Perioperative Management of a Patient With Cushing Disease

Elena V. Varlamov; Greisa Vila; Maria Fleseriu

J Endo Soc. 2022;6(3)

Abstract and Introduction

Abstract

Patients with Cushing disease (CD) may present with both chronic and acute perioperative complications that necessitate multidisciplinary care. This review highlights several objectives for these patients before and after transsphenoidal surgery. Preoperative management includes treatment of electrolyte disturbances, cardiovascular comorbidities, prediabetes/diabetes, as well as prophylactic consideration(s) for thromboembolism and infection(s). Preoperative medical therapy (PMT) could prove beneficial in patients with severe hypercortisolism or in cases of delayed surgery. Some centers use PMT routinely, although the clinical benefit for all patients is controversial. In this setting, steroidogenesis inhibitors are preferred because of rapid and potent inhibition of cortisol secretion. If glucocorticoids (GCs) are not used perioperatively, an immediate remission assessment postoperatively is possible. However, perioperative GC replacement is sometimes necessary for clinically unstable or medically pretreated patients and for those patients with surgical complications. A nadir serum cortisol of less than 2 to 5μg/dL during 24 to 74 hours postoperatively is generally accepted as remission; higher values suggest nonremission, while a few patients may display delayed remission. If remission is not achieved, additional treatments are pursued. The early postoperative period necessitates multidisciplinary awareness for early diagnosis of adrenal insufficiency (AI) to avoid adrenal crisis, which may also be potentiated by acute postoperative complications. Preferred GC replacement is hydrocortisone, if available. Assessment of recovery from postoperative AI should be undertaken periodically. Other postoperative targets include decreasing antihypertensive/diabetic therapy if in remission, thromboprophylaxis, infection prevention/treatment, and management of electrolyte disturbances and/or potential pituitary deficiencies. Evaluation of recovery of thyroid, gonadal, and growth hormone deficiencies should also be performed during the following months postoperatively.

Introduction

Cushing syndrome (CS), comprising all etiologies of cortisol excess, is associated with important morbidities including cardiovascular (CV), thromboembolic, metabolic, infectious, musculoskeletal, psychiatric, and other complications.^[1–4] Cushing disease (CD), the most frequent cause of endogenous CS, is due to an adrenocorticotropin (ACTH)-producing corticotroph pituitary adenoma leading to cortisol overproduction. Mortality in patients with untreated CS is high and mostly due to CV, thromboembolic, and infectious causes.^[1,2,5] The management of patients with CS is complex and requires clinicians to address multiple aspects of this multimorbid condition from the moment of initial diagnosis.

The first line treatment for most patients with CD is transsphenoidal pituitary surgery (TSS), which generally achieves remission in 70% to 90% of microadenoma cases but is lower for macroadenomas.^[3,4] Surgery should ideally be performed in a high-volume center by an experienced pituitary surgeon.^[3,4] While surgery is expected to induce remission and improve cortisol-related morbidities, the perioperative period, from the time of diagnosis until at least 3 months postoperatively, is marked by the highest rate of morbidity and mortality.^[6,7] Therefore, it is crucial to assess and treat hypertension, hypokalemia, hyperglycemia/diabetes, as well as assess the risk of thromboembolic and infectious complications and use preventive measures to reduce this risk. Notably, the risk of complications such as stroke, thromboembolism, and sepsis could persist even during long-term remission.^[8]

Furthermore, besides management of complications, the immediate postoperative period is critical in assessment for surgical success. Adrenal insufficiency (AI) indicates postoperative remission, and requires adequate glucocorticoid (GC) replacement to prevent severe GC withdrawal symptoms or even adrenal crisis.^[3] Additionally, sodium derangements are common and require close monitoring and treatment.^[3,9,10]

In this review, we discuss in detail the aforementioned aspects of care. We aim to provide comprehensive and evidence-based information to help clinicians with perioperative care of patients with CD (Figure 1).^[4,9,11,12]

(Enlarge Image)

Figure 1.

