Clinical trial NCT04755881: SHARED Study (Saguenay Hospitals Anaphylaxis Rule for Early Discharge)
Official title: SHARED (Saguenay Hospitals Anaphylaxis Rule for Early Discharge) - Phase 2 : a Prospective Theoretical Validation
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Anaphylaxis
Biphasic Anaphylactic Reaction
Rebound Anaphylactic Reaction
Keywords: biphasic anaphylactic reaction
anaphylaxis
allergic reaction
clinical decision rule
anaphylactic reaction
predictors of biphasic anaphylactic reaction
epinephrin
anaphylaxis NIAID/FAAN
Lead sponsor: Université de Sherbrooke
Sponsor class: OTHER
First posted: 2021-02-16
Enrollment: 191
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study aims to recruit 533 patients of all ages from three sites of Saguenay-Lac-St-Jean's hospitals' emercgency services (Chicoutimi, Alma and Jonquiere).

Recruiting started in december 2019 following approval from the ethics comity, sciencitic validity evaluation and institutional convenience.

Faced with a case of anaphylaxis, the emergency doctor will have to answer a short questionnaire developed with the variables present in each of the three rules.

Brief summary: Anaphylaxis is a potentially fatal condition with a prevalence between 0.05 and 2% in the general population. This is therefore a frequent reason for emergency visits. Its diagnosis is mainly based on the NIAID / FAAN2 criteria, developed in 2006. The treatment of the condition consists of administration of intramuscular (or intravenous) epinephrine and the hemodynamic support of the patient, if necessary. Various other agents are frequently administered (class I and II antihistamines, corticosteroids) but their role is recognized to be less central than that of epinephrine. The relevance of corticosteroids in reducing the risk of rebound reaction is even questioned.

After anaphylaxis, a serious phenomenon called a "biphasic reaction" can occur. This reaction is the return of symptoms of anaphylaxis resolution of the initial episode. The theoretical risk of a rebound reaction, or biphasic reaction, is conventionally described up to 72 hours after the initial anaphylactic event. Biphasic reaction is defined as a recurrence or occurrence of new signs or symptoms after resolution of the initial reaction, without re-exposure to the allergen. The potential occurrence of a biphasic reaction often warrants observation of patients for several hours in emergency departments following management of the initial anaphylaxis. Although recommendations and guidelines generally suggest observation times of four to six hours, there is no clear consensus or convincing evidence to guide this conduct. It sometimes even is suggested to observe patients for up to 24 hours.

Problem: To date, there are no prognostic factors to identify a patient at greater risk who would benefit from such an observation. As these reactions are a relatively rare phenomenon (i.e. 4 to 5%, but which could go up to 20% according to some sources and the symptoms observed are usually less significant than during the initial presentation, it is therefore possible that a prolonged observation period may not be necessary for some patients who do not have high risk factors for biphasic reaction. In the current context of the growing number of people in emergency rooms and limited ressources, it seems essential to identify low risk patients in order to discharge them quicker and safely by limiting unnecessary observation periods.

Objective: Identify and evaluate in a prospective manner previously derived (literature review and preliminary rules derivation already completed) clinical decision rules that are simple, generalizable and valid which could therefore become an interesting assets for the modern practice of emergency medicine as regards to post anaphylaxis rebound reaction risk stratification. It appears likely that some patients who have suffered an anaphylactic reaction could be safely discharged much earlier than in current practices. The rules would give clear guidelines to clinicians especially those working in lower flow settings, where clinical experience with the disease is less developed. Ultimately, these rules would also be relevant for teaching purposes for the various learners who do internships in emergency rooms.

Detailed description: This study is part of an ongoing projet to create, derive and validate a clinical decision rule with regards to the stratification of the biphasic reaction risk following an anaphylaxis event that has mandated an emergency room visit.

Phase 0: Systematic literature review (completed)

Phase 1: Statistical derivation of two clinical decision rules (retrospective observational study) - (completed)

Phase 2: Validation of clinical decision rules (prospective observational study - theoretical) - (Prematurely terminated)

Objective: The objective of phase 2 was to test the applicability and performance of our clinical decision rules in a prospective observational manner.

