Stopping and Restarting Medications in the Perioperative Period RALPH CYGAN, MD, HOWARD WAITZKIN, MD, PhD WHEN TO STOP a n d w h e n to restart medications are questions frequently a s k e d during the perioperative period. Consultants in internal medicine often receive such questions from their surgical colleagues. Unfortunately, although useful textual materials on this subject h a v e a p p e a r e d during recent years, TM the literature generally is sparse a n d unsystematic. The purpose of this selective review is to present a n analysis of some critical issues involved in decisions about discontinuing a n d resuming medications a n d to offer suggestions about some of the more commonly used agents. In light of the limited literature on these problems, we try to point out those instances w h e n recommendations must r e m a i n tentative a n d w h e n clinicians might r e a s o n a b l y take alternative a p p r o a c h e s . We emphasize the clinical circumstances of the perioperative period, the differing p h a r m a c o l o g y of the a g e n t s considered, a n d the benefits a n d risks of discontinuing specific a g e n t s before surgery. Table 1 presents a s u m m a r y of our recommendations.

ENDOCRINOLOGIC DISORDERS AND MEDICATIONS Diabetes Mellitus Diabetic patients face a series of potential problems in the perioperative period. Hyperglycemia frequently a c c o m p a n i e s the stress of surgery. L 3. 5 G e n e r a l a n e s t h e s i a tends to m a s k hypoglycemic symptoms a n d signs, s, 6 Uncontrolled diabetes c a n result in ketoacidosis, hyperosmolar coma, impairment of w o u n d healing, a n d altered phagocytosis a n d lymphocyte function.7 In the context of surgery, overly tight control should be avoided, since the morbidity of h y p o g l y c e m i a (particularly complications affecting the heart a n d brain) is potentially much more severe t h a n that of mild hyperglycemia. For insulin-dependent diabetics undergoing elective surgery, the classic r e c o m m e n d a t i o n of giving a smaller t h a n usual dose of insulin a n d providing a subsequent infusion of glucose is appropriate, since this a p p r o a c h g e n e r a l l y avoids the h a z a r d s of extreme shifts in blood sugar. Specifically, the patient should receive 50 per cent of the usual dose of intermediate insulin subcutaneously on the morning Receivedfrom the Division of GeneralInternal Medicineand Primary Care, Department of Medicine, University of California, Irvine, Irvine, California. Supported in part by grant PE 19154 from the Divisionof Medicine, U.S. Public Health Service. Address correspondence and reprint requests to Dr. Waitzkin: North Orange County Community Clinic, 300 W. Romneya Drive, Anaheim, CA 92801.

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of surgery, with a continuous infusion of 5 per cent dextrose at a rate of about 2 m l / k g / h r during the intraoperative a n d postoperative periods. ~'3, 8 Situations in which intravenous insulin m a y be n e c e s s a r y usually involve brittle diabetes, urgent surgery in patients with ketoacidosis or hyperosmolar state, a n d diabetic patients who c a n n o t tolerate oral intake for prolonged periods or who a r e nourished by intravenous hyperallmentation.9' ~0 Insulin-dependent patients who u n d e r g o brief, minor procedures u n d e r local a n e s t h e s i a m a y hold their morning insulin dose until after the procedure. This method requires that the procedure occur early in the morning a n d that the patient will be able to resume oral intake following surgery.zz Postoperatively, we r e c o m m e n d that blood sugar should be a s s e s s e d at the bedside every four to six hours. Blood c a n be obtained easily by fingerstick a n d m e a s u r e d by one of a n u m b e r of rapid methods (for example, Dextrostix with a Glucometer, Chemstips, or Visidex strips). Since individual sensitivities to insulin v a r y greatly, particularly during the stress of the perioperative period, careful monitoring of the response to a given dose of insulin is necessary. In general, 5 - 10 units of regular insulin c a n be given for blood sugars in the 13.88-16.65 retool/1 (250-300 mg/dl) range, a n d 10-15 units c a n be given for blood sugars in the 16.65-19.43 mmol/1 (300- 350 mg/dl) range. Diabetic patients who take oral hypoglycemic a g e n t s raise some interesting problems of perioperative m a n a g e m e n t . One of the most commonly used agents, chlorpropamide, h a s a relatively long halflife of about 35 hours. Chlorpropamide should be stopped two to three d a y s before surgery if possible, since h y p o g l y c e m i a with c o m a associated with surgery c a n occur as long as 60 hours after the last dose. Such d e v a s t a t i n g outcomes are predisposed by starvation, renal disease, a n d hepatic dysfunction. *~ Short-acting a g e n t s such as tolazamide a n d tolbutamide h a v e less potential for complications. Their half-life is approximately seven hours, a n d they should be stopped the night before surgery. The n e w e r agents, glyburide (with a ten-hour half-life) a n d glipizide (with a two- to four-hour half-life) also should be discontinued on the night before a surgical procedure. As in insulin-dependent diabetes, a fasting blood sugar level should be m e a s u r e d on the d a y of surgery a n d should be r e p e a t e d every six hours until oral intake resumes. Elevated blood sugars should be treated with regular insulin as outlined above.

TABLE 1

Stopping and Restarting Medications in the Periopertive Period: Summary Medication

1. Endocrinologic A. Diabetes mellitus 1. Insulin 2. Oral hypoglycemics B. Corticosteroids C. Thyroid medications 1. Hypothyroidism 2. Hyperthyroidism D. Estrogens/progestins 1. Oral contraceptives 2. Replacement I1. Cardiac A. Cardiac glycosides B. Antiarrhythmic agents

C. Nitrates D. Diuretics E. Calcium channel blocking agents 111. Antihypertensives A. General

Recommendations*

1/2 dose, intermediate DsW (about 2 ml/kg/hr) Sliding scale Discontinue 1 - 3 days preop ACTH stimulation test Perioperative coverage

Vll. Antiepileptic medications

VIII. Psychotropics A. Antidepressants B. Tranquilizers C. Lithium

13 - 17

33,34

Continue Continue Continue Continue Continue Methyldopa, beta blocker, hydralazine

Vl. Pulmonary medications

Risk of adrenal insufficiency

Limited use as CHF prophylaxis Continue unless toxicity Prophylactic lidocaine if history of VT or complex VPCs Continue digoxin for supraventricular tachyarrhythmias Continue beta blockers unless contraindicated Continue See section lllB below Continue for CAS, severe CAD, CABG

E. F. G. H. I. J.

Nonsteroidal antiinflammatory drugs

12

26-29

Continue

V. Aspirin

Chlorpropamide long-acting

Stop 3 weeks preop Consider DVT prophylaxis May continue

D. Cionidine

IV. Anticoagulants

1,3,8- 11

18-21

C. Beta blockers

Methyidopa Reserpine Prazosin Hydralazine Captopril Choosing an agent

References

No need to delay urgent surgery L-thyroxine long-acting Prepare with antithyroid drug, iodide, and/or beta blocker

Search for nonessential causes (e.g., pheochromocytoma) Achieve diastolic BP < 110 mm Hg Consider discontinuation and fluid expansion 2 days preop Continue

B. Diuretics

Comment

Depends on patient risk and surgical procedure; see text Discontinue at least 7 days preop Discontinue 1 - 2 days preop Continue until surgery, resume postop Continue if for grand mal seizures

Discontinue several days to 1 week preop Taper and discontinue several days preop Taper and discontinue several days preop

1,2,22-25

31 - 3 2

35-41

42 Risk of rebound CAS Potential complications of anesthesia

43-50

Hypertension not established as major independent risk factor for surgery Potential volume depletion and low K

35-37,51

Important risks of discontinuation syndrome Important risks of discontinuation syndrome Long-acting effects Long-acting effects

37,52, 55-61 62-67

Caution with parenteral doses Monitor K

52-56

68 54,69-71 72,73 34,74-79

Potential bleeding and metabolic problems Check bleeding time

80-85

90 Phenobarbital, phenytoin relatively long-acting Primidone, mephobarbital, mesantoin short-acting; coverage needed Avoid IM phenytoin

91

Long-acting; drug interactions; surgical risks Infrequent surgical risks; taper because of withdrawal syndrome Potential perioperative risks

92-96 92,97 92

*Some recommendations are better supported than others by existing literature; see text for details. Abbreviations: CABG = coronary artery bypass graft surgery; CAD = coronary artery disease; CAS = coronary artery spasm; CHF = congestive

heart failure; CNS = central nervous system; DVT = deep venous thrombosis; IM = intramuscular; K = potassium; postop = postoperatively; preop = preoperatively; VPCs = ventricular premature contractions; VT = ventricular tachycardia.

