preoperative management of endocrine, hormonal, and

THEMATIC REIVEW ON PERIOPERATIVE MEDICINE

Preoperative Management of Endocrine,Hormonal, and Urologic Medications: Societyfor Perioperative Assessment and QualityImprovement (SPAQI) Consensus StatementKurt J. Pfeifer, MD; Angela Selzer, MD; Carlos E. Mendez, MD;Christopher M. Whinney, MD; Barbara Rogers, MD, MBOE; Vinaya Simha, MD;Dennis Regan, MD; Richard D. Urman, MD, MBA; and Karen Mauck, MD, MSc

Abstract

Perioperative medical management is challenging due to the rising complexity of patients pre-senting for surgical procedures. A key part of preoperative optimization is appropriate manage-ment of long-term medications, yet guidelines and consensus statements for perioperativemedication management are lacking. Available resources utilize the recommendations derivedfrom individual studies and do not include a multidisciplinary focus or formal consensus. TheSociety for Perioperative Assessment and Quality Improvement (SPAQI) identified a lack ofauthoritative clinical guidance as an opportunity to utilize its multidisciplinary membership toimprove evidence-based perioperative care. SPAQI seeks to provide guidance on perioperativemedication management that synthesizes available literature with expert consensus. The aim ofthis Consensus Statement is to provide practical guidance on the preoperative management ofendocrine, hormonal, and urologic medications. A panel of experts with anesthesiology, periop-erative medicine, hospital medicine, general internal medicine, and medical specialty experiencewas drawn together and identified the common medications in each of these categories. The au-thors then utilized a modified Delphi approach to critically review the literature and generateconsensus recommendations.

ª 2020 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2021;96(6):1655-1669

From the Department ofMedicine, Medical Collegeof Wisconsin, Milwaukee(K.J.P.); Department ofAnesthesiology, Universityof Colorado School ofMedicine, Aurora (A.S.);Department of Medicine,Medical College of Wis-consin, Milwaukee(C.E.M.); Department ofHospital Medicine, Cleve-land Clinic Lerner Collegeof Medicine, OH(C.M.W.); Department ofAnesthesiology, The Ohio

Affiliations continued atthe end of this article.

M anagement of chronic medicationsis an essential part of preoperativeoptimization of patients requiring

invasive procedures. Although continuationof many medications is important to main-tain control of chronic health problems, cli-nicians must be aware of and mitigate therisks of potential perioperative complica-tions from some. For any medication, a clini-cian must ascertain whether the medicationcould affect bleeding risk (both for surgeryand regional anesthesia) or interact withanesthetic or analgesic agents. Furthermore,some medications can elevate the risk ofcommon postoperative complications, suchas perioperative neurocognitive dysfunction

Mayo Clin Proc. n June 2021;96(6):1655-1669 n https://doi.org/10.www.mayoclinicproceedings.org n ª 2020 Mayo Foundation for M

and postoperative urinary retention.Balanced against these risks are the potentialrisks caused by medication withdrawal (eg,uncontrolled systemic disease and with-drawal syndromes).

Recognizing and managing possiblemedication issues in surgical patients ischallenging because of the proliferation oftherapies approved by the US Food andDrug Administration (FDA) and the ongoingevolution of anesthetic and surgical tech-niques. Coupled with the lack of robust liter-ature on perioperative medicationmanagement, clinicians are left without clearguidance regarding best practices. The Soci-ety for Perioperative Assessment and Quality

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Improvement (SPAQI) recognized thispractice gap and the potential to leverage itsresources to fill this need.

SPAQI is an international, multidisci-plinary society dedicated to the promotionof evidence-based perioperative medicine,and it has produced a number of recommen-dation papers and consensus statements inthis field.1-3 SPAQI drafted a comprehensiveplan for developing consensus recommenda-tions for perioperative medication manage-ment using perioperative medicine,anesthesiology, internal medicine, hospitalmedicine, and medical subspecialty experts.This consensus statement contains thework of a subgroup focused on providingguidance on the perioperative managementof endocrine, hormonal, and urologicmedications. This statement is targeted topractitioners providing general medical careto patients before surgery, and it representsa synopsis of available literature and expertopinion related to preoperative medicationmanagement. Burgeoning research,specialty-level care, and the nuances of post-operative medication management arebeyond the scope of this article.

PARTICIPANTS AND METHODSThe clinical areas for the SPAQI consensusstatements were chosen by SPAQI leadershipon the basis of knowledge and practice gapsidentified in a variety of the organization’seducational forums. Endocrine, hormonal,and urologic medications were combinedfor one consensus group based on the num-ber of medications and the goal of balancingthe content of all previous and forthcomingconsensus statements. The members of theconsensus group were faculty members atseveral different academic institutions andexperts in the fields of perioperativemedicine, anesthesiology, general internalmedicine, hospital medicine, and subspe-cialty internal medicine. Before the start ofthe project, a leader was designated for guid-ing the consensus development process.

After identifying all common FDA-approved medications in the selected classes,the group used a modified Delphi methodol-ogy described in the first publication of

Mayo Clin Proc. n June 2021;

SPAQI’s series of medication consensusstatements.4 To derive its recommendations,the consensus group used the followingguiding principles:

d Preference given to not interruptingtherapy unless there were potential risksfrom continuation.

d Focus placed on management of chronicmedications.

d Preoperative initiation of therapy, supple-mental treatment (eg, “stress dosesteroids”), and postoperative managementare beyond the scope of this article.

