Posts filed under Pharmacology

Journal Club: Do Emergency Physician Opioid Prescribing Practices Impact Long-Term Opioid Use?

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Written by: Jon Andereck, MD (NUEM PGY-3) Edited by: Rachel Haney, MD, (NUEM Graduate 2017) Expert
commentary by:  Seth Trueger, MD


Introduction

Figure 1. Opioid Pain Reliever Sales, Related Treatment Admissions, and Related Deaths from 1999-2010 (CDC).

Over the past two decades, rates of opioid prescribing in the United States have skyrocketed, with the total amount of opioids distributed quadrupling from  1999 to 2010 (see Fig. 1). [1]  Rates of opioid related unintentional overdoses and deaths have risen in concurrent fashion, from 4,030 in 1999 to 14,800 in 2008. Public health experts, policy makers, and physicians have slowly come around to acknowledging the epidemic of opioid abuse now facing the country.

Much like in other care settings, there has been an increasing push to reduce the volume of opioids prescribed from the ED. The exact role of Emergency Department (ED) opioid prescriptions in this epidemic has been difficult to quantify. Among people aged 10-29, EDs represented 12% of opioid prescriptions and ranked as the third most common setting for which opioids were prescribed. [2]

Indeed, nearly 4 in 5 heroin users reported prior exposure to non-medical prescription pain relievers, and prior exposure to narcotic pain medications carried a 19-fold increased risk of future heroin use. [3] A study from 2014 estimated that as many as 13.8% of patients discharged from ED's across the country in 2010 were written a prescription for opioid pain medications, up from 11% in 2005. [2] Still, a large amount of uncertainty persists about the true impact of prescribing habits of Emergency Physicians (EP's) on the incidence of narcotic abuse. This study helps shed some light on how EP prescribing practices impact long-term narcotic use.


Study

Barnett ML, Olenski AR, Jena AB. Opioid-Prescribing Patterns of Emergency Physicians and Risk of Long-Term Use. N Engl J Med. Feb 16 2017. 376(7): 663-673.

Study Design

Retrospective analysis.

Population

Medicare Beneficiaries who visited any ED in the US from Jan 1, 2008 – Dec 31, 2011 who had not received an opioid prescription in the preceding 6 months and who were not admitted to the hospital on the index ED visit studied. Patients with cancer or on hospice were also excluded.

Measurement Protocol

Using Medicare Part D data, the authors calculated the morphine equivalents dispensed both in the 7 days following the index ED visit and any further opioid prescriptions over the following 12 months.

Treating EPs were categorized as either high-intensity or low-intensity opioid prescribers based on comparison with their peers at the same hospital. The authors calculated the percentage of patients that filled an opioid prescription after seeing any provider in a given hospital, and then divided providers into quartiles of rates of opioid prescribing within their own hospital. Physicians in the top quartile were designated high-intensity prescribers; those in the bottom quartile were designated low-intensity prescribers.

Outcome Measures

The primary outcome of interest was rate of long-term opioid use among patients in the 12 months following a visit in which they were seen by either a low-intensity or high-intensity opioid prescriber. Long-term use was defined as at least 180 days of opioids supplied in the 12 months after the initial ED visit, excluding the first 30 days following the ED visit.

Secondary measures included rate of hospital encounters possibly related to the adverse effects of opioids in the 12 months following the index ED visit. The authors also measured repeat ED visits at 14 and 30 days for the same primary diagnosis to assess for possible undertreated pain.

Results

Long-term opioid use was significantly higher among those treated by high-intensity prescribers, with an odds ratio of 1.3 (p<0.001) and an absolute rate of 1.51% as compared to 1.16% in the low-intensity group. The authors calculate a number needed to harm of 48 patients receiving an opioid prescription to lead to one excess long-term opioid user.

Long-term opioid use increased in a stepwise fashion for patients treated by physicians in each quartile of prescribing intensity (Fig 1).

A total of 377,629 patients were included in this retrospective analysis; 215,678 were seen by low-intensity EPs and 161,951 were seen by high-intensity EPs. Characteristics of each patient population were similar, though several of these were significant given the large sample size (see Table 1).

Over three times as many patients seen by a high-intensity prescriber were discharged with an opioid prescription than those seen by a low-intensity prescriber (24.1% vs. 7.3%), though there was no difference between the two groups in the median dose of morphine equivalents per prescription.

