Anaphylaxis presents as hypotension, and the dose follows the grade

Why it matters

Anaphylaxis in the recovering patient is rare and mistaken for common things. It presents as hypotension in 46% of cases, as bronchospasm in 18%, and as a rash rarely enough that waiting for one is a way to miss it; every patient in the national audit was hypotensive at some point harper-2018-nap6. Some triggers act slowly: onset was rapid with neuromuscular blocking agents and antibiotics but delayed with chlorhexidine and Patent Blue dye, which is why a reaction can begin after the patient has left the operating room harper-2018-nap6.

The consequence of getting this wrong is a hypotensive patient treated with fluid and a vasopressor for the wrong diagnosis while the epinephrine stays in the drawer, or treated with an arrest dose of epinephrine for a reaction that needed a fiftieth of it.

Mechanism

Mast-cell and basophil degranulation, whether IgE-mediated or not, releases histamine, tryptase and other mediators that dilate vessels, leak plasma from the circulation, constrict bronchial smooth muscle and, in the severe grades, depress the myocardium. The vasodilatation and the plasma loss are why hypotension is the presenting sign and why the skin signs, which need perfused skin to show, may be absent until the circulation is restored garvey-2019. The rate of onset depends on how the trigger reaches the mast cell: intravenous drugs act within minutes, while an antiseptic absorbed from a mucosal surface or a dye taken up from tissue can produce a reaction long after the exposure harper-2018-nap6. Epinephrine is the treatment because it addresses every limb at once, and its dose has to match the severity because the same drug that reverses a Grade III reaction can cause an arrhythmia in a patient with a Grade I rash.

Evidence

NAP6 collected 266 Grade 3 to 5 reports over one year across the UK National Health Service and estimated the incidence at about 1 in 10,000 anesthetics, with the true figure possibly around 70% higher harper-2018-nap6. Of 199 identified culprits, antibiotics accounted for 94, neuromuscular blocking agents 65, chlorhexidine 18 and Patent Blue dye 9; there were no reports of local anesthetic or latex-induced anaphylaxis harper-2018-nap6. Teicoplanin was 12% of antibiotic exposures but 38% of antibiotic anaphylaxis; succinylcholine was twice as likely as other neuromuscular blockers to be the culprit, mainly with bronchospasm harper-2018-nap6. Presenting features were hypotension 46%, bronchospasm 18%, tachycardia 9.8%, desaturation 4.7%, bradycardia 3% and reduced or absent capnography 2.3%; there were 10 deaths and 40 cardiac arrests, usually pulseless electrical activity and often with bradycardia; and poor outcome was associated with ASA class, obesity, beta-blocker use and ACE-inhibitor use harper-2018-nap6.

The 2019 international consensus recommendations grade reactions on a modified Ring and Messmer scale: Grade I, skin or mucosal signs only; Grade II, moderate multi-organ involvement; Grade III, life-threatening involvement with life-threatening hypotension, tachycardia or bradycardia, severe bronchospasm, with or without skin or gastrointestinal signs; Grade IV, cardiac or respiratory arrest; and skin signs may be absent, especially in Grades III and IV, until adequate perfusion is restored garvey-2019. Adult doses: Grade II, intravenous epinephrine 20 µg, escalating to 50 µg if the response is inadequate at 2 min and repeated every 2 min, 300 µg intramuscularly if there is no intravenous access, and crystalloid 500 mL; Grade III, 50 µg, or 100 µg if unresponsive to other vasopressors or bronchodilators, escalating to 200 µg at 2 min and repeated every 2 min, with crystalloid 1 L repeated up to 30 mL/kg; Grade IV, 1 mg repeated per advanced life support, with external cardiac massage suggested if systolic pressure is below 50 mmHg or end-tidal carbon dioxide below 20 mmHg garvey-2019. For a refractory reaction with an inadequate response after more than 10 min: double the epinephrine dose; after more than three boluses add an infusion of 0.05 to 0.1 µg/kg/min; for hypotension consider vasopressin 1 to 2 IU, glucagon 1 to 2 mg if the patient is on a beta-blocker, norepinephrine 0.05 to 0.5 µg/kg/min, and extracorporeal support; and send tryptase at 1 h, at 2 to 4 h, and a baseline at 24 h or later garvey-2019. The panel notes that some of its members held that 10 µg was more appropriate than 20 µg as the Grade II starting dose, and it is explicit that sugammadex has no immediate role in the resuscitation of suspected anaphylaxis garvey-2019.

The non-allergic differential in the same document is the PACU’s checklist for the hypotensive patient: relative anesthetic overdose, neuraxial vasodilatation, bone cement implantation syndrome, amniotic fluid embolism, pulmonary embolism, tricyclic drugs, bleeding and other shock for isolated hypotension; asthma, airway hyperreactivity, inadequate depth, tube malposition and aspiration for isolated bronchospasm; and airway manipulation, ACE-inhibitor angiedema with onset 1 to 8 h after surgery, and hereditary or acquired angiedema for isolated angiedema garvey-2019.

What this does not show

NAP6 is a national audit of reported cases, and the consensus recommendations are a Delphi exercise among 26 experts harper-2018-nap6 garvey-2019. No trial compares epinephrine doses in perioperative anaphylaxis, and the doses are the panel’s suggestions, offered with the acknowledgement that the group did not agree on the Grade II starting dose garvey-2019. The grading is a clinical tool, not a validated prognostic score.

The director’s content list pairs latex with chlorhexidine as delayed presentations. The sources support half of that: chlorhexidine and Patent Blue produced delayed onset, but NAP6 recorded no latex anaphylaxis at all and the consensus paper describes latex reactions as decreasing with primary and secondary prevention harper-2018-nap6 garvey-2019. No source retrieved supports a latex-specific delayed-presentation claim, and this page does not make one.

NAP6 is a UK audit; its culprit distribution, in particular the prominence of teicoplanin and chlorhexidine, reflects UK practice and may not transfer directly harper-2018-nap6. [PRACTICE VARIES: the antibiotics, antiseptics and dyes in routine use, and therefore the likely culprits, differ between countries and institutions.]

At the bedside

Put anaphylaxis on the differential of every unexplained hypotension in the PACU, and do not wait for a rash to confirm it; the skin signs are the ones most likely to be missing when the reaction is severe garvey-2019. Ask what the patient received in the last hour and whether it included chlorhexidine or a dye, because those are the triggers that arrive late harper-2018-nap6.

Grade the reaction, then dose the epinephrine to the grade: 20 µg for Grade II, 50 µg for Grade III, 1 mg only for arrest, escalating at 2-min intervals and adding an infusion after three boluses garvey-2019. Give the fluid the grade calls for at the same time.

Do not reach for sugammadex as a treatment for suspected anaphylaxis, whatever the neuromuscular blocker was; the consensus is explicit that it has no immediate role garvey-2019. Send the tryptase at the times the consensus specifies, and refer for investigation, because the next anesthetic depends on knowing the culprit garvey-2019.

Check yourself

Three items. Every option carries an explanation. Progress is not saved.