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Do antihistamines prevent biphasic allergic reactions?

Three Part Question

In [children after an allergic reaction] do [antihistamines] prevent [biphasic reactions]?

Clinical Scenario

A 14 girl presents to Paediatric A&E with her mother with a widespread urticarial rash and swollen lips after eating some egg to which she is allergic. You administer antihistamines and her symptoms improve. You prescribe antihistamines for discharge and wonder if they will prevent a biphasic reaction?

Search Strategy

Medline 1946 to June Week 1 2013
EMBASE 1980 to 2013 Week 26

‘((exp hypersensitivity/) OR (exp anaphylaxis/) OR (anaphyla$.mp) OR (aller$.mp) OR (acute ADJ allergic ADJ reaction)) AND (( OR (exp recurrence/) OR (early ADJ phase ADJ reaction) OR (late ADJ phase ADJ reaction) OR (delayed ADJ reaction)) AND ((exp Histamine H1 antagonists/) OR (exp Chlorphenamine/) OR (exp cetirizine/) OR (antihistamin$.mp) OR (hayfever LIMITS – Humans, English Language, Children aged 0 – 18.

Cochrane Library; Title, Abstract, Keywords (antihistamine) and Title, Abstract, Keywords (allergy) and Title, Abstract, Keywords (biphasic)

Search Outcome

3 relevant papers, of which one is a Cochrane Review

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Sheikh, A et al
All eligible papers including patients experiencing anaphylaxis caused by food, insect venom, medication, anaesthetics, latex or exercise Systematic Review Clinical improvement anaphylaxis by antihistamines There were no high quality randomised or quasi-randomised controlled trials comparing antihistamines with placebo or no intervention. Only considers antihistamine effect on anaphylaxis and not mild allergic reactions
Nielsen, PN at al
Ten subjects, all allergic to grass pollen on no antihistamine medication Single centre randomised, double blind, placebo controlled, cross over trial. Skin reactions to intradermal histamine and grass pollen injectionsWeal reactions to histamine and grass pollen were significantly reduced by cetirizine (Placebo 2663±238mm2 vs. cetirizine 1934±370mm2)Small sample size
Allergic reaction mediator levels in the blood Histamine and tryptase levels in the blood after allergen exposure were not altered by cetirizine
Brady, WJ et al
1261 allergic reaction patients. Retrospective chart review of out of hospital, ED and hospital records over a 4.5 year period Rate of biphasic reactions67 anaphylactic reactions of which 2 (3%) were biphasicOnly analysis of biphasic anaphylactic reactions rather than mild reactions included.
Antihistamine use in biphasic reactions Both cases received on-going antihistamine use after discharge for first reaction then returning 26 and 40 hours later with urticaria


From the literature available the use of antihistamines for allergic reaction is commonplace. However there is a lack of high quality evidence to support their use in anaphylaxis as demonstrated by the Cochrane review. Nielsen et al conducted a randomised double-blind trial to illicit the effects of cetirizine on histamine levels and reactions in the body, they deduced that cetirizine did help to reduce the size and number of wheals found on the skin after intradermal injection of grass pollen and of histamine but it has no effect on histamine levels in the blood. They conclude histamine is not one of the key mediators in late phase reactions, suggesting that antihistamine medication will not be able to prevent biphasic or late phase reactions. Although considering only anaphylactic biphasic reactions, Brady et al encountered only 2 patients, of who both were on antihistamines at the time of their biphasic reactions.

Clinical Bottom Line

More research is needed in this area, there is currently no evidence to suggest antihistamines reduce the occurrence of biphasic reactions therefore they should still be prescribed on discharge until more evidence is available.


  1. Sheikh, A., ten Broek, V., Brown, S. G. & Simons, F. E. H1-antihistamines for the treatment of anaphylaxis with and without shock Cochrane Database Syst Rev, August 2006
  2. Nielsen PN, Skov PS, Poulsen LK, Schmelz M, Petersen LJ. Cetirizine inhibits skin reactions but not mediator release in immediate and developing late-phase allergic cutaneous reactions. A double-blind, placebo-controlled study Clin Exp Allergy 2001;31(9):1378-84
  3. Brady WJ, Luber S, Carter CT, Guertler A, Lindbeck G. Multiphasic anaphylaxis: an uncommon event in the emergency department. Acad Emerg Med. 1997;4(3):193-7.