Perioperative medication management - UpToDate 03.02.

2020, 13:12

Authors: Visala Muluk, MD, Steven L Cohn, MD, MACP, SFHM, Christopher Whinney, MD
Section Editors: Andrew D Auerbach, MD, MPH, Natalie F Holt, MD, MPH
Deputy Editor: Lisa Kunins, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2020. | This topic last updated: Apr 12, 2019.

INTRODUCTION

At least 50 percent of patients undergoing surgery take medications on a regular basis [1].
Clinicians often must decide if chronic medications should be continued in the perioperative
period. Unfortunately, there are few outcome data about the majority of medications taken in
the perioperative period.

This lack of medical evidence is reflected by the large variation in perioperative management
recommendations [2]. The recommendations in this review are to a large degree expert
opinion, based on information from other reviews [3,4] and textbooks, along with clinical
experience and theoretic considerations.

This topic will focus on medications known to have perioperative effects, those known to
interact with anesthetic agents, and those in common use. An overview of preoperative
patient assessment and details about perioperative management for specific medications are
presented separately. (See "Overview of the principles of medical consultation and
perioperative medicine" and "Perioperative management of hypertension" and "Perioperative
management of patients receiving anticoagulants" and "The management of the surgical
patient taking glucocorticoids".)

PRINCIPLES OF MEDICATION MANAGEMENT

The following principles inform the management of chronic medications in the perioperative
period:

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● A complete medication history should be obtained, and all clinicians involved in patient
management (eg, surgeon, anesthesiologist, medical consultants) should review the
medication history. Medication use reported by the patient should be verified (medication
reconciliation) to address accuracy of drugs and doses [5]. This should include all over-
the-counter and herbal/complementary medications, as well as prescription drugs. In
addition, substance use information (including alcohol, nicotine, and illicit drugs) should
be elicited.

● Medications associated with known medical morbidity if withdrawn abruptly should be

continued in the perioperative period or tapered if feasible. Intravenous, transdermal, or
transmucosal medicines should be substituted when absorption will be impaired because
of loss of gastrointestinal function or restrictions on oral intake. Medications thought to
increase the risk of anesthetic or surgical complications and not essential for the short-
term should be held through the perioperative period [3]. Other medications can be
discontinued or continued based upon clinician judgment.

● The many medications administered perioperatively during a relatively short period

increase the potential for drug-drug interactions.

● The metabolism and elimination of medications and their metabolites may be altered
during the perioperative period. In particular, gastrointestinal absorption of oral
medications may be impaired due to changes in splanchnic blood flow and edema [6].

● The majority of medications can be resumed once the patient is able to tolerate oral
intake. The main exceptions to this are medications that impact the bleeding or
thromboembolic risk and are discussed in detail in the relevant medication sections
below.

CARDIOVASCULAR MEDICATIONS

For elective surgery, preoperative planning and care should be optimized to reduce risk and
minimize the need for acute changes in medication management perioperatively (table 1). For
example, we suggest control of clinical signs of heart failure (HF) for one week or longer
preoperatively if time permits. (See "Perioperative management of heart failure in patients
undergoing noncardiac surgery", section on 'Intraoperative hemodynamic monitoring' and
"Perioperative management of heart failure in patients undergoing noncardiac surgery",

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section on 'Preoperative management'.)

Beta blockers

● Benefit/risk – Beta blockers have a number of potential beneficial effects when taken
perioperatively. Beta blockers reduce ischemia by decreasing myocardial oxygen demand
due to increased catecholamine release. They may also help prevent or control
arrhythmias. Patients who take beta blockers chronically for management of angina are
at risk of ischemia with withdrawal of beta blockade. Acute withdrawal of a beta blocker
pre- or postoperatively can lead to substantial morbidity and even mortality [7-9].
Withdrawal issues are of less concern when beta blockers are used for hypertension or
migraine prophylaxis.

Whether to initiate beta blockers as prophylaxis for ischemia in the perioperative period in
patients at increased risk for coronary disease is complex and discussed separately [10].
(See "Management of cardiac risk for noncardiac surgery", section on 'Beta blockers'.)

Potential adverse effects of perioperative beta blockade include bradycardia and

hypotension. Nonselective beta blockers can interact with epinephrine, used for
infiltration anesthesia or management of intraoperative anaphylaxis [11]. (See
"Management of cardiac risk for noncardiac surgery" and "Major side effects of beta
blockers", section on 'Beta blocker withdrawal'.)

● Continue/discontinue – In light of the potential benefits of perioperative beta blockade,

minimal adverse effects, and consequences of acute withdrawal, we recommend that
beta blockers be continued in the perioperative period and continued throughout the
hospital stay. The dose of the beta blocker should be closely regulated throughout the
perioperative period to maintain the blood pressure and heart rate (rate-pressure product)
below the patient's ischemic threshold.

Since adequate beta blockade can take weeks to achieve safely in patients with systolic
heart failure, we prefer initiation of beta blockade in the preoperative period only if acute
decompensated heart failure is not present and surgery can be substantially delayed. If
surgery is urgent, we prefer postponing beta blockade until a later date. (See
"Perioperative management of heart failure in patients undergoing noncardiac surgery",
section on 'Beta blockers'.)

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● Formulations/alternatives – Intravenous forms of beta blockade, such as metoprolol,

propranolol, and labetalol, should be given if the patient cannot take oral medications
[12,13]. Esmolol is also available to be used intraoperatively or in an intensive care unit
(ICU) but cannot be administered on a regular hospital floor. We have a slight preference
for beta 1 cardioselective beta blockers, since they are less likely to cause adverse
pulmonary and peripheral vascular effects and may be associated with a lower risk of
postoperative stroke. Several studies suggest that the risk of perioperative stroke may
vary with the specific beta blocker used, and that metoprolol, compared with atenolol, has
been associated with a greater risk of perioperative stroke [14-18].

However, patients who are taking a nonselective beta blocker (eg, propranolol)
chronically do not need to be switched to a beta 1 selective agent perioperatively.

Alpha 2 agonists

● Benefit/risk – Although earlier smaller randomized trials suggested that centrally acting
sympatholytic drugs such as clonidine may improve perioperative outcomes [19-21], the
larger POISE-2 randomized trial in 10,010 patients undergoing noncardiac surgery found
that preoperative initiation of low-dose clonidine resulted in increased harm (no change in
mortality or myocardial infarction but increase in clinically significant hypotension and
nonfatal cardiac arrest) [22]. A substudy of the trial also found no benefit of
perioperatively administered clonidine in reducing the risk of acute kidney injury [23].

For patients already taking clonidine, abrupt withdrawal of clonidine can precipitate
rebound hypertension [24-26]. This usually occurs after abrupt cessation of fairly large
oral doses (eg, greater than 0.8 mg/day) but has also been noted in patients using
transdermal clonidine [27]. Withdrawal symptoms have also been reported with
methyldopa and guanfacine but are less likely because of their slower onset of action
[27]. (See "Withdrawal syndromes with antihypertensive drug therapy".)

● Continue/discontinue – Given the possible negative consequences of withdrawal, we

recommend that alpha 2 agonist drugs be continued in the perioperative period, but not
initiated.

● Formulations/alternatives – Transdermal clonidine is available for patients who likely

will not be able to resume oral medications by 12 hours after surgery. The decision to
substitute this form of therapy must be made before surgery; an equivalent dose of the

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transdermal preparation should be started three days prior to surgery while the oral
clonidine is tapered. The persistent effect of transdermal clonidine for 24 to 48 hours after
patch removal should be considered when transitioning back to the oral form.

Other centrally acting sympatholytic agents (eg, methyldopa or guanabenz) are rarely
used today. Withdrawal from abrupt discontinuation has been reported but is less
common because of their slower onset of action [28,29]. For patients unable to take oral
medications perioperatively, we recommend withholding methyldopa and guanabenz and
using other parenteral hypertensive agents if hypertension becomes a problem [24]. An
intravenous form of methyldopa is available in the rare cases in which abrupt stoppage
appears to be leading to a withdrawal syndrome.

Calcium channel blockers

● Benefit/risk – Data are limited regarding the risks and benefits of calcium channel
blockers in the perioperative setting. Small trials have shown a more stable intraoperative
hemodynamic profile in patients treated with continuous diltiazem, compared with
placebo, during coronary bypass surgery [30], but these studies are not large enough to
demonstrate improved outcomes. In an observational study, continued use of calcium
channel blockers was associated with reduced mortality for patients undergoing cardiac
surgery [31]. A meta-analysis found that use of calcium channel blockers was associated
with reduced ischemia and atrial arrhythmia in patients undergoing noncardiac surgery
[32].

