Expert consensus on the diagnosis and treatment of severe allergic reactions in the perioperative period (2020)

Expert consensus on the diagnosis and treatment of severe allergic reactions in the perioperative period, direction Ming Li Xu (co-author) Wu Xinmin (co-author) Cang Jing Gao Hong Xu Guiping Yang Rui Zhao Jing Zhang Xiuhua Zhao Xian Huang Yuguang (responsible person) Severe allergic reaction refers to a substance caused by a certain substance Triggered life-threatening systemic hypersensitivity reactions that manifest clinically as life-threatening respiratory and circulatory failure, often with cutaneous and mucosal symptoms
.

In China, there is no exact data on the incidence of severe allergic reactions during the perioperative period; in foreign countries, the incidence data reported by different studies are quite different, ranging from 1/18600 to 1/353
.

Studies have shown that the main drugs or substances causing perioperative allergic reactions are muscle relaxants (succinylcholine first, followed by rocuronium, vecuronium, micuronium, atracurium, and cis atracurium), antibiotics, latex, gelatin, lipid local anesthetics, blood products, and protamine
.

The incidence of women is higher than that of men, about 2 to 2.
5 times that of men
.

Severe allergic reactions are often sudden and difficult to predict
.

Therefore, it is necessary for anesthesiologists to make timely diagnosis and make prompt and correct treatment in order to maintain stable vital signs of patients
.

Relevant reports show that even with timely and effective treatment, the mortality rate of severe allergic reactions can still reach 3%
.

1.
Pathogenesis The main mechanism of severe allergic reaction is specific allergic reaction caused by specific substances, mainly IgE-mediated antigen-antibody reaction (50~60%), and a small part of IgG-mediated antigen-antibody reaction ( such as dextran)
.

After the antigen-antibody reaction is initiated, mast cells will be activated, causing mast cells to degranulate and release a variety of inflammatory mediators such as histamine, tryptase, interleukin, bradykinin, and platelet activating factor, thereby causing skin and mucous membranes, respiratory tract, digestive Signs and symptoms appear in the tract and circulatory system
.

There is also a class of non-allergic mechanisms, including non-specific complement system activation, direct activation of mast cells or basophils through specific receptors (such as the MRGPRX2 receptor), and COX-1 or the kinin-kallikrein system activation,
etc.

Some perioperative drugs can cause severe allergic reactions through multiple mechanisms simultaneously (eg, muscle relaxants and sugammadex)
.

2.
Clinical Symptoms Severe allergic reactions in the perioperative period mostly occur during anesthesia induction.
Patients often have skin and mucous membrane symptoms.
In severe cases, bronchospasm and circulatory failure may occur
.

According to the severity of perioperative immediate hypersensitivity reaction, its clinical manifestations are divided into 4 grades
.

Grade I: Only skin and mucous membrane symptoms appear
.

It manifests as extensive skin flushing, erythema, and extensive urticaria, with or without angioedema; grade II: Moderate involvement of multiple organ systems
.

In addition to skin and mucous membrane symptoms, hypotension, tachycardia, bronchospasm, or gastrointestinal symptoms may be associated; grade III: life-threatening clinical manifestations of single or multiple organ systems
.

Manifests as life-threatening hypotension, tachycardia or bradycardia, cardiac rhythm disturbance; may be accompanied by severe bronchospasm, skin and mucosal symptoms, or gastrointestinal symptoms; grade IV: cardiac arrest and/or respiratory arrest
.

The severity of allergic reactions is related to the speed of clinical symptoms and the involved organ systems.
If symptoms appear very quickly, skin symptoms are absent, and bradycardia occurs, it indicates a serious condition.
If treatment is not timely at this time, the prognosis is extremely poor.

.

In addition, the severity of allergic reactions is also closely related to the type of sensitized substances, the route, speed and dose of sensitized substances into the body, and also closely related to the patient's underlying diseases, especially the functional status of the circulatory and respiratory systems
.

In patients receiving beta-blockers, angiotensin-converting enzyme inhibitors, or neuraxial blockade, anaphylaxis is often severe and resuscitation is extremely difficult
.

Patients with severe allergic reactions may develop heart failure due to vasodilation, increased capillary permeability, decreased return to the heart, decreased cardiac output, coronary spasm, myocardial ischemia, and impaired myocardial contractility
.

It can also cause suffocation and hypoxia due to angioedema, bronchospasm, increased secretions, and airway obstruction
.