Consensus was established for allreviewed medications, and the completedset of recommendations was reviewed andendorsed by the Executive Committee ofSPAQI. What follows are specific recommen-dations for each medication class.

ENDOCRINE AND HORMONALMEDICATIONS

InsulinsAppropriate adjustment of insulin therapy inthe perioperative period is essential tomaintain good glucose control to avoid post-operative complications of both hyperglyce-mia and hypoglycemia. Insulin decreasesblood glucose by stimulating peripheralglucose uptake and decreasing hepaticglucose release. The time course of insulinaction differs across the different insulinpreparations, which primarily determinestheir perioperative dose adjustments. Asmuch as possible, clinicians should consultwith a patient’s diabetologist regardingperioperative diabetes management. Howev-er, the majority of patients will benefit fromdevelopment and adherence to evidence-based, institutional protocols for periproce-dural insulin management. Table 1summarizes the following consensusrecommendations for the perioperative man-agement of insulins.

Long-Acting Insulins. The three primarylong-acting insulin preparations used asbasal therapy are glargine, detemir, anddegludec, with half-lives ranging from 13 to

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TABLE 1. Summary of Recommendations for the Preoperative Management of Insulins

Medication class Examples

Administrationbefore day of

surgery

Administrationon morning of

surgery Additional Considerations

Insulin, intermediate-acting

NPHa Continueb Continueb Decrease dose by 50% on morning of surgery and consider 25%dose reduction on evening before surgery

Insulin, long-acting Glargine, detemir,degludec

Continueb Continueb Administer 60%-80% of usual dose the evening before surgery (orthe morning of surgery, if normally taken in the morning) inthose with type 2 diabetes and those prone to hypoglycemia

Insulin, premixed Human NPH/regular70/30; insulin lisproprotamine/lispro 75/

25

Continue Continueb If fasting hyperglycemia (>200 mg/dL), use half the usual dose ofpremixed insulin on the morning of surgery; otherwise, do notadminister and give half the dose of the intermediate- or long-

acting component as intermediate- or long-acting insulin

Insulin, pump Continue Continueb Continue basal infusion at 60%-80% of usual rate and do notprovide boluses

Insulin, short-/rapid-acting

Regular, aspart, lispro,glulisine

Continue Hold May use on the morning of surgery for urgent treatment ofhyperglycemia

Insulin, U-500 Continue Continueb Reduce dose on morning of surgery based on patient’s bloodglucose and risk factors for hypoglycemia

aNPH, neutral protamine Hagedorn.bSee additional considerations.

ENDOCRINE AND UROLOGIC PREOPERATIVE MEDICATION MANAGEMENT

24 hours. For patients with type 1 diabetesmellitus (DM), it is important that there isno interruption in long-acting basal insulintherapy due to the risk of ketoacidosis. Thenormal basal insulin dose should be giventhe day before and the day of surgery unlessthere is increased concern for hypoglycemia.Patients with elevated risk for hypoglycemiainclude those who experience frequent epi-sodes of nocturnal hypoglycemia, regularlyeat a bedtime snack to avoid hypoglycemia,experience an overnight decrease in bloodglucose readings by over 40 mg/dL, aremalnourished, or have renal or hepaticinsufficiency. In such patients, a 25%-50%reduction in long-acting insulin dose wouldbe reasonable either the evening before orthe morning of surgery, whenever thepatient usually takes basal insulin. In aretrospective analysis of patients with type 2DM undergoing ambulatory surgery,administration of 60%-87% (mean dose 73%and mode dose 75%) of the usual basal dosethe evening before surgery was noted toresult in a greater number of patients havingoptimal fasting blood sugars on the morningof surgery compared with those receivingless than 50% or 100% of the full dose.5 In a

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prospective, randomized, open-label trial of410 patients with both type 1 and type 2diabetes, empiric 20% reduction of basalglargine dose the evening before surgery wasfound to be just as efficacious as physician-or dosing tableedirected insulin adjust-ments for optimal glucose levels on themorning of surgery.6 American DiabetesAssociation (ADA) guidelines recommendprovision of 80% of usual long-acting insulinon the morning of surgery.7

Consensus Recommendation. Continuebasal insulin both before and on the day ofsurgery. Administration of only 60%-80%of the usual dose the evening before surgery(or the morning of surgery, if normally takenin the morning) may be reasonable,especially in patients with type 2 DM andthose prone to hypoglycemia.

Intermediate-Acting Insulins. Neutral prot-amine Hagedorn (NPH) insulin usually hasa 12-hour duration of action, and it issometimes used as basal insulin in combi-nation with short- or rapid-acting insulin;however, it does have a peaking effect and itprovides prandial coverage for the mid-day

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meal, thus necessitating a dose reduction onthe morning of surgery. Similarly, mild dosereduction in patients with type 2 DM theevening before surgery might be appropriate.ADA guidelines recommend patients takeonly half of their usual NPH dose on themorning of surgery.7

Consensus Recommendation. Continueintermediate-acting insulin before surgeryand on the day of surgery; however, reducethe dose by 50% on the morning of surgery,and consider 25% dose reduction theevening before surgery, especially in patientswith type 2 DM and those at increased riskfor hypoglycemia.

Short- and Rapid-Acting Insulins. This sub-category includes regular human insulinand analogues, such as aspart, lispro, andglulisine, which all have a total duration ofaction less than 4 hours and are used to pro-vide prandial coverage. They should becontinued the day before surgery but heldon the day of surgery when a patient is fast-ing. However, these insulins can be used onthe day of surgery as necessary for correctionof hyperglycemia. In this setting, short-acting insulins should be administered sub-cutaneously or via infusion based on insti-tutional protocols.