There are no serious interactions between calcium channel blockers and anesthetic
agents [33]. A withdrawal syndrome is not typical of calcium channel blockers, although
abrupt discontinuation of these drugs has been reported to cause severe vasospasm in
patients undergoing coronary revascularization [34].

Concerns have been raised about a possible association between calcium channel
blockers and an increased risk of bleeding [35]. A randomized trial in valvular surgery
patients found that, compared with placebo, patients receiving nimodipine had increased
bleeding [36,37]. Reports conflict on whether there is a greater incidence of anemia in
patients receiving calcium channel blockers after hip surgery [38,39]. Two large trials in
cardiac surgery patients did not find any association between bleeding risk and use of
calcium channel blockers [40].

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● Continue/discontinue – Despite little data regarding calcium channel blockers during

the perioperative period, these agents appear safe and have theoretic benefit [41]; data
regarding bleeding risk are contradictory. Thus, we recommend that calcium channel
blockers be continued in patients who are already taking them preoperatively [41].

● Formulations/alternatives – Intravenous diltiazem is available for patients who are

unable to tolerate oral agents.

Most oral calcium channel blockers are formulated as extended release and should not
be crushed for administration in enteral tubes. Short-acting calcium channel blockers are
available (diltiazem, verapamil) and can be substituted with appropriate dosing interval
adjustments. Short-acting nifedipine should be avoided, however, because it can cause
rapid decreases in blood pressure. Amlodipine has a long washout period, and short-
acting substitutes may not be necessary.

ACE inhibitors and angiotensin II receptor blockers

● Benefit/risk – The management of patients taking angiotensin-converting enzyme (ACE)

inhibitors and angiotensin II receptor blockers (ARBs) preoperatively is controversial.
ACE inhibitors and ARBs can theoretically blunt the compensatory activation of the renin-
angiotensin system during surgery and result in prolonged hypotension. Also, the effect of
these drugs may be different in noncardiac and cardiac surgery as well as with general
and neuraxial anesthesia.

Data regarding use of ACE inhibitors and ARBs in the perioperative period are
inconsistent, with most studies indicating some increased risk for peri- and postoperative
hypotensive episodes but variable adverse effect on cardiovascular outcomes or
respiratory outcomes when the medications are continued. Representative studies of
outcomes involving noncardiac surgery include the following [42-46]:

• In a randomized controlled trial of 275 patients on ACE inhibitors undergoing

noncardiac (mainly orthopedic and spine) surgery, those who omitted their last
preoperative ACE inhibitor dose were compared with those who continued the
medication uninterrupted [44]. Intraoperative and postoperative hypotension
occurred less frequently in the group who omitted the last dose, but postoperative
hypertensive events were more frequent (RR 1.95, 95% CI 1.14 to 3.34).

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• In an observational cohort study of almost 15,000 patients (with 4802 taking either
ACE inhibitors or ARBs for unspecified indications), withholding the ACE
inhibitor/ARB 24 hours before noncardiac surgery was associated with a reduction in
composite 30-day all-cause death, stroke, or myocardial injury (adjusted relative risk
[ARR] 0.82, 95% CI 0.70-0.96) and intraoperative hypotension (ARR 0.80, 95% CI
0.72-0.93) [46]. Withholding perioperative ACE inhibitor/ARB was not associated
with risk of myocardial infarction or postoperative hypotension.

• In an observational study of over 12,000 patients on chronic diuretic therapy

undergoing noncardiac surgery, ACE inhibitor/ARB treatment was associated with
more frequent episodes of hypotension [42]. However, there were no differences in
the rates of postoperative myocardial infarction or renal failure between the two
groups.

• In a propensity match study of 18,000 patients undergoing noncardiac surgery, no

association was found between continued use of ACE inhibitors and intraoperative or
postoperative upper-airway complications [43]. Furthermore, uninterrupted
perioperative ACE inhibitor use was not associated with in-hospital complications or
increased 30-day mortality.

• In a meta-analysis including nine studies and over 6000 patients taking ACE
inhibitors or ARBs undergoing noncardiac surgery, withholding these medications
preoperatively was associated with significantly less intraoperative hypotension
(odds ratio [OR] 0.63; 95% CI 0.47-0.85). There was, however, no difference in
mortality (OR 0.97; 95% CI 0.62-1.52) or in the occurrence of major cardiovascular
events (OR 1.12; 95% CI 0.82-1.52) [45].

Additional studies have evaluated the effect of ACE inhibitor therapy in patients
undergoing coronary artery bypass graft (CABG) surgery:

• A trial randomly assigned 40 patients with good left ventricular function who were
undergoing CABG surgery to continue or omit ACE inhibitors before surgery [47].
Patients who omitted their ACE inhibitors required less vasopressors during surgery
but required more vasodilators to control hypertension in the early postoperative
period.

• A randomized trial of 47 patients on ramipril undergoing CABG on cardiopulmonary

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bypass (CPB) found that ACE inhibitor therapy predisposed to hypotension upon
induction and in the post-CPB period, but prophylactic low-dose vasopressin infusion
prevented post-CPB hypotension [48].

• Nonrandomized studies suggest a possible myocardial protective effect of ACE

inhibitors in patients undergoing CABG surgery [49,50].

• Reports conflict on the effect of ACE inhibitors on the risk of acute kidney injury (AKI)
[51-55].

● Continue/discontinue – We individualize the decision to continue or discontinue ACE

inhibitors based on the indications for the drug, the patient's blood pressure, and the type
of surgery and anesthesia planned. For most patients, we usually withhold them on the
morning of surgery. However, when the indication is for heart failure or poorly controlled
hypertension, we continue them to avoid further exacerbation of these conditions. Many
anesthesiologists may prefer to withhold these medications on the morning of surgery
based on concerns about possible hypotension, and in such cases when we favor
continuation, we inform the anesthesiologist of our justification.

We recommend resuming these agents as soon as possible postoperatively, as failure to

restart ARBs within 48 hours after surgery has been associated with increased 30-day
mortality (see "Anesthesia for noncardiac surgery in patients with heart failure", section
on 'Medications'). A number of organizations have issued guidelines regarding the
perioperative use of ACE inhibitors and ARBs [56-60].

As above, most findings suggest that continuing ACE inhibitors up to the time of surgery
increases perioperative hypotension but possibly reduces the incidence of postoperative
hypertension.

● Formulations/alternatives – Enalapril is available for short-term intermittent intravenous

administration, although it is used infrequently.

Diuretics

● Benefit/risk – The two major physiologic effects of concern of loop and thiazide-type
diuretics are hypokalemia and hypovolemia.

Hypokalemia can theoretically increase the risk of perioperative arrhythmia, although

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observational studies of patients with structural heart disease have failed to find such a
relationship [61,62]. Additionally, hypokalemia might potentiate the effects of muscle
relaxants used during anesthesia, as well as provoke paralytic ileus.

Systemic vasodilatation induced by anesthetic agents may cause hypotension in patients

who are intravascularly depleted from diuretics. However, in a study of elective,
noncardiac surgeries in patients chronically treated with furosemide, the administration of
furosemide on the day of surgery did not significantly increase the risk for intraoperative
hypotension [63].

● Continue/discontinue – There is no consensus on whether diuretics should be

discontinued prior to elective surgery [2]. Our approach depends upon the reason for
diuretic use and on an individual patient's history.

• We advise patients who are taking diuretics for hypertension to hold the medication
on the morning of surgery. Diuretics may theoretically increase the risk of
intraoperative hypotension, and although unlikely to occur in patients on chronic
therapy, it is reasonable to hold the medication for this reason.

• For patients receiving diuretic therapy to treat heart failure, diuretic continuation is
based upon assessment of volume status, which should be evaluated and optimized
preoperatively whenever possible. For patients with well-controlled heart failure and
stable volume status, we generally recommend holding the morning dose of diuretic
on the day of surgery. For patients with heart failure in whom fluid balance has
historically been more difficult to control, we recommend continuing the diuretic
without interruption.

If diuretics are held the morning of surgery and volume overload develops, a quick
diuresis can be initiated by intravenous administration perioperatively. (See
"Perioperative management of heart failure in patients undergoing noncardiac
surgery", section on 'Diuretics' and "Perioperative management of heart failure in
patients undergoing noncardiac surgery", section on 'Fluid management'.)

For patients who require perioperative diuretics, clinicians should pay close attention
to potassium replacement.

● Formulations/alternatives – Intravenous preparations of loop diuretics are available.

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Non-statin hypolipidemic agents

● Benefit/risk – Niacin and fibric acid derivatives (gemfibrozil, fenofibrate) cause myopathy
and rhabdomyolysis. The risk is higher when these agents are used in combination with
statins, and surgery may also increase the risk of myopathy [64-68]. (See "Statin muscle-
related adverse events".)