3.
Diagnosis and Differential Diagnosis (1) When suspicious clinical symptoms appear in the differential diagnosis, general spinal anesthesia, deep general anesthesia, pulmonary embolism, pneumothorax, cardiac tamponade, airway hyperresponsiveness (bronchial asthma) and hemorrhagic shock should be excluded (see Table 1)
.

Table 1.
Differential diagnosis of clinical symptoms associated with anaphylaxis in the perioperative period Hypotension and anaesthetic overdose Vasodilatation caused by spinal anesthesia Bone cement syndrome Amniotic fluid embolism Pulmonary embolism Cardiac tamponade Tricyclic antidepressants Shock bronchospasm Asthma or chronic obstructive pulmonary disease Airway hyperresponsiveness (often with high-risk factors such as asthma, smoking, or a history of upper respiratory tract infection) Shallow depth of anesthesia Abnormal placement of endotracheal tube Aspiration Angioedema or pharyngeal edema Supraglottic Local soft tissue injury due to airway placement or difficult intubation and swelling Angioedema due to angiotensin-converting enzyme inhibitors (usually occurs 1-8 hours after surgery) Hereditary or acquired angioedema rash or rash combination Hypotension, tachycardia, non-specific histamine release, chronic urticaria or angioedema, acute exacerbation of oxytocin excess, mesenteric traction syndrome, other clonal or non-clonal mast cell diseases The above typical symptoms appear after the drug or substance, the serum tryptase and plasma histamine levels are transiently increased, the serum specific IgE antibody is positive, and the corresponding skin test is also positive 4 to 6 weeks after the operation, which can be determined as A serious allergic reaction to this drug or substance
.

1.
Plasma histamine concentration is significantly increased (> 9nM) in severe allergic reactions to histamine, and its positive predictive value is 75%
.

However, it peaks in a few minutes in the blood, and only lasts for 15-30 minutes before returning to the baseline level, which coincides with the time window for the treatment of severe allergic reactions, and is difficult to routinely detect in clinical practice
.

2.
During severe allergic reaction to tryptase, tryptase in blood reaches its peak value within 30-90 minutes, and its half-life is 2h
.

Therefore, tryptase levels should be measured within 2 hours (acute phase) and 24 hours after the onset of clinical symptoms (baseline level)
.

It has also been suggested that blood should be taken every 1 hour and 2-4 hours in the acute phase to improve the sensitivity of diagnosis, but it is difficult to achieve clinically
.

If its blood concentration is >11.
4ng/ml or >(2 + 1.
2 × baseline value) ng/ml is positive, its positive predictive value can reach 93%, and its specificity can reach 88%
.

A detection system for tryptase should be established as soon as possible in China to help diagnose severe allergic reactions
.

3.
Specific IgE antibody If the specific IgE antibody of a drug or substance can be detected, it can prompt the patient to be sensitized to the drug or substance
.

However, since allergens do not necessarily cause allergy symptoms, it is necessary to combine medical history and other test results to confirm the diagnosis
.

4.
Skin test When a severe allergic reaction occurs, the inflammatory mediators in mast cells and basophils will be released and consumed in large quantities
.

Therefore, skin pricks and intradermal tests of suspicious drugs or substances should be completed 4 to 6 weeks after the occurrence of severe allergic reactions and after the body returns to normal to determine the allergen (see Table 2 for the skin test concentrations of commonly used anesthetic drugs)
.

The false-positive rate of skin test is high, and there is a potential risk of inducing severe allergic reactions in the whole body, but its positive results have high diagnostic value for judging allergens
.

Table 2.
Skin test concentration of commonly used anesthetics Drug stock solution (mg/ml) Prick test (maximum dose, mg/ml) Intradermal injection (maximum dose, μg/ml) Muscle relaxant succinylcholine 5010100 Atracurium 10110 cis-atracurium 2220 Micuronium 20.
22 Pancuronium 22200 Rocuronium 101050 Vecuronium 44400 Sedative-hypnotic Etomidate 22200 Midazolam 55500 Propofol 10101000 Thiopental 25252500 Anesthesia Sexual analgesics Alfentanil 0.
50.
550 Fentanyl 0.
050.
055 Morphine 10110 Remifentanil 0.
050.
055 Sufentanil 0.
0050.
0050.
5 Local anesthetic Bupivacaine 2.
52.
5250 Lidocaine 10101000 Ropivacaine 1022005.
Basophil activation test (BAT) Severe allergic reactions mediated by various mechanisms can lead to degranulation of basophils, resulting in the expression of the marker molecule CD203c on basophils Significant increase, new expression of CD63, these two are the best observation indicators of basophil activation, which can directly reflect the degree of basophil activation
.