Suggested algorithm for perioperative management of Cushing disease. AI, adrenal insufficiency; DI, diabetes insipidus; DST, dexamethasone suppression test; GC, glucocorticoids, HPA, hypothalamic-pituitary-adrenal; I&O, intake and output; IPSS, inferior petrosal sinus sampling; LNSC, late-night salivary cortisol; Na⁺, sodium; SIADH, syndrome of inappropriate antidiuretic hormone; UFC, urinary free cortisol. *See Tables 1 and 2. Adjust antihypertensive and antihyperglycemic regimen proactively if remission is achieved postoperatively. Urine osmolality/specific gravity may be checked daily and/or as needed paired with serum sodium every 6 to 12 hours depending on local protocols.

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Table 1. Thromboprophylaxis agents
Agent class	Examples	Comments
Low-molecular-weight heparin	Enoxaparin	–Subcutaneous daily administration
	Dalteparin	–Dose adjustment is necessary for renal impairment and weight
	Tinzaparin
Unfractionated heparin		–Subcutaneous twice or thrice daily administration
		–May not be available in the outpatient setting
		–No adjustment needed for renal impairment
Factor Xa inhibitor	Fondaparinux	–Subcutaneous daily administration
		–Sometimes used in patients with heparin induced thrombocytopenia
		–Contraindicated in severe renal impairment
Direct anticoagulants	Rivaroxaban	–Oral administration
	Dabigatran	–Rivaroxaban is approved for acutely ill hospitalized medical patients and for orthopedic patients (knee and hip replacement)^a
	Apixaban	–Dabigatran is approved for hip replacement and apixaban for knee and hip replacementa
		–Not used in severe renal impairment
		–Levoketoconazole increases levels of dabigatran (avoid combination) [27]
		–Ketoconazole increases levels of rivaroxaban (avoid combination), dabigatran, and apixaban (consider therapy modification) [28]
Acetyl salicylic acid	Aspirin	–Very rarely used in nonorthopedic patients
		–May be used if other agents are contraindicated or not available
		–Consider concomitant use of gastrointestinal prophylaxis with a proton-pump inhibitor
Warfarin		–Very rarely used for routine thromboprophylaxis; concurrent use of ketoconazole results in increased level of warfarin [28]

Mechanical prophylaxis using intermittent pneumatic compression or elastic stockings in addition to pharmacologic agents for higher-risk patients.
^aFood and Drug Administration–approved indications.