Lipid-lowering agents that are bile sequestrants (cholestyramine and colestipol) interfere
with bowel absorption of multiple medications that may be required perioperatively.

The benefits or risks of ezetimibe in the perioperative period are unknown.

● Continue/discontinue – We recommend temporary discontinuation of niacin, fibric acid

derivatives, bile sequestrants, and ezetimibe perioperatively. Discontinuation is likely to
be safe since these agents are given for the goal of long-term reduction in vascular
morbidity [65].

The optimal interval to discontinue these agents before surgery is unknown; we

recommend they be stopped the day before surgery to allow for drug elimination.

Digoxin

● Benefit/risk – Studies on digoxin in the perioperative period are limited. The two
indications for digoxin are to prevent hospitalization and readmission in patients with
reduced left ventricular function and to control ventricular response in atrial fibrillation.
One study found perioperative use of digoxin to be a predictor of postoperative ischemia,
but this was probably because it was a marker of underlying cardiac disease [69]. A
subgroup analysis of patients undergoing intrathoracic surgery found that digoxin
decreased the incidence of postoperative supraventricular arrhythmias [70].

● Continue/discontinue – We recommend continuing digoxin perioperatively. Obtaining a

drug level preoperatively is not usually required.

● Formulations/alternatives – Intravenous digoxin is available if needed.

Statins — Evidence has become convincing that HMG CoA reductase inhibitors (statins) may
prevent vascular events in the perioperative period. This is discussed in detail separately.
(See "Management of cardiac risk for noncardiac surgery", section on 'Statins'.)

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GASTROINTESTINAL AGENTS

Recommendations for perioperative management of these agents are summarized in the

table (table 2).

H2 blockers and proton pump inhibitors

● Benefit/risk – There are several potential advantages of continuing H2 blockers or

proton pump inhibitors perioperatively. The stress of surgery and other conditions (eg,
intensive care unit [ICU] stay and mechanical ventilation) can increase the risk of stress-
related mucosal damage, which may be minimized by administration of these drugs. (See
"Stress ulcers in the intensive care unit: Diagnosis, management, and prevention".)

In addition, gastric aspiration during anesthesia, though rare, can lead to severe
pulmonary injury. Both H2 blockers and proton pump inhibitors decrease gastric volume
and raise gastric fluid pH, thereby reducing the risk of chemical pneumonitis from
aspiration [71,72]. (See "Aspiration pneumonia in adults", section on 'Chemical
pneumonitis'.)

Although H2 blocker therapy is generally safe, rare central nervous system (CNS)
reactions including confusion and delirium are associated with the use of intravenous H2
blockers in critically ill postoperative patients [73]. Patient risk factors for CNS reactions
include advanced age, organ dysfunction, and preexisting cognitive impairment. It is
uncertain whether any H2 blocker is less likely to cause CNS effects than others. (See
"Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on
'Adverse effects'.)

An increased risk of Clostridioides difficile infection has been associated with proton
pump inhibitor use. (See "Clostridioides (formerly Clostridium) difficile infection in adults:
Epidemiology, microbiology, and pathophysiology" and "Clostridioides (formerly
Clostridium) difficile infection in adults: Epidemiology, microbiology, and pathophysiology",
section on 'Gastric acid suppression'.)

Neither H2 blockers nor proton pump inhibitors have been shown to interact with
common anesthetic agents, although cimetidine can alter the metabolism of several
drugs.

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● Continue/discontinue – Based upon the potential benefits and lack of contraindications,

we recommend that patients who are taking either H2 blockers or proton pump inhibitors
remain on these medications in the perioperative period.

● Formulations/alternatives – Patients who are unable to take oral medications for a

prolonged period should be switched to an intravenous form of H2 blocker or proton
pump inhibitor (table 2). Intravenous H2 blockers are less costly.

PULMONARY AGENTS

Recommendations for perioperative management of these agents are summarized in the

table (table 2).

Inhaled beta agonists and anticholinergics

● Benefit/risk – Inhaled medications used to control obstructive pulmonary disease, such

as beta agonists (albuterol, salmeterol, formoterol) and anticholinergics (ipratropium,
tiotropium), have been found to reduce the incidence of postoperative pulmonary
complications in patients with asthma and chronic obstructive pulmonary disease and
should be continued perioperatively. (See "Strategies to reduce postoperative pulmonary
complications in adults".)

● Continue/discontinue – We recommend continuing beta agonists in the perioperative

period, including the day of surgery.

● Formulations/alternatives – Inhaled beta agonists and anticholinergics are normally

administered on the morning of surgery. The drugs can be administered through a
nebulizer or in the circuit of the ventilator when use of metered-dose inhalers is not
possible.

Theophylline

● Benefit/risk – There are no data indicating whether continuation of theophylline in the

perioperative period decreases pulmonary complications. Theophylline has the potential
to cause serious arrhythmias and neurotoxicity at a level just beyond the therapeutic
range, and theophylline metabolism is affected by many common perioperative
medications.

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● Continue/discontinue – We recommend theophylline medications be discontinued the

evening before surgery.

● Formulations/alternatives – Other medications for treatment of obstructive lung disease

can be initiated or adjusted, including inhaled beta agonists, glucocorticoids, and
anticholinergic medications. (See "Strategies to reduce postoperative pulmonary
complications in adults".)

Glucocorticoids

● Benefit/risk – Patients with pulmonary disease who are maintained on glucocorticoids

(corticosteroids) are at risk of adrenal insufficiency if steroids are abruptly withdrawn,
particularly in the face of increased stress related to surgery. Additionally, glucocorticoids
in such patients may be necessary to maintain optimal lung functions. The risk of
possible perioperative complications related to glucocorticoids, including wound
infections, is low [74].

● Continue/discontinue – Both inhaled and systemic glucocorticoids should be continued

during the perioperative period. Issues related to preoperative stress dosing are
discussed below. (See 'Glucocorticoids' below.)

Leukotriene inhibitors

● Benefit/risk – The leukotriene inhibitors zafirlukast and montelukast help maintain

asthma control but are not used for acute therapy. (See "Antileukotriene agents in the
management of asthma".)

The elimination half-life of these agents is relatively short, but their effect on asthma
symptoms and pulmonary function continues for up to three weeks after cessation of
treatment [75].

There is no evidence of a withdrawal syndrome with abrupt stoppage of these agents. We

are aware of no evidence of harmful interactions of these drugs with anesthetics.

● Continue/discontinue – We recommend that leukotriene inhibitors be given on the

morning of surgery and resumed when the patient is tolerating oral medications.

● Formulations/alternatives – No parenteral substitution is available or necessary given

the long duration of action for leukotriene inhibitors.

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ENDOCRINE AGENTS

Glucocorticoids — The management of patients taking glucocorticoids preoperatively is

discussed in detail separately. (See "The management of the surgical patient taking
glucocorticoids" and "Preoperative evaluation and perioperative management of patients with
rheumatic diseases", section on 'Medication management'.)

Diabetic medications — The management of diabetes mellitus, including management of

oral agents and insulin in the perioperative period, is discussed in detail separately. (See
"Perioperative management of blood glucose in adults with diabetes mellitus".)

Oral contraceptives

● Benefit/risk – Oral contraceptives (OCs) are statistically the most frequent cause of
thrombosis in young women due to their widespread use. The risk of thrombosis
increases within four months of initiation and decreases to previous levels within three
months of stopping treatment. Surgery itself is a risk factor for thrombosis and
compounds the risk associated with oral contraceptive use.

OCs with higher estrogen content (≥35 mcg) have a greater risk of thromboembolism
compared with those with lower estrogen content (≤30 mcg). Nevertheless, even the
lower estrogen content pills are associated with an increased risk of thrombosis [76,77].
Estrogen/progestin patches also increase thrombosis risk. Risk also varies with type of
progestin. (See "Combined estrogen-progestin contraception: Side effects and health
concerns", section on 'Cardiovascular effects'.)

● Continue/discontinue – In general, we typically recommend continuation of OCs and

provision of appropriate perioperative thromboprophylaxis (table 3). In patients at higher
risk for VTE who are undergoing high-risk surgery (table 4), discontinuation of OCs may
be reasonable to mitigate the additional VTE risk; if the decision is made to discontinue,
OCs should be stopped four weeks prior to surgery. Women who discontinue OCs that
are used for contraceptive purposes should use an alternative method of birth control,
which should be continued for the first week after resuming OCs postoperatively; if they
cannot or prefer not to use an alternative method, continuing the OC is appropriate (with
appropriate perioperative thromboprophylaxis). Prevention of thromboembolic disease in
the surgical patient is discussed elsewhere. (See "Prevention of venous thromboembolic

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disease in adult nonorthopedic surgical patients".)

We recommend a serum pregnancy test prior to surgery in all women of childbearing age.

