Management of Medications in the Perioperative Period:An Evidence Based Approach

Eric J Milie, D.O.

Medical Consultant

Primary role: understand the patient and his/ her diseases

Medications: to continue or not? Need to understand risk/ benefit of

continuing or holding a medication

Medical Consultant continued

Medications thought to increase the risk of surgical complications that are not essential for short term improvement in quality of life should be held in the perioperative period

Muluk V, Macpherson DS. Perioperative medication management. UpToDate Online

Case 1

A 28 year old female patient scheduled for a wisdom tooth extraction has a history of migraines, for which she takes Fiorinol (aspirin, caffeine, and butalbitol) almost daily.

When to Discontinue Aspirin

Irreversible inhibitor of of platelet cyclo-oxygenase

Leads to increased intraoperative blood loss and transfusion requirements¹

CABG, Peripheral vascular surgeries: increased in hospital mortality with aspirin withdrawal²’³

1. Taggart DP, Siddiqui A, Wheatley DJ. Low dose preoperative aspirin therapy, postoperative blood loss, and transfusion requirements. Snn Thorac Surg 1990; 50:424-428.

2. Mangano DT. Aspirin and mortality from cornoary bypass surgery. NEJM 2002; 347:1309-1317.

Dacey LJ, et al. Effect of preoperative aspirin use on mortality in coronary artery bypass grafting patients. Ann Thorac Surg 2000; 70:1986-1990.

3. Nelipovitz DT, et al. The effect of perioperative aspirin therapy in peripheral vascular surgery: a decision analysis. Anesth Annalg 2001;93:573-580

Case 1 continued

Aspirin should be withheld before surgery in which perioperative hemorrhage could be catastrophic (CNS surgery)

Circulating platelet pool replaced every 7-10 days

Cheng A, Zaas A. The Osler Medical Handbook. St Louis, MO:C.V.Mosby; 2003:518-519.

Case 2

A 68 year old woman with severe osteoarthritis is scheduled for a total hip replacement. She takes acetaminophen and ibuprofen for her arthritis, and she is also receiving postmenopausal hormone replacement therapy (HRT).

Case 2 continued

Acetaminophen relatively safe Little bleeding risk Can be continued safely in patients

undergoing surgery

Case 2 continued

NSAID usageReversible inhibitors of platelet cyclo-oxygenase

Can induce renal failure, especially in the face of ACE inhibitors, particularly in the setting of hypotension and dehydration (common in perioperative period)

Generally accepted to hold 3 days before surgery (no evidence to support this)¹

Goldenberg NA, Jacobson L, Manco-Johnson MJ. Brief communication: duration of platelet dysfunction after a 7-day course of ibuprofen. Ann Int Med 2005; 142:506-509.

Case 2 continued

HRTHeart and Estrogen/progestin Replacement Study (HERS) 2000

Postmenopausal HRT increases risk for DVT and PE in women with CAD¹

Risk increased after lower extremity fracture

Risk magnified after surgery, and remained elevated for 3 months post-op

General consensus is to hold for 4 weeks preop

HERS study evaluated only women with known CAD; routine discontinuation of HRT for noncardiac surgery controversial

Recent case-control study with 108 cases and 210 controls found no association between HRT and venous thromboembolism²

1. Grady D, Wenger NK, Herrington D et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Int Med 2000; 132:689-696.

2. Hurdanek JG, Jaffer AK, Morra N, Brotman DJ. Postmenopausal hormone replacement and venous thromboembolism following hip and knee arthroplasty. Thromb Haemost 2004; 92:337-343.

Key findings of HERS trial of hormone replacement therapy and venous thromboembolic risk♦HRT increased risk of VTE 2.7-fold overall

♦HRT increased risk of VTE 18-fold in patients with lower

extremity fracture

♦HRT increased risk of VTE approximately 5-fold in the 90

days following inpatient surgery

♦HRT increased risk of VTE 5.7-fold in the 90 days following

hospitalization

Case 3

A 64 year old man with a history of stable angina, congestive heart failure, ventricular tachycardia, and COPD is scheduled for inguinal hernia repair.