Table 2. Management considerations for cardiovascular and metabolic complications in Cushing syndrome
Complication	Agent	Considerations	Drug-drug interactions^a
DM	Metformin	First-line agent in all patients unless contraindicated	Levoketoconazole increases levels of metformin [27]
		Beneficial in insulin resistant states [47, 49, 50, 55]	- Monitor
	SGLT-2 inhibitors	Demonstrated CV benefit for DM2 patients with atherosclerotic CV disease or kidney disease [44, 47, 49, 50, 55]
		Risk of genitourinary infections might be higher in CS
		Risk of fractures
	GLP-1 agonist	Demonstrated CV benefit for DM2 patients with atherosclerotic CV disease
		May be beneficial in CS given impaired insulin secretion/incretin effect induced by glucocorticoids [48, 49, 55]
	DPP4 inhibitors	May be beneficial in CS given impaired insulin secretion/incretin effect induced by glucocorticoids [48, 49, 55]	Ketoconazole may increase levels of saxagliptin [54]
			- Monitor
	Sulfonylureas	May be less effective in CS	Mifepristone may increase levels of sulfonylureas [53] - Monitor
	Thiazolinediones	Cause fluid retention and contraindicated in heart failure	Ketoconazole increases levels of pioglitazone [54]
		Side effects may outweigh insulin-sensitizing benefit	- Monitor
	Insulin	Use for severe hyperglycemia and when rapid reduction of blood glucose is necessary
-Monitor hypertension	Mineralocorticoid	Block effects of cortisol and cortisol/aldosterone precursors at MR receptor	Ketoconazole increases levels of eplerenone [54]
	Receptor blockers	Effective for hypokalemia, edema, and hypertension in CS and during treatment with mifepristone, metyrapone, and osilodrostat	- Contraindicated
		Additional cardiovascular benefits [44, 47]	Mifepristone increases levels of eplerenone [52]
			- Avoid
	ACE inhibitors/ARBs	Target activated RAAS system in CS	Ketoconazole increases levels of losartan [54]
		Reduce risk of CV events in patients with DM and atherosclerotic disease [44]	- Monitor
		Potential benefit for hypokalemia	Mifepristone increases levels of losartan [52]
	Thiazide diuretics	Reduce risk of CV events in patients with DM [44]	- Monitor
		May worsen hypokalemia
	Loop diuretics	Beneficial in edematous states May worsen hypokalemia
	Dihydropyridine calcium channel blockers	Reduce risk of CV events in patients with DM	Ketoconazole increases levels of nifedipine [28]
			- Consider therapy modification
			Mifepristone may increase levels of carvedilol [52]
			- Monitor
			Ketoconazole increases levels of amlodipine [28]
	β-Blockers	May be used for patients with previous MI, active angina, or heart failure	Osilodrostat may increase levels of carvedilol and propranolol [39]
Hyperlipidemia	Statins	First-line in all patients with DM and atherosclerotic disease	Ketoconazole and levoketoconazole increase levels of simvastatin and lovastatin [27, 54]
		For patients with DM but without established atherosclerotic disease, use based on ADA guidelines [44]	- Contraindicated
			Ketoconazole and Levoketoconazole increase levels of atorvastatin [27, 28]
			- Monitor
			Mifepristone increases levels of simvastatin and lovastatin [53]
			- Contraindicated
			Osilodrostat increases level of simvastatin [51]
			- Monitor
			Mifepristone increases level of atorvastatin [52]
			- Monitor
	Ezetimibe	Add-on therapy to maximally tolerated statin in patients with very high CV risk [44]
	PCSK9 inhibitors	Add-on therapy to maximally tolerated statin in patients with very high CV risk [44]
Antithrombotic therapy	Aspirin (or clopidogrel if allergy to aspirin)	Secondary prevention in patients with DM and atherosclerotic CV disease [44]Primary prevention in patients with DM who are at increased CV risk (after risk-and-benefit discussion) [44]	Ketoconazole decreases effects of clopidogrel [54]; consider alternative
Hypokalemia	Potassium replacement	Oral in most cases, intravenous in severe cases
	Mineralocorticoid	Block effects of cortisol and cortisol/aldosterone precursors at MR receptor	Ketoconazole increases levels of eplerenone [54]
	Receptor blockers	Effective for hypokalemia in CS and during treatment with mifepristone, metyrapone, and osilodrostat	- Contraindicated
			Mifepristone increases levels of eplerenone [52]
			- Avoid
	ACE inhibitors/ARBS	Potential benefit for hypokalemia	Ketoconazole increases level of losartan [54]
			- Monitor
			Mifepristone increases levels of losartan [52]
			- Monitor
Screening for CV disease	Multidisciplinary evaluation in conjunction with PCP, cardiology and preoperative medicine
	History, symptoms (eg, dyspnea, chest pain, edema), physical exam
	Resting EKG preoperatively; additional CV testing and imaging may be needed based on clinical evaluation
	CV risk assessment using established tools (eg, revised cardiac risk index, American College of Surgeons surgical risk calculator) prior to surgery
	Referral to cardiology for established CV disease and/or if CV disease is highly suspected

Abbreviations: ACE, angiotensin-converting enzyme; ADA, American Diabetes Association; ARB, angiotensin II receptor blocker; CS, Cushing syndrome; CV, cardiovascular; DM, diabetes mellitus; DM2, type 2 diabetes mellitus; EKG, electrocardiogram; GLP-1, glucagon-like peptide 1; MI, myocardial infarction; MR, mineralocorticoid receptor; PCP, primary care provider; RAAS, renin-angiotensin-aldosterone system; SGLT-2, sodium-glucose cotransporter 2.
^aSummary of major drug-drug interactions.