Manufacturer product package inserts state that estrogen-containing OCs should be

stopped four weeks prior to elective major operations and surgery to the legs, and they
can be restarted at the first menses occurring at least two weeks after surgery or after full
mobilization. However, evidence to support these recommendations is insufficient and
these recommendations are inconsistent with typical clinical practice.

Postmenopausal hormone therapy

● Benefit/risk – The estrogen content of preparations used for postmenopausal hormone

therapy (HT) is much lower than in oral contraceptive pills. However, use of HT, with
either estrogen alone or estrogen plus a progestin, still appears to increase the risk of
venous thromboembolism (VTE) [78,79]. Although a case-control study did not find an
increased risk of thromboembolism in women undergoing arthroplasty who received HT
(odds ratio [OR] 0.66, 95% CI 0.35-1.18), the results may have been confounded by
women at lower risk for thromboembolism being more likely to be prescribed HT [80].

The risks associated with temporary discontinuation of hormone therapy are mainly
discomfort from hot flashes and other menopausal symptoms.

● Continue/discontinue – We usually individualize the decision to continue HT

perioperatively based on the VTE risk of the procedure and the woman’s preference, but
overall we feel the risk of continuing HT is relatively low (table 3). Ideally, women
undergoing procedures associated with moderate to high risk for VTE should stop
hormone therapy at least two weeks prior to elective surgery and resume treatment
postoperatively once the period of elevated risk for VTE has resolved. HT can be
continued uninterrupted for surgical procedures associated with a low risk of VTE .
Definitions of low-, moderate-, and high-risk procedures, and appropriate VTE
prophylaxis, are discussed elsewhere (table 4). (See "Prevention of venous
thromboembolic disease in adult nonorthopedic surgical patients".)

Manufacturers recommend that estrogens should be discontinued at least four to six

weeks prior to a surgical procedure with increased risk of VTE or during periods of
prolonged immobilization, but evidence to support this recommendation is insufficient,

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particularly for HT, as above.

Selective estrogen receptor modulators

● Benefit/risk – The indications for use of selective estrogen receptor modulators (SERMs)
such as tamoxifen and raloxifene include breast cancer treatment, breast cancer
chemoprevention, and, at least for raloxifene, the prevention and treatment of
osteoporosis (see "Selective estrogen receptor modulators and aromatase inhibitors for
breast cancer prevention" and "Selective estrogen receptor modulators for prevention
and treatment of osteoporosis"). Both tamoxifen and raloxifene increase the risk of VTE
[81,82].

Brief discontinuation of SERMs used for the prevention/treatment of osteoporosis or the

prevention of breast cancer is unlikely to result in harm. For patients with breast cancer
who are being treated with SERMs, the risk of disease progression with preoperative
cessation of treatment is a consideration.

● Continue/discontinue – SERMs can be continued without interruption for low- and

moderate-risk surgeries while providing appropriate VTE prophylaxis (table 3). Definitions
of low-, moderate-, and high-risk procedures, and appropriate VTE prophylaxis, are
discussed elsewhere (table 4). (See "Prevention of venous thromboembolic disease in
adult nonorthopedic surgical patients".)

For surgeries with a high-risk of VTE, our approach depends upon the specific SERM
and the indication for its use:

• For patients taking raloxifene for osteoporosis treatment/prevention or breast cancer

prevention, we suggest discontinuing the medication three days prior to a surgical
procedure associated with a high risk of VTE. The raloxifene can be resumed as
soon as the period of elevated VTE risk is resolved. However, if the patient has taken
the medication within three days of the procedure, we do not recommend
postponing the surgery for this reason; the procedure can be done as planned and
appropriate VTE prophylaxis provided. (See "Prevention of venous thromboembolic
disease in adult nonorthopedic surgical patients".)

• For patients taking tamoxifen for breast cancer prevention (ie, in women without a
history of breast cancer), we suggest discontinuing the medication two weeks prior to

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a surgical procedure associated with a high risk of VTE. The tamoxifen can be
resumed as soon as the period of elevated VTE risk has resolved. However, if the
patient has taken the medication within two weeks of the procedure, we do not
recommend postponing the surgery for this reason; the procedure can be done as
planned and appropriate VTE prophylaxis provided. (See "Prevention of venous
thromboembolic disease in adult nonorthopedic surgical patients".)

• For patients taking a SERM (eg, tamoxifen) for breast cancer treatment, the decision
to discontinue is more difficult, and consultation with an oncologist is recommended.
We typically recommend continuing SERMs in this setting while providing
appropriate VTE prophylaxis. (See "Prevention of venous thromboembolic disease in
adult nonorthopedic surgical patients".)

The package insert for tamoxifen states that in the case of surgery and immobility, the
medication should only be stopped if the risk of tamoxifen-induced thrombosis clearly
outweighs the risks associated with interrupting treatment. If continued, all patients
should receive appropriate thrombosis prophylactic measures. The manufacturers of
raloxifene, however, recommend stopping it at least three days before surgery.

Drugs used for thyroid disease — The management of medications to control hypothyroid
and hyperthyroid states is discussed in detail separately. (See "Nonthyroid surgery in the
patient with thyroid disease".)

● Continue/discontinue – We recommend perioperative continuation of therapy for both

hyperthyroidism and hypothyroidism.

In the case that a patient cannot take oral medications for several days, the approach
depends upon the thyroid medication:

• Thyroxine (T4) has a long half-life, and patients on chronic T4 therapy who are
unable to take oral medication for several days do not need parenteral T4. If oral T4
cannot be resumed within five to seven days, it should then be administered
parenterally (intravenously or intramuscularly).

• The antithyroid thionamide medications (methimazole and propylthiouracil) have a

very short half-life. The decision on how long to hold antithyroid medications for a
patient who is unable to take oral medications must be individualized based upon

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several factors, including the patient's history of thyroid disease and length of
previous treatment with antithyroid medications. (See "Nonthyroid surgery in the
patient with thyroid disease", section on 'Preexisting hyperthyroidism'.)

● Formulations/alternatives – T4 can be given intravenously or intramuscularly. When

administered parenterally, the dose of T4 should be reduced to approximately 80 percent
of the patient's usual oral dose to reflect the fraction of oral T4 that is absorbed.

There are rectal (suppository and retention enema) options for administration of either of
the antithyroid medications (table 5).

Drugs used for osteoporosis/osteopenia

● Benefit/risk – Bisphosphonate use, especially in malignancy, has been associated with

osteonecrosis of the jaw in patients undergoing dental surgery. The absolute risk is very
low, but osteonecrosis is difficult to manage. The duration of effect of bisphosphonates on
bone remodeling is long, and the discontinuation of these agents for weeks or even
months before surgery has not been shown to decrease the risk of osteonecrosis.
Likewise, there is no evidence that short-term discontinuation of these agents results in
reduction in treatment efficacy for prevention of osteoporotic bone fractures.

● Continue/discontinue – We recommend withholding bisphosphonates only on the

morning of surgery, as they are typically taken with at least 8 ounces of water and the
patient is supposed to remain upright for at least 30 minutes and until after eating a meal.

For patients undergoing dental surgery, we advise that bisphosphonates not be held in
advance of the procedure nor dental surgery delayed since the absolute risk of jaw
osteonecrosis is low and the benefit of holding the medication in advance is not clear. For
patients believed to be at very high risk due to need for extensive bony surgery,
concomitant glucocorticoid or chemotherapy, or long-term bisphosphonate use, a delay of
surgery for two months is reasonable but these cases are uncommon. (See "Risks of
bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the
jaw'.)

Guidelines from the American Association of Oral and Maxillofacial Surgeons

recommend proceeding as usual with dental surgery in patients who have been treated
with oral bisphosphonates for less than four years and have no clinical risk factors [83].

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They suggest discontinuing bisphosphonates for two months prior to performing the
dental surgery if a patient has been treated for more than four years or has taken
concomitant glucocorticoids. Bisphosphonates are restarted when the bone has healed.

MEDICATIONS AFFECTING HEMOSTASIS

Many patients undergoing surgery are taking medications that are intended to impair normal
hemostasis or appropriate thrombosis (eg, warfarin, aspirin, or other antiplatelet agents), or
take medications for another indication that have an unintended effect on hemostasis, such as
nonsteroidal antiinflammatory drugs (NSAIDs) (table 6).

Aspirin

● Benefit/risk – Aspirin irreversibly inhibits platelet cyclooxygenase, which may increase

intraoperative blood loss and hemorrhagic complications [84-89]. However, the same
effect can help to prevent perioperative vascular complications, in particular cardiac and
thromboembolic complications. The perioperative benefits and risks of aspirin depend on
the patient's indication for aspirin and the planned surgery.