Consensus Recommendation. Administerusual dose before the day of surgery buthold on the day of surgery unless requiredfor correction of hyperglycemia.

Other Insulin Preparations. Some patientsuse premixed insulin preparationscombining intermediate and short rapid-acting insulin, such as human insulin NPH/regular 70/30, insulin aspart protamine/aspart 70/30, or insulin lispro protamin/lis-pro 75-25, and 50-50 suspensions. Thesepreparations should continue to be admin-istered the day before surgery, but eitherheld or administered at a reduced dose onthe morning of surgery on the basis of thepatient’s blood sugar measurement. If thereis fasting hyperglycemia (>200 mg/dL), halfthe usual dose of premixed insulin can be


administered on the morning of surgery;otherwise, only half the basal componentshould be administered as intermediate- orlong-acting insulin.8

Patients who use concentrated regularinsulin U500 should also receive the usualdose on the day before surgery and anadjusted dose on the morning of surgerybased on blood sugars.

For patients on insulin pump therapy, oneshould consult with their diabetologist. Thepump basal rate should usually be continuedat 60%-80% of usual until the patient presentsto the anesthesia preparation area on themorning of surgery.7 Further managementon the morning of surgery (eg, managementof hypoglycemia or severe hyperglycemia),intraoperatively, and postoperatively is beyondthe scope of this article.

Non-Insulin DM Medications (Table 2)Alpha-Glucosidase Inhibitors. Acarbose andmiglitol are the two AGIs available in theUnited States. They decrease blood glucoseby interfering with the breakdown of carbo-hydrates in the gut, thus decreasing the ab-sorption of sugars. Although sugarsdecrease postprandial glucose excursionsand carry a low risk of hypoglycemia, theincreased delivery of carbohydrates to thecolon often results in increased gas produc-tion and GI discomfort.9,10 No studies eval-uating AGIs during the perioperative periodwere available at the time of this review, butADA guidelines recommend holding theseon the morning of surgery.7

Consensus Recommendation. Continuebefore surgery, but do not take AGIs onthe morning of surgery.

Metformin. Metformin is the mostcommonly used medication for the manage-ment of type 2 DM in the United States. Met-formin exerts its antihyperglycemic effect bysuppressing excessive hepatic glucose pro-duction through gluconeogenesis inhibition;it does not lead to hypoglycemia when usedas monotherapy. Metformin has been re-ported to increase the risk of lactic acidosis,but a 2010 Cochrane systematic review




TABLE 2. Summary of Recommendations for the Preoperative Management of Non-Insulin Diabetes Medications

Medication class Examples


surgery

Administration onmorning ofsurgery Additional considerations

Alpha-glucosidaseinhibitors

Acarbose, Miglitol Continue Hold d

Biguanides Metformin Continue Hold In patients without contraindications and with preservedrenal function (GFRa >50 mL/min) undergoing

ambulatory surgeries for which no more than one mealis expected to be omitted, non-interruption may be

acceptable.

DPP-4 inhibitors Vildagliptin, sitagliptin,saxagliptin, linagliptin,

alogliptin

Continue Hold For patients undergoing ambulatory surgeries for which nomore than one meal is expected to be omitted, non-

interruption may be acceptable.

GLP-1 agonists Liraglutide, lixisenatide,semaglutide, dulaglutide

Continueb Hold Before day of surgery: For GI surgeries or when concernfor nausea, vomiting, or gut dysfunction, considerholding weekly dose within 7 days before surgery.

Day of surgery: If weekly dose is due on morning ofsurgery, delay until later in day after surgery is complete.

Insulin secretogogues(sulfonylureas,glinides)

Glipizide, glyburide, glimepiriderepaglinide, nateglinide

Continue Hold d

SGLT-2 inhibitors Dapagliflozin, canagliflozin,empagliflozin, ertugliflozin

Hold Hold Canagliflozin, dapagliflozin, and empagliflozin should eachbe discontinued at least three days before scheduledsurgery. Ertugliflozin should be discontinued at least four

days before scheduled surgery.

Thiazolidinediones Pioglitazone Continue HoldaDPP-4, dipeptidyl peptidase-4; GFR, glomerular filtration rate; GLP-1, glucagon-like peptide-1; SGLT-2, sodium glucose co-transporter 2.bSee additional considerations.


reported no increase in the number of casesof lactic acidosis in ambulatory patientsacross 347 clinical trials with 70,490patient-years of metformin use.11 In theperioperative period, data on the safety andpotential benefits of metformin have beenlimited to observational and single-centerinterventional studies.12-15 Possible sug-gested benefits of recent (8-24 hours preop-eratively) metformin ingestion in cardiacsurgical patients have not beenconfirmed.12,13 However, no definitive evi-dence of harm from continuation of met-formin up to the day of surgery was foundfor this review.12-15 Given that the use ofmetformin is contraindicated during condi-tions that carry an inherent increased risk oflactic acidosis, including several seen duringthe perioperative period such as impairedkidney function, heart failure, and contrastdye exposure, extending recommendations


to routinely take metformin on the dayof surgery is difficult to justify at the timeof this review. ADA guidelines alsorecommend holding metformin on theday of surgery, but they do not recommendthe past common practice of withholdinglonger than this.7 Similarly, we do notrecommend cancellation or delay ofsurgical procedures if metformin is takenon the morning of surgery. In patientswithout contraindications and with pre-served renal function (glomerular filtrationrate [GFR] > 50 mL/min) undergoingambulatory surgeries for which no morethan one meal is expected to be omitted,continuation of metformin therapy may beacceptable.