Case 3: Med List

Digoxin 0.125 mg Atenolol 50 mg Atorvastatin 40 mg Amiodarone 100 mg Furosemide 40 mg Clopidogrel 75 mg Lisinopril 10 mg “Inhalers”

Case 3 continued

Clopidogrel

Nitrates, Digoxin, Clonidine, Beta Blockers, Calcium Channel Blockers, and Antiarrhythmic drugs

Irreversible platelet inhibitor

Discontinue 7-10 days prior to major surgery

Essentially safe to continue perioperatively

For patients who cannot take PO and therapy cannot be interrupted, consider transdermal or intravenous routes of administration

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Diuretics, ACE Inhibitors, ARBS

Non-statin cholesterol medications

consensus recommendation to hold the AM of surgery, especially if given for CHF¹

If indication is HTN and patient hypertensive, may be used at physician discretion

Risk of renal failure with ACEI/ARB usage and induction from anesthesia²

Carry theoretical risk of rhabdomyalysis and myositis

No impact of short-term cardiovascular mortality

Hold 1 day before surgery 1. Coriat P, Richer C, Douraki T, et al. Influence of chronic angiotensin converting enzyme inhibition on anesthetic induction. Anesthesiology 1994; 81:299-307.

2. Brabant SM, Bertrand M, Eyraud D, Darmon PL, Coriat P. the hemodynamic effects of anesthetic induction in vascular surgical patients chronically treated with angiotensin II receptor antagonists. Anesth Analg, 1999; 89:1388-1392.

Case 3 continued

StatinsMay prevent vascular events through mechanisms other than cholesterol reduction

Benefit lost with statin discontinuation

Animal models suggest statin discontinuation may promote pro-thrombotic state

Proposed mechanisms for protection include anti-inflammatory properties and clot adherence

Durazzo AE, Machado FS, Ikeoka DT et al. Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. J Vasc Surg 2004; 39:967-975.

Lindenauer PK, Pekow P, Wang K, Guiterrez B, Benjamin EM. Lipid-lowering therapy and in-hospital mortality following major noncardiac surgery. JAMA 2004; 291:2092-2099.

Poldermans D, Bax JJ, Kertai MD, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003; 107:1848-1851.

Perioperative recommendations for common cardiovascular drugsDrug/ Drug Category Recommendations

Clopidogrel Discontinue 7-10 days before major surgery (irreversible antiplatelet effect)

Nitrates, Digoxin, Clonidine, β-blocker, CCB, Antiarrhythmics

Continue up to and including day of surgery, particularly clonidine and β-blockers. Consider IV or transdermal route if PO not option

Diuretics, ACEI, ARB Hold on morning of surgery, especially if indication is heart failure

Niacin, Fibric acid derivatives, Cholestyramine, Colestipol

Hold at least 1 day prior to surgery

Statins Continue in perioperative period

Case 3 continued

Theophylline

Other Pulmonary Medications

Pulmonary Medications

No data regarding the role of theophylline in the perioperative period

Generally held, beginning the evening prior to surgery, secondary to its potential toxicities and pro-arrhythmic properties

Inhaled agents should be continued throughout the perioperative period, may reduce perioperative pulmonay complications

Leukotriene inhibitors should be given the morning of surgery and resumed when the patient tolerates oral medications

Kroenke, K, Lawrence, VA, Theroux, JF, et al. Operative risk in patients with severe obstructive pulmonary disease. Arch Intern Med 1992; 152:967

Lawrence, VA, Cornell, JE, Smetana, GW. Strategies to Reduce Postoperative Pulmonary Complications after noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern Med 2006;144:596.

Case 4

A 44 year old man is referred for medical clearance for elective total R knee replacement. His medical history is significant for known CAD, with drug eluting stent placed 8 weeks ago.

Case 4 continued

Medication ListAspirin 81mg

Plavix 75mg

Atenolol 50mg

Atorvastatin 40mg

Recommendations???

Case 4 continued

ß-blocker and statin discussed already- continue both

Question comes from antiplatelt agents

Mounting evidence to suggest premature discontinuation of antiplatelet agent leads to increased mortality¹ ²

1. Ferrari, E, Benhamou, M, Cerboni, P, Marcel, B. Coronary syndromes following aspirin withdrawal. A special risk for late stent thrombosis. J Am Coll Cardiol 2005; 45:456.

2. Kaluza, GL, Joseph, J, Lee, JR, et al. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000; 35:1288.

Case 4 continued

Paclitaxel-eluting stent: minimum 6 months of uninterrupted antiplatelet therapy

Sirolimus-eluting stent: minimum 3 months uninterrupted antiplatelt therapy

Eagle, KA, Guyton, RA, Davidoff, R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation 2004; 110:e340.