Using the above principle, BAT uses flow cytometry to observe the new expression of the marker molecule CD63 and/or the increase in the expression of CD203c after the basophils are stimulated by the analyte to detect the specific activation of basophils.
, effectively identify drugs or substances that induce severe allergic reactions
.

BAT has high specificity but poor sensitivity and can be used as a supplement to skin testing
.

At present, this detection method is still in the research stage in China
.

4.
Once the symptoms related to allergic reactions occur in the treated patients, they should be evaluated in time, the diagnosis should be made quickly, and the corresponding treatment should be given in time according to the severity of the patients
.

Adrenaline therapy is not recommended for grade I patients with only relevant skin and mucous membrane symptoms.
Allergens should be removed first and oxygen, breathing, and circulation support should be given in a timely manner
.

For patients with grade II and above allergic reactions, epinephrine is the first choice for treatment, and other corresponding measures are taken at the same time to stabilize the respiratory and circulatory system and save the patient's life
.

(1) Immediately stop giving suspicious drugs or remove suspicious incentives, call for help, notify the surgeon to suspend the operation, and prepare an ambulance for use
.

The inspired oxygen concentration is adjusted to 100% to protect or establish the airway
.

(2) Stable circulation 1.
Adrenaline is preferred
.

The β2-receptor agonism of adrenaline can relieve bronchial smooth muscle spasm, and the α-receptor agonism can constrict skin, mucous membranes, and splanchnic blood vessels, excite the myocardium, increase cardiac output, and increase blood pressure; at the same time, it can inhibit inflammatory mediators Release, is the first choice rescue drug for anaphylactic shock
.

For class II patients, 10-20 μg can be intravenously injected, and if there is still no response after 2 minutes of the first dose, it can be increased to 50 μg
.

For patients who have not yet established intravenous access, intramuscular injection of epinephrine can be given at 300-500 μg; for patients with grade III, intravenous injection of 50-100 μg can be given.
If there is no response to the first dose, it can be increased to 100-200 μg.
-0.
1 μg/kg/min
.

For grade IV patients, 1 mg of epinephrine should be administered intravenously immediately, and Cardiopulmonary Resuscitation (CPR) therapy should be initiated
.

2.
Perform rapid fluid resuscitation to supplement fluid loss due to capillary leakage and maintain effective circulatory capacity
.

For grade II and III patients, the initial dose of fluid resuscitation is 0.
5L and 1L of crystalloid, respectively
.

If the effect is not good, crystalloid can be supplemented according to clinical needs
.

In severe cases, advanced hemodynamic evaluation should be performed as soon as possible to determine patient volume status
.

Fluid resuscitation in class IV patients should follow advanced life support (ALS) protocols
.

(3) Glucocorticoids and antihistamines There is no clinical evidence that the use of glucocorticoids and antihistamines will harm patients with perioperative allergic reactions, and no studies have shown that they have any benefit on prognosis
.

Therefore, glucocorticoids or antihistamines are recommended after adequate epinephrine use and fluid therapy
.

Glucocorticoids do not relieve initial symptoms and signs, but they can theoretically prevent the delayed effects of some severe allergic reactions
.

Hydrocortisone 1-2 mg/kg/d can be used, and it can be stopped after 1-2 days or methylprednisolone 125 mg
.

In terms of antihistamines, the role of H1-receptor antagonists is to relieve itching and urticaria.
At present, only the first-generation H1 antihistamines have parenteral dosage forms, and diphenhydramine 50mg can be given
.

(4) Norepinephrine (0.
05-0.
5μg/kg/min) can be pumped when other drugs have poor effect of epinephrine
.

Patients with hypotension after resuscitation for more than 10 minutes can try vasopressin (1-2 IU bolus followed by 2 IU/h pump)
.

For those patients who do not respond well to adequate epinephrine and fluid resuscitation after long-term use of beta-blockers, intravenous glucagon 1-2 mg may be considered
.

For persistent severe bronchospasm, inhaled or intravenous bronchodilators such as albuterol are recommended
.

Treatment with sugammadex is not recommended for patients with suspected rocuronium allergy, as sugammadex also carries a proportional allergy risk
.