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Patients Taking Corticosteroids Patients w h o are taking corticosteroid medication on a chronic basis present high risks during the perioperative period, because of the danger of adrenal insufficiency. If adrenal suppression is present, serious complications, including hypotension, cardiovascular collapse, and death, are more likely. The degree of adrenal suppression that develops in patients taking corticosteroids depends on a n u m b e r of variables, including dose, timing and route of administration, and duration of therapy. Is In general, patients receiving less than replacement dosage (equivalent to prednisone, 7.5 m g per day) should not manifest adrenal suppression. Treatment with less than 40 m g of prednisone per day or its equivalent for less than seven days usually does not cause a d r e n a l suppression. A l t e r n a t e - d a y t h e r a p y with less t h a n 40 mg of p r e d n i s o n e also is not g e n e r a l l y a s s o c i a t e d with diminished a d r e n a l reserve. 14 On t h e other h a n d , short courses of higher d o s e s of corticosteroids or long courses of lower d o s e s m a y prod u c e suppression, a n d patients m a y require up to nine months after stopping corticosteroids for full rec o v e r y of the h y p o t h a l a m i c - p i t u i t a r y - a d r e n a l axis.iS, ~6 If time permits, o n e c a n e v a l u a t e a d r e n a l res e r v e b y the ACTH stimulation test. This test utilizes 250 mg of synthetic ACTH (cosyntropin), given intramuscularly. P l a s m a cortisol is m e a s u r e d at b a s e l i n e a n d a g a i n 30 to 60 minutes after administration of cosyntropin. An i n c r e m e n t in p l a s m a cortisol of 165 to 550 nmol/1 (6 to 20/~g/dl) or m o r e is n o r m a l a n d suggests complete r e c o v e r y of a d r e n a l reserve. Unfortunately, these d a t a a r e not usually a v a i l a b l e at the time of surgery, a n d the consultant is forced to m a k e r e c o m m e n d a t i o n s b a s e d on a clinical e v a l u a tion of the likelihood of a d r e n a l suppression. In this setting, it is p r o b a b l y safest to a s s u m e that a n y patient w h o h a s b e e n taking corticosteroids in low d o s e chronically or in high d o s e for e v e n short periods h a s a d r e n a l suppression a n d will require p e r i o p e r a t i v e glucocorticoid supplementation. For m a j o r surgical procedures, hydrocortisone sodium succinate or hydrocortisone sodium phospate, 100 rag, is given intravenously or intramuscularly, b e g i n n i n g the night before surgery. This d o s e is r e p e a t e d e v e r y six hours for 24 hours after surgery. Assuming satisfactory p o s t o p e r a t i v e recovery, o n e c a n t a p e r this d o s a g e b y 50 per cent e a c h d a y for the next three days, or until the patient r e s u m e s oral intake. Hydrocortisone, 20 m g or equivalent, is continued p a r e n t e r a l l y or orally twice a d a y until the s e v e n t h p o s t o p e r a t i v e day, w h e n the previous d o s e of oral medication c a n b e resumed. For minor surgical procedures, t r e a t m e n t with p a r e n t e r a l h y d r o c o r tisone usually c a n b e confined to o n e or two d o s e s on the d a y of surgery, with rapid t a p e r i n g to the p r e o p erative d o s a g e if r e c o v e r y is satisfactory. 17

Thyroid Medications For the h y p o t h y r o i d patient w h o is taking L-thyroxine a n d is clinically euthyroid, in principle o n e c a n withhold the medication for a s long a s a week, b e c a u s e of its long half-life of s e v e n days. The d r u g c a n b e r e s t a r t e d orally or p a r e n t e r a l l y after s u r g e r y if n e c e s s a r y . Intraoperatively, hypothyroid patients t e n d to b e sensitive to most drugs a n d therefore often require smaller a m o u n t s of anesthetic a n d a n a l g e s i c medications. I n t r a o p e r a t i v e a n d postoperative m a n a g e m e n t also should include monitoring for hypothermia, hypoventilation, h y p o n a t r e m i a , a n d h y p o g l y c e m i a . While p r e o p e r a t i v e correction of hypothroidism is d e s i r a b l e before elective surgery, there is little e v i d e n c e to justify deferring u r g e n t surg e r y until mild or m o d e r a t e hypothyroidism is corrected.le, lg In e m e r g e n c y s u r g e r y for the s e v e r e l y hypothyroid patient, L-thyroxine should b e given intravenously, with a n initial d o s e of 500 # g followed b y 50 - 100/lg p e r d a y . S o m e authors r e c o m m e n d the addition of p a r e n t e r a l corticosteroids for 24 to 48 hours to c o v e r for possible p i t u i t a r y - a d r e n a l h y p o function.20,21 Hyperthyroidism generally is m u c h more dangerous than hypothyroidism in the perioperative period, because of the possibilities of thyroid storm and systemic complications. Therefore, preoperative preparation of hyperthyroid patients should occur if at all possible, i'2,2~.,2s Antithyroid drugs such as propylthiouracil (PTU), which inhibits the synthesis and conversion of thyroxine to triiodothyronine, should be used at a dosage of 250 m g orally or by nasogastricroute every six hours; an alternative is methimazole, 30-40 m g daily. Together with an antithyroid agent, it is appropriate to use an iodide, which blocks release of hormone from the gland; alternatives are sodium iodide, 250 m g orally or intravenously every six hours, or saturated solution of potassium iodide (SSKI), five drops orally every six hours. These medications usually are given one to three hours after the administration of P T U or methimazole, to prevent thyroid accumulation of iodide that could be used later for synthesis of thyroid hormones. 4 A beta-blocking agent is often useful in conjunction with an antithyroid drug and an iodide, to control the systemic effects of hyperthyroidism. In addition, especially in urgent situations, a beta blocker alone can serve as a rapid, safe, and effective preparation for thyrotoxic patients.~4 A commonly used agent is propranolol, 20-40 m g orally every six hours, or l - 2 m g intravenously every four to six hours. Postoperatively, antithyroid drugs should be restarted again as soon as possible, in the nasogastric or oral dosages noted above. For the hyperthyroid patient w h o is receiving treatment with antithyroid medication and has bec o m e euthyroid, the risks of interrupting treatment briefly during the perioperative period are low.

JOURNALOFGENERALINTERNALMEDICINE, Volume 2

About half of hyperthyroid patients who take antithyroid medications for a y e a r or more remain in remission. Short-term antithyroid treatment for about five months leads to remission for about a third of hyperthyroid patients. 2s The commonly u s e d a g e n t s h a v e short half-lives: two hours for PTU a n d six to 13 hours for methimazole. However, the duration of action of antithyroid medications does not correlate well with p l a s m a levels, but rather correlates with the size of the administered dose a n d the intrathyroidal concentration of the drug. For example, a 30-mg dose of methimazole h a s a duration of action of at least 24 to 36 hours. For the patient taking antithyroid medication who h a s b e c o m e euthyroid, we r e c o m m e n d continuing the medication until the night before surgery a n d resuming it by the oral or nasogastric route if possible by 24 hours after surgery. If such resumption is not possible, the patient should be followed closely for the r e a p p e a r a n c e of hyperthyroidism, which generally would present less d a n g e r o u s a problem postoperatively t h a n intraoperatively.

