Does perioperative exposure to immunosuppressants (e.g. azathioprine, tacrolimus), corticosteroids (e.g. prednisone), or other medications that impair tissue integrity and wound healing increase the risk of anastomotic leak or surgical site infection in adults undergoing colorectal surgery, particularly those with a history of autoimmune diseases or transplant recipients?

Perioperative Immunosuppressants and Surgical Complications in Colorectal Surgery

Corticosteroids significantly increase the risk of both anastomotic leak and surgical site infection in colorectal surgery, while most other immunosuppressants (biologics, thiopurines) do not increase these risks and can be safely continued perioperatively. 1

Corticosteroids: High-Risk Medication

Patients on corticosteroids have substantially elevated complication rates and require specific risk mitigation strategies:

• Corticosteroids increase postoperative infectious complications with an odds ratio of 1.68 (95% CI 1.24-2.28) and an adjusted pooled OR of 1.7 (95% CI 1.38-2.09). 1

• All postoperative complications increase with an OR of 1.41 (95% CI 1.07-1.87) in steroid-exposed patients. 1

• The anastomotic leak rate is 6.77% in corticosteroid-treated patients versus 3.26% in non-steroid patients, representing more than double the baseline risk. 2

• Patients on long-term corticosteroids (≥20 mg prednisone daily or equivalent for >6 weeks) face up to a doubling of surgical site infections. 1

• One prospective study found a 50% anastomotic leak rate in patients on long-term corticosteroids and 19% leak rate with perioperative corticosteroids. 3

Mechanism of Harm

• Corticosteroids impair wound healing through increased susceptibility to infections and direct negative effects on tissue repair. 1

• The FDA label for prednisone explicitly warns that corticosteroids suppress the immune system and increase infection risk with any pathogen. 4

Risk Mitigation Strategy for Steroid-Exposed Patients

When corticosteroids cannot be discontinued:

• Taper steroids to the lowest possible dose before elective surgery, ideally to <20 mg/day prednisone equivalent or complete cessation when medically feasible. 1, 5

• Cut-offs for increased surgical complications range between 10-40 mg prednisolone daily for more than 3-6 weeks. 1

• Consider a staged procedure with temporary diverting stoma when high-dose steroids cannot be weaned (especially in emergency surgery) or when other risk factors coexist (sepsis, malnutrition, smoking). 1, 5

• In patients with pulmonary comorbidity taking long-term or perioperative corticosteroids, strongly consider protecting anastomoses with a diverting stoma or performing a Hartmann procedure. 3

• Patients on chronic steroids have a 7-fold increased risk of anastomotic leak in colorectal surgery. 5

Biologic Agents: Safe to Continue

Modern evidence demonstrates that biologic immunosuppressants do NOT increase perioperative complications and can be safely continued:

Anti-TNF Therapy (Infliximab, Adalimumab)

• The most recent PUCCINI prospective study (955 abdominal operations) confirmed that neither pre-operative anti-TNF exposure nor detectable drug levels before surgery increased the risk of overall infectious complications or surgical site infections. 1

• Recent Cochrane review and meta-analyses show no increased risk of postoperative complications in IBD patients on biological treatment. 1

• Meta-analysis of 1,407 patients on infliximab versus 4,589 controls showed no differences in major complications (OR 1.41,95% CI 0.85-2.34), minor complications, infectious complications (OR 1.23,95% CI 0.87-1.74), or anastomotic leak. 1

Vedolizumab

• Recent meta-analyses adjusting for disease severity and surgery type demonstrate a favorable safety profile with no increase in postoperative infections. 1

• Comparing 307 vedolizumab patients versus 490 anti-TNF patients and 535 patients without biologics revealed no differences in postoperative infectious or overall complications (OR 0.99 and 1.00 respectively). 1

Ustekinumab

• Recent large multicentre cohorts and meta-analyses indicate no increased risk of post-surgical complications in ustekinumab-exposed patients. 1

Immunomodulators (Thiopurines): Safe to Continue

Azathioprine and mercaptopurine do not adversely affect postoperative outcomes:

• Systematic reviews of 11 studies found no increase in risk of postoperative complications associated with thiopurines or cyclosporine. 1

• Thiopurines can be safely continued perioperatively and restarted immediately postoperatively when oral intake resumes. 1

• Stopping thiopurines immediately before surgery has no measurable impact on complication risk because these agents take 3 months to reach therapeutic levels and 3 months to fully wash out (elimination half-life 1-2 hours). 1

• A retrospective analysis of 484 consecutive abdominal CD operations found no difference in overall complication rate (18.6%), major complications (8.7%), or anastomotic leakage (3.3%) between patients with and without immunosuppression (corticoids and thiopurines). 6

Tacrolimus and Calcineurin Inhibitors

Limited specific data exist for tacrolimus in colorectal surgery, but general transplant data suggest increased infection risk:

• The FDA label for tacrolimus warns of serious infections as a major adverse reaction and notes that immunosuppression increases infection risk. 7

• Tacrolimus is associated with nephrotoxicity, neurotoxicity, and thrombotic microangiopathy, which may complicate perioperative management. 7

• In the absence of colorectal-specific data, exercise caution with tacrolimus-exposed patients and consider enhanced surveillance for infectious complications, though no specific dose adjustment guidelines exist for colorectal surgery. 7

Critical Clinical Algorithm

For patients scheduled for elective colorectal surgery:

1. If on corticosteroids ≥20 mg/day prednisone equivalent for >6 weeks:

   • Attempt to taper to <20 mg/day or discontinue if medically feasible 1, 5
   • If unable to taper, plan for diverting stoma or staged procedure 1, 3
   • If dose 10-20 mg/day, consider diverting stoma based on other risk factors 1

2. If on anti-TNF therapy, vedolizumab, or ustekinumab:

   • Continue perioperatively without interruption 1
   • No need for dose adjustment or timing modifications 1

3. If on thiopurines (azathioprine, mercaptopurine):

   • Continue perioperatively 1
   • Restart immediately when oral intake resumes 1

4. If on tacrolimus or other calcineurin inhibitors:

   • Continue at therapeutic levels for underlying condition 7
   • Monitor closely for infectious complications postoperatively 7

Common Pitfalls to Avoid

• Do not unnecessarily discontinue biologic agents or thiopurines before surgery—this provides no benefit and may worsen underlying disease control. 1

• Do not underestimate the risk of corticosteroids—even moderate doses (10-20 mg/day) for 3-6 weeks increase complication rates. 1, 3

• Do not assume all immunosuppressants carry equal risk—corticosteroids are uniquely problematic while biologics and thiopurines are safe. 1

• Do not delay necessary surgery in patients on immunosuppression (except corticosteroids)—the decision for surgery should not be postponed due to thiopurine or biologic use. 6

• Do not administer supraphysiologic "stress-dose" steroids to patients on chronic steroids—continue their usual equivalent IV dose instead, as stress dosing increases infection risk without hemodynamic benefit. 5