Consensus Recommendation. Continuebefore surgery, but do not take metforminon the morning of surgery.

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Insulin Secretagogues. Sulfonylureas andglinides exert their antidiabetic effect bystimulating endogenous insulin secretionindependently of glycemia or food intake.They increase the risk of hypoglycemia,especially in patients with impaired renalfunction or decreased oral intake.16 In theinpatient setting, the use of sulfonylureashas been shown to increase the prevalence ofhypoglycemia, especially in patients olderthan 65 years and with a GFR < 30 mL/min.17 Significant drug interactions are alsoa limiting factor. Drugs that inhibit hepaticcytochrome CYP2C9, includingfluoroquinolones, fluconazole, amiodarone,trimethoprim-sulfamethoxazole, and val-proate, can exaggerate the effect ofsulfonylureas, thereby increasing the risk ofhypoglycemia.18,19

Glinides available in the United States arerepaglinide and nateglinide. They alsoenhance b-cell insulin production, but resultin faster onset and shorter duration of ac-tion.20 These agents are not recommended inthe perioperative setting because of the poten-tial risk of hypoglycemia and lack of random-ized trials evaluating their safety and efficacy.7

Consensus Recommendation. Continuebefore surgery, but do not take sulfonylureasor glinides on the morning of surgery.

Thiazolidinediones. Pioglitazone is the onlythiazolidinedione (TZD) readily accessiblein the US. TZDs are considered insulinsensitizers and increase peripheral glucoseuptake through direct activation of theperoxisome proliferator-activated receptorgamma.21 TZDs have been associated withfluid retention and are contraindicated inpatients with congestive heart failure,hemodynamic instability, or evidence of he-patic dysfunction.16 Given the potential forundesired effects, and lack of evidenceshowing its safety or efficacy during theperioperative period, its use on the day ofsurgery is not recommended.

Consensus Recommendation. Continuebefore surgery, but do not take thiazolidine-diones on the morning of surgery.


Sodium Glucose Co-Transporter 2 (SGLT-2)Inhibitors. This class of antidiabetic medica-tions increases urinary glucose excretion bydecreasing renal glucose reabsorption inthe proximal convoluted tubules. The useof SGLT-2 inhibitors in the inpatientsetting is discouraged given the increasedrisk of urogenital infections, acute kidneyinjury, dehydration, and hypotensionbecause of their glycosuric effects.22,23 Inaddition, euglycemic diabetic ketoacidosishas been reported as a significant complica-tion of these agents in the perioperativesetting.24 Considering these adverse events,the FDA recently released a special bulletinreporting a drug label change recommendingtemporary discontinuation before scheduledsurgery.25

Consensus Recommendations. Canagli-flozin, dapagliflozin, and empagliflozinshould each be discontinued at least 3 daysbefore scheduled surgery. Ertugliflozinshould be discontinued at least 4 days beforescheduled surgery. Blood glucose levelsshould be carefully monitored after discon-tinuation of the SGLT-2 inhibitor andmanaged as necessary with alternatemethods before surgery.

Glucagon-Like Peptide-1 Ago-nists. Glucagon-like peptide-1 (GLP-1)agonists are popular in the management oftype 2 DM because of their potent antidia-betic, weight loss, and cardiovascular bene-fits.26 They exert their antihyperglycemiceffects through increased insulin productionin a glucose-dependent manner along withglucagon suppression. They are also knownto slow gastric emptying, which can increaserisk of hypoglycemia when used with insulinand lead to adverse GI effects, such as nauseaand vomiting.27 Newer GLP-1 agonists allowfor weekly injections and are bettertolerated, causing less nausea and vomiting.

In the perioperative setting, small studieshave evaluated the use of GLP-1 during car-diac and noncardiac surgery and have showneffectiveness in achieving glycemic controlwhile decreasing insulin requirements.28-30

Counter to these benefits, increased nausea





when using liraglutide the night before sur-gery has been reported.29 We identified nostudies in which the safety of these agentswas assessed in patients undergoing surgeryinvolving bowel manipulation whereperistalsis and gastric emptying might beaffected. Given the limited perioperativedata available and the high prevalence ofnausea in the postoperative period, larger tri-als will be needed before the use of GLP-1agonists can be widely endorsed for mostsurgeries. In some scenarios, especially thosenot involving GI surgery or concerns fornausea and vomiting, its continued usethroughout the perioperative period mightbe acceptable.

Consensus Recommendations. ContinueGLP-1 agonists before the day of surgeryunless heightened concern for postoperativenausea, vomiting or gut dysfunction (eg, GIsurgery). In these situations, considerholding 24 hours for once or twice dailypreparations, and up to 1 week before sur-gery for weekly preparations (includingholding dose within 7 days before surgery).Closer monitoring and adjustment toantidiabetic regimen may be necessary toavoid possible hyperglycemia before surgery.Withhold GLP-1 agonists on the morning ofsurgery. If a weekly dose is due on morningof surgery, delay taking until later in the dayafter surgery.