Estrogens and Progestins A seldom recognized problem c a n arise with patients taking oral contraceptive pills (OCPs). These a g e n t s c a n prolong the central nervous system d e p r e s s a n t actions of m a n y anesthetic a n d analgesic agents, but especially those of meperidine. 2e The m e c h a n i s m probably involves r e d u c e d hepatic metabolism of anesthetic a n d analgesic drugs if given w h e n a patient h a s b e e n taking OCPs. Another interesting issue r e g a r d i n g patients who receive OCPs or hormone replacement t h e r a p y is w h e t h e r they are at increased risk of thromboembolic p h e n o m e n a during the perioperative period. OCPs c a u s e a number of thrombus-promoting c h a n g e s in hemostatic function, including increases in factor VII a n d factor VIII levels a n d d e c r e a s e s in the antithrombin III level. Numerous studies implicate the estrogen component of OCPs a s the principal c a u s e of these hematologic c h a n g e s . Epidemiologic studies h a v e s h o w n a roughly four- to fivefold increase in the risk of thromboembolism in w o m e n who were using OCPs. Although the risk seems greatest in those w o m e n who use OCPs containing more t h a n 100/~g of estrogen, it remains slightly elev a t e d with lower doses as well. 27' 28 In view of this well-established risk of thromboembolic d i s e a s e a n d the possibly additive effects of bed rest a n d postoperative c h a n g e s in clotting function, one should consider discontinuing OCPs prior to elective surgery. How rapidly the risk of thrombosis declines after stopping estrogens is not clear. Therefore, some authors h a v e r e c o m m e n d e d discontinuing OCPs at least three weeks prior to elective surgery. 29 Another form of birth control should be substituted during this time. Postoperatively, the OCP c a n be

(Jul/Aug).

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273

restarted with the next menstrual cycle. When early discontinuation of OCPs before surgery is not possible, we r e c o m m e n d the use of prophylactic minidose h e p a r i n (about 5,000 units subcutaneously every 12 hours), with the aim of reducing the risk of thromboembolism. The situation of p o s t m e n o p a u s a l w o m e n who a r e receiving estrogen or estrogen/progestin replacement t h e r a p y is quite different from that of patients on OCPs. Studies of patients with both natural a n d surgical m e n o p a u s e h a v e failed to find a n y strong or consistent relationship b e t w e e n hormone use a n d i n c r e a s e d risk of thrombosis. 3° Hormone replacement in this setting, whether with estrogens alone or estrogen a n d progestin in combination, does not a p p e a r to induce the s a m e c h a n g e s in coagulation p a r a m e t e r s s e e n in p r e m e n o p a u s a l women. In fact, several studies h a v e shown that replacement t h e r a p y in p o s t m e n o p a u s a l patients tends to e n h a n c e fibrinolytic activity, which m a y protect a g a i n s t thrombus formation, sl' s2 In view of these studies, it does not a p p e a r n e c e s s a r y to discontinue estrogen or estrogen/progestin for postm e n o p a u s a l w o m e n prior to surgery. Of course, w h e n the risk of thrombosis is felt to be increased by other factors, prophylactic m e a s u r e s should be used.

CARDIAC MEDICATIONS Cardiac Glycosides Historically, digitalis h a s b e e n used as a surgical "prophylaxis" in cardiac patients, including those not previously taking the medication, e v e n w h e n they did not h a v e congestive heart failure. The rationale w a s to counteract the myocardial depression s e e n with anesthesia. However, this practice led to problems of digitalis toxicity a n d difficulties with arrhythmias. Currently there a p p e a r s to be little indication for prophylactic digitalis in patients without congestive heart failure who previously were not digitalized. Possible exceptions include patients with past histories of congestive heart failure, who m a y be at g r e a t e r risk, patients with prior supraventricular tachycardias, a n d elderly patients undergoing p n e u m o n e c t o m y (who more commonly experience postoperative supraventricular tachyarrhythmias).Ss Since digoxin c a n be given easily b y the parenteral route, there is no strong r e a s o n except toxicity to withhold digoxin on the d a y of surgery. For appropriate dosing, one should consider the 15 to 20 per cent lower bioavailability of oral as c o m p a r e d with intravenous administration. Because of prior reports suggesting a n increased risk of perioperative arrhythmias in digitalized patients, some clinicians prefer to withhold digoxin during the 12 hours before surgery. 34 In two situations, however, it is important not to interrupt digoxin, e v e n on the d a y of surgery.

Cygan and Waitzkin. PERIOPERATIVEMEDICATIONMANAGEMENT

274

First, digoxin should not be omitted w h e n it is used for rate control, as in rapid atrial fibrillation. Second, digoxin should be continued w h e n it is controlling other supraventricular tachyarrhythmias, such as that associated with the "sick sinus syndrome."

Antiarrhythmic Agents Decisions about antiarrhythmic m a n a g e m e n t in the perioperative period should begin with a careful review of the therapeutic indications for the drug. In g e n e r a l life-threatening a r r h y t h m i a s - - v e n t r i c u l a r tachycardia, frequent a n d / o r multifocal premature ventricular contractions, a n d rapid supraventricular t a c h y c a r d i a s m should be treated during the perioperative period. Patients with less severe rhythm d i s t u r b a n c e s - - i n f r e q u e n t premature atrial or ventricular contractions a n d well-tolerated supraventricular t a c h y c a r d i a s - - generally c a n h a v e their medications discontinued shortly before surgery a n d c a n be monitored expectantly; there is no evid e n c e that the suppression of such arrhythmias reduces surgical morbidity or mortality.35-38 Quinidine, used to treat both supraventricular a n d ventricular arrhythmias, h a s a half-life of five to nine hours. Quinidine's interaction with digoxin a n d its potential to depress myocardial contractility should be taken into account in the perioperative period. We r e c o m m e n d giving the last dose of quinidine on the night prior to surgery a n d substituting intravenous lidocaine either prophylactically or in the event that significant ventricular arrhythmias develop intraoperatively. For supraventricular arrhythmias, intravenous propranolol or verapamil c a n be substituted. Postoperatively, quinidine c a n be restarted as soon as the patient resumes oral intake. Like quinidine, procainamide c a n depress m y o c a r d i a l contractility a n d c a n c a u s e hypotension, especially w h e n given intravenously. Procainamide's half-life varies m a r k e d l y a m o n g patients but generally is b e t w e e n four a n d six hours. As with quinidine, the last oral dose should be given the night before surgery, a n d ventricular arrhythrnias should be treated with intravenous p r o c a l n a m i d e or lidocaine. Again, propranolol or verapamfl c a n be u s e d to treat poorly tolerated supraventricular arrhythmias if they develop. Disopyramide, with a six- to nine-hour half-life, exerts negative inotropic effects that are especially troublesome for patients with preexisting congestive heart failure. Anticholinergic side effects, including constipation a n d urinary retention, heighten the perioperative risks associated with this drug. For these reasons, we r e c o m m e n d discontinuing disop y r a m i d e on the night before surgery a n d treaating the arrhythmia with intravenous lidocaine as appropriate.