Figure 1

Table 1

In the secondary analysis, the authors found a small but significant increase in rates of opioid-related encounters (OR 1.03, p = 0.02) as well as ED visits for fall or fracture (OR 1.07, p < 0.001) for patients treated by high-intensity prescribers. In contrast, there was no difference in rates of hospital encounters for non-opioid related complaints. Additionally, rates of short-term ED visits for the same chief complaint were no different at 14 or 30 days for patients treated by either low- or high-intensity prescribers (See Table 3).

 

 

Table 3

 

Interpretation

This study does an impressive job of looking at an important but poorly understood issue in the field of emergency medicine – how do prescribing practices of physicians affect long-term opioid abuse their patients?

This retrospective study design is limited in that it was not randomized-controlled, but it was the most logical design to answer the question at hand. The number of patients included was certainly adequate to detect a meaningful difference. The study was limited by the fact that only Medicare beneficiaries were studied, in part because this was the most accessible database for such a large retrospective study. However, it therefore excludes many in the 19-39 age range in which long-term abuse potential is highest. Designing a randomized-controlled trial to attempt to answer this question would be difficult as it would require standardization of discharge prescriptions; few physicians would be amenable to ceding their right to determine the analgesic plan for their own patients.

The primary outcome of interest – long-term opioid use among patients seen by either type of provider – demonstrated that there is a correlation between high-intensity prescribers and long-term opioid use among patients they see. The authors calculate a number needed to harm (NNH) of 48 among patients prescribed opioids on discharge. This means that for every 48 patients given a discharge prescription for an opioid analgesic by a high-intensity prescriber, one will go on to use opioids long-term (as defined by this study) that could have been avoided if the patient had been seen by a low-intensity prescriber.

One of the most interesting results from this study is not even the question the authors set out to answer, but is the difference in opioid prescribing rates between high-intensity and low-intensity prescribers. This difference was over three-fold (7.3% to 24.1%) and represents an extraordinarily wide practice variability that underscores the lack of standard practice for opioid use. However, this variation was only in the number of prescriptions written and not for the amount of morphine equivalents per prescription as demonstrated in Fig. S3 above.

The counter-measure of pain control adequacy is an important one. The authors attempt to address whether patients treated by low-intensity providers had inadequate analgesia at home. While this question was not directly answered by the study, a surrogate measure of return visits to the ED with the same chief complaint demonstrated no significant difference between the two groups, which suggests but does not prove that there was no meaningful difference in analgesia between the groups.

Is this article practice changing? Perhaps. It does provide evidence that there is a correlation, small though it may be, between prescribing practices of EPs and long-term opioid use of patients. There are also small but significant differences in complications from the opioids given by high-intensity prescribers. The study further highlights the profound variability among EPs regarding their opioid prescribing practice, which I argue is an area to target for improvement especially without any known deficiency of pain treatment by doing so. We can all strive to only prescribe opioids that are truly necessary to treat acute pain, and this article serves as further motivation that over-prescribing can in fact cause our patients direct harm.


Take Home Points

  •  Variability of opioid prescribing within departments is large
  •  Opioid prescribing patterns do have an impact on long-term opioid use
  •  Fewer opioids do not lead to worse pain control, at least as measured by the return rate to the ED

Expert Commentary

This is a great overview of an impactful article. While ultimately there will always be some variation in opioid prescribing (by chance, some physicians will likely see more patients with more painful conditions), this paper suggests that the prescriber variability is high and its not due to chance. Regardless, my takeaway here is that there does seem to be a dose-response to opioid prescribing in the ED and longer term opioid use.

Both the sheer scale and physicians’ role in the opioid epidemic is startling and a number of factors are at play. Years of focus on oligo-analgesia were likely a mix of genuine concern for undertreating pain but unfortunately also driven by those with specific financial interests. Similarly, the increasing focus on patient satisfaction/experience and even with the link to payments, I suspect physicians are too quick to shift blame to others and we need to prescribe more responsibly. While most emergency department opioid prescriptions are short (75% are for 20 pills or fewer [4]), as Barnett and others have shown, a startling fraction of ED patients receive opioid prescriptions. And to borrow from Lewis Nelson, everyone who is addicted to opioids had to have had a first exposure.