Dipeptidyl Peptidase-4 Inhib-itors. Dipeptidyl peptidase-4 (DPP-4) in-hibitors increase availability of native GLP-1by decreasing its enzymatic breakdown.They induce insulin production similarly toGLP-1 agonists, but with the difference thatDPP-4 inhibitors rely on intestinal secretionof GLP-1 triggered by food intake.31 Thesafety and effectiveness of the DPP-4 in-hibitors for the inpatient management ofdiabetes and hyperglycemia have beendemonstrated recently in medical and sur-gical patients.32-34 However, treatment witha DPP-4 inhibitor 1 or 2 days before cardiacand noncardiac surgery showed no benefit inpreventing postoperative hyperglycemiacompared to placebo in patients without


diabetes.35,36 Although these drugs have arelatively safe profile, in older patients withknown or suspected heart failure, the use ofDPP-4 inhibitors has been associated withworsening of heart failure.37 Given thelimited data showing significant benefit fromDPP-4 inhibitors in preventing postoperativehyperglycemia, recommending theircontinued use on the day of surgery is notwarranted for most patients. However, forpatients undergoing ambulatory surgeriesfor which no more than one meal is expectedto be omitted, uninterrupted DPP-4 inhibitortherapy might be acceptable.

Consensus Recommendation. Continuebefore surgery, but do not take DPP-4inhibitors on the morning of surgery.

Thyroid MedicationsHypothyroidism is treated with thyroidreplacement therapy in the form of levothyr-oxine, liothyronine, or dessicated thyroidpreparations. The usual replacement dosecan be administered on the day of surgeryvia the enteral route without the need forany additional supplementation or conver-sion to a parenteral route of administra-tion.38 There are no studies on the safetyand efficacy of antithyroid medications(methimazole and propylthiouracil) in theperioperative period. To avoid the possiblerisk of thyroid storm in the perioperativeperiod, these medications should becontinued uninterrupted.

Consensus Recommendation. Continueboth thyroid replacement and antithyroidmedications without dose adjustmentsbefore and on the day of surgery.

CorticosteroidsThe corticosteroid group has many similarmedications that are used primarily for adrenalinsufficiency, autoimmune diseases, and in-flammatory conditions. Most of thesemedications, including betamethasone,triamcinolone, hydrocortisone, cortisone,prednisone, methylprednisolone, budesonide,and dexamethasone, have different degrees of

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glucocorticoid and mineralocorticoidactivity, and they come inmultiple administra-tion forms (eg, oral, intravenous, intramus-cular, inhaled, topical). Fludrocortisonediffers from these in that it has onlymineralocorticoid activity.

Most perioperative literature for cortico-steroids is focused on new use in the surgicalsetting (eg, postoperative nausea prevention)and supplementation of chronic doses (ie,“stress dosing”). These studies haveinconsistently shown the potential for corti-costeroids to cause hyperglycemia, but fewother adverse effects.39,40 Although severalsmall studies have investigated the provisionof supplemental corticosteroids to patientswith adrenal insufficiency or chronic corti-costeroid usage, none have investigated theeffects of continuation or interruption oflong-term therapy. Available guidelinesrecommend that patients not interruptlong-term corticosteroid therapy, althoughwhen it is used for treatment of inflamma-tory arthritis, the American College of Rheu-matology and American Association of Hipand Knee Surgeons recommend titratingthe daily dose to less than 20 mg of predni-sone equivalent, if possible.41,42 The role andindications for supplemental (ie, “stress-dose”) steroids is a matter of ongoing debateand is beyond the scope of this article.

Consensus Recommendations. Continuechronic corticosteroid treatment before andon the day of surgery. Patients receivinglonger-term, higher-dose therapy mightneed supplemental dosing intraoperativelyand postoperatively.

Pituitary MedicationsPituitarymedications are used in the treatmentof a variety of disorders. Patients with isolatedanterior and posterior pituitary deficiency, orpanhypopituitarism, receive replacement ther-apy that can include recombinant growth hor-mone (somatotropin) and desmopressin inaddition to glucocorticoids, thyroid hormone,and androgen or estrogen therapy (discussedlater). The dopamine agonists cabergolineand bromocriptine are used in the treatmentof pituitary prolactinomas. Mecasermin is


recombinant insulin-like growth factor-1 thatis used in the treatment of growth hormonedeficiency in children. Tesamorelin is a growthhormoneereleasing hormone analog used fortreatment of human immunodeficiencyviruseassociated lipodystrophy. Repositorycorticotropin is used in the treatment of infan-tile spasms, and rarely for recalcitrantmultiplesclerosis and other rheumatic conditions.Although there are no studies examining thesafety and efficacy of these agents in the peri-operative period, it is reasonable to continuethese both on the day before surgery and theday of surgery. Similarly, medical therapiesfor growthhormone excess, including somato-statin analogues (octreotide, lanreotide, andpaseriotide) and growth hormone antagonists(pegvisomont) have also not been studied inthe perioperative period, but they aretypically continued without interruption.

Consensus Recommendation. Continuepituitary medications both before and onthe day of surgery.

Androgenic HormonesThe category of androgenic hormones in-cludes testosterone and methyltestosterone,which are used for the treatment of hypogo-nadism in men and advanced breast cancerin women, and oxymetholone, which isused for the treatment of cancer-associatedanemia. Another indication for androgenichormone use is transgender hormonetherapy. Despite concerns for increased riskfor thromboembolism in the nonsurgicalpopulation, available literature has notdemonstrated an association betweenperioperative thromboembolic events andandrogenic hormone use.43,44

Consensus Recommendation. Continueandrogenic hormones medications bothbefore and on the day of surgery, butconsider the potential for postoperativevenous thromboembolism (VTE) risk.