Tocainide is a n oral agent, similar to lidocaine, that recently h a s g a i n e d a p p r o v a l for the treatment of ventricular arrhythmias. Its half-life is 12 to 16 hours. This drug is potentially useful in patients with severe ventricular arrhythmias that a r e unresponsive to more conventional oral antiarrhythmics, sg' 40 Tocainide does not significantly depress myocardial contractility. During the perioperative period, one a p p r o a c h is to continue the drug until the night before surgery a n d then to substitute intravenous lidoc a i n e as n e c e s s a r y . Alternatively, a dose c a n be given with a sip of w a t e r on the morning of surgery, with the hope of maintaining a therapeutic blood level. Postoperatively, if the patient continues to take nothing by mouth after the first day, intravenous lid o c a i n e c a n be used until the patient resumes oral intake. The perioperative m a n a g e m e n t of beta blockers is discussed in the section on antihypertensive a g e n t s below. Amiodarone possesses a number of important properties which should be kept in mind in m a n a g ing the perioperative patient. 4~As a noncompetitive adrenergic-blocking agent, a m i o d a r o n e prolongs atrial a n d ventricular action potential durations a n d produces c o r o n a r y vasodilation. It h a s a very long duration of action, 30 to 60 days, b e c a u s e of extensive fat deposition. It is u s e d in patients with lifethreatening ventricular a n d supraventricular arrhythmias, including recurrent ventricular fibrillation. Because of its m e c h a n i s m of action, a m i o d a r o n e c a n produce myocardial depression, atropine-resistant b r a d y c a r d i a , a n d peripheral vasodflatation. Its adrenergic-blocking effects c a n antagonize the action of adrenergic agonists a n d c a n necessitate the use of larger t h a n s t a n d a r d doses in the event of perioperative hypotension or c a r d i a c arrest. Since most patients who receive this drug h a v e life-threatening arrhythmias, the drug should be continued until the night before surgery. The exceptionally long half-life of a m i o d a r o n e should provide effective antiarrhythmic protection throughout the perioperative period. It c a n be restarted w h e n the patient is able to tolerate oral intake. No intravenous form of a m i o d a r o n e is available. If perioperative arrhythmias develop, conventional intravenous drugs should be used. The only calcium c h a n n e l blocking a g e n t currently a p p r o v e d for use as a n antiarrhythmic is verapamil, which is effective in the treatment of paroxy s m a l atrial tachycardia, atrial fibrillation, a n d atrial flutter. Verapamfl h a s a half-life of three to s e v e n hours. As a result of extensive first-pass hepatic metabolism, the oral dose n e e d s to be about eight to ten times larger t h a n the intravenous dose to produce a c o m p a r a b l e p l a s m a level. Patients who h a v e b e e n treated with verapamil for significant su-

JOURNALOF GENERALINTERNALMEDICINE. Volume Z (Jul/Aug), 1987

praventricular arrhythmias c a n receive the usual dose of the drug with a sip of w a t e r on the morning of surgery. If arrhythmias occur perioperatively, intravenous verapamil m a y be given as a bolus (10 mg) or as a continuous infusion (0.005 m g / k g / m i n ) until the patient resumes oral intake. Intravenous verapamil c a n c a u s e hypotension, b r a d y c a r d i a , a n d occasional ventricular asystole, especially in the prese n c e of beta blockade; these complications should be kept in mind w h e n e v e r use of this drug is considered. s9 We present additional comments on calcium c h a n n e l a g e n t s in a s e p a r a t e section below.

Nitrates For patients with c o r o n a r y artery d i s e a s e who a r e m a i n t a i n e d on nitrates, nitroglycerine should be given during the entire perioperative period, unless unusual circumstances are present. Nitroglycerine ointment is useful intraoperatively a n d postoperatively, a n d should be applied to achieve continuous coverage. Intravenous nitrates are a n alternative but are difficult to administer without invasive hemod y n a m i c monitoring. The hypotensive effects of nitrates generally should not be a disincentive to their use in perioperative m a n a g e m e n t , in view of their protective effects in ischemic disease. 42

Diuretic Agents These drugs are considered in the section on antihypertensive agents.

Calcium Channel Blocking Agents Additive h e m o d y n a m i c d e p r e s s a n t effects a r e s e e n w h e n calcium c h a n n e l blockers such as verapamil, nifedipine, a n d diltiazem a r e used in combination with inhalational anesthetic a g e n t s such as halothane, isoflurane, or enflurane. During anesthesia, nifedipine exerts a predominantly vasodflating effect, while verapamil tends to depress m y o c a r d i a l contractility as well. Verapamfl also m a y interfere with atrioventricular conduction in anesthetized patients, as shown by prolongation of the PR interval on electrocardiogram. Regarding narcotics, both verapamil a n d nifedipine a p p e a r to d e c r e a s e blood pressure a n d peripheral vascular resistance w h e n narcotics a r e used during anesthesia. Verapamfl a n d nifedipine also potentiate the effects of both depolarizing a n d nondepolarizing neuromuscular blocking drugs, although the clinical significance of this observation remains to be established. 4s' 44 At this time, there is little useful experience concerning the discontinuation of calcium c h a n n e l blockers in the perioperative period. During recent years, considerable sensitivity to the d a n g e r s of abrupt discontinuation h a s arisen, especially in relation to the b e t a blockers a n d other antihyperten-

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sive agents, a s discussed below. The possibility of increased ischemia, infarction, a n d hypertension after discontinuation of calcium c h a n n e l blockers should be t a k e n seriously, e v e n though only a few observations of this p h e n o m e n o n h a v e b e e n m a d e . 4s-48 For this reason, despite the complexities of a n e s t h e s i a in the face of calcium c h a n n e l blockers,49, 5o we r e c o m m e n d continuing them during the entire perioperative period for patients with c o r o n a r y artery spasm, those with severe coronary artery disease, a n d those who a r e undergoing coron a r y artery b y p a s s surgery. Calcium c h a n n e l blockers should be given on the d a y of surgery a n d at regular intervals thereafter, with equivalent oral or p a r e n t e r a l doses, or with sublingual nffedipine (usually 10 mg every four to six hours). For patients without c o r o n a r y artery s p a s m or severe c o r o n a r y artery disease, calcium c h a n n e l blockers should be continued until the night before surgery a n d res u m e d a s soon a s the patient begins oral intake. If e v i d e n c e of rebound vasospasm, such as R a y n a u d ' s phenomenon, hypertension, or chest pain, occurs, intravenous verapamil or sublingual nifedipine c a n be used as outlined above.

ANTIHYPERTENSIVE AGENTS General Considerations In the studies of G o l d m a n a n d colleagues, high blood pressure w a s not clearly correlated with a d v e r s e surgical outcomes. They h a v e a r g u e d that there a r e no d o c u m e n t e d negative cardiac effects from surgery with uncomplicated a n d untreated hypertension w h e n the preoperative diastolic blood pressure is <- 1 i0 m m Hg. sT' 51However, w h e n hypertension h a s produced e n d - o r g a n effects (manifested by congestive heart failure or renal failure with a blood u r e a greater t h a n 17.85 mmol/1 (50 mg/dl) a n d / o r a creatinine greater t h a n 265 /lmol/1 (3 mg/dl), the probability of a d v e r s e cardiac outcome in the perioperative period increases significantly.SS, s8 From this work, it seems clear that mild or e v e n m o d e r a t e hypertension in itself poses little perioperative risk, unless other major c a r d i a c risk factors a r e present. For this reason, prior r e c o m m e n d a tions to a c h i e v e strict control of blood pressure n e e d careful reconsideration, especially in view of the negative c o n s e q u e n c e s of some antihypertensive medication in the perioperative period. Several g e n e r a l recommendations seem appropriate. It is n e c e s s a r y to screen for surgically correctable c a u s e s of hypertension through a careful history a n d physical examination. One crucial concern in the preoperative evaluation is the rare possibility of u n d i a g n o s e d pheochromocytoma, which c a n l e a d to perioperative mortality of more than 50 per cent if it remains undetected w h e n surgery is done. It is advisable to a c h i e v e a d e q u a t e preopera-

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tive control of hypertension, which m a y be defined as diastolic pressure < 110 mm Hg. Aggressive attempts to lower the diastolic pressure to below 110 m m Hg a r e difficult to justify from the existing literature. s* The a d e q u a c y of control should be b a s e d on a series of blood pressure readings over 12 to 24 hours. Since hurried attempts at controlling hypertension c a n result in d e h y d r a t i o n a n d wide swings in blood pressure perioperatively, elective surgery might best be postponed until outpatient control h a s b e e n achieved.

