Thursday, December 14, 2017

Anaphylaxis in a Nutshell

Authors: Eli Brown, MD; Kaycie Corburn, MD; Jacqueline Shibata, MD; Lee Grodin, MD
Edited by: Jay Khadpe, MD FAAEM; Michael Bond, MD FAAEM
Originally Published: Common Sense January/February 2015

The emergency department (ED) is the most common place for treatment of anaphylaxis. While epinephrine is clearly indicated, the Emergency Medicine Practice Update Guidelines of 2011 state, “Despite a unified consensus around epinephrine as first-line treatment, patients are more likely to receive corticosteroids and antihistamines.” Prospective randomized controlled trials comparing medications for the treatment of anaphylaxis in humans are lacking, thus guidelines are based primarily on theory and anecdotal evidence. This summary examines various therapies and evaluates recommended ED observation times and dispositions.

Simons F, Gu X, Simons K. Epinephrine absorption in adults: Intramuscular versus subcutaneous injection. Journal of Allergy and Clinical Immunology. 2001;108:871-3.

Due to its β1-adrenergic effects such as vasoconstriction, increased peripheral vascular resistance, and decreased mucosal edema, epinephrine is the mainstay of anaphylaxis treatment. Epinephrine’s β2-adrenergic effects include bronchodilation and decreased release of histamine as well as other inflammatory mediators. The authors note that low plasma levels of epinephrine are associated with enhanced release of inflammatory mediators, vasodilation, and hypotension.

This prospective, randomized, blinded, placebo-controlled, six-way crossover study investigated the plasma concentration of epinephrine in healthy volunteers 180 minutes after injection of 0.3mg either subcutaneously (SC) in the deltoid region or intramuscularly (IM) in the vastus medialis or deltoid. This small study (13 males enrolled) showed that plasma concentrations of epinephrine were significantly higher (p<0.01) with IM administration in the thigh compared to SC administration in the arm. Surprisingly, neither SC nor IM injections into the arm resulted in significantly higher plasma levels than endogenous levels triggered by placebo (normal saline) injections.

The authors suggest that the high blood flow in the vastus medialis and the localized vasoconstriction associated with subcutaneous injections may account for this difference. While it is not known whether these results can be extrapolated to patients having anaphylaxis reactions, this data is consistent with other published pediatric data. The authors recommend IM injection in the thigh as the preferred route of epinephrine administration for the treatment of anaphylaxis.

Brown S, Blackman KE, Stenlake V, Heddle RJ. Insect sting anaphylaxis: Prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emergency Medicine. 2004;21:149-154.
Brown and colleagues published the first-ever prospective evaluation of the treatment of anaphylaxis with IV epinephrine and volume resuscitation. This Australian study initially investigated the efficacy of venom immunotherapy in 68 patients with known hypersensitivity to Myrmecia pilosula (Jack Jumper Ant).

The placebo group did not undergo immunotherapy and thus offered a rare insight into anaphylactic reactions in a monitored setting with a chronological record of allergen-exposure, onset of signs and symptoms, and initiation and response to therapy. All 21 placebo patients had systemic reactions to the ant sting. The time from envenomation to symptom onset was two to 27 minutes. The most common initial symptoms were generalized itching and perioral sensations; 21 (100%) experienced generalized erythema; 19 (90%) developed anaphylaxis and required epinephrine; five (24%) required fluid resuscitation; and nine (43%) required continued epinephrine infusion due to recurrence of the reaction after the initial epinephrine treatment. Symptoms resolved upon reinstitution of epinephrine for all nine of these patients. Hypotensive patients required significantly longer and higher total doses of epinephrine, p=0.02.

All cases of hypotension were associated with relative bradycardia. Two patients required atropine, which appeared to prevent them from impending cardiac arrest. All but two of the patients in this study recovered within four hours suggesting epinephrine infusion and volume resuscitation are an effective treatment for anaphylaxis. Atropine may also be an important adjunct for patients with hypotension and bradycardia.

Schummer C, Wirsing M, Schummer W. The pivotal role of vasopressin in refractory anaphylactic shock. Anesth Anal. 2008;107:620-664.

Cardiovascular collapse from severe anaphylaxis can be difficult to manage and does not always respond to epinephrine. Such cases are referred to as refractory anaphylactic shock. This article describes six case reports in which vasopressin was used to restore hemodynamic function.

Vasopressin restores vascular tone by a number of mechanisms including the activation of Vq receptors that mediate vasoconstriction, the closing of ATP-sensitive K+ channels, the modulation of nitric oxide, and the enhancement of adrenergic and other vasoconstrictor drugs. It is also hypothesized that vasopressin acts as an anti-inflammatory agent during anaphylactic shock by antagonizing the effects of nitric oxide.

The estimated incidence of anaphylaxis during anesthesia is 5-10 per 100,000 cases, and when it occurs is lethal 3%-10% of the time. While epinephrine and fluid resuscitation are the mainstays of treatment, further treatment options are less well described. Anecdotal evidence supports using a potent vasoconstrictor such as norepinephrine or vasopressin. The case reports in this article describe an immediate positive effect of vasopressin in restoring intraoperative hemodynamic stability in the setting of general anesthesia.