EstrogensEstrogens are used for treatment of postmen-opausal estrogen withdrawal symptoms(estradiol, conjugated estrogens, and





estropipate) and as part of estrogen-containing contraceptives (ethinyl estradiol).Like androgens, they are also used as genderaffirmation therapy. Estrogens are associatedwith an increased risk of VTE, and the riskrises with increasing estrogen content andage. Despite the widespread use of estrogens,data on the risk of postoperative VTE withestrogens are sparse and limited to small,older studies. One study of patients takingpostmenopausal hormone replacement ther-apy (which contains much lower doses ofestrogen) showed no increased VTE risk af-ter major orthopedic surgery.45 Manufac-turer package inserts for both oralcontraceptives and hormone replacementtherapy recommend discontinuation of thesemedications 4 weeks before major surgery,but this is based on evidence of VTE riskin the general population. The risks ofdiscontinuation, including undesired preg-nancy (even when alternative contraceptionmethods are used), must be carefullybalanced against the potential for VTE.

Consensus Recommendation. Continueestrogens both before and on the day of sur-gery, but consider potential for increasedrisk of VTE if continued and pregnancyrisk if withheld (if taken for contraception).

ProgestinsAvailable progestins include megestrol,levonorgestrel, progesterone, hydroxypro-gesterone, norethindrone, medroxyproges-terone, etonogestrel, and drospirenone.There is no literature addressing periopera-tive management of these medications.Evidence from general population studiesof progestins shows minimal VTE risk asso-ciated with progestin-only contraceptives.46

Consensus Recommendation. Continueprogestins both before and on the day ofsurgery.

Selective Estrogen Receptor ModulatorsSelective estrogen receptor modulators(SERMs) are used primarily for breast cancerprevention and treatment (toremifene,tamoxifen, and raloxifene), but they are


also prescribed for osteoporosis (raloxifene)or postmenopausal vaginal atrophy (ospemi-fene). All SERMs are associated withincreased thrombotic risk, although onestudy of patients undergoing breast cancersurgery found no association betweentamoxifen use and VTE.47 Studies have iden-tified increased risk of breast reconstructionwound complications in patients takingtamoxifen.47,48 Balanced against these risksare the unknown consequences of short-term cessation of antiestrogen therapy inpatients with breast cancer.

Consensus Recommendations. ContinueSERMs both before and on the day of surgeryif taken for breast cancer prevention or treat-ment, but consider potential for increasedwound complication and VTE risk ifcontinued. If SERMs are taken for otherindications and additional patient- orsurgery-specific risk factors for VTE arepresent, stop SERMs at least 7 days beforesurgery.

Aromatase InhibitorsAromatase inhibitors, including anastrozole,exemestane, and letrozole interfere withperipheral tissue production of estradiol,and they are used in the treatment of breastcancer. One retrospective cohort studyfound an association between perioperativearomatase inhibitor use and wound compli-cations, but no other data on perioperativemanagement are available.47 The risk ofbreast cancer recurrence from temporarycessation is not known.

Consensus Recommendation. Continuearomatase inhibitors both before and onthe day of surgery, but consider potentialfor increased wound complications ifcontinued.

Bone and Calcium Disorder MedicationsThe category of bone and calcium disordermedications includes recombinant parathy-roid hormone preparations (teriparatideand abaloparatide), which can be used inthe treatment of osteoporosis or hypopara-thyroidism, and calcimimetics, such as

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TABLE 3. Summary of Recommendations for the Preoperative Management of Hormonal and Non-Diabetes Endocrine Medications

Medication Class Examples


surgery

Administrationon morning of

surgery Additional Considerations

Androgenic hormones Testosterone, methyltestosterone Continue Continue Consider potential for increasedrisk for postoperative VTE.a

Antidiuretic hormone Desmopressin Continue Continue

Antithyroid medications Methimazole, propylthiouracil Continue Continue

Aromatase inhibitors Anastrozole, exemestane, letrozole Continue Continue Consider potential for increasedwound complications.

Bisphosphonates Continue Hold

Calcimetics Cinacalcet, etelcalcetide Continue Continue

Calcitonin Continue Continue

Corticosteroids, systemic Betamethasone, triamcinolone,hydrocortisone, cortisone, prednisone,

methylprednisolone, budesonide,dexamethasone, fludricortisone

Continue Continue Patients on longer term, higherdose therapy may needsupplemental dosingintraoperatively andpostoperatively.

Denosumab Continue Continue

Dopamine agonists, pituitary Cabergoline, bromocriptine Continue Continue

Estrogens Estradiol, conjugated estrogens, estropipate,ethinyl estradiol

Continue Continue Consider potential for increasedrisk of postoperative VTE if

continued and pregnancy risk ifwithheld (if taken for

contraception).

Growth hormone Somatotropin Continue Continue

Growth hormone antagonist Pegvisomont Continue Continue

Growth hormone-releasinghormone analog

Tesamorelin Continue Continue

Parathyroid analogues Teriparatide, abaloparatide Continue Continue

Progestins Megestrol, levonorgestrel, progesterone,hydroxyprogesterone, norethindrone,medroxyprogesterone, etonogestrel,

drospirenone

Continue Continue

Recombinant insulin-like growthfactor-1

Mecasermin Continue Continue

Repository corticotropin Continue Continue

SERMs Toremifene, tamoxifen, raloxifene,ospemifene

Continueb Continueb Consider potential for increasedwound complications and VTErisk if continued. If not taken forbreast cancer prevention andadditional patient- or surgery-specific risk factors for VTE arepresent, stop at least 7 days

prior to surgery.

Somatostatin analogs Octerotide, lanreotide, paseriotide Continue Continue

Thyroid replacement Levothyroxine, liothyronine, thyroid extract Continue ContinueaSERMs, selective estrogen receptor modulators; VTE, venous thromboembolism.bSee additional considerations.