Diuretics Several observations point to d a n g e r s of diuretic treatment in the perioperative period. These considerations, which a r e seldom recognized, a r e important since practitioners use diuretics so commonly for the treatment of hypertension, s2 For example, diuretics reduce still further the a l r e a d y r e d u c e d p l a s m a volume that is frequently s e e n in patients with essential hypertension. This p h e n o m e n o n complicates the usual intraoperative a n d postoperative effective volume loss b e c a u s e of transudation, "third spacing" (especially in a b d o m i n a l surgery), a n d related effects. 53 In addition to the problem of volume depletion, diuretics c a n l e a d to hypokalemia. As Hall notes in a comprehensive review, there are at least three reasons w h y h y p o k a l e m i a is undesirable during surgery. 5~-First, h y p o k a l e m i a tends to potentiate the effects of muscle relaxants by raising the resting m e m b r a n e potential (RMP) of cells. With a n increase in RMP, h y p o k a l e m i a also c a n l e a d to a relative resistance to the usual action of acetylcholine. In short, h y p o k a l e m i a m a y simulate the effects of lowdose muscle relaxants. Outcomes m a y include prolonged a p n e a a n d overresponsiveness to muscle relaxants u s e d during anesthesia. Second, h y p o k a l e m i a increases the probability of cardiac arrhythmias. 52. 54. ss Atrial premature contractions a n d ventricular premature contractions a r e the most common, but h y p o k a l e m i a also is associated with a variety of other rhythm disturbances, including atrial flutter, atrioventricular conduction defects, ventricular tachycardia, a n d ventricular fibrillation. Hypokalemia sensitizes the m y o c a r d i u m to the arrhythmogenic effects of cardiac glycosides a n d e x a c e r b a t e s rhythm disturbances connected with digitalis toxicity. In addition, h y p o k a l e m i a tends to increase the risk of succinylcholine-induced c a r d i a c arrhythmias. Third, h y p o k a l e m i a heightens the likelihood of paralytic fleus, s2 When h y p o k a l e m i a is present, abdominal distention a n d d e c r e a s e d bowel sounds m a y be observed without frank intestinal obstruction. Such signs m a y be confused with postoperative peritonitis or intestinal obstruction itself.

Volume depletion a n d h y p o k a l e m i a thus c a n l e a d to major problems in perioperative m a n a g e ment. Diuretics as antihypertensive a g e n t s c a n exacerbate volume depletion a n d c a n c a u s e hypokalemia. The risks of diuretics c a n be h e i g h t e n e d by the vasodilating effects of anesthetic agents, as well as other medications such as calcium c h a n n e l blockers, nitrates, synergistic antihypertensive drugs, a n d psychotropic agents. These issues h a v e led us to r e c o m m e n d that discontinuation of diuretics at least 48 hours before elective surgery be considered. Such a recommendation (which we a c k n o w l e d g e is s o m e w h a t different from common practice currently) is applicable especially for patients with prior tendencies toward volume depletion a n d / o r hypokalemia, s-56 Temporarfly withholding diuretics is not appropriate for all patients. However, we believe that consulting internists at least should caution about the risks of volume depletion a n d h y p o k a l e m i a in patients m a i n t a i n e d on chronic diuretic therapy, a n d should r e c o m m e n d preoperative replacement of volume a n d potassium as appropriate. Beta Blockers Beta blockers are the most common class of drugs associated with the "discontinuation syndrome." A similar s y n d r o m e also h a s b e e n reported after the discontinuation of clonidine, methyldopa, reserpine, a n d saralasin. Clinically, the s y n d r o m e involves increased nervousness, anxiety, palpitations, a b d o m i n a l pain, n a u s e a a n d vomiting, h e a d ache, a n d insomnia. These symptoms m a y present in a variety of combinations. The signs a n d complications of discontinuation s y n d r o m e include rapidly increasing hypertension, a n g i n a pectoris, a n d occasional m y o c a r d i a l infarction. Studies of betablocker discontinuation s y n d r o m e in hypertensive patients reveal that mild symptoms a r e common (about 43 per cent), while patients with severe coron a r y artery d i s e a s e c a n experience unstable angina (25 per cent), acute myocardial infarction (10 per cent), s u d d e n d e a t h (5 per cent), a n d arrhythmias (2 per cent)Y In the 1970s there w a s considerable d e b a t e about stopping beta blockers preoperatively. 37, 52. 58. s9 Observations of patients with coronary artery dise a s e who received propranolol until the d a y of surg e r y s h o w e d some e v i d e n c e of m y o c a r d i a l depression, intraoperative congestive heart failure, hypotension, b r a d y a r r h y t h m i a s , a n d d e c r e a s e d responsiveness to sympathomimetic amines. For these reasons, a r e c o m m e n d a t i o n w a s put forward that b e t a blockers should be withdrawn preoperatively. During recent years, however, this earlier recomm e n d a t i o n h a s completely reversed. Later reports s h o w e d no increased risk of continuing propranolol

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until the time of surgery, s°' s~ Abrupt discontinuation of propranolol actually i n c r e a s e d the probability of arrhythmias, a n g i n a pectoris, m y o c a r d i a l infarction, a n d d e a t h in patients with coronary artery disease. Certain positive effects of the beta blockers during the perioperative period also h a v e b e e n noted. The b e t a blockers tend to prevent arrhythmias provoked by catecholamines, especially during e n d o t r a c h e a l intubation or surgical manipulation. The cardiovascular response to hypoxia remains intact with the b e t a blockers. In addition, propranolol releases erythrocyte-membrane-bound 2,3-DPG a n d thus shifts the o x y g e n dissociation curve to the right, facilitating delivery of o x y g e n to tissues. For all these reasons, it is prudent to continue beta blockers during the entire perioperative period, especially for those patients in w h o m the conseq u e n c e s of the withdrawal s y n d r o m e would be most dangerous. These high-risk patients include those who h a v e histories of severe hypertension a n d coron a r y artery disease. For example, the p l a s m a halflife of propranolol is three to six hours. Assuming that surgery takes place in the morning, one c a n give the last preoperative dose of oral propranolol b e t w e e n 10 PM on the evening before surgery a n d 8 AMon the d a y of surgery. For those patients who will remain NPO for more t h a n 24 hours postoperatively, propranolol m a y be given either intermittently by boluses or by continuous infusion. The intermittent technique uses propranolol in doses of 0.25 to 0.5 rag, to as much as 2 to 5 mg every four hours. An alternative method is a continuous infusion of propranolol (3 m g per hour in the a b s e n c e of significant hepatic or renal dysfunction, or 2 mg per hour if either problem is present). W h e n oral intake is resumed, the usual oral d o s a g e of beta blocker c a n be substituted.