Case 4 continued

Additional Factors: Surgery is prothrombotic state

True incidence of stent thrombosis and post-op MI in patients undergoing noncardiac surgery is unknown

Most surgeons will not operate on patients currently taking antiplatelet therapy

More research underway

Surgery is elective: delay until completed course of antiplatelet

If surgery urgent or nonelective, needs to be managed on case by case basis

Case 5

A 72 year old white male presents with a diabetic foot infection which has not healed, despite six weeks of IV antibiotics. His diabetes is managed with both oral medications and insulin. He is scheduled to undergo amputation tomorrow.

Case 5 continued

Medication ListNPH Insulin 20U in AM, 10U in PM

Lispro 8U with meals

Metformin 1000mg BID

Actos 30mg daily

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InsulinCurrent consensus supports giving long acting insulin at half normal dosing

For long, complicated procedures, insulin infusion superior to subcutaneous insulin¹

Safety of continuous infusion well established, less variability than “sliding scale”

Peters, A, Kerner, W. Perioperative management of the diabetic patient. Exp Clin Endocrinol Diabetes 1995; 103:213.

Pezzarossa, A, Taddei, F, Cimicchi, MC, et al. Perioperative management of diabetic subjects. Subcutaneous versus intravenous insulin administration during glucose-potassium infusion. Diabetes Care 1988; 11:52.

van den Berghe, G, Wouters, P, Weekers, F, et al. Intensive insulin therapy in the surgical intensive care unit. N Engl J Med 2001; 345:1359.

Case 5 continued

Oral Medications¹Metformin: held two days prior to surgery secondary to increased risk of lactic acidosis

Other oral agents: held morning of surgery to prevent hypoglycemia in the post-operative period

Jacober, SJ, Sowers, JR. An update on perioperative management of diabetes. Arch Intern Med 1999; 159:2405.

In general, patients with type 2 diabetes who need to undergo surgery should be triaged to the first surgical cases of the day so as not to become too hypo- or hyperglycemic

Case 6

A 36 year old woman with severe depression is scheduled for a mastectomy for breast cancer.

Case 6 continued

MedicationsFluoxetine

Olanzapine

lorazepam

Case 6 continued

SSRIsMay increase need for transfusions during surgery because of effect on platelet aggregation¹

Long washout period (3 weeks) and little effect with reinitiation for weeks could lead to exacerbation in depression, mood disorder

Patients in whom bleeding could be catastrophic (CNS procedures) should have sufficient washout; all others generally recommend continuation of medication

Movig, KL, Janssen, MW, de Waal, Malefijt J, et al. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med 2003; 163:2354

Case 6 continued

Tricyclic AntidepressantsMay potentiate proarrhythmic state in perioperative period in presence of volatile anesthetics¹

Abrupt withdrawal leads to insomnia, sweating, nausea, increased salivation, and sweating

General consensus is to continue through perioperative period²

1. Depaulo, JR, Barker, LR. Affective disorders. In: Barker, LR, Burton, JR, Zieve, PD (Eds), Principles of Ambulatory Medicine, Baltimore, Williams and Wilkins, 1995, pp. 166-166.

2. Kroenke, K, Gooby-Toedt, D, Jackson, JL. Chronic medications in the perioperative period. South Med J 1998; 91:358.

Case 6 continued

MAOIsIntraoperative exposure to ephedrine can lead to hypertensive crisis

Perioperative exposure to meperidine or dextromethorphan can lead to serotonin syndrome¹

MAO-safe anesthetic techniques exist for patients requiring emergency surgery²

If psychiatrist feels medication necessary and anesthesiologist comfortable, may be continued

In general, MAOI should be discontinued 2 weeks prior to elective surgery

1. Mason, PJ, Morris, VA, Balcezak, TJ. Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore) 2000; 79:201.

2. Stack, CG, Rogers, P, Linter, SP. Monoamine oxidase inhibitors and anaesthesia. A review. Br J Anaesth 1988; 60:222

Case 6 continued

Benzodiazepines

Antipsychotics

Very safe in perioperative period, and abrupt withdrawal may lead to agitation, mood exacerbation, so continued throughout perioperative course

Remote reports of antipsychotic associated arrhythmias, but none reported in perioperative period¹

Continue throughout perioperative period

Whitwam, JG, Russell, WJ. The acute cardiovascular changes and adrenergic blockade by droperidol in man. Br J Anaesth 1971; 43:581

Case 7

A 75 year old female presents to the office for clearance to undergo a total right hip replacement. She has a history significant for hypertension, osteoporosis, and osteoarthritis.

Case 7 continued

MedicationsMetoprolol

HCTZ

Alendronate

Ginko Baloba

Echinacea

How do we manage the herbal products?