1664 Mayo Clin Proc. n June 2021;96(6):1655-1669 n https://doi.org/10.1016/j.mayocp.2020.10.002www.mayoclinicproceedings.org




cinacalcet and etelcalcetide, which are usedfor the treatment of hyperparathyroidism.Calcitonin inhibits osteoclasts and is usedto reduce bone resorption in osteoporosisand Paget disease; it is also used to treathypercalcemia of malignancy. In the absenceof any data suggesting potential harm, allthese medications should be continued inthe perioperative period. Similarly, othermedications used in the treatment of osteo-porosis, including bisphosphonates anddenosumab, have no data suggesting periop-erative risks. Calcium and vitamin D alsoappear to be safe, and recommendations forthese supplements are provided in anotherarticle in this series. However, given therisk of esophagitis when lying supine shortlyafter ingestion and the potential fordecreased lower esophageal sphincterpressure from anesthetics, bisphosphonatesshould not be taken on the morning ofsurgery.

Consensus Recommendation. Continueparathyroid hormone, calcimimetics, calci-tonin, and denosumab before surgery andon the day of surgery. Bisphosphonates canbe taken before surgery, but they shouldnot be taken on the day of surgery.

Recommendations for hormonal andnondiabetes endocrine medications are sum-marized in Table 3.

UROLOGIC MEDICATIONS (TABLE 4)

Alpha-1 Adrenergic AntagonistsAmong the urologic medications discussedin this section, alpha-1 adrenergic antago-nists are the most commonly prescribeddrugs for initial medical treatment of benignprostatic hypertrophy (BPH). These medica-tions antagonize the alpha-1 adrenoreceptor,thereby inhibiting smooth muscle contrac-tion, leading to decreased smooth muscletone in the prostatic urethra and bladderneck.49 Medications of this class have similarefficacies, but they differ in their level of uro-selectivity. Less uroselective medications(eg, doxazosin, terazosin, prazosin) aremore likely to result in hypotension than


the more uroselective medications(eg, alfuzosin, tamsulosin, silodosin).49,50

Literature supports that there may be areduced incidence of postoperative urinaryretention when these medications arecontinued perioperatively.51 Cataractsurgeries in patients who are taking thesemedications are associated with floppy irissyndrome, and patients who take tamsulosinseem to be at the highest risk.52,53 However,discontinuation of the medication beforesurgery does not necessarily eliminate therisk.

Consensus Recommendations. Continuealpha-1 adrenergic antagonists up to andincluding the day of surgery. In patientsundergoing cataract surgery, consider dis-cussion with the ophthalmologist.

5-Alpha Reductase Inhibitors5-Alpha reductase inhibitors (5-ARIs) inhibitthe enzyme 5-alpha reductase, which con-verts testosterone to dihydrotestosterone inthe prostate, reducing overall prostatic size.Dutasteride and finasteride are the 5-ARIsprescribed in the United States. No interac-tion between 5-ARIs and anesthesia hasbeen noted in the literature, and somestudies show a reduction in estimated surgi-cal blood loss during transurethral resectionof the prostate surgery in patients who takefinasteride.54-56

Consensus Recommendation. Continue 5-ARIs up to and including the day of surgery.

Anticholinergic Bladder DysfunctionMedicationsAnticholinergic agents inhibit muscarinicactivity of the parasympathetic nervoussystem and contribute to bladder detrusoractivity. Detrusor overactivity is responsiblefor the symptoms of overactive bladder syn-drome, which includes urinary frequency,urgency, urge incontinence, and nocturia.Most medications in this class act as compet-itive antagonists to acetylcholine at themuscarinic receptors with varyingselectivity. Available medications includedarifenacin, fesoterodine, oxybutynin,

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TABLE 4. Summary of Recommendations for the Preoperative Management of Urologic Medications

Medication class ExamplesManagement prior to the

morning of surgeryManagement on themorning of surgery Additional considerations

5-Alpha reductase inhibitors Dutaseride, finasteride Continue Continue

Alpha-1 adrenergic antagonists Alfuzosin, doxazosin, prazosin,silodosin, tamsulosin, terazosin

Continue Continue Prior to cataract surgery notifyophthalmologist of

increased risk of floppy irissyndrome

Anticholinergic bladderdysfunction medications

Darifenacin, fesoterodine,flavoxate, oxybutynin,

solifenacin, tolterodine, trospium

Continue Hold May reduce catheter-relatedbladder discomfort but carryhigh potential for adverseeffects in older patients

Anti-neoplastic urologicmedications

Abiraterone acetate, apalutamide,bicalutamide, degarelix,

enzalutamide, goserelin acetate,leuprolide acetate, nilutamide

Continue Continue

Betha chloride Continue Hold

Mirabegron Continue Hold

PDE-5a inhibitors Avanafil, sildenafil, tadalafil,vardenafil

Hold for 3 days (seeadditional

considerations)

Hold Recommendation is forurologic use of thesemedications. Continueuninterrupted if used forpulmonary hypertension.

aPDE-5, Laukkanen phosphodiesterase-5.


1666

tolterodine, and trospium. Flavoxate actsdirectly on the bladder smooth muscle toreduce contraction.

Although literature supports the use ofthese medications perioperatively to reducecatheter-related bladder discomfort forpatients undergoing urologic surgery pa-tients, they have undesirable anticholinergicadverse effects and can contribute todelirium.57,58 For this reason, all medica-tions in this class are considered cautionaryin older patients.59,60

Consensus Recommendation. Continuebefore surgery but do not take anticholin-ergic bladder dysfunction medications onthe morning of surgery.