UPDATE (March 2023) This unfortunately failed, the rule showed underperformance and clinical utility wasn't attained / maintained in the derivation phase. Furthermore, we tried combining data for the derivation study (phase 1) and the validation study (phase 2) and found that since the phenomenon of biphasic reaction was so heterogeneous, we would need to recruit an unrealistic number of anaphylaxis cases. This endeavor for which we have nor the time, nor the ressources and nor the organizational capabilities would also statistically lead to a clinical decision rule still subject to failure in its further external validations because of the very heterogeneous nature of allergens and the subjects immune reactions to them (projected frailty index).

Methods: Based on the three clinical decision rules (2 derived from phase 1and one based on the literature review), a prospective observational study was carried out in the emergency rooms of Chicoutimi, Jonquière and Alma. Data collection for this theoretical validation phase has been underway since December 2019 and stopped in march 2023, having received the approval of the various local research committees (ethics, science and convenience).

A questionnaire was developed from the three rules derived in the previous phases. All the elements present in these rules have been grouped by categories (history, allergen, symptoms and treatment). In this way, the criteria for each rule were not placed one after the other so that no rule could be recognized or inferred. This questionnaire was presented during department meetings. It is placed on the charts of patients with suspected anaphylaxis at triage and also is available at strategic locations in all three emergency rooms (for example, in the reanimation room).

Doctors were therefore invited to complete the questionnaire anonymously following their initial management of an anaphylactic reaction. Thereafter, they treat the patient as they would have done according to their usual practice. No rules was applied to the patients and the answers provided had no impact on their future care. The questionnaires were then deposited in a secured location determined for this purpose, in each of the emergencies.

The collection of files began in December 2019 and is now terminated. The inclusion and exclusion criteria were the same as in phase 1. However, a patient who did not yet meet the criteria for anaphylaxis, but who, according to the clinician's assessment, would inevitably progress to an anaphylactic reaction could also be included if treated in this way. This was then clearly indicated on the questionnaire.

At the end of the preliminary recruitment period, all completed questionnaire files will be reviewed to determine if a biphasic reaction has occurred. The three clinical decision rules will then be applied to the population to test their performance, validity and safety. The planned interim analysis which led to preliminary termination of the study included 191 cases of anaphylaxis and 11 biphasic reactions (only 6 of which were deemed clinically significant as per protocol criteria).

Some number of anaphylaxis cases were included in the study in between the preliminary analysis (march 2022) and its the results and decision to terminate the study (march 2023). This remaining will of course be analyzed and we propose to publish our data sets in hopes it can be used by other researchers in the field.

Lastly, the investigators were proposing to run a phase 3 trial, if the phase 2 trial had identified valid and clinically usable clinical decision rule(s). That phase 3 trial would have aimed to prospectively validate in real clinical setting and in a different patient population subset the selected rule(s). This phase 3 will unfortunately not be taking place as the trial was prematurely terminated during planned interim analysis in its phase 2 due to clinical uselessness of all 3 rules being tested. Of note, investigators tried to combine data sets from both phases 1 and 2 and still could not derive a rule for which statistical solidity could be expected in the face of such an heterogeneous process as the biphasic allergic reaction is.

Eligibility criteria: Inclusion Criteria:

* Patients of all ages with anaphylaxis (meeting the NIAID/FAAN criteria)
* Patients of all ages considered to be inevitably evolving torwards overt anaphylaxis by the threading physician

Exclusion Criteria:

* Adverse reaction to a medication (eg ACEI)
* Hereditary angioedema
* Known immune mediated Angioedema
* Anaphylactoid reaction

Primary outcomes:
measure: Rules maintain their sensitivity and negative predictive value with a different sample of patients from the same population pool (prospectively).
timeFrame: December 2019 - 2022
Secondary outcomes:
Other outcomes:
Locations:
city: Saguenay
country: Canada
facility: Service d'urgence CIUSSS du Saguenay - Lac-St-Jean
state: Quebec
Study officials:
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