For example, observational studies suggest that withdrawal of aspirin preoperatively is

associated with increased in-hospital mortality in patients undergoing coronary artery
bypass graft surgery (CABG) [90,91]. However, in patients undergoing noncardiac
surgery, the large randomized POISE-2 trial found that perioperative aspirin increases
bleeding risk but does not improve cardiovascular or mortality outcomes [92]. A substudy
of the trial also found no benefit for perioperative aspirin administration at reducing the
risk of acute kidney injury [23] and no benefit for prevention of venous thromboembolism
(VTE), although two-thirds of the patients also received anticoagulants and there were
few VTE events overall [93]. (See "Medical therapy to prevent complications after
coronary artery bypass graft surgery", section on 'Aspirin' and "Management of cardiac
risk for noncardiac surgery", section on 'Antiplatelet therapy'.)

● Continue/discontinue – Recommendations to continue or discontinue aspirin vary

depending on what surgery is planned and the patient’s indication for aspirin. As
examples:

• Patients undergoing CABG (see "Medical therapy to prevent complications after

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coronary artery bypass graft surgery", section on 'Aspirin')

• Patients undergoing vascular surgery (see "Carotid endarterectomy", section on

'Antiplatelet therapy' and "Surgical and endovascular repair of popliteal artery
aneurysm", section on 'Antiplatelet therapy')

• Patients who have undergone percutaneous coronary interventions and are on

aspirin as part of dual antiplatelet therapy (see "Noncardiac surgery after
percutaneous coronary intervention", section on 'Our approach')

• Patients who have recently had an acute coronary syndrome (see "Management of
cardiac risk for noncardiac surgery", section on 'Patients with a recent acute
coronary syndrome')

• Patients with cardiac risk who are undergoing non-cardiovascular surgery (not
including cataract surgery) (see "Management of cardiac risk for noncardiac
surgery", section on 'Antiplatelet therapy')

• Patients undergoing cataract surgery (see "Cataract in adults", section on 'Aspirin

and other antiplatelet agents')

Aspirin can be safely continued in most patients undergoing minor dental surgery or
dermatologic procedures. For other patients taking aspirin for secondary prevention, the
risks and benefits of perioperative aspirin should be discussed with the patient, surgeon,
cardiologist, or neurologist.

Guidelines from the American Society of Regional Anesthesia (ASRA) indicate that
NSAIDs, including aspirin, do not create a level of risk that will interfere with the
performance of neuraxial blocks, and should not impact catheter techniques, timing of
neuraxial catheter removal, or postoperative monitoring [94].

● Formulations/alternatives – Aspirin is not available in parenteral forms but is available

as a rectal suppository for patients who are felt to need ongoing therapy but cannot take
oral medication.

Other antiplatelet agents

● Benefit/risk – The platelet P2Y12 receptor blockers clopidogrel, prasugrel, ticagrelor, and
ticlopidine are used in patients who have had previous cerebrovascular events, recent

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acute coronary syndromes, or recent percutaneous coronary or vascular interventions

with stenting. Issues related to continuation or discontinuation, as well as postoperative
reinstitution of clopidogrel and other P2Y12 receptor blockers, are discussed separately.
(See "Noncardiac surgery after percutaneous coronary intervention", section on 'Our
approach'.)

Dipyridamole has both vasodilator and antiplatelet activity. With the publication of the
ESPS-2 trial [95], its use has become more common in patients with past stroke or
transient ischemic attack (TIA). The half-life of the modified-release preparation is
approximately 10 hours. (See "Antiplatelet therapy for secondary prevention of stroke"
and "Secondary prevention for specific causes of ischemic stroke and transient ischemic
attack".)

Cilostazol is a selective phosphodiesterase-3 enzyme inhibitor with weaker reversible

antiplatelet activity than the P2Y12 receptor blockers and is used primarily for treatment of
claudication symptoms. Its half-life is approximately 21 hours. (See "Management of
claudication due to peripheral artery disease".)

● Continue/discontinue – Many patients take both aspirin and platelet P2Y12 receptor
blocker therapy to prevent coronary stent thrombosis. Premature cessation of dual
antiplatelet therapy is associated with an increased risk for stent thrombosis.
Management of such patients is discussed elsewhere. (See "Noncardiac surgery after
percutaneous coronary intervention".)

There are no data on the safety of dipyridamole if continued in the perioperative period.
Like aspirin, factors to consider in deciding whether to continue or hold dipyridamole
reflect a balance between the risk of bleeding and risk of ischemic events. If
discontinued, the drug should be stopped at least two days before surgery. Aggrenox
(combination aspirin and dipyridamole) should be discontinued 7 to 10 days before
surgery.

Cilostazol should be discontinued for at least two to three days prior to elective surgery,
but the manufacturer recommends stopping it at least five days before. Claudication
symptoms may recur when the medication is stopped, but should respond once cilostazol
is reinitiated postoperatively.

Nonsteroidal antiinflammatory drugs

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● Benefit/risk – The antiplatelet effects of NSAIDs are due to reversible inhibition of

cyclooxygenase (COX)-1, an isoform of cyclooxygenase, leading to decreased
production of thromboxane A2 (TxA2). TxA2 is released by platelets in response to a
number of agonists, leading to platelet aggregation (see "Nonselective NSAIDs: Overview
of adverse effects", section on 'Antiplatelet effects'). These antiplatelet effects increase
the bleeding risk perioperatively but, like aspirin, may reduce the risk of perioperative
vascular events [96].

The selective COX-2 inhibitors, such as celecoxib, have minimal effects on platelet
function [97], although the potential for renal toxicity remains [98]. Most selective COX-2
inhibitors and nonselective NSAIDs appear to have deleterious cardiovascular effects.
(See "Overview of COX-2 selective NSAIDs" and "NSAIDs: Adverse cardiovascular
effects".)

Non-acetylated nonsteroidals, such as salsalate, do not have an antiplatelet effect.

● Continue/discontinue – On balance, we recommend discontinuing NSAIDs, including

selective COX-2 inhibitors, prior to surgery. For certain patients, however, pain control
may not permit extensive periods of time without these medications, and consultation
with the surgeon regarding risk of procedural bleeding should be weighed against pain
control. For patients whose pain is dramatically responsive to COX-2 inhibitors,
consideration may be given to continuing these agents since they have minimal effects
on platelet function.

Although some experts recommend discontinuing NSAIDs based upon drug-specific

elimination half-lives [99], the elimination half-life correlates poorly with cyclooxygenase
inhibition and effects on platelet aggregation [100,101]. In healthy individuals receiving
ibuprofen for one week, platelet function appears to return to normal within 24 hours after
the last dose [102]. However, the relationship between time of discontinuation of NSAIDs
with intra- and postoperative clinical bleeding is not well-defined. For most NSAIDs,
platelet function normalizes within three days of discontinuation [103], suggesting that
NSAIDs should generally be discontinued at least three days before surgery; ibuprofen
can be stopped 24 hours prior to surgery.

Nonacetylated NSAIDs (eg, diflunisal, choline magnesium trisalicylate, salsalate) can be

continued in the perioperative period and may be considered as alternatives to other
NSAIDs for pain control. The nonacetylated NSAIDs have a slow onset of effect which

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may limit their usefulness in the perioperative period.

● Formulations/alternatives – Intravenous preparations of ketorolac and ibuprofen are

available for short-term treatment of moderate acute pain and febrile conditions when oral
administration is not available and as an adjunct to other analgesics for the treatment of
moderate to severe postoperative pain. Patients should be well-hydrated and without
significant renal impairment.

Intravenous acetaminophen (paracetamol) is also available and is a useful alternative for

patients at risk for NSAID-associated gastropathy or renal impairment. Selection and use
of the non-opiate analgesics is discussed separately. (See "Sedative-analgesic
medications in critically ill adults: Selection, initiation, maintenance, and withdrawal".)

Anticoagulants — The perioperative management of patients taking warfarin and other oral
anticoagulants is discussed separately. (See "Perioperative management of patients receiving
anticoagulants".)

MEDICATIONS AFFECTING RENAL FUNCTION

Several medications and agents used during the perioperative period may lead to acute
kidney injury, including nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin-converting
enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), diuretics, antibiotics (eg,
aminoglycosides, vancomycin), and intravenous contrast agents [104]. The benefits and risks
vary based on each drug. (See "Major side effects of angiotensin-converting enzyme
inhibitors and angiotensin II receptor blockers", section on 'Reduction in GFR' and
"Epidemiology and pathogenesis of analgesic-related chronic kidney disease", section on
'Nonsteroidal antiinflammatory drugs' and "Aminoglycosides", section on 'Nephrotoxicity' and
"Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section
on 'Renal reactions' and "Prevention of contrast nephropathy associated with angiography"
and "Loop diuretics: Dosing and major side effects", section on 'Diuresis related'.)

