Adverse (Anaphylactoid) Reactions to Intravenous Drugs

Clinical use:
A decision making system has evolved based on laboratory analysis of sequential plasma samples. The most urgent requirement is to decide whether the reaction is indeed “drug specific” and involves mast cell activation or whether it predominantly involves administration or other operator error. In the past this has relied upon the comparison of the movements of complement, immunoglobulin and other acute phase proteins within the sequential samples, after correction for haemodilution effect. The basic assessment is now being supplied by plasma tryptase assays.

Tryptase is, like histamine, contained within the mast cell. However, unlike histamine which is widely distributed amongst other cells, tryptase is almost entirely confined to the mast cell and its release is specific for activation of that cell type. Mast cell degranulation may be immune or non-immune mediated but both mechanisms are indicative of drug involvement. Tryptase release cannot be initiated by other means, such as vasovagal stimulation. The enzyme is highly stable in vitro and may be readily quantified by immunoassay.

The plasma tryptase concentration reflects both the clinical severity of the reaction and the reaction mechanism. With a half-life in vivo of 2.5 hrs ( cf.histamine 2.5 mins.) and against a background concentration of 2-14 m g/L, the following general observations have statistical significance:

Peak tryptase concentration
Systolic BP (mmHg)
Mechanism
>75 mg/L
0
Type I
20 – 50 mg/L
20 – 80
Non-immune(a) direct release(b) complement activation
2 – 20 mg/L
100 – 120
Error or essentially bronchospasmic reaction

Ideally the causative agent in the Type I reactions should be identified by a non-invasive technique involving the blood samples taken at the time of the adverse reaction. Unfortunately, at present, the only satisfactory assay is that for the specific IgE to suxamethonium, itself the most potent immunogenic drug employed in anaesthesia. Specific IgE assays to some commonly used antibiotics are also available. Advice will be given on such follow-up investigations after the results of the initial decision making process. Likewise, follow-up for non-immune reactions, direct chemical and complement mediation, with further characterisation and elucidation can be achieved with specialised assays.

Following completion of the tests and careful examination of the clinical history the results will be communicated to the anaesthetist. Suggestions will also be made regarding safer or alternative drugs which he may wish to consider for future use in his patient. These comments will be supplied in a written report.

In the absence of suitable in vitro assays for drug-specific IgE class antibody, it may be necessary to recommend skin prick testing. This should only be carried out by an experienced practitioner in a specialist allergy clinic with full rescusitation facilities available. Intradermal testing should NOT be employed.

Documentation
This should be comprehensive, but brief, and should include the following (although any other factor which the anaesthetist thinks could be a cause of the reaction should be indicated, eg surgical stimulation, undiagnosed hypovolaemia etc).

  • Patient’s name, date of birth, hospital number, gender.
  • The sender and contact address.
  • Surgical procedure.
  • Date of reaction.
  • Drugs administered (including premedication and sequences where possible).
  • Clinical manifestations.
  • Management of reaction and outcome (eg residual effects or death).
  • Previous medical and anaesthetic history if known.
  • Any particular risk factors? (eg known asthmatic, penicillin allergy, anaesthetic reaction or extremely anxious patient etc).
  • The haematological data, if available.

THIS DOCUMENTATION SHOULD ACCOMPANY THE PLASMA SAMPLES.

Telephone contact: At any stage of the reaction the user of the service is encouraged to telephone the PRU Sheffield (0114-271-5552) for advice. This advice is based on the cumulative experiences of NARCOS in the assessment of emergency situations. NARCOS provides a 24 hour advisory service via the Hospital switchboard (0114-243-4343).

Sample requirement:
The basic requirements for investigating adverse drug reactions are as follows:

Blood and urine samples
Preservative
: All blood samples should be collected in tubes containing EDTA. It is possible to perform the tryptase assay on serum samples but EDTA plasma is to be preferred.

Sample volume: 5 – 10 mL blood samples are adequate.
10 mL aliquots of urine should also be submitted if possible – vide infra brochospasm.

Sample frequency: The first sample should be taken as soon as possible after commencement of the reaction and ideally within the first 30 minutes. Further samples should be taken 3, and 24 hours after reaction.

It is recommended that the blood samples are taken in duplicate, one sample being despatched to the hospital’s own Haematology Department for ‘routine haematology’ including full differential white cell count and haematocrit. Copies of the haematology reports should be included in the patient documentation sent with the samples.

It is also recommended that two urine samples are collected, particularily in those reactions manifest only, or predominently, in bronchospasm. The first should be that first passed by the patient at least two hours following the reaction, the second being collected 24 hours later. Excess methyl histamine in the first sample is a marker of mast cell degranulation in a reaction initiated through the lung as the major shock organ. The second sample is used as the patient specific baseline and is essential for interpretation. There is a propensity for the drugs Propofol and Vecuronium to act through this mechanism which may involve a prostaglandin response.

Sample handling: Blood samples for plasma tryptase assay should be separated as soon as possible, preferably within three hours of venesection. The separated plasma should be stored at -20C until ALL the samples have been collected, when they should be carefully sealed, securely wrapped and despatched by FIRST CLASS MAIL to the Sheffield PRU.

Special Situations: It is recognised that on many occasions the above protocol will be unworkable and and that death may have intervened. Single blood samples, even when collected post mortem, may still be of value in distinguishing unforeseen underlying causative pathology. In such cases telephone to discuss the situation.

Centres offering this service: 
Sheffield Northern General’s PRU Diagnostic Service

Further information may be obtained from www.immqas.org.uk/narcos.htm

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