allergy and Clinical Immunology.Allergy. 2014; 69: 1026-1045Crossref PubMed Scopus (639) Google Scholar yet a lack of response to initial epinephrine may be due to insufficient drug delivery secondary to reduced venous return.1Ruiz-Garcia M. Bartra J. Alvarez O. Lakhani A. Patel S. Tang A. et al.Cardiovascular changes during peanut-induced allergic reactions in human subjects [published online ahead of print July 21, 2020].https://doi.org/10.1016/j.jaci.2020.06.033Google Scholar We therefore advocate for rapid escalation with early intravenous fluid therapy where anaphylaxis is refractory to initial IM epinephrine, even in patients without obvious hemodynamic instability. We thank our study participants, who were recruited through the TRACE Peanut study (funded by the UK Food Standards Agency ). We are grateful to the study investigators (chief investigator A Clark) and the Food Standards Agency for their support; and to the members of our Data Safety Monitoring Board: Professor Stephen Till, Dr Hazel Gowland, and Dr Mich Erlewyn-Lajeunesse. We are also grateful to Olaya Alvarez, Joan Bartra, Emily Wilson, Louise Cross, and staff at the Respiratory Clinical Research Facility at the Royal Brompton Hospital for their clinical support. Table E1Characteristics of the study populationCharacteristicOverall cohort (N = 57)IM epinephrine given (N = 14)Age at enrollment (y)24 (20, 29)23 (19, 27)Sex (female)30 (53%)7 (50%)Asthma29 (51%)9 (64%)Rhinitis40 (70%)10 (71%)Eczema27 (47%)6 (43%)Total IgE (kUA/L)221 (107, 576)153 (87, 234)Specific IgE to peanut (kUA/L)10.2 (3.3, 31.9)11.4 (3.6, 25.6)Specific IgE to rAra h 2 (kUA/L)7.4 (2.0, 20.4)6.6 (2.1, 14.9)SPT wheal size to commercial peanut extract11 mm (9, 15)13 mm (9, 19)Cumulative reaction dose (mg peanut protein)133 (33, 433)183 (33, 683)Baseline mast cell tryptase (ng/mL)2.7 (2.2, 3.7)2.6 (2.1, 3.2)Continuous variables are described as median (IQR) for nonparametric data.IM, Intramuscular; IQR, interquartile range; SPT, skin prick test. Open table in a new tab Continuous variables are described as median (IQR) for nonparametric data. IM, Intramuscular; IQR, interquartile range; SPT, skin prick test.