Optimizing volume status and medications to prevent acute tubular necrosis are discussed
elsewhere. (See "Possible prevention and therapy of ischemic acute tubular necrosis", section
on 'Prevention'.)

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PSYCHOTROPIC AGENTS

The perioperative management of patients taking psychotropic agents varies with the class of
drugs used (table 7) and severity of mental illness. Evidence-based guidelines for these drugs
are lacking; data are primarily derived from case reports and open trials [105]. Perioperative
decisions about use of these drugs must balance their potential for side effects and interaction
with anesthetic agents with psychiatric and physiologic consequences of withdrawal of these
agents. In general, psychotropic medications for treatment of patients with serious or unstable
mental illness should be continued throughout the perioperative period to avoid psychiatric
decompensation. However, the optimal choice of anesthesia and analgesia in combination
with many psychotropic agents is unknown. Other than antipsychotics, many psychotropic
agents do not have a parenteral delivery mode. Appropriate pharmacologic management
includes consideration of parenteral alternatives of the same or different class to maintain
mood and behavior stability.

Tricyclic and tetracyclic antidepressants

● Benefit/risk – Cyclic antidepressants inhibit the uptake of norepinephrine and serotonin

at the synaptic cleft. Unlike most newer antidepressants, cyclic antidepressants lower the
seizure threshold and possess significant anticholinergic, antihistaminic, and alpha-1
blocking properties. These agents delay gastric emptying, prolong the QTc interval, and
may increase the risk for arrhythmias in combination with some volatile anesthetics or
sympathomimetic agents, although literature to support this concern is scant. Abrupt
withdrawal of tricyclic antidepressants can lead to insomnia, nausea, headache,
increased salivation, and sweating and should be avoided if feasible [106]. (See "Tricyclic
and tetracyclic drugs: Pharmacology, administration, and side effects".)

Cyclic antidepressants can amplify the systemic pressor effects of norepinephrine and
epinephrine; however, use with epinephrine-containing local anesthesia is generally safe.
Use with atropine or scopolamine may increase postoperative confusion. Due to additive
serotoninergic effects, use with tramadol and meperidine is not recommended. (See
"Serotonin syndrome (serotonin toxicity)".)

● Continue/discontinue – Most textbooks and journals recommend continuing these

agents in the perioperative period [2]. However, the US Food and Drug Administration
(FDA) and some experts advise that tricyclic antidepressants (imipramine, amitriptyline,

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nortriptyline, desipramine, and clomipramine) be discontinued prior to elective surgery,

when possible, and this information is provided in package labelling for these medications
[105]. The stability of the patient's depression should be considered prior to tapering or
discontinuing the medication to avoid worsening of depression. If depression is moderate
or severe, best practice would be to continue the antidepressant and notify the
anesthesia team to monitor for cardiac arrhythmias in the perioperative period. If
depression is mild, the antidepressant is not felt to be essential for short-term quality of
life, and if arrhythmias are of concern, the agent should be tapered to minimize the
chance of withdrawal.

We generally recommend continuation of cyclic agents throughout the perioperative

period, in particular for patients on high doses without cardiac disease. For patients on
low doses or in whom the risk of perioperative arrhythmia is increased, the agents should
be tapered off over a period of 7 to 14 days before surgery. The elimination half-life of
various cyclic antidepressants ranges from one to three days or more. For detail, refer to
the Lexicomp drug monographs included with UpToDate.

● Formulations/alternatives – Parenteral amitriptyline and clomipramine preparations are

available in many countries, but not in the United States. In consultation with the patient's
psychiatrist, consider substitution of another class of agent, such as a selective serotonin
reuptake inhibitor, if it is felt that the tricyclic antidepressant is truly contraindicated.

Selective serotonin reuptake inhibitors

● Benefit/risk – Selective serotonin reuptake inhibitors (SSRIs) may increase bleeding risk
and the consequent need for transfusion with surgery, perhaps because of their effects
on platelet aggregation. Bleeding risk with SSRIs has been documented primarily in
association with antiplatelet or nonsteroidal antiinflammatory drug (NSAID) use [107-
109]. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and
side effects", section on 'Bleeding'.)

Results from several studies differ regarding risk and type of surgery. In the largest
multicenter study (375 hospitals, more than 530,000 patients), after adjusting for multiple
morbidities, patients who received SSRIs had a small increase in risk of perioperative
bleeding (odds ratio [OR] 1.09, 95% CI 1.04-1.15) [110]. A prospective cohort study
involving 767 patients undergoing cardiac, vascular, spinal, and intracranial surgery at
two academic medical centers found that preoperative use of SSRIs was associated with

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a twofold increase (OR = 2.2; 95% CI 1.2-3.98) in exposure to allogeneic hemostatic

blood products in surgical patients at high risk for perioperative bleeding [111].

Smaller studies suggest that the risk in orthopedic surgery is likely to be clinically
insignificant, if present. One retrospective study in total hip arthroplasty patients noted a
statistically significant 95 mL higher mean blood loss in patients on SSRIs compared with
non-serotonergic antidepressants and controls; however, the authors felt this was of
limited clinical significance [112]. An association between bleeding risk and SSRI
continuation in patients undergoing orthopedic surgeries was not found in other studies
that controlled for confounding variables (eg, use of NSAIDs) [113].

Several studies noted no increased risk of bleeding with coronary artery bypass
procedures and with plastic surgery [114-117]. A large metaanalysis found SSRIs to be
associated with an increased risk of transfusion but not an increase in mortality [118].

Stopping SSRIs could lead to exacerbation of mood and other disorders. The washout
period for SSRIs may be as long as three weeks, and reinitiation may not lead to clinical
benefit for several weeks. Half-life varies widely from 15 hours (ie, paroxetine,
fluvoxamine, sertraline) up to seven days (fluoxetine). Abrupt withdrawal of short-acting
SSRIs should be avoided, as it can cause a discontinuation syndrome including
dizziness, chills, muscle aches, and anxiety (see "Discontinuing antidepressant
medications in adults"). Determining whether perioperative continuation or withdrawal of
SSRIs produces a net clinical benefit requires randomized controlled trials.

● Continue/discontinue – For most patients, we recommend continuing SSRI therapy

through the perioperative period. The decision to withhold SSRIs perioperatively should
balance the consequences of bleeding with the severity of the underlying psychiatric
disorder.

For patients undergoing surgical procedures with substantial risks of postoperative

bleeding that could lead to significant morbidity (such as central nervous system
procedures), or in patients requiring ongoing antiplatelet therapy for secondary
prevention (eg, aspirin and thienopyridine for a drug-eluting cardiac stent), consider
discontinuing SSRIs by tapering several weeks prior to surgery and starting an alternative
antidepressant regimen, in consultation with a psychiatrist if possible. Patients with
severe mood disorders and those undergoing surgery with low to moderate risks of
abnormal bleeding should generally be maintained on SSRIs through surgery.

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Antiplatelet agents should be discontinued preoperatively if at all possible in patients

taking SSRIs. If aspirin or thienopyridine therapy is required for secondary prevention
through surgery (eg, presence of a drug-eluting cardiac stent), then the SSRI should be
discontinued in advance of surgery and an alternative antidepressant regimen
considered, in consultation with a psychiatrist if possible.

Selective norepinephrine reuptake inhibitors and bupropion

● Benefit/risk – There are limited data regarding selective norepinephrine reuptake

inhibitor (SNRI) agents in the perioperative period. A retrospective study of 4136 patients
undergoing coronary artery bypass graft (CABG) surgery showed that SNRI use was
associated with an increased risk of renal dysfunction and prolonged ventilation but not
bleeding events or long-term mortality [115]. This has not been replicated in other studies.

No literature exists regarding perioperative considerations with bupropion.

● Continue/discontinue – Considerations regarding cessation versus continuation in the

perioperative period should be similar as with SSRIs. (See 'Selective serotonin reuptake
inhibitors' above.)

Monoamine oxidase inhibitors

● Benefit/risk – Nonselective irreversible monoamine oxidase (MAO) inhibitors for use as

antidepressants (isocarboxazid, pargyline, phenelzine, and tranylcypromine) are
prescribed far less commonly than other antidepressants but are used in patients with
refractory mood disorders in whom withdrawal and recurrent depression may be
problematic. MAO inhibitors are also used for treatment of conditions other than
depression (table 8).