Of course there are no easy answers – plenty of patients we see in the emergency department are in substantial pain, and we do not have a lot of tools. But it is not hopeless. My approach to pain management is similar to patients with URIs and antibiotics: sometimes we cut corners (“they’re just here for a z pack / Norco prescription”) and underestimate how satisfied our patients can be being taken care of by a physician who cares and explains things. Some of the things I focus on:

  1.  Acknowledge the patient’s pain: just because I’m not writing for a ton of opioids doesn’t mean I don’t believe they’re not in pain
  2.  Set realistic goals: I don’t have a silver bullet to make pain go away. My goal is to make their pain manageable, not gone.
  3.  Emphasize our priorities: Our main goal in the ED is to make sure there isn’t anything dangerous causing the patient’s symptoms.
  4.  The door isn’t shut when I discharge the patient: “The good news is you don’t need an MRI now but you do need to follow up with your primary doctor over time who will keep an eye on your symptoms and help determine if you do eventually need more testing or to see a specialist.”
  5. Information, information, information: what concerning symptoms to look for at home, when to call your doctor, when to come back to the ED.
  6.  What to do for symptoms: What works well for this? I find a lot of patients are very happy to hear me thoughtfully say “what works really well for this is prescription-strength ibuprofen.” I’ve also had a lot of success with lidocaine patches. Anecdotally they seem to work well, but more importantly, I think it demonstrates to the patient that we’re paying attention and being thoughtful (especially as I need to explain that sometimes insurance doesn’t cover them well but there are over the counter versions so here is how to approach that…)

Incidentally I rarely prescribe or co-prescribe benzodiazepines as we have some data they aren’t very helpful (e.g. Friedman [5]) and that we vastly underestimate their harms, particularly when patients take both opioids and benzos (e.g. Sun [6]).

We have a tight needle to thread between oligoanalgesia and the opioid epidemic, but right now I think it’s clear that the pendulum has swung too far. I don’t think we can nor should stop using opioids altogether (yet) but we can be thoughtful and careful as we care for our patients.

Seth Trueger MD MPH

Assistant Professor of Emergency Medicine, NUEM

 


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How to cite this post

[Peer-Reviewed, Web Publication]  Andereck J,  Haney R  (2018, Jan 29). Journal Club:  Do Emergency Physician Opioid Prescribing Practices Impact Long-Term Opioid Use? [NUEM Blog. Expert Commentary By Trueger S]. Retrieved from http://www.nuemblog.com/blog/opioids. 


Resources

  1.  “Vital Signs: Overdoses of Prescription Opioid Pain Relievers --- United States, 1999-2008.” Morbidity and Mortality Weekly Report. Centers for Disease Control and Prevention. Nov 4, 2011. 60(43): 1487-1492. < https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6043a4.htm#fig2>. 
  2.  Cantrill SV, Brown MD et al. Clinical Policy: Critical Issues in the Prescribing of Opioids for Adult Patients in the Emergency Department. From the American College of Emergency Physicians Opioid Guideline Writing Panel. Ann Emerg Med. 2012. 60:499-525.
  3.  Muhuri PK, Gfroerer JC, and Davies MC. Associations of Nonmedical Pain Reliever Use and Initiation of Heroin Use in the United States. Center For Behavioral Health Statistics and Quality. CBHSQ Data Review. August 2013.
  4. Hoppe JA, Nelson LS, Perrone J, Weiner SG. Opioid Prescribing in a Cross Section of US Emergency Departments. Ann Emerg Med. 2015 Sep;66(3):253-259.
  5. Friedman BW, Irizarry E, Solorzano C, Khankel N, Zapata J, Zias E, Gallagher EJ. Diazepam Is No Better Than Placebo When Added to Naproxen for Acute Low Back Pain. Ann Emerg Med. 2017 Aug;70(2):169-176.
  6. Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ. 2017 Mar 14;356:j760. doi: 10.1136/bmj.j760.

 

The Waiting Game: Biphasic Anaphylaxis

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Written by: Kumar Gandhi, MD, MPH (NUEM PGY-2) Edited by: Andrew Moore, MD, MS (NUEM PGY-4) Expert Commentary by: Aaron Kraut, MD


Case Scenario

18 y.o. female with history of asthma and multiple food allergies presents with rash and
shortness of breath following ingestion of assortment of cookies at a Halloween party. A diffuse erythematous pruritic rash started fifteen minutes following the ingestion of cookies. Associated symptoms include tingling in the back of the throat and wheezing. The patient reports one prior episode requiring use of an EpiPen, but she never refilled her prescription.