All six incidents occurred during general anesthesia for major surgery. The trigger substances identified in these cases were aprotinin, metamizol, and gelatin (substances known for their anaphylactic potential). All patients received epinephrine (cumulative dose range: 1mg-3mg), methylprednisolone (1000mg), crystalloid infusion (range: 1000mL-2000mL), and norepinephrine infusions (range: 0.4 mcg/kg/min to 1.2 mcg/kg/min). In addition, three cases received 6% hydroxylethylstarch (range: 250mL-1000mL); one case received dimitenden (8mg), ranitidine (50mg) and lidocaine (100mg); and one case received an unreported dose of H1 and H2 blockers. All six cases received vasopressin (range: 2-5 units). Hemodynamic stabilization was achieved in all cases; however, the exact timeline of events was not included in the case series.

While largely anecdotal, these cases demonstrate that vasopressin may help if circulatory function deteriorates quickly despite adequate standard treatment. The American Heart Association has conceded that their treatment guidelines for anaphylaxis are based more on consensus than evidence. These authors advocate that vasopressin administration be included in the guidelines for management of anaphylactic shock.

Yin R, et al. Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Annals of Emergency Medicine. 2000;36(5):462-468.

Antihistamines, H1-blockers, are a standard component of the treatment of patients with allergic symptoms. There is little data on how the addition of an H2 blocker affects patients with on-going allergic syndromes. In this study, the authors hypothesized that the addition of an H2 blocker would improve outcomes for patients presenting with acute allergic syndromes.

Subjects were eligible to participate in the study if they had acute urticaria, acute angioedema, acute unexplained stridor, or acute pruritic rash after exposure to food, medication, or latex. Pregnant patients and patients who had symptoms for more than 12 hours were excluded. The subjects were randomized into two groups. All subjects received diphenhydramine 50mg IV. In addition, one group received ranitidine 50mg IV while the other group received an equal volume of normal saline IV. Supplemental medications such as epinephrine, corticosteroids, bronchodilators, intravenous fluids, oxygen, and additional antihistamine doses were given at the clinician’s discretion. Data including heart rate, blood pressure, physical findings, side effects, and symptoms were collected at baseline, one hour, and two hours after treatment. The primary outcome was resolution of urticaria or angioedema at two hours post-treatment.

One hundred patients were recruited for the study over 12 months between May 1998 and April 1999. There were no significant baseline differences between the two groups. Resolution of urticaria was greater in the ranitidine group both at one hour and at two hours (93.7% vs. 73.8%, p=.02). Additionally, the number of areas of urticaria was significantly less in the ranitidine group. Overall, significantly more patients in the placebo group received additional H1 antihistamines.

Of the patients with urticaria, 30 also had angioedema. Nineteen patients had angioedema without urticaria. Resolution of angioedema and urticaria at two hours was significantly greater in the ranitidine group (70.5% vs. 46.5%, p=.02). Heart rate decreased in both groups with a slightly greater decrease in the ranitidine group at one hour. Subjective symptom scores were not different between the two groups.

This study showed the advantages of adding H2 blockers to the standard H1 blocker treatment for ongoing allergic syndromes. This study was not sufficiently powered to analyze the benefits of H2 blockers on anaphylaxis as only two patients in the study had hypotension and only 12 patients had wheezing without a history of asthma. While the addition of H2 blockers to the treatment regimen for allergy syndromes appears to improve cutaneous manifestations, the benefit on hypotension and bronchospasm is unknown. Additional studies are needed to explore these patient populations.

Mehr S, et al. Clinical predictors for biphasic reactions in children presenting with anaphylaxis. Clinical & Experim. Allergy. 2009;39:1390-1396.

How long should a patient be observed after being treated for anaphylaxis? The reason for observation is the dreaded biphasic reaction, which in this study was defined as a second phase reaction (not caused by antigen re-exposure) occurring after a one-hour symptom-free period following the initial anaphylactic reaction. This study aimed to identify risk factors associated with patients who experienced biphasic reactions.

This was a retrospective record review case study of children in one tertiary pediatric ED in Melbourne, Australia from 1998-2003. Anaphylaxis was defined as an episode involving the respiratory or cardiovascular system associated with one or more features involving the skin or GI tract. Only admitted patients were included. Exclusion criteria were patients taking beta-blockers, immunosuppressants, antihistamines, or corticosteroids.