Antineoplastic Urologic MedicationsMedications used for the treatment ofprostate cancer primarily work by inhibitingandrogen release, synthesis, or activity. Theyare also prescribed for other indications,such as breast or uterine cancers, adrenal


hyperplasia, polycystic ovary syndrome,alopecia, and gender affirmation therapy.Abiraterone inhibits the CYP17A1 enzyme,which is required for synthesis of androgens.Apalutamide, bicalutamide, enzalutamide,and nilutamide are nonsteroidal androgenreceptor inhibitors. Degarelix and goserelininhibit pituitary gonadotropin-releasinghormone (GnRH) secretion, leading to areduction in testosterone release. Leuprolideacetate is an agonist at the pituitary GnRHreceptors, and this eventually leads toGnRH desensitization and decreasedhormone levels.

Known adverse effects of these medica-tions include: increased cardiovascularrisk, anemia, hepatic dysfunction, QT pro-longation, interstitial lung disease, anddecreased bone density. However, thereare no perioperative studies for these medi-cations, and most of these adverse effectsare chronic in nature or can be obviatedwith appropriate screening and periopera-tive precautions.





Consensus Recommendation. Continueantineoplastic urologic medications up toand including the day of surgery.

Phosphodiesterase Type 5 (PDE-5)InhibitorsPDE-5 inhibitors are used in the treatment oferectile dysfunction, BPH, and pulmonaryhypertension (discussed in a separateconsensus statement in this series). Thesemedications selectively block the degrada-tion of cyclic GMP by the PDE-5 enzyme,thereby leading to an increased productionof nitric oxide, relaxation of endothelialsmooth muscle cells, and vasodilation.Available PDE-5 inhibitors in the UnitedStates are avanafil, sildenafil, tadalafil, andvardenafil, and these vary substantially intheir onset and duration of action (half-liferanges 4-15 hours).

Investigations of safety during anesthesiaare applicable only to patients with pulmo-nary hypertension. All these medicationshave the potential to cause intraoperativehypotension, and no studies have deter-mined safe timing of anesthesia after use.

Consensus Recommendation. If taken forerectile dysfunction or BPH, hold PDE-5inhibitors for 3 days before surgery.

Other Urologic MedicationsBethanechol chloride stimulates the releaseof acetylcholine with selective activity atthe muscarinic receptor, thereby leading todetrusor muscle stimulation and treatmentof urinary retention. Bethanechol has beenstudied for the prevention of postoperativeurinary retention, and it has shown a modestbenefit.61 However, given its effects onacetylcholine, it also has the potential forinteraction with anesthetic agents.

Mirabegron is used in the treatment ofoveractive bladder syndrome; similar to anti-cholinergic agents, it works by relaxingdetrusor smooth muscles, but it does so bystimulating the beta-3 adrenoreceptorlocated in the detrusor muscle. Mirabegroncan lead to hypertension, but no periopera-tive data on this medication were identified.


Consensus Recommendation. Continuebethanechol and mirabegron up to the daybefore surgery, but hold on the morning ofsurgery.

CONCLUSIONPerioperative medication management is acritical part of optimal care of surgicalpatients. Instructional literature to supportbest practices in this area remains lacking,and perioperative decision making isprimarily guided by knowledge of medica-tion mechanisms of action and adverse effectprofiles. Summarized in Tables 1-4, thisconsensus statement provides recommenda-tions of experts in anesthesiology, internalmedicine, perioperative medicine, andmedical subspecialties for the managementof common endocrine, hormonal, andurologic medications.

Abbreviations and Acronyms: 5-ARI = 5-alpha reductaseinhibitors; ADA = American Diabetes Association; AGI = a-glucosidase inhibitor; BPH = benign prostatic hypertrophy;DM = diabetes mellitus; DPP-4 = dipeptidyl peptidase-4;FDA = US Food and Drug Administration; GFR =glomerular filtration rate; GI = gastrointestinal; GLP-1 =glucagon-like peptide-1; GnRH = gonadotropin-releasinghormone; NPH = neutral protamine Hagedorn; PDE =phosphodiesterase; PDE-5 = phosphodiesterase type 5;SGLT-2 = sodium glucose co-transporter 2; SPAQI = So-ciety for Perioperative Assessment and Quality Improve-ment; VTE = venous thromboembolism

Affiliations (Continued from the first page of thisarticle.): State Wexner Medical Center, Columbus (B.R.);Division of Endocrinology, Mayo Clinic, Rochester, MN(V.S.); Division of General Internal Medicine, Mayo Clinic,Rochester, MN (D.R.); Department of Anesthesiology, Peri-operative and Pain Medicine, Brigham and Women’s Hospi-tal, Boston, MA (R.D.U.); and Division of General InternalMedicine, Mayo Clinic, Rochester, MN (K.M.)

Potential Competing Interests: The authors report nocompeting interests.

Correspondence: Address to Kurt J. Pfeifer, MD, Depart-ment of Medicine, Medical College of Wisconsin, 9200West Wisconsin Ave, Milwaukee, WI 53226 ([email protected]; Twitter: @KurtPfeifer).

ORCIDKurt J. Pfeifer: https://orcid.org/0000-0003-3982-8190;Barbara Rogers: https://orcid.org/0000-0002-5135-6475

1016/j.mayocp.2020.10.002 1667

mailto:[email protected]

mailto:[email protected]

https://orcid.org/0000-0003-3982-8190

https://orcid.org/0000-0003-3982-8190

https://orcid.org/0000-0002-5135-6475




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