Original Article
Predictors of Repeat Epinephrine Administration for Emergency Department Patients with Anaphylaxis Ronna L. Campbell, MD, PhDa, Curtis J. Bashorea, Sangil Lee, MDb, Venkatesh R. Bellamkonda, MDa, James T.C. Li, MD, PhDc, John B. Hagan, MDc, Christine M. Lohse, MSd, and M. Fernanda Bellolio, MD, MSa Rochester and Mankato, Minn
What is already known about this topic? Epinephrine is the treatment of choice for anaphylaxis. Some patients require more than 1 dose. Studies of risk factors for repeat epinephrine use have had mixed results. What does this article add to our knowledge? Among emergency department patients of all ages and trigger types, a history of anaphylaxis and presenting signs of flushing, diaphoresis, or dyspnea were associated with the need for more than 1 dose of epinephrine. How does this study impact current management guidelines? Our findings support the current guidelines that patients with anaphylaxis should be prescribed more than 1 epinephrine autoinjector.
BACKGROUND: Risk factors that predict which patients with anaphylaxis might require repeat doses of epinephrine are poorly understood. OBJECTIVE: The objective of this study was to identify risk factors associated with the need for multiple doses of epinephrine during an anaphylactic reaction. METHODS: Patients were included if they met diagnostic criteria for anaphylaxis on presentation to the emergency department (ED) at our academic medical center between April 2008 and February 2014. Data were collected on allergic history, a
Department of Emergency Medicine, Mayo Clinic, Rochester, Minn Department of Emergency Medicine, Mayo Clinic Health System in Mankato, Mankato, Minn c Division of Allergic Diseases, Mayo Clinic, Rochester, Minn d Department of Health Sciences Research, Mayo Clinic, Rochester, Minn No funding was received for this work. Conflicts of interest: R. L. Campbell received consulting fees from the American College of Allergy, Asthma and Immunology. S. Lee has received travel support from Food Allergy Research and Education; and has received research support from the Mayo Foundation. J. T. Hagan has received research support from the National Heart Lung and Blood Institute (NHLBI) (R01 HL 110539), National Institute of Allergy and Infectious Diseases (NIAID) (R01 AI 71106), NHLBI (R01 HL 117823), NIAID (R01 AI 71106), and NHLBI (R01 HL 117823), GlaxoSmithKline (Protocol Number: MEA115661); Astra Zeneca (SOW #3/ Study Code D5134C00001); Mayo Clinic; MedImmune, Inc. (MedImmune Protocol No. MEDI9929-1146); AstraZeneca; and Small Grants Program. The rest of the authors declare that they have no relevant conflicts. This abstract was presented as an oral presentation at the 2014 Society of Academic Emergency Medicine Midwest Regional Meeting, Detroit, Michigan, September 11, 2014. Received for publication December 9, 2014; revised April 17, 2015; accepted for publication April 20, 2015. Available online May 29, 2015. Corresponding author: Ronna L. Campbell, MD, PhD, Department of Emergency Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: campbell.