Vitals: HR: 90, RR: 25, BP: 105/70, Temp: 98.6, SpO2: 97% on room air


Pertinent findings on physical exam include:

  • Mild pharyngeal edema with no uvular deviation.
  • Moderatewheezing in bilateral lung fields
  • Diffuse abdominal tenderness
  • Blanching (urticarial) rash on the back,nabdomen, axilla, femoral creases, and posterior legs.

An Epi-Pen injection in the right thigh, coupled with concomitant 125mg of methylprednisolone IV Push, 25mg of Benadryl IV push [1] results in decreased wheezing and resolution of the urticarial rash.


Now that the patient is stable we need to ask ourselves a few important questions:

  1. Was this an allergic reaction or anaphylaxis?
  2. When can we discharge the patient?

Anaphylaxis: Overview


Anaphylaxis is a life-threating systemic hypersensitivity reaction. Pathophysiology includes [1]:

  • IgE-mediated Type 1 hypersensitivity reaction
  • Degranulation of mast cells releases vasoactive mediators including histamine, prostaglandins, and leukotrienes
  • Histamine mediates systemic vasodilation, cardiac contractility, and vascular permeability
  • Leukotrienes mediate vascular permeability and in combination with prostaglandins cause bronchoconstriction

 

Common Triggers:

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  • Foods: Peanut, tree nut, shellfish, finned fish, milk, egg
  • Insects: Insect stings and Insect bites
  • Medications: Antibiotics, Aspirin, and NSAID’s
  • Biologic materials: Monoclonal antibodies, chemotherapy, vaccines
  • Physical Factors: Exercise, cold, heat
  • Iatrogenic: Latex and radiocontrast agents

 

Signs and Symptoms of Anaphylaxis [2]:

  • Skin and mucosal symptoms occur in 90% of episodes
  • Respiratory symptoms and signs occur in up to 70% of episodes
  • GI symptoms such as nausea, vomiting, and diarrhea occur in 45% of episodes
  • Cardiovascular symptoms such syncope, dizziness, and tachycardia can occur in 45% of episodes

 


NIAID/FAAN Criteria for the Diagnosis of Anaphylaxis [3]

Diagnosis of Anaphylaxis:

  • Anaphylaxis is primarily a clinical diagnosis.
  • Diagnosis of anaphylaxis is made when any one of three NIAID/FAAN diagnostic criteria are fulfilled.

A 2012 retrospective cohort study of the NIAID/FAAN criteria demonstrated 97% sensitivity and 82% specificity for the diagnosis of anaphylaxis in 214 ED patients [3].

 

 

What is Biphasic Anaphylaxis?

Biphasic anaphylaxis is an anaphylactic episode followed by an asymptomatic period with return of anaphylactic symptoms in the absence of further exposure to the triggering antigen [4]. Incidence of secondary reaction following primary anaphylactic reaction can range from 1% to 23%, and
occurs in up to 23% of adults and up to 11% of children. [4] [5] [6]. The time interval from primary to secondary reaction ranges from 1 to 72 hours, though predominantly occurs within 8 hours of primary event [6].


Risk Factors for Biphasic Anaphylaxis


Predicting the occurrence of a biphasic reaction poses a diagnostic challenge. Previously studied risk factors for the development of biphasic anaphylaxis include [4]:

  • Severity of the primary anaphylactic reaction
  • Time from exposure of antigen to development of the primary response
  • Presence of hypotension or laryngeal edema
  • History of a previous biphasic reaction or asthma
  • Time to delivery of epinephrine for primary anaphylaxis [7]
  • Initial dosing of epinephrine in treatment of primary anaphylaxis [8]

 

How long should we watch patients?


Previous Practice
World Allergy Organization 2011 guidelines recommend an individualized approach, ranging from at
least 4 hours for patients with moderate respiratory or cardiovascular compromise to up to 8-10 hours or
longer if indicated for a protracted anaphylactic response. [9]


Often referenced in the anaphylactic observation time conundrum, Ellis et al. performed a 3-year
prospective study in a Canadian tertiary hospital, which found 103 cases of true anaphylaxis with a
19.4% occurrence of biphasic reactivity and an average time of secondary reaction onset of 10 hours.
Biphasic reactivity occurred in 60% cases before 10 hours [8]. The increased prevalence of biphasic reactions in this study is likely secondary to inclusion of all biphasic reactivity, including recurrent minor reactions and reactions that were not truly biphasic requiring epinephrine. [8] [10].