Use of nonselective MAO inhibitors results in the accumulation of biogenic amines in

central and autonomic system neurons. Concomitant administration of sympathomimetic
agents, like ephedrine during anesthesia, can result in massive release of stored
norepinephrine and severe hypertensive crisis. In addition, two types of central nervous
system (CNS) reactions may occur relevant to surgery and anesthesia. The "Type I"
reaction occurs with the administration of anticholinergics (such as dextromethorphan)
and meperidine with MAO inhibitors, leading to a serotonin syndrome (agitation,
headache, fever, and seizures, with possibility of coma and death) [105] (see "Serotonin

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syndrome (serotonin toxicity)"). The "Type II" reaction occurs when the MAO inhibitor
inhibits hepatic microsomal enzymes involved in opiate metabolism, subsequently
leading to accumulation of free narcotic, sedation, respiratory depression, and
cardiovascular collapse [119]. As the use of morphine and fentanyl are recommended to
avoid a Type I reaction, patients continuing MAO inhibitors requiring these opiates should
be monitored closely for CNS depressive effects. Phenelzine may prolong the effect of
succinylcholine. Use with epinephrine-containing local anesthetics is generally safe.

A designated MAO-safe anesthetic technique has been reported for use in patients
unable to discontinue the MAO inhibitor, such as in emergency procedures [120]. This
involves avoidance of meperidine and dextromethorphan and cautious use of only direct
acting intravenous sympathomimetic agents such as norepinephrine, epinephrine,
phenylephrine, and isoproterenol.

● Continue/discontinue – The decision to continue or withhold nonselective MAO

inhibitors before surgery requires close collaboration with the anesthesiologist and
psychiatrist.

MAO inhibitors generally should be continued when two criteria are met: (1) the
anesthesiologist is comfortable with use of MAO-safe procedures; and (2) the psychiatrist
believes temporary withdrawal of the agent will exacerbate or precipitate a depressive
syndrome.

In the absence of either criteria, we recommend discontinuing MAO inhibitors before

surgery. Many MAO inhibitors are irreversible antagonists, and recovery of MAO function
requires two weeks after discontinuation of the drug. Thus, patients should taper and
discontinue MAO inhibitors two weeks before elective surgery. An alternative drug
regimen for depression, such as tricyclic antidepressant or SSRI therapy, may be used
for the perioperative period.

If MAO inhibitors are continued perioperatively, the patient must be prescribed a diet that
excludes foods containing high amounts of tyramine while an inpatient to avoid
precipitating a hypertensive crisis (table 9). Intraoperative and perioperative drug
interactions must be closely monitored. Specific interactions of MAO inhibitors with other
medications may be determined using the Lexicomp drug interactions tool included in
UpToDate.

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Mood stabilizing agents (lithium and valproate)

● Benefit/risk – Lithium has a number of physiologic effects that may be important

perioperatively. Lithium decreases release of neurotransmitters and may prolong the
effect of neuromuscular blockers. Lithium has a narrow therapeutic index, is highly
dependent upon maintained renal function for clearance, and is subject to drug
interactions with diuretics, NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, and
serotoninergic drugs (eg, meperidine, methylene blue, tramadol). Chronic lithium use has
a multitude of effects on the thyroid. (See "Lithium and the thyroid" and "Bipolar disorder
in adults and lithium: Pharmacology, administration, and management of side effects",
section on 'Managing lithium side effects'.)

In addition, nephrogenic diabetes insipidus has been described in up to 20 percent of

patients taking lithium. Patients who have impaired renal concentrating ability maintain
euvolemia and a normal serum sodium through polydipsia. Access to free water may be
impaired during the perioperative period and lead to volume depletion and
hypernatremia. (See "Renal toxicity of lithium".)

Valproate (valproic acid) is another mood stabilizer used in patients with bipolar disorder.
Valproate drug interactions include NSAIDs and some antibiotics. There are no reports
demonstrating problems in patients continuing valproic acid perioperatively.

● Continue/discontinue – Lithium and valproate are used for treatment of serious mental
illness. We therefore recommend continuation of lithium perioperatively with increased
attention to fluid and electrolyte monitoring and a low threshold to check thyroid function
tests before surgery.

We recommend that valproic acid be continued.

Serum levels of lithium and valproate should be monitored regularly. Serum lithium levels
are affected by medications that affect sodium and fluid balance. (See "Bipolar disorder in
adults and lithium: Pharmacology, administration, and management of side effects",
section on 'Laboratory tests and monitoring' and "Bipolar mania and hypomania in adults:
Choosing pharmacotherapy", section on 'Valproate or divalproex'.)

● Formulations/alternatives – Lithium must be temporarily discontinued in patients who

cannot take oral medications since no parenteral substitution is available. Restarting

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enteral lithium (with close monitoring of electrolytes) within 24 hours postoperatively

should avoid the need for alternative pharmacologic coverage.

Valproate sodium is available as a parenteral form. Valproate or second-generation

antipsychotics (eg, risperidone, aripiprazole, olanzapine, or ziprasidone) may be used in
lieu of lithium for patients who cannot take oral medications. (See "Bipolar disorder in
adults: Choosing maintenance treatment".)

Antipsychotics

● Benefit/risk – Antipsychotics are effective in controlling psychoses that may become

problematic in the perioperative period in patients with underlying psychiatric illness.
However, findings from a large observational study indicate that use of antipsychotics,
both typical and atypical, is associated with an increased risk for sudden death [121].
Both typical and atypical antipsychotics may prolong the QT interval and cause
arrhythmia, particularly when coadministered with volatile anesthetic agents or drugs
such as erythromycin, quinolones, amiodarone, and sotalol. (See "First-generation
antipsychotic medications: Pharmacology, administration, and comparative side effects"
and "Second-generation antipsychotic medications: Pharmacology, administration, and
side effects" and "Acquired long QT syndrome: Definitions, causes, and
pathophysiology".)

In a randomized trial of 495 patients at risk for delirium undergoing joint replacement
surgery, olanzapine versus placebo was administered to prevent delirium [122]. The
incidence of delirium decreased from 40 to 1 percent, although those who experienced
delirium in the olanzapine group had more severe and longer-lasting delirium. Resource
use during hospitalization (sitters, consultations) did not decrease. More patients in the
olanzapine arm were discharged to home versus rehabilitation facilities. A randomized
controlled trial in intensive care unit (ICU) patients in China showed that the
administration of prophylactic haloperidol for seven days after noncardiac surgery
significantly decreased the incidence of postoperative delirium, while the mean time to
onset of delirium and the mean number of delirium-free days was significantly longer
[123]. ICU stay was significantly shorter. No difference in mortality or drug-related side
effects was noted. Further studies are needed prior to widespread use of perioperative
antipsychotics for delirium prevention.

● Continue/discontinue – Antipsychotics should be used cautiously in patients at risk for

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exacerbation of psychoses. These agents should be withheld in patients whose baseline

or follow-up electrocardiogram (ECG) demonstrates prolongation of the QT interval.
Shorter-acting and low-dose antipsychotics should be considered, and complete
discontinuation may be preferable after consultation with a psychiatrist. The half-life of
antipsychotics varies widely. Rarely, withdrawal symptoms (eg, nausea, vomiting,
insomnia) or rebound psychoses can occur following abrupt discontinuation.

Antipsychotics may potentiate sedative and hypotensive effects of anesthetics and opiate
analgesics. They variably cause extrapyramidal side effects and, rarely, neuroleptic
malignant syndrome (see "Neuroleptic malignant syndrome") Several antipsychotics
undergo or inhibit CYP2D6 and/or CYP3A4 drug metabolism and thereby can interact
with other drugs used perioperatively (eg, antibiotics, midazolam, ketamine). Parenteral
administration of antipsychotics seems to increase the perioperative risk of additive
sedation, hypotension, or QTc prolongation with other drugs.

● Formulations/alternatives – Many typical antipsychotics are available in short-acting

intramuscular form, with the high-potency agents more likely to cause extrapyramidal
effects and low-potency agents more likely to cause hypotension and sedation. Both
haloperidol decanoate and fluphenazine decanoate are long-acting depot preparations
that are given monthly and every two weeks, respectively. Haloperidol, although not
approved by the US Food and Drug Administration (FDA) for intravenous use, is the most
common intravenous antipsychotic used in the hospital setting. It has minimal
hemodynamic or extrapyramidal side effects [124] and progressive dosing guidelines
have been published for the agitated patient [125,126].

Several parenteral formulations of atypical antipsychotics are available, including short-

acting forms of intramuscular olanzapine and ziprasidone, and a long-acting risperidone
preparation used as a maintenance treatment. Olanzapine and risperidone have an oral
dissolvable tablet formulation that can be used for the patient in need of an antipsychotic
who cannot take oral medication (table 10) [127].

Antianxiety agents

● Benefit/risk – Abrupt withdrawal of chronic benzodiazepines can lead to an excitatory

state with hypertension, agitation, delirium, and seizures. Many of these agents have
active metabolites, and withdrawal can occur several days to weeks after discontinuation.
Withdrawal symptoms can occur in less than 24 hours following abrupt discontinuation of

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chronic alprazolam use. Conversion to an extended release preparation of alprazolam

prior to surgery may be useful for delaying the need for postoperative re-dosing.