Clonidine Severe problems c a n arise after the abrupt discontinuation of clonidine, e2-Se Mild symptoms are s e e n in as m a n y as 36 per cent of patients, while rebound hypertension occurs less often, usually with daffy doses e x c e e d i n g 0.8 r a g . 57 Various reports h a v e d o c u m e n t e d rapidly increasing hypertension w h e n clonidine is discontinued on the d a y prior to surgery. Another difficulty is that p a r e n t e r a l clonidine is not generally available in the United States. A r e a s o n a b l e r e c o m m e n d a t i o n is to continue oral clonidine without interruption on the morning of surgery. The order to give clonidine at that time should contradict the "NPO after midnight" order. Until the patient c a n resume oral medication postoperatively, a n o t h e r appropriate parenteral antihypertensive a g e n t should be used. Parenteral methyldopa, which h a s a similar m e c h a n i s m of action, would be a good substitute in this situation. The treatment of

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rapidly increasing hypertension after clonidine withdrawal h a s included methyldopa, nitroprusside, a n d phentolamine. Transdermal administration of clonidine m a y alleviate the problems of discontinuation, but currently there is no substantial literature on its use in the perioperative period, s7

Methyldopa In patients receiving chronic m e t h y l d o p a therapy, a residual pressure-lowering effect m a y persist for 48 hours or more after its discontinuation, es Therefore, a n acute increase in blood pressure is not typically observed on the d a y of surgery in patients who h a v e received the usual dose on the evening before surgery. A morning dose generally is not necessary, but the treatment should be resumed, by the p a r e n t e r a l route if necessary, during the early postoperative period.

Reserpine During the 1960s, concern w a s expressed reg a r d i n g impaired circulatory responses during surg e r y in patients taking reserpine. These problems included hypotension, poor response to vasopressors, a n d b r a d y c a r d i a , sg' 70 Therefore, a n early reco m m e n d a t i o n w a s m a d e to discontinue Rauwolfia compounds ten to 14 d a y s preoperatively. However, later studies h a v e found that circulatory reflexes generally r e m a i n intact during the perioperative period in patients on chronic reserpine therapy, a n d the risk of hypotension is not appreciably greater, s4. 71 Currently there a p p e a r s to be no n e e d to discontinue reserpine earlier t h a n the d a y before surgery if blood pressure is controlled. The drug should be res u m e d postoperatively as the patient's blood pressure a n d overall condition warrant.

Prazosin The literature is extremely sparse in r e g a r d to this alpha-blocking agent, which c a u s e s selective inhibition of the postsynaptic alpha-1 receptors. No major a d v e r s e effects h a v e b e e n reported with anesthesia a n d surgery. For this reason, a n appropria t e r e c o m m e n d a t i o n is to continue prazosin a s usual until the d a y before surgery a n d to resume it as the patient's condition w a r r a n t s during the postoperative period.

Hydralazine To avoid reflex tachycardia, h y d r a l a z i n e often is prescribed with a sympatholytic a g e n t or a b e t a blocker. The hypotensive effect of h y d r a l a z i n e generally lasts 18 to 24 hours after discontinuation. Especially w h e n it is used with beta blockers, h y d r a l a zine should be continued until the d a y before surgery a n d should be r e s u m e d postoperatively by

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the oral route w h e n possible. Caution should be used with equivalent parenteral doses, which a r e much smaller t h a n oral doses; typical p a r e n t e r a l doses a r e in the r a n g e s of 10 to 20 mg every two to four hours.

Captopril This drug is a vasodilator u s e d in the treatment of hypertension a n d as a n afterload reducer in severe congestive heart failure. Its m e c h a n i s m of action involves inhibition of angiotensin-converting e n z y m e a n d effects o n vasoactive peptides. Diuretics, nitrates, a n d other vasodflators h a v e a n additive effect with captopril; alone or in combination with these agents, captopril c a n predispose to intraoperative hypotension which is responsive to volume expansion. Captopril also c a n elevate serum potassium b e c a u s e of its inhibition of the r e n i n a n g i o t e n s i n - a l d o s t e r o n e axis. Although such elevations of potassium a r e usually mild, severe hyperkalemia h a s been s e e n w h e n potassium supplements, potassium-sparing diuretics, or nonsteroidal antiinflammatory drugs h a v e b e e n u s e d in conjunction with captopril. 7z 7s In addition, e n d o g e nous potassium loads from tissue necrosis, acidosis, hemolysis, or acute renal failure in the perioperative period could l e a d to major problems with h y p e r k a lemia. Rebound hypertension following abrupt discontinuation of captopril h a s not b e e n described. Therefore, it seems prudent to give the last preoperative dose of captopril on the night before surgery, to check the potassium level, a n d to resume the medication as soon as the patient c a n tolerate oral intake.

Choosing an Agent For the untreated patient with hypertension, which a g e n t should be chosen? As noted earlier, the risk of untreated hypertension in the perioperative a n d postoperative periods h a s not b e e n demonstrated for diastolic pressures - 110 m m Hg. Diuretic t h e r a p y a p p e a r s not to be completely appropriate preoperatively b e c a u s e of volume depletion a n d hypokalemia. In addition, diuretics usually require d a y s to weeks for optimal blood pressure control. Methyldopa does a p p e a r to be a suitable a g e n t u n d e r most circumstances, a s s u m i n g liver function is normal. Hydralazine also is a n a c c e p t a b l e agent; b e c a u s e of reflex c a r d i a c stimulation, beta blockers also should be considered with hydralazine. Beta blockers a r e appropriate w h e n there is no contraindication (including bronchospasm, congestive h e a r t failure, diabetes mellitus, b r a d y c a r d i a , heart block, or extensive peripheral vascular disease). For patients with severe hypertension n e e d i n g control for w h o m oral medications c a n n o t be used, potent parenteral a g e n t s are available; these include nitro-

prusside, nitroglycerine, hydralazine, methyldopa, diazoxide, a n d phentolamine.

ANTICOAGULANTS The perioperative m a n a g e m e n t of patients who a r e taking oral anticoagulants is a challenging task. A n u m b e r of factors to be considered in m a k i n g decisions include: the indication for anticoagulant therapy, the site a n d extent of surgery, the u r g e n c y of surgery, a n d the p r e s e n c e of a n y contributing medical problems a n d / o r drugs that affect the risk of bleeding. In general, the probability of thrornboembolism is highest in patients with prosthetic heart valves, atrial fibrillation a n d / o r a large left atrium with prior emboli, or recurrent d e e p venous thrombosis a n d / o r p u l m o n a r y embolism. A m o n g patients who h a v e prosthetic valves, the greatest risk of perioperative thromboembolism h a s b e e n a s s o c i a t e d with mitral valve prostheses, particularly the older uncovered caged-baU a n d caged-disc valves, a n d the risk is i n c r e a s e d in the p r e s e n c e of atrial fibillation a n d a n e n l a r g e d left atrium. The risk a p p e a r s to be less in patients who h a v e isolated aortic valves a n d the n e w e r mitral xenografts, although published d a t a on the perioperative m a n a g e m e n t of xenografts a r e lacking. 74-77 Less risk of thromboembolism also is s e e n in those patients being treated with anticoagulants for cerebrovascular disease, remote venous thrombosis a n d / o r p u l m o n a r y embolism, or history of m y o c a r d i a l infarction. M a n y minor surgical procedures, such as dental extractions or soft tissue biopsy, a n d invasive diagnostic procedures, such a s arteriography, carry only minimal risk of hemorrhagic complications, e v e n in the p r e s e n c e of therapeutic anticoagulation. 76. 78 On the other hand, for certain neurosurgical, ophthalmologic, a n d plastic surgical procedures, a n y inc r e a s e d risk of h e m o r r h a g e is unacceptable. For most other major procedures, the risk posed by perioperative bleeding is intermediate. For a particular patient, the internist a n d surgeon must review the specific risks of the proposed procedure a n d be willing to alter r e c o m m e n d a t i o n s appropriately. The following g e n e r a l recommendations m which categorize patients according to the u r g e n c y of surgery a n d the risk of thrombosis m c a n be m a d e , b a s e d on available literature a n d the authors' experience, s4, 74 For elective or e m e r g e n c y m i n o r procedures (such as dental extractions), patients at high risk of thrombosis should continue full-dose anticoagulation. Depending on the circumstances, patients at intermediate or low risk of thrombosis m a y also continue anticoagulants, or m a y discontinue them two or three d a y s before the procedure a n d resume them afterward. In e m e r g e n c y m a j o r procedures, anticoagulation in high-risk patients should be reversed with