Current Literature
New literature indicates a much lower prevalence of clinically significant biphasic anaphylaxis. Gruanau et al. performed a retrospective chart review of 2,819 adult ED patients at two large urban ED’s
over a five-year span. 496 patients were classified as anaphylactic, of the total number of anaphylactic
patients evaluated only 5 (0.18%) had clinically significant biphasic reactions and zero mortality. Of the 3
patients that actually left the ED, the biphasic reaction occurred up to 6-days post-discharge, indicating
these reactions could occur at any time after discharge. This study concluded given such a low prevalence
of biphasic anaphylaxis, zero mortality, and variability in time to the secondary reaction it is unnecessary
to observe patients following resolution of symptoms [10] [11] [12].


Rohacek M et al. also performed a retrospective chart review 1,334 adult ED patients in a Swiss tertiary
care hospital over a 12-year span. 495 patients met the diagnosis of anaphylaxis, of which only 12 (2.3%)
were clinically significant anaphylactic reactions, with only 2 (0.36%) occurring in the hospital. Similar to
the Gruanau et al. study there were no deaths during the 10-day follow-up period. The study also
demonstrated no difference in the biphasic response rate for those patients watched for less than 8-
hours vs greater than 8 hours. [10] [13].


The new literature indicates a prevalence of 0.18%-2.3% clinically significant biphasic anaphylactic
reactions and zero mortality over the 4100 patients who were included in both studies. This indicates it is
likely safe to discharge patients home following resolution of their anaphylactic episode.


Recommendations/Take Home Points


Consider 1-hour observation period following resolution of symptoms for those patients [10]:

  • Promptly and adequately treated with Epi-Pen and demonstrate early resolution of symptoms
  • Patients who can be trusted with strong return precautions and with ability to access medical interventions should a biphasic response occur and demonstrate competence with utilizing an Epi-Pen at home [9]
  • 1-hour observation period is to ensure no recurrence of anaphylaxis following complete metabolism of epinephrine [10]

Consider observation time of 4-8 hours for those patients with:

  • Previous episodes of biphasic anaphylaxis or history of asthma [4]
  • Anaphylaxis with severe features including refractory hypotension, laryngeal edema, and respiratory compromise [4]
  • Patients who may have experienced significant delays in treatment with epinephrine or received a subtheraputic initial dose of epinephrine [7] [8]

Anaphylaxis Discharge Instructions
The discharge process presents a critical opportunity to educate patients about the signs and symptoms of a potential biphasic episode of anaphylaxis as well as provide the necessary education and tools for a patient to quickly intervene should a future episode of anaphylaxis occur. Per World Allergy Organization guidelines for the assessment and management of anaphylaxis, discharge management should include [9]:

World Allergy Organization Discharge Management Guidelines [9]


Expert Commentary

This is a great summary of an important and controversial topic. In my relatively short career as an emergency physician, I’ve probably heard 17 different answers to the seemingly simple question of how long to observe someone with anaphylaxis in the ED.  

You did a very nice job of summarizing the best available evidence to guide our practice as emergency physicians. A few key points I’ll highlight again for emphasis:

  1.  Not all allergic reactions are anaphylaxis- in a nutshell, you need multisystem organ involvement (usually skin/mucosa +respiratory or GI) or skin/mucosal involvement and hypotension to have anaphylaxis.

  2.  Severe biphasic responses are RARE and vary greatly in their time to onset

One of my biggest take homes on this topic comes from the Grunau 2014 Annals of EM article.  In that study, all of the severe/clinically significant biphasic anaphylactic reactions occurred in patients who did not meet the diagnostic criteria for anaphylaxis on their initial ED visit.   In my mind, this represents a huge opportunity for education and preemptive intervention in our emergency department patients who present with moderate/severe allergic reactions in general.

If I treat a patient for a moderate/severe allergic reaction with diphenhydramine and steroids, I universally discharge that patient with a prescription for an EpiPen and an explicit warning about the rare event of a biphasic reaction. Ideally, if they are one of those rare few who has a biphasic reaction because of an ‘inadequately treated’ initial reaction (one of the risk factors for a biphasic reaction), I’d like them to be able to administer life-saving epinephrine before they arrive back to the ED.

As far as the question of how long to observe once we’ve pulled the trigger on IM epinephrine in the ED, there is still no magic formula despite the several well-conducted studies you’ve reviewed here.

For me, it comes back to patient education. Since we know we cannot reliably predict the time to onset of biphasic symptoms, I do not put a strict time limit on patient observation after Epi administration. However, I will offer several criteria that a patient must meet before I’m comfortable with discharge.

