Is hypercortisolism (Cushing's syndrome) a contraindication for knee replacement surgery in a middle-aged to older adult patient with a history of managing this condition and related comorbidities such as diabetes and hypertension?

Hypercortisolism and Knee Replacement Surgery

Hypercortisolism is not an absolute contraindication for knee replacement surgery, but it significantly increases perioperative risks and requires aggressive preoperative optimization, with surgery ideally delayed until cortisol levels are controlled or at least 3 months after any intra-articular glucocorticoid injections. 1

Key Perioperative Risks in Hypercortisolism

Patients with active hypercortisolism face multiple serious surgical complications:

• Hypercoagulability and venous thromboembolism (VTE) are major concerns, as hypercortisolism creates a prothrombotic state that substantially increases risk during major orthopedic surgery 1
• Infection risk is elevated due to immunosuppression from chronic cortisol excess 1, 2
• Poor wound healing results from protein catabolism and impaired tissue repair mechanisms 2
• Cardiovascular complications including hypertension (present in >80% of cases), diabetes, and increased atherosclerosis risk 1, 3, 2
• Osteoporosis and fracture risk are significantly elevated, potentially compromising surgical outcomes 2
• Proximal myopathy with impaired muscle function may affect rehabilitation 1

Preoperative Management Strategy

Cortisol Control Before Surgery

• Ideally, hypercortisolism should be treated and controlled before elective knee replacement to minimize the complications listed above 1, 4
• For patients with Cushing's disease, transsphenoidal surgery is first-line treatment, achieving remission in approximately 80% of microadenomas and 60% of macroadenomas 4
• Medical therapy with steroidogenesis inhibitors (ketoconazole, metyrapone, or osilodrostat) should be considered for patients with severe hypercortisolism when surgery must be delayed, as this may favorably affect glucose, cardiovascular, and coagulation parameters 1, 5

Thromboprophylaxis Requirements

The 2021 Endocrine Society guidelines provide specific recommendations for patients with hypercortisolism undergoing surgery:

• Prophylactic anticoagulation should be considered for all patients at risk for VTE, including those with severe preoperative hypercortisolism, poor mobility, or extended hospital stays 1, 4
• Low molecular weight heparin is strongly preferred over oral anticoagulants due to the long half-life of oral agents and lack of reversal therapy, which is especially concerning perioperatively 1
• Early postoperative ambulation and compression stockings should be used for all patients 1
• Anticoagulation duration recommendations range from 2-4 weeks postoperatively, though some experts suggest up to 2-3 months in high-risk cases 1

Timing Considerations

• If intra-articular glucocorticoid injections have been given, knee replacement should be delayed at least 3 months to minimize infection risk, as injections within 3 months of surgery increase prosthetic infection rates from 0.5% to 1.0% 1
• This timing consideration is particularly relevant since patients may have received IA injections for symptomatic management while awaiting surgery 1

Surgical Stress Response Considerations

• Total knee arthroplasty produces a significant surgical stress response, with a 17-fold increase in cortisol production in normal patients 6
• In patients with hypercortisolism, this stress response occurs on top of already elevated baseline cortisol levels, potentially exacerbating metabolic, cardiovascular, and thrombotic complications 6
• The cortisol response peaks on the day of surgery and remains significantly elevated through postoperative day 3 6

Specific Management Algorithm

For patients with known or suspected hypercortisolism requiring knee replacement:

1. Confirm diagnosis using 24-hour urinary free cortisol, nocturnal salivary cortisol, and/or 1 mg dexamethasone suppression test 3

2. Assess severity and source by measuring plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes 3

3. For severe hypercortisolism (which represents a medical emergency): delay elective surgery and initiate urgent treatment with steroidogenesis inhibitors or consider definitive treatment of the underlying cause 7, 1

4. For mild-to-moderate hypercortisolism: consider preoperative medical therapy for 4 months to normalize cortisol, though this may complicate postoperative assessment 1, 5

5. Optimize comorbidities including diabetes (present in majority of cases), hypertension (>80%), and cardiovascular disease according to standard guidelines 1, 3, 2

6. Implement aggressive thromboprophylaxis with low molecular weight heparin starting preoperatively and continuing for at least 2-4 weeks postoperatively 1, 4

7. Ensure surgery is performed at a high-volume center with experience managing complex medical comorbidities 4

Critical Pitfalls to Avoid

• Do not proceed with elective knee replacement in patients with uncontrolled severe hypercortisolism, as this represents a medical emergency requiring urgent intervention 7
• Do not use oral anticoagulants for thromboprophylaxis in this population due to inability to rapidly reverse anticoagulation if bleeding occurs 1
• Do not assume that subclinical hypercortisolism is benign—even mild cortisol excess is associated with cardiovascular risk factors, increased mortality, and surgical complications 8, 9
• Do not forget that complications may persist even after cortisol normalization, requiring ongoing monitoring and management of cardiovascular risk and bone health 2