The study included 104 patients with 95 having uniphasic reactions, 12 with biphasic reactions, and two with protracted reactions. There were no significant differences between uniphasic and biphasic patients in regard to demographics, atopic history, anaphylactic trigger, or clinical features. Biphasic reactors were significantly more likely to have received >1 dose of epinephrine during the initial episode of anaphylaxis (58% vs. 22%, p=0.02), although route or time to epinephrine did not differ. Biphasic reactors were also more likely to receive IV fluid boluses (42% vs. 8%, p=0.01) although interestingly, the total amount of fluid received and the rate of hypotension did not differ between the groups. The need for >1 dose of epinephrine or a fluid bolus during the initial reaction was a sensitive predictor, 92% (95% CI 62-100%) of a biphasic reaction with a negative predictive value (NPV) of 99%. Specificity was 76% with a positive predictive value (PPV) of 32%. Of note, there was no difference in use of steroids or antihistamines between uniphasic and biphasic reactors. The median time from onset of initial anaphylactic reaction to onset of biphasic reaction was 8.8 hours (1.3-20.5 hours). Of the 12 biphasic reactors, one was more severe, four were similarly severe, and seven were milder than the initial reaction.

This study is limited by its retrospective design, inability to measure biphasic reactions in non-admitted individuals, single center study at a dedicated pediatric facility, small numbers, and inadequate documentation. Also, reactors who only had skin or GI symptoms, which are now included in the definition of anaphylaxis, were excluded, leaving unanswered the question of whether a lack of cardiovascular symptoms or respiratory symptoms puts a patient at lower risk for biphasic reactions.

Biphasic reactions were seen in 11% of patients in this study. They were very unlikely in patients who only received one dose of epinephrine or no fluid bolus. If a pediatric patient requires multiple doses of epinephrine, the authors suggest a longer period of observation may be necessary as these patients may be at higher risk for biphasic reactions, although prospective studies are needed to confirm this conclusion.

Grunau B, et al. The incidence of clinically important biphasic reactions in emergency department patients with allergic reactions or anaphylaxis. Annals of Emergency Medicine. 2014;63(6):736-744.e2.

The goal of this study was to find the incidence of clinically important biphasic anaphylactic reactions. Included were 2,819 ED visits with an allergic (2,323) or anaphylactic reaction (496). Anaphylaxis was defined as having three organ systems involved or allergen exposure with two systems affected or systolic blood pressure (SBP) <90mmHg. A biphasic reaction was defined as an anaphylactic reaction occurring after complete resolution of the original reaction without antigen re-exposure.

This retrospective cohort study took place in two urban academic hospitals in Vancouver, Canada from 2007-2012. Exclusion criteria were: age <17, asthma as a primary diagnoses, or known to have non-allergic angioedema. The authors used a seven-day follow-up period and a regional ED database to identify return visits throughout the province.

185 patients had subsequent ED visits, with five (0.18%) meeting criteria for a clinically significant biphasic reaction. Two of these occurred while the patient was still in the ED and three occurred post-discharge. There were no fatalities. Twenty patients (0.70%) were lost to follow-up.

Limitations of the study include its retrospective design, subjective definition of allergic reaction, inclusion of only two hospitals (urban Canadian), and documentation dependence (i.e. may have missed diagnoses of “rash” that returned to have anaphylaxis which actually may have been a biphasic reaction). Authors note 147 patients self-administered epinephrine and it is unclear if they met definitions for anaphylaxis before being evaluated by providers.

In this study, biphasic reactions were rare (<0.18%) and occurred anywhere from minutes to days after the initial episode which makes determining an appropriate observation period challenging. The incidence of biphasic reactions in this study is quite different than the incidence in the preceding study of a pediatric population. The authors emphasize the importance of clear discharge instructions and prescription of epinephrine auto-injectors.

Clark S, et al. Multicenter study of emergency department visits for insect sting allergies. J. of Allergy and Clinical Immunology. 2005;116(3):643-649.

Guidelines for anaphylaxis recommend use of epinephrine, teaching of proper techniques for self-administration of epinephrine, and referral to an allergist. This study found that compliance with these guidelines is very low. This was a multi-center retrospective cohort study looking at 11 academic EDs in the US and Canada from 1999 to 2001.

The authors identified 617 patients with allergic reactions (58% local allergic, 11% generalized allergic, and 31% anaphylaxis). 13% of patients received epinephrine while in the ED (16% received epinephrine before arrival). 97% of patients were discharged home, but only 15% received discharge instructions to avoid an offending agent. 27% received a prescription for self-injectable epinephrine and 20% had a documented referral to an allergist. Only six of 259 (2.3%) patients received all three recommended interventions.

Study limitations are mainly related to its retrospective design and documentation issues. Despite these limitations, there is likely room for improvement in compliance with the guidelines. The authors conclude that there is an “untapped opportunity” for ED staff to prevent potentially life-threatening allergic reactions.

Despite a lack of high quality studies on the subject, several useful clinical pearls can be garnered from the literature on allergic reactions and anaphylaxis. Patients with anaphylaxis generally do well when treated with intramuscular epinephrine given in the lateral thigh. In refractory cases, atropine and vasopressin may be helpful. Anti-histamines and corticosteroids need to be studied more, but H2-blockers are likely helpful for cutaneous allergic reactions. Most patients with anaphylaxis can be safely discharged home after a short observation period with a prescription for epinephrine and clear discharge instructions to watch for biphasic reactions. Additionally, these discharge instructions should include education on trigger avoidance, indications to return to the ED, and how to use an epinephrine auto-injector. Close follow up with an allergist should be arranged.

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