(5) Follow-up treatment Whether to continue the operation needs to be comprehensively considered according to the urgency of the operation, the severity of the symptoms, and the progress of the operation when an allergic reaction occurs
.

If the patient's vital sign status is stable after adequate treatment, the risk of recurrent severe allergic reaction is less than 5%
.

Studies have shown that continuing surgery in patients with grades I-III does not affect prognosis
.

However, the patients should be closely monitored for at least 4-6 hours after surgery.
It is recommended that patients with grade III-IV should return to the intensive care unit for continuous monitoring after surgery, and adjust the treatment plan at any time
.

V.
Prevention (1) Risk Factors Previous severe allergic reactions or unexplained perioperative events are the only risk factors for severe allergic reactions during subsequent operations, and allergen screening should be performed for such patients
.

Atopic (allergic) constitution, food allergy, other drug allergy, previous successful anesthesia history, or family history of anesthesia drug allergy were not risk factors for severe perioperative allergic reactions
.

(2) Preoperative preparation All patients with severe allergic reactions of grade II-IV and grade I with generalized urticaria and erythema in the perioperative period should be referred to an allergy specialist for allergen screening
.

Allergen screening should be done in collaboration between an anesthesiologist and an allergist with experience in perioperative allergen screening
.

Preoperative asthma patients should control their respiratory symptoms as much as possible before anesthesia
.

Beta-blockers can exacerbate severe anaphylaxis and reduce responsiveness to epinephrine; angiotensin-converting enzyme inhibitors (ACEI) may interfere with the body's compensatory physiologic response to severe anaphylaxis , and aggravate the vascular changes caused by bradykinin.
Therefore, for patients with a higher risk of severe allergic reactions during the perioperative period, especially when the sensitizing drug cannot be finally determined, the patient's underlying disease should be combined to decide whether to re-anesthesia.
Both types of drugs were discontinued
.

Antibiotics should be administered separately from other drugs and infused slowly
.

There is currently no evidence that H1 receptor antagonists (eg, diphenhydramine), H2 receptor antagonists (eg, ranitidine), or glucocorticoids prevent or reduce the severity of IgE-mediated allergic reactions
.

However, for patients suspected of allergy to opioids, muscle relaxants, and vancomycin, pre-administration of H1 receptor antagonists, or combined with glucocorticoids, and slow infusion of drugs may reduce the risk of non-specific histamine release.
Class I reaction
.

Reference 1.
Muraro A, Roberts G, Worm M, et al.
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.
Allergy 2014; 69(8):1026-1045.
2.
Panesar SS, Javad S, de Silva D , et al.
The epidemiology of anaphylaxis in Europe: a systematic review.
Allergy 2013; 68(11):1353-1361.
3.
Tacquard C, Collange O, Gomis P, et al.
Anaesthetic hypersensitivity reactions in France between 2011 and 2012: the 10th GERAP epidemiologic survey.
Acta Anaesthesiol Scand 2017; 61(3):290-299.
4.
Dong SW, Mertes PM, Petitpain N, et al.
Hypersensitivity reactions during anesthesia.
Results from the ninth French survey (2005-2007).
Minerva Anestesiol 2012; 78(8):868-878.
5.
Volcheck GW, Mertes PM.
Local and general anesthetics immediate hypersensitivity reactions.
Immunol Allergy Clin North Am 2014; 34(3):525-546.
6.
Harper NJN, Cook TM, Garcez T, et al.
Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6).
Br J Anaesth 2018; 121(1):159-171.
7.
Baldo BA, Pham NH.
Histamine- releasing and allergenic properties of opioid analgesic drugs: resolving the two.
Anaesth Intensive Care 2012; 40(2):216-235.
8.
Garvey LH, Dewachter P, Hepner DL, et al.
Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations.
Br J Anaesth 2019;123(1):e50-e64.
9.
Garvey LH, Ebo DG, Mertes PM, et al.
An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions.
Allergy.
2019 Oct; 74(10):1872-1884.
10.
Takazawa T, Sabato V, Ebo DG.
In vitro diagnostic tests for perioperative hypersensitivity, a narrative review:potential, limitations, and perspectives.
Br J Anaesth.
2019 Jul;123(1):e117-e125.
11.
Berroa F, Lafuente A, Javaloyes G, et al.
The usefulness of plasma histamine and different tryptase cut-off points in the diagnosis of peranaesthetic hypersensitivity reactions.
Clin Exp Allergy.
2014 Feb;44(2):270-7.