[email protected]. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2015.04.009 b
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presenting signs and symptoms, anaphylaxis management, and disposition. Univariable and multivariable analyses were performed to estimate associations between possible risk factors and the need for multiple doses. RESULTS: Of 582 ED patients with anaphylaxis, 45 (8%) required multiple doses of epinephrine. By multivariable analysis, factors associated with the need for repeat doses were a history of anaphylaxis (odds ratio [OR], 2.5 [95% CI, 1.3-4.7]; P [ .005), the presence of flushing or diaphoresis (OR, 2.4 [95% CI, 1.3-4.5]; P [ .007), and the presence of dyspnea (OR, 2.2 [95% CI, 1.0-5.0]; P [ .046). Patients who received more than 1 dose were more likely to be admitted to the general medical floor (OR, 2.8 [95% CI, 1.1-7.2]; P [ .03) or intensive care unit (OR, 7.6 [95% CI, 3.7-15.6]; P < .001). CONCLUSION: Patients with a history of anaphylaxis, flushing or diaphoresis, or dyspnea may require multiple doses of epinephrine to treat anaphylactic reactions. Patients who require more than 1 dose are more likely to be admitted to the hospital, thus increasing health care resource utilization. Ó 2015 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2015;3:576-84) Key words: Allergy criteria; Anaphylaxis; Emergency department; Epinephrine; Hypersensitivity; Risk factors
Anaphylaxis is an allergic reaction that frequently involves multiple organ systems and varies in severity. It is most commonly treated in the emergency department (ED).1 The treatment of choice for anaphylaxis is intramuscular administration of epinephrine.2 However, a single dose of epinephrine is not always sufficient for treatment of anaphylaxis.3-11 A previous study of patients presenting to the ED with anaphylaxis to any trigger showed that 13% required more than 1 dose of epinephrine during the management of the reaction.8 Studies of ED patients with anaphylaxis to food have found that 5% to 16% required more than 1 dose of epinephrine.6,9,11
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Abbreviations used BP- Blood pressure DMS- Display Manager System ED- Emergency department EDOU- Emergency department observation unit FAAN- Food Allergy and Anaphylaxis Network ICU- Intensive care unit NIAID- National Institute of Allergy and Infectious Diseases OR- Odds ratio
Despite the well-established fact that many patients will require more than a single dose of epinephrine, little is known about the possible associated factors that predict the need for multiple doses.3-11 Prior studies evaluating such risk factors are limited by the small number of patients and reviews that included only 1 or a few triggers.3-11 Thus, the elucidation of risk factors has been challenging. The objective of this study was to identify factors associated with the need for multiple doses of epinephrine in patients presenting to the ED with anaphylaxis.
METHODS Study design and setting This observational cohort study examined consecutive patients who presented to the ED of Mayo Clinic Hospital, Saint Marys Campus, Rochester, Minn, a tertiary care academic medical institution with approximately 73,000 ED patient visits annually. The Mayo Clinic Institutional Review Board approved the study protocol.
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Definition and Management of Anaphylaxis (adapted from Sampson et al;12 used with permission). Only those patients who met these criteria were included. Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled: 1. Acute onset of an illness (minutes to several hours) with an involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula), and at least 1 of the following: a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia) b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, incontinence) 2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula) b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia) c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): a. Infants and children: low systolic BP (age specific; defined as less than 70 mm Hg from 1 month to 1 year, less than 70 mm Hg plus 2age from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years) or greater than 30% decrease in systolic BP b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline.
Selection of study patients Patients of all ages were eligible for inclusion in the study if they or their caregiver had previously or currently provided informed consent for the use of their medical records for research purposes. Both prospective and retrospective data were recorded and analyzed. For patients who had multiple ED visits, only data from the first visit were abstracted.
Retrospective enrollment. The retrospective review of the electronic medical records of patients whose ED diagnoses included the text “anaph-,” “allerg-,” or “sting” from April 2008 through February 2014 was conducted. We searched all ED patient records (Picis ED PulseCheck) for the specified diagnoses by using an electronic patient tracking system that was designed at our institution to facilitate ED clinical research. An additional small cohort of potentially eligible patients with other diagnoses was identified by the study coordinator during the review process. Data on allergic history, presenting signs and symptoms, anaphylaxis management, and disposition were extracted from the electronic medical record using a standardized extraction procedure, and data were entered into an SAS-Display Manager System (DMS) database. The SAS-DMS database was programmed to determine whether the National Institute of Allergy and Infectious Diseases (NIAID) and the Food Allergy and Anaphylaxis Network (FAAN) criteria for anaphylaxis were met on the basis of the acuity of symptom onset, presence of a likely or known trigger, and individual patient signs and symptoms. Case definition. Anaphylaxis was defined on the basis of the criteria agreed on by the NIAID/FAAN Second Symposium on the