Case 7 continued

Ang-Lee, Moss, and Yuan looked at 8 commonly used herbals in the perioperative setting¹

General consensus is to discontinue herbals prior to surgery because of potential deleterious effects

1. Ang-Lee, MK, Moss, J, Yuan, CS. Herbal medicines and perioperative care. JAMA 2001; 286:208.

Case 7 continued

Ginko

Ginseng

Garlic

THE THREE ‘G’s

Can cause bleeding through inhibition of platelet-activating factor. D/C at least 36 hours prior to surgery

Inhibits platelet aggregation (potentially irreversible), increases risk of hypoglycemia, and inhibits warfarin’s anticoagulation activity. D/C 7 days prior to surgery

Inhibits platelet aggregation (potentially irreversible), may promote fibrinolysis, and has antihypertensive activity. Should be discontinued at least 7 days prior to surgery

Case 7 continued

Ephedra (ma huang)

Echinacea

Kava

Increased risk of heart attack, stroke, and hemodynamic instability

D/C 24 hours prior to surgery

Potential for immune system dysfunction and allergic reactions secondary to its effect on cell-mediated immunity

Limited perioperative data; general consensus is to discontinue 24 hours prior to surgery

Increases sedative effect of anesthetic; D/C 24 hours pre-op

FDA warning about fatal hepatotoxicity

Case 7 continued

St. John’s Wort

Valerian

Many potential drug-drug interactions through induction of cytochrome P-450 enzymes

D/C 5 days prior to surgery

Sedative pharmacologic effect; may increase effect of anesthesia

Ideally tapered weeks prior to surgery, as there is benzodiazepine-like withdrawal

Withdrawal symptoms treated with benzo’s

Perioperative data limited

Case 7 continued

What about vitamins????Many surgical patients are likely taking vitamins¹

Multivitamins safe perioperatively

Vitamin E: associated with increased risk of bleeding, D/C 10 days prior to surgery

Kaye, AD, Clarke, RC, Sabar, R, et al. Herbal medicines: current trends in anesthesiology practice--a hospital survey. J

Clin Anesth 2000; 12:468.

Case 8

A 58 year-old female is scheduled to undergo laproscopic cholecystectomy in 2 weeks. She has a history significant for rheumatoid arthritis. Her medications include methotrexate and hydroxychloroquine.

Recommendations??

Case 8 continued

Hydroxychloroquine

Methotrexate

Few potential side effects

Can be safely continued in perioperative period if patient taking oral meds

Limited data

No increase in infection rate in patients who continue to take methotrexate¹

Continue in the face of normal renal function

Rosandich, PA, Kelley JT, 3rd, Conn, DL. Perioperative management of patients with rheumatoid arthritis in the era of biologic response modifiers. Curr Opin Rheumatol 2004; 16:192.

Case 8 continued

Sulfasalazine/ Azothiaprine

Leflunamide

Hold one week prior to surgery, resume after surgery

Hold two weeks prior to surgery, resume after surgery

Case 8 continued

GlucocorticoidsPatients taking 5 to 20 mg/day of prednisone or its equivalent for more than three weeks may or may not have suppression of the HPA axis

In patients whose HPA axis status is uncertain, one can give glucocorticoids perioperatively or, if time permits, test for the responsiveness of the adrenal to ACTH stimulation

HPA axis suppression should be assumed to be present in patients taking prednisone at a dose greater than 20 mg/day for three weeks or more, and in patients with a Cushingoid appearance

Salem, M, Tainsh, RE, Bromberg, J, et al. Perioperative glucocorticoid coverage: a reassessment 42 years after the emergence of a problem. Ann Surg 1994; 219:416.

Shaw, M, Mandell, BF. Perioperative management of selected problems in patients with rheumatic diseases. Rheum Dis Clin North Am 1999; 25:623.

Case 8 continued

Glucocorticoids continuedFor minor procedures or surgery under local anesthesia (eg, inguinal hernia repair) take usual morning steroid dose. No extra supplementation is necessary

For moderate surgical stress (eg, lower extremity revascularization, total joint replacement) take usual morning steroid dose. Give 50 mg hydrocortisone intravenously just before the procedure and 25 mg of hydrocortisone every 8 hours for 24 hours. Resume usual dose thereafter

For major surgical stress (eg, esophagogastrectomy, total proctocolectomy) take usual am steroid dose. Give 100mg of intravenous hydrocortisone before induction of anesthesia, and 50mg every 8 hours for 24 hours. Taper dose by half per day to maintenance level