  1. Objective airway findings must be resolved (uvular, lip/tongue edema, change in voice)
  2. Skin findings must be stable or improving
  3. Hemodynamics must be normal

Some patients may satisfy those criteria 45 minutes after Epi administration, while others may take 120 minutes or longer.  If my patient has worsening skin findings or continued objective airway findings at >120minutes, I will usually admit them for close monitoring and consideration of repeat epi dosing. 

If a patient meets the aforementioned discharge criteria, then it’s time for the education piece. If I know that the patient understands the signs and symptoms of a recurrent or biphasic anaphylactic reaction, has an Epi-Pen and knows how to use it, and understands that he/she must return to the ED immediately if he/she uses the Epi-Pen, I will discharge the patient as early as 40min-1hr after ED arrival. My thought is that there isn’t much to be gained from observation, where any worsening of symptoms would prompt re-administration of epinephrine (which the patient can accomplish themselves). The key, however, is that the patient understands the necessity of immediately returning to the ED upon re-dosing of epinephrine.

Finally, I am not personally a fan of the 4-8 hour observation, as I don’t believe there is much to be gained by keeping a patient in the ED for that amount of time. Either they respond to epinephrine and rapidly improve, or they do not respond and require repeated dosing or close airway monitoring/intervention for continued objective airway involvement. I’ll decide to admit many of these patients within the first 15 minutes of their ED stay. These rapid “decision to admit” patients also include those with anaphylactic shock (persistent hypotension or altered mental status/end-organ dysfunction), or severe objective airway findings (e.g. stridor, hypoxemia) on ED arrival.

And with that, you have an 18th different answer to the question of how long to observe someone with anaphylaxis in the ED. But do remember that biphasic anaphylaxis can also occur in patients who did not present with frank anaphylaxis on their initial ED visit. Be mindful of your discharge instructions for all allergic reactions and consider prescribing Epi-Pens to those whom you treat with diphenhydramine and steroids.

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Aaron Kraut, MD

Assistant Professor, Assistant Program Director, University of Wisconsin Emergency Medicine


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How to cite this post

[Peer-Reviewed, Web Publication] Gandhi K,  Moore A (2017, Sep 12). The Waiting Game: Biphasic Anaphylaxis.  [NUEM Blog. Expert Commentary By Kraut A]. Retrieved from http://www.nuemblog.com/blog/anaphylaxis


References

  1. Adams, James “immune System Disorders. “Emergency Medicine: Clinical Essentials. Philadelphia, PA: Elsevier/Saunders, 2013 924-28. Print.
  2. Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis--a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115:341.
  3. Campbell RL, Hagan JB, Manivannan V, et al. Evaluation of national institute of allergy and infectious diseases/food allergy and anaphylaxis network criteria for the diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol 2012; 129:748
  4. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol. 2005;95:217e226. III
  5.  Rohacek, M, H Edenhofer, A Bircher, and R Bingisser. 2014. Biphasic anaphylactic reactions: occurrence and mortality. Allergy, no. 6 ( 12). doi:10.1111/all.12404. 
  6. Tole JW, Lieberman P. Biphasic anaphylaxis: review of incidence, clinical predictors, and observation recommendations. Immunol Allergy Clin North Am 2007;27:309–326.
  7.  Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000; 106:762.
  8. Ellis AK, Day JH. Incidence and characteristics of biphasic anaphylaxis: a prospective evaluation of 103 patients. Ann Allergy Asthma Immunol 2007; 98:64.
  9. Simons FE, Ardusso LR, Bilo MB, El-Gamal YM, Ledford DK, Ring J et al. World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011;4:13–37.
  10. Swaminathan, Anand, and Salim Rezaie. "REBELcast Episode 1." Audio blog post. REBEL E.M. N.p., 1 July 2014. Web.
  11. Grunau BE et al. Incidence of Clinically Important Biphasic Reactions in Emergency Department Patients with Allergic Reactions or Anaphylaxis.
  12. Swaminathan, Anand. "SGEM#57: Should I Stay or Should I Go (Biphasic Anaphylactic Response)." Blog post. N.p., 13 Dec. 2013. Web.
  13. Rohacek, M, H Edenhofer, A Bircher, and R Bingisser. 2014. Biphasic anaphylactic reactions: occurrence and mortality. Allergy, no. 6 ( 12). doi:10.1111/all.12404. 

Posted on September 11, 2017 and filed under Pharmacology.