In one center, anxiolytic medication use on admission (present in 16 percent of 1846

patients) was associated with a greater risk of postoperative complications after
noncardiac surgery (OR = 1.72, 95% CI: 1.08-2.73) [128]. However, it is uncertain as to
whether the risk was attributable to medication or to the presence of anxiety.

Benzodiazepines are commonly used short-term to relieve preoperative anxiety and are
generally safe, with proper monitoring, in the perioperative period. Additive sedation or
increased tolerance to perioperative anesthetic and sedative agents may be observed.

Buspirone is felt to be safe in the perioperative period; it has been reported to reduce the
shivering threshold intraoperatively in conjunction with dexmedetomidine with minimal
sedation and no respiratory depression [129]. It has a slow onset of effect (ie, weeks) and
does not prevent withdrawal reactions due to discontinuation of benzodiazepines. Due to
its serotoninergic effect, its use with meperidine and tramadol is not recommended.

Continue/discontinue – We recommend that benzodiazepines or buspirone used

chronically for antianxiety or sedative effects be continued perioperatively.

● Formulations/alternatives – Parenteral forms of benzodiazepines are available,

including diazepam and lorazepam. Buspirone is only available in oral formulation;
parenteral benzodiazepines can be substituted if the patient cannot take oral medications
and anxiety is a significant problem. Intravenous administration can cause blood pressure
lability.

Psychostimulants — Psychostimulant medications, used in the treatment of attention deficit

hyperactivity disorder, may increase risk for hypertension and arrhythmias, lower the seizure
threshold, and interact with medications that could be needed in the perioperative period (eg,
vasopressors). There is a risk of sudden blood pressure increase when halogenated
anesthetics are used in conjunction with methylphenidate, and, per drug labeling, the
stimulant should be withheld on the day of surgery.

A case series report of eight patients found no adverse effects when amphetamines were
continued on the day of surgery [130]. However, none of the patients required vasopressor
support.

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● Benefit/risk – Psychostimulants are not associated with adverse effects when

discontinued in the non-abusing patient. Patients generally do not need to be concerned
about alertness on the day of surgery.

● Continue/discontinue – Data are limited but risks are low of temporarily discontinuing
psychostimulant medications. We recommend they be withheld on the day of surgery and
resumed when the patient is stable.

CHRONIC OPIOID THERAPY

Peri- and postoperative pain management in opioid dependent patients (including those
taking buprenorphine and methadone) are discussed elsewhere. (See "Management of acute
perioperative pain", section on 'Opioid-dependent patients'.)

NALTREXONE

● Benefit/risk – Naltrexone is a derivative of oxymorphone that acts as a competitive

antagonist at opioid receptor sites, showing the highest affinity for mu receptors. It
decreases cravings and helps maintain abstinence in opioid addicted patients and is also
used for the treatment of alcoholism [131]. (See "Pharmacotherapy for opioid use
disorder", section on 'Naltrexone'.)

As with buprenorphine, chronic naltrexone use may increase central nervous system
(CNS) opioid receptor concentration, potentially resulting in a transient exaggerated
response to agonists in an acute pain situation.

● Continue/discontinue – Naltrexone should be discontinued (or the intramuscular dose

held) in anticipation of surgery, and a multimodal approach to pain management should
be implemented, including the use of local anesthetics with or without sedation,
nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, corticosteroids, tricyclic
antidepressants, or nerve stabilizers such as gabapentin. Opioids should be used for
acute pain, and agents with a higher affinity for the mu receptor (such as morphine,
fentanyl, or hydromorphone) are recommended. In addition, a "reverse ladder" approach
has been suggested to de-escalate opioid agonist therapy in the postoperative period,
utilizing nonopioid alternatives for pain control in conjunction with resumption of the

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antagonist agent [132].

● Formulations/alternatives – Naltrexone is available in both intramuscular and oral form.

NEUROLOGIC AGENTS

The drugs taken by patients with neurologic disease around the time of surgery are discussed
in detail separately (See "Perioperative care of the surgical patient with neurologic disease".).

RHEUMATOLOGIC AGENTS

Perioperative medication management of patients with rheumatic diseases is discussed in

detail separately. (See "Preoperative evaluation and perioperative management of patients
with rheumatic diseases".)

GOUT THERAPY

● Benefit/risk – Surgery is known to precipitate acute gouty arthropathy [133]. The optimal
management strategy for patients who are maintained on chronic hypouricemic therapy
or colchicine in the perioperative period is unknown. Colchicine has a narrow therapeutic
index and can cause muscle weakness and polyneuropathy in the setting of renal
impairment or drug interactions [134].

● Continue/discontinue – We recommend that colchicine be held on the morning of

surgery and resumed when the patient is able to tolerate oral medications. Allopurinol
can be continued.

● Formulations/alternatives – There are no parenteral substitutions for allopurinol or

probenecid. Parenteral colchicine is no longer available in the United States; it can cause
myelotoxicity, as well as significant skin necrosis if infiltration occurs [135].

Should an acute gouty flare occur in a postoperative patient unable to tolerate oral
medications, intraarticular steroids or systemic steroids can be used. (See "Treatment of
gout flares".)

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MEDICATIONS FOR BENIGN PROSTATIC HYPERTROPHY

● Benefit/risk – Some patients treated with alpha-1-antagonists (eg, terazosin, doxazosin,

tamsulosin, alfuzosin) have developed intraoperative floppy iris syndrome (IFIS), a
condition involving intractable intraoperative iris prolapse with cataract surgery [136-138].

● Continue/discontinue – Patients should be asked about use of alpha-1-antagonists

during the preoperative evaluation. It is not known if discontinuing alpha-1-antagonists
reduces the risk of IFIS; clinical impression is that the drug effect is long-lasting (weeks,
months, or years), and most eye surgeons do not insist that these agents be
discontinued. Various operative regimens can reduce the occurrence of IFIS. It is
important to make sure the surgeon is aware if the patient was receiving such a
medication. Otherwise, these drugs should be continued as they may be beneficial in
preventing postoperative urinary retention. (See "Cataract in adults".)

HERBAL MEDICATIONS

Herbal medications, used frequently, may have effects that could be deleterious in the
perioperative period, including clotting abnormalities and interactions with anesthetics [139].
Clinicians should specifically inquire about herbal medication use in presurgical patients, as
patients often do not readily disclose use.

There is no evidence that herbal medications improve surgical outcomes, and there are
theoretic reasons that these agents may increase perioperative morbidity. For simplicity and
because the purity and nature of some herbal medications is unclear, we recommend
stopping herbal agents at least one week before surgery. (See "Overview of herbal medicine
and dietary supplements".)

A review that examined eight commonly used herbal remedies found the following [140]:

● Ephedra (ma huang) may increase the risk of heart attack and stroke and should be
discontinued at least 24 hours prior to surgery.

● Garlic may increase bleeding risk and should be discontinued at least seven days prior to
surgery.

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● Ginkgo may increase bleeding risk and should be discontinued at least 36 hours prior to
surgery.

● Ginseng lowers blood sugar and may increase bleeding risk and should be discontinued
at least seven days prior to surgery.

● Kava may increase the sedative effect of anesthetics and should be discontinued at least
24 hours prior to surgery. An association between kava use and fatal hepatotoxicity has
been reported. (See "Hepatotoxicity due to herbal medications and dietary
supplements".)

● St. John's wort may diminish the effects of several drugs by induction of cytochrome
P450 enzymes and should be discontinued at least five days prior to surgery.

● Valerian may increase the sedative effect of anesthetics and is associated with
benzodiazepine-like withdrawal. There are no data on preoperative discontinuation.
Ideally it is tapered weeks before surgery; if not, withdrawal is treated with
benzodiazepines.

● Echinacea is associated with allergic reactions and immune stimulation. There are no
data on preoperative discontinuation.

ANTIRETROVIRAL AGENTS

The perioperative management of patients taking antiretroviral agents is discussed separately.

(See "Surgical issues in HIV infection".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Preoperative risk
assessment".)

RECOMMENDATIONS

General recommendations for the management of several medications are summarized as

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follows:

● Cardiovascular agents (table 1)

● Gastrointestinal and pulmonary agents (table 2)
● Estrogen and related hormonal agents (table 3)
● Agents affecting hemostasis (table 6)
● Psychotropic agents (table 7)
● Opioids (see "Management of acute perioperative pain", section on 'Opioid-dependent
patients')
● Neurologic agents (see "Perioperative care of the surgical patient with neurologic
disease")
● Rheumatologic agents (see "Preoperative evaluation and perioperative management of
patients with rheumatic diseases")

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge David

Macpherson, MD, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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