Issues for surgery
For suppression of transplant rejection – risk of rejection if omitted.
For rheumatology, dermatology, and inflammatory bowel disease (IBD) conditions – risk of perioperative flare in disease activity if omitted.
For myasthenia gravis – risk of return of symptoms, relapse or myasthenic crisis if omitted.
Risk of post-operative infection if continued (see Further Information).
Advice in the perioperative period
Elective surgery
Check full blood count (FBC), particularly if neuraxial anaesthesia is planned.
Check liver function tests (LFTs) if not recently checked.
Suppression of transplant rejection indication
Continue – the patient’s relevant specialist should be involved in the planning for surgery.
Supplemental steroids to cover the perioperative period may not be necessary unless the patient has recently discontinued them or is currently on corticosteroid treatment.
Rheumatology indications
Continue – see Further information
EXCEPT:
- patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) with systemic lupus erythematosus (SLE) that is not severe – consider withholding azathioprine 1-week pre-operatively – see Further information.
Individualised decisions should be made for procedures with a high risk of infection and should be balanced against the risk of disease flare (see Further information). The surgical team and the patient’s rheumatologist should be involved in the planning for elective surgery. If the decision is made to stop azathioprine, it could be stopped 1-2 days pre-operatively due to its short half-life.
Steroid exposure should be minimised before surgical procedures, and pre-operative increases in steroid dose (‘stress’ doses) are not routinely required unless clinically indicated (e.g., adrenal insufficiency). Consideration should be given to delaying high-infection-risk elective surgery if the steroid dose is equivalent to prednisolone ≥ 20mg/day.
Ideally, in patients with high rheumatic disease activity, elective surgery should not be performed until disease has been stabilised.
Other indications (e.g., dermatology indications, IBD indications)
The decision to continue should be made on an individual patient basis in conjunction with the surgical team and the patient’s specialist.
If the decision is made to stop azathioprine prior to surgery, it could be stopped 1 – 2 days pre-operatively due to its short half-life.
Emergency surgery
Continue – the patient should be closely monitored for signs of infection following emergency surgery.
Suppression of transplant rejection indication
Inform the patient’s relevant specialist at the earliest opportunity.
Post-operative advice
Suppression of transplant rejection indication
Restart treatment in the immediate post-operative period when next dose due. If the patient cannot take their usual oral medication post-operatively, their relevant specialist must be consulted for advice on an alternative medication, dose, route, and frequency.
Monitor renal function. If renal function deteriorates post-operatively, the patient’s specialist should be consulted.
Rheumatology indications / Other indications (e.g., dermatology indications, IBD indications)
For high-risk surgical procedures or where there are patient factors that may increase surgical infection risk, i.e., age and / or co-morbidity, consider withholding azathioprine in the immediate post-operative period.
If suitable to continue, restart once the next dose is due and enteral intake has been resumed.
If discontinued, restart as soon as possible (ideally within 3 – 5 days), once wound healing is satisfactory, and there are no signs of infection.
Where azathioprine is continued, close monitoring of renal function is important so that inadvertent drug accumulation does not occur.
Interactions with common anaesthetic agents
Non-depolarising neuromuscular blocking drugs (NMBDs)
Use of azathioprine may increase the dose of atracurium, pancuronium and vecuronium required, but this appears not to be clinically significant.
Suxamethonium
Azathioprine can potentiate the effects of suxamethonium according to the manufacturer, although there is no further information on the significance of this.
Interactions with other common medicines used in the perioperative period
Antimicrobials
There is some evidence that there is an increased risk of haematological toxicity in patients taking azathioprine when treated with co-trimoxazole or trimethoprim. Although there is evidence to suggest that it is safe to use the combination.
Whilst single surgical prophylactic doses should not pose a problem, continued post-operative treatment may require close monitoring, particularly of full blood count. If any abnormalities occur, there should be consideration of this interaction as a possible cause.
Further information
Infection risk
Some data suggest that not all DMARDs carry the same infection risk. There is limited data available regarding the use of azathioprine and perioperative infection. A retrospective study of joint surgeries in rheumatoid arthritis patients found that two-thirds of patients receiving DMARDs, including azathioprine, demonstrated no association with perioperative infection. Azathioprine is considered an immunomodulator (as opposed to an immunosuppressant), and the evidence for perioperative use of immunomodulators suggests they do not increase adverse perioperative outcomes.
In general, evidence of an increased risk of post-operative infection with continued azathioprine use in patients undergoing orthopaedic surgery has not been reported. One study by Colombel et al., who reviewed patients with IBD undergoing surgery for their IBD, found there was no association between use of azathioprine and septic or total complications.
Factors influencing the risk of perioperative infection include current disease activity / severity, use of glucocorticoid replacement (prednisolone ≥ 20mg daily), older age, smoking, co-morbidities (i.e., diabetes mellitus), previous infections, and type of surgical procedure. These should be considered when making individualised decisions about the perioperative management of azathioprine.
Recommendations for suppression of transplant rejection
One study of patients undergoing elective plastic and reconstructive surgeries who have had a solid organ transplantation found no statistically significant increased risk of wound complication or infection associated with immunosuppressant therapy.
Recommendations for rheumatology indications
RA flares develop in 10-20% of patients undergoing surgery and have the potential to adversely impact post-operative recovery. In addition, active RA increases infection risk, further complicating decisions regarding DMARD interruption.
Recommendations from the German Society of Rheumatology state that azathioprine may be paused for 1 – 2 days pre-operatively where there is a low risk of relapse. Although there is recognition that a lack of available data, generally limited to observational studies, makes evidence-based recommendations difficult given the short pre-operative cessation period, there is likely to be limited effect on disease relapse.
Systemic lupus erythematosus (SLE)
The recommendations for the continuation of azathioprine for severe SLE in patients undergoing THA / TKA relate to the concerns about flare of disease and risk of organ damage in severe SLE that could occur if medication is held pre-operatively. However, it may be safe to discontinue azathioprine in the perioperative period if a patient with severe SLE has been stable for more than 6 months or has a history of recurrent / severe infections.
Recommendations for other surgeries
The evidence and consensus used for the recommendations are primarily drawn from orthopaedic literature, although the principles may be extrapolated and applied to other surgical procedures.
References
Albrecht K, Poddubnyy D, Leipe J et al. Perioperative management of patients with inflammatory rheumatic diseases: Updated recommendations of the German Society for Rheumatology. Zeitschrift für Rheumatologie. 2023;82:1–11
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