Prospective enrollment. A cohort of prospective patients was identified at the time of their ED visit from April 2010 to March 2013 on the basis of their chief concern. Patients were identified if they had a concern that included “allergic,” “reaction,” “anaphy-,” “angio-,” “sting,” “hives,” or “rash.” At our institution, the patient’s chief concern is entered by the triage nurse before any significant clinical evaluation has occurred. In contrast, the patient diagnosis is not entered into the medical record until after the patient has been evaluated by the provider. Although the diagnosis can be entered into the medical record while the patient is still undergoing evaluation or observation, it frequently occurs after the patient has been dismissed from the ED. Thus, we searched for chief concerns and kept the range of eligible concerns intentionally broad to increase the sensitivity for identifying patients with anaphylaxis. Study coordinators received a text page that was automatically generated by the ED electronic patient-tracking system whenever an ED patient registered with any of the specified chief concerns. Study coordinators then approached the ED provider caring for the patient to determine if the patient was eligible for the study. Any patient whom the ED provider suspected of having anaphylaxis or an allergic reaction was considered eligible for enrollment, and consent was obtained. Data on allergic history, presenting signs and symptoms, and prehospital management were obtained from the patient or caregiver. The primary provider caring for the patient completed a questionnaire on physical findings. Additional data on anaphylaxis management and disposition were extracted from the electronic health record using a standardized extraction procedure. All data were entered into an SAS-DMS database programmed to determine
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FIGURE 1. Flowchart of patient enrollment. aSubgroups had overlapping patients (sum of subgroups exceeds total). NIAID/FAAN indicates National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network.
if NIAID/FAAN criteria were met. Prospectively enrolled patient charts and questionnaires were subsequently independently reviewed by 2 American Board of Allergy and Immunologyecertified allergists-immunologists (J.T.C.L. and J.B.H.). Patients were included if they met NIAID/FAAN criteria and were considered to have anaphylaxis after expert review (Figure 1). There were no documented refusals of consent during the study period in this cohort. Patients missed at prospective enrollment were eligible for inclusion in the retrospective cohort on the basis of their discharge diagnosis through electronic record review as described above.
Data collection and outcome measures A consecutive sample of patients was included to reduce the risk of selection bias. We developed, tested, and used a standardized data collection form. Data were recorded directly into an electronic database. Any conflicting entries were resolved using information from the staff physician first, the medical resident second, and the nurse third. We piloted and revised the data collection form. The abstractors met periodically with the primary investigator (R.L.C.) to review any questions that arose during the data abstraction process. The study hypothesis and objectives were not masked for abstractors. Data were collected on demographics, medical history, suspected trigger at the time of the ED visit, clinical signs and symptoms of the reaction, ED management and disposition, and ED observation unit (EDOU) management and disposition. More than 1 dose of epinephrine was defined as receipt of more than 1 standard dose (0.30.5 mg for adults; 0.01 mg/kg for children).2 Routes of epinephrine administration included intramuscular autoinjectors, intramuscular injections, subcutaneous injections, intravenous bolus, and continuous intravenous infusions. Nebulized epinephrine treatments were not included. Multiple possible settings of epinephrine administration were included, including home treatment or self-treatment;
prehospital, ambulance, or emergency medical services treatment; ED treatment; and EDOU treatment. Epinephrine administration was not included if it occurred on a general medical floor or in the intensive care unit (ICU) after the patient had left the ED or the EDOU. Only epinephrine that was administered for an initial reaction during the visit was included; therefore, any epinephrine administered for a biphasic reaction was not included. Each dose of epinephrine counted equally, regardless of route of administration.
Statistical analysis Continuous data are presented as median (interquartile range). Categorical data are presented as frequency (percentage) of occurrence. Comparisons between the retrospective and prospective cohorts were evaluated using Wilcoxon rank sum, c2, and Fisher exact tests. Univariable logistic regression models were used to evaluate associations between predictor variables and epinephrine treatment. A multivariable logistic regression model was developed using stepwise selection of clinical variables that were significant in univariable analysis. The strength and direction of each association was estimated by calculating odd ratios (ORs) with corresponding 95% CIs. All P values represent a 2-sided hypothesis, and P values
