Drug Reactions

Adverse drug reactions

More than 80% of deaths directly attributable to anaesthesia are caused by problems with drugs. Half of these come from drug errors in which either the wrong drug is administered, or the correct drug is given at the wrong dose.

The other type of drug reaction occurs when the correct drug is given in the correct dose but the effects are unexpected. Such unexpected effects can be exaggerated side-effect responses or idiosyncratic effects.

Exaggerated side-effects reflect the variability in response to drugs by individual patients. The likelihood of any specific drug causing such effects to a dangerous level depends on its therapeutic window. The therapeutic window is a means of expressing the difference in dose that is required to produce the desired effect and the dose that will produce a serious unwanted effect.

Idiosyncratic reactions may or may not have distinct genetic factors predisposing the patient. Malignant hyperthermia is an idiosyncratic reaction determined by genetic predisposition. Other anaesthetic adverse drug reactions with a strong genetic component are acute porphyrias and suxamethonium apnoea caused by plasma cholinesterase deficiency. Anaphylaxis is an idiosyncratic reaction that does not have a major genetic determinant, as far as we know.

MDT anaesthetic anaphylaxis clinic

About 10 years ago I was approached by clinical immunology colleagues who had been asked for opinions on potential cases of anaphylaxis occurring during general anaesthesia.

We realised that a referral service for such reactions within the Yorkshire region would be useful and since that time we have conducted a multidisciplinary anaesthetic anaphylaxis clinic at St James’s Hospital.

In this clinic we jointly review the anaesthetic records and other contemporaneous medical notes to ascertain whether the clinical picture was consistent with anaphylaxis or whether there was an alternative explanation.
A medical and allergy history is also acquired before proceeding to skin testing. The initial skin testing involves skin prick testing in which a solution of the drug is placed on the skin and through which the skin is broken using a small sterile lancet. A positive response is indicated by the production of a skin wheal and flair.
In addition to doing skin prick testing with the drugs that the patient was exposed to we also test with alternative agents, especially the neuromuscular blocking drugs. This is to identify a safer alternative when one member of the class of drugs is shown to be the culprit.

When the clinical picture is consistent with anaphylaxis and all of the skin prick tests are negative we proceed to intradermal skin testing. Here a dilute solution of the drug is injected into the intradermal layer of the skin to raise a small bleb. A positive response is indicated by an increase in size of the bleb over a 15 to 20 minute period.

Positive skin prick tests and/or old intradermal tests indicate an IgE mediated anaphylaxis.

Non-IgE mediated anaphylaxis is diagnosed in the absence of positive skin prick or intradermal test results and a clinical picture consistent with anaphylaxis.

Usually the clinical picture is supported by an increase in the mast cell tryptase, if these blood test have been done within a suitable time frame following the clinical reaction. If mast cell tryptase are not taken at appropriate times, the diagnostic process can be much more difficult.

Anaesthetic anaphylaxis packs

A major help in obtaining the relevant information from referring clinicians has been anaesthetic anaphylaxis packs.

The original idea came from Dr Maria Garside at Bradford Royal Infirmary and was subsequently developed further by Louise Savic, Sinisa Savic and myself in Leeds.

We published an article in the Bulletin of the Royal College of Anaesthetists and these packs are now used throughout the UK with a great benefit in the quality of referral information to anaesthetic allergy clinics such as ours.

Non-allergic anaphylaxis

When there is clear evidence of an anaphylactic response and skin testing is negative it is possible that the mechanism underlying the reaction is non-allergic anaphylaxis. This is a diagnosis of exclusion and can one of several classes of drugs.

One of the difficulties in making a diagnosis of non-allergic anaphylaxis is the lack of sensitivity of the skin tests. The drug that this has most recently been highlighted with is teicoplanin, an antibiotic that is being used much more frequently especially in orthopaedic and trauma surgery.

With colleagues in Manchester we have published the largest case series to date of teicoplanin anaphylaxis and some of these patients failed to respond to the skin test challenges. There is still a lot to learn about the mechanism of drug allergy and the best diagnostic pathways and we will be developing research programmes to address these.