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intravenous vitamin K or fresh frozen p l a s m a until the prothrombin time is normal or within 2 - 3 seconds of control. The precise goal will d e p e n d on the risk of hemorrhage, a n d the difficulties of re-anticoagulating if too much vitamin K is given should be recognized. 79In high-risk patients, full-dose intravenous h e p a r i n should begin about 12 hours after surgery, following consultation with the surgeon. Oral anticoagulants should be restarted three to five d a y s after the procedure or w h e n the patient resumes oral intake. For intermediate- or low-risk patients, m a n a g e m e n t is similar, except there is less n e e d to start full-dose h e p a r i n if the patient c a n resume anticoagulants three to five d a y s postoperatively. However, if the patient continues to take nothing by mouth b e y o n d three to five days, one should consider starting h e p a r i n at that point. For elective major procedures, high-risk patients should discontinue oral anticoagulants one or two d a y s preoperatively; if necessary, anticoagulation should be further reversed with intravenous vitamin K to a c h i e v e a normal or n e a r normal (within 2 - 3 seconds of control) prothrombin time. Following surgery, full-dose intravenous heparin t h e r a p y should be started as outlined above. With the intermediate- or low-risk patient, oral anticoagulation should be discontinued two to three d a y s preoperatively. Prothrombin time should be monitored a n d corrected to normal or n e a r normal with p a r e n t e r a l vitamin K. Oral anticoagulation m a y be restarted three to five d a y s postoperatively, or heparin should be initiated if the patient cannot resume oral intake.

ASPIRIN AND NONSTEROIDAL ANTllNFLAMMATORY DRUGS Aspirin impairs platelet function by irreversibly acetylating the e n z y m e cyclooxygenase, thereby inhibiting the synthesis of thromboxane A2, a plateleta g g r e g a t i n g prostaglandin. This effect c a n be ind u c e d by as little as one 325-mg tablet a n d is m a x i m a l with only four tablets per d a y . The irreversible effect on a g g r e g a t i o n takes four to seven d a y s to be corrected by the synthesis of n e w platelets. W h e n one considers the large number of patients who take aspirin, the risk of perioperative h e m o r r h a g e associated with this drug a p p e a r s to be quite low. s° However, others h a v e found a significant increase in blood loss a n d a t t e n d a n t morbidity following dental extraction, facial plastic surgery, tonsillectomy, a n d c a r d i o p u l m o n a r y bypass, s~-ss In general, we recomm e n d discontinuation of aspirin at lest s e v e n d a y s prior to elective surgical procedures, particularly w h e r e normal hemostasis is crucial. For e m e r g e n c y surgery, a bleeding time should be c h e c k e d preoperatively. The operation should be d e l a y e d if possible a n d platelet transfusion given ff the bleeding time is significantly prolonged.

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Other nonsteroidal antiinflammatory drugs (such as indomethacin, ibuprofen, a n d so forth) also c a u s e a defect in platelet aggregation. However, this effect is more readily reversible t h a n with aspirin, a n d significant bleeding resulting from these drugs is rare. Most of the a g e n t s h a v e short half-lives a n d c a n be stopped one or two d a y s prior to surgery. Aspirin a n d nonsteroidal antiinflammatory drugs also put patients at g r e a t e r risk of renal failure a n d hyperkalemia, especially in the setting of hypotension, dehydration, or tissue necrosis, se~s9This observation provides a n additional rationale for discontinuing these a g e n t s preoperatively.

PULMONARY MEDICATIONS Although there is a d e a r t h of literature on stopping a n d restarting pulmonary medications in the perioperative period, certain features of these medications are clinically important. As noted above, patients taking steroids preoperatively n e e d special evaluation a n d c o v e r a g e for a d r e n a l suppression. Oral theophylline h a s a half-life of about four hours but h a s effects that c a n last as long as 16 hours in some patients. Intravenous aminophynine c a n c a u s e arrhythmias a n d seizures w h e n given in excessive d o s a g e or at a rapid rate. Inhaled anesthetic a g e n t s m a y e n h a n c e the arrhythmogenic effects of the theophyllines, a n d interactions with drugs such as erythromycin a n d cimetidine also m a y l e a d to theophylline toxicity. Beta-adrenergic a g e n t s c a n contribute to c a r d i a c irritability associated with surg e r y a n d anesthesia. For m a n y patients who h a v e obstructive lung disease, preoperative a n d postoperative treatment with aminophyUine a n d beta-adrenergic drugs c a n help reduce the pulmonary risks of surgery. °° However, w h e n such a g e n t s a r e continued during the perioperative period, the theophylline level should be checked preoperatively if possible, a n d patients should be monitored closely for toxicity. Generally, in patients with a d v a n c e d obstructive disease, one should cautiously continue theophylline a n d / o r beta-adrenergic medications until the time of surgery. If warranted, parenteral doses c a n be used intraoperatively a n d postoperatively until oral intake is resumed.

ANTIEPILEPTIC MEDICATIONS G r a n d real (major motor) seizures c a n increase the risks of surgery substantially. Considerable morbidity m a y fonow g r a n d mal seizures in the perioperative period a n d m a y include pulmonary aspiration, w o u n d dehiscence, a n d disruption of r e d u c e d fractures or prostheses. On the other hand, neither petit real nor focal seizures appreciably increase the risk

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of surgery a n d anesthesia. As a g e n e r a l principle, ff control of epilepsy h a s b e e n a d e q u a t e during the y e a r before surgery, it is u n n e c e s s a r y to m e a s u r e blood levels of antiepileptic medications or to r e p e a t a n electroencephalogram. The patient should continue to receive antiepileptic medication, parenterally if necessary. However, if control h a s b e e n poor or if seizures reflect ethanol withdrawal, surgery should be postponed if feasible. 9! In p l a n n i n g perioperative m a n a g e m e n t , it is important to consider the p h a r m a c o l o g y of specific antiepfleptic agents. Because phenytoin h a s a half-life of 12 to 24 hours, one dose c a n be omitted safely. If the patient c a n n o t take oral medication for more t h a n 12 hours, equivalent intravenous doses should be substituted. Slow intravenous administration of phenytoin is essential, at a rate not to e x c e e d 50 mg per minute. Intramuscular administration should be a v o i d e d b e c a u s e of irregular absorption. Phenytoin's m a i n t e n a n c e dose generally is 100 mg e v e r y six hours. For phenobarbital, with a half-life of 12 to 96 hours, one or p e r h a p s two doses c a n be missed. Replacement of oral phenobarbital c a n be given b y either the intravenous or the intramuscular route, usually with a dose of 30-60 mg three times a day, b a s e d on prior therapeutic levels. Primidone, mephobarbital, a n d mesantoin all h a v e short half-lives of six to 12 hours a n d therefore should not be omitted, since a missed dose c a n result in seizures. No parenteral form of these a g e n t s is readily available. For these reasons, phenobarbital a n d / o r phenytoin should be substituted for these drugs, preferably on the night before surgery. (Although phenobarbital is a n active metabolite of primidone, additional covera g e with phenobarbital is w a r r a n t e d to maintain suitable therapeutic levels.) C a r b a m a z e p i n e , valproic acid, a n d c l o n a z e p a m often are prescribed for petit mal or focal seizures, in which c a s e their omission in the perioperative period is not critical. However, if they are used to prevent g r a n d real seizures, their half-lives a n d the lack of suitable parenteral formulations justify c o v e r a g e with phenobarbital or phenytoin.

PSYCHOTROPIC AGENTS Psychotropic preparations d e m a n d close attention during the perioperative period. They pose a series of risks a n d potential difficulties in m a n a g e ment. These problems particularly include drug interactions a n d common complications of the drugs that surgery a n d a n e s t h e s i a c a n exacerbate.

Antidepressants The tricyclic antidepressants manifest a number of important drug interactions a n d related problems. 9~-95For example, they h a v e a r e d u c e d antidepressant effect w h e n used with barbiturates; they

diminish the antihypertensive effects of clonidine a n d guanethidine; they d e c r e a s e the antiparkinsonian effect of n-dopa; they increase the risk of phenytoin toxicity; a n d they e n h a n c e the probability of hypertensive crisis with sympathomimetic amines. The tricyclics c a n c a u s e difficulties with anesthetic a g e n t s that h a v e anticholinergic or sympathomimetic properties, e v e n local a g e n t s that are combined with epinephrine. The tricyclics also inc r e a s e the responses to central nervous system depressants such as ethanol, barbiturates, a n d hypnotic agents. Although the frequency of drug interactions with the tricyclic antidepressants h a s not b e e n established, there are numerous c a s e reports documenting serious sequelae, including death, hypertensive crisis, hyperthermia, a n d stroke. 9e Because of this risk, we r e c o m m e n d that tricyclics should be stopped a w e e k before surgery if possible a n d restarted w h e n the patient is stabilized postoperatively. Such a course of action b e a r s little h a z a r d of worsening depression during the postoperative period. 92 The m o n o a m i n e oxidase (MAO) inhibitors a r e in some w a y s e v e n more d a n g e r o u s t h a n the tricyclics. A variety of common drugs manifest important interactions with the MAO inhibitors. For instance, the MAO inhibitors c a n increase the hypoglycemic effects of oral hypoglycemic agents; they c a n precipitate hypertensive crisis w h e n given in combination with L-dopa or the sympathomimetic amines; a n d they c a n c a u s e either severe hypertension or hypotension w h e n u s e d with meperidine. Although the frequency of perioperative complications with MAO inhibitors h a s b e e n questioned recently, 93 a reasonable r e c o m m e n d a t i o n is to discontinue MAO inhibitors about a w e e k before surgery a n d to resume them as appropriate w h e n the patient is stable postoperatively. If surgery is urgent, anesthetic a g e n t s a n d other medications should be given with caution to the patient who h a s b e e n taking MAO inhibitors. 92

Tranquilizers The phenothiazines, butyrophenones, a n d benzodiazepines h a v e relatively long half-lives. They generally continue to act for a d a y or more w h e n they a r e discontinued. During the perioperative period, they c a n create problems with hypotension a n d myocardial depression in patients with heart disease. Postural hypotension also c a n occur a n d c a n c a u s e difficulties in surgery requiring unusual positions, although this problem is less likely if a patient h a s b e e n taking a tranquilizing a g e n t for a long period of time. While such problems arise infrequently, w e r e c o m m e n d discontinuing tranquilizing a g e n t s several d a y s preoperatively a n d resuming them as n e e d e d on the second or third postoperative day, if the patient's cardiovascular status is stable. The frequently observed withdrawal s y n d r o m e following

JOURNALOFGENERALINTERNALMEDICINE,Volume 2 (Jul/Aug), 1987

the discontinuation of benzodiazepines justifies a tapering dose, if the regular dose is not to be r e s u m e d after surgery. 92'97

Lithium This widely used drug raises some complex issues for perioperative m a n a g e m e n t , although little helpful literature on this subject is available. Lithium tends to c a u s e sodium retention, increased intravascular volume, a n d congestive heart failure in patients with limited c a r d i a c reserve. It also elicits renal a n d thyroid toxicities in some patients. ~ For all these reasons, increased care should be exerted during a n e s t h e s i a with patients taking lithium. A suitable r e c o m m e n d a t i o n about discontinuing lithium is not entirely clear from the literature. In general, lithium probably should be t a p e r e d a n d discontinued ff possible several d a y s before surgery a n d should be r e s u m e d postoperatively w h e n the patient is able to take oral medication.

CONCLUSION Although questions about stopping a n d restarting medications during the perioperative period arise frequently, this issue h a s received little systematic attention. We h a v e considered this problem selectively, in relation to frequently used drugs. A few g e n e r a l recommendations are appropriate in conclusion. First, it is important to consider the potential complications of drugs that a patient h a s b e e n taking preoperatively. Even if a patient h a s not yet experienced such complications, the stress of anesthesia a n d surgery m a y precipitate them. When these problems a r e likely to be serious, it is worthwhile to consider discontinuing the medication with e n o u g h l e a d time that its effects will not be present at the time of surgery. This decision, of course, should be w e i g h e d a g a i n s t the risk of e x a c e r b a t i n g the condition for which the medication w a s prescribed. Second, the importance of the discontinuation s y n d r o m e cannot be overemphasized. M a n y drugs c a u s e serious complications w h e n they are abruptly discontinued. This difficulty, which h a s attracted attention only recently, h a s arisen especially with beta-blocking medications a n d certain other antihypertensive agents. W h e n the possibility of serious a d v e r s e c o n s e q u e n c e s exists a n d w h e n sufficient l e a d time is present, such drugs should be t a p e r e d as appropriate a n d alternative drugs substituted if possible. If surgery is urgent, the drugs should be continued during the entire perioperative period. Dosa g e s both before a n d after surgery should take into account the kinetics of the specific agents. Third, careful attention must be paid to the possibility of drug interactions. M a n y commonly used medications interact in major or minor w a y s with

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drugs that predictably m a y be e m p l o y e d for perioperative m a n a g e m e n t . Anesthetic a g e n t s a n d analgesics m a y b e c o m e especially problematic in the p r e s e n c e of other drugs that m a y be n e c e s s a r y to continue. In this situation, judicious decisions about tapering or withholding medications m a y be required. Such decisions should be b a s e d in large part on patients' underlying d i s e a s e processes a n d the h a z a r d s of discontinuation. The rationale for stopping a n d restarting drugs in the perioperative period deserves considerably more basic a n d clinical research. This issue also calls for closer collaboration a m o n g surgeons, anesthesiologists, a n d their consultants in internal medicine a n d clinical pharmacology. The authorsthank Mr. StephenClancyand Ms. SusanRussellfor excellentbibliographicassistance.

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ANNOUNCEMENT A M E R S A , the A s s o c i a t i o n for M e d i c a l E d u c a t i o n a n d R e s e a r c h in S u b s t a n c e A b u s e , a n n o u n c e s its 1987 n a t i o n a l c o n f e r e n c e on m e d i c a l e d u c a t i o n a n d r e s e a r c h in d r u g a n d a l c o h o l a b u s e , c o s p o n s o r e d b y SGIM. The c o n f e r e n c e will b e held: November 1 0 - 1 3 , 1987 at the Crowne Plaza Hotel, Rockville, Maryland Convenient to the NIH Campus and Washington, D.C. P r o g r a m highlights include: • • • • • •

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A d v a n c e s in Drug Addiction R e s e a r c h A d v a n c e s in Alcoholism R e s e a r c h S h o w c a s e P r e s e n t a t i o n s of Promising E d u c a t i o n a l P r o g r a m s Teaching Videotapes Scientific P a p e r s S m a l l G r o u p Discussion

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