426 / Advanced Therapy in Gastroenterology and Liver Disease this can frequently be accomplished using oral rehydration solutions (ORSs). Some patients with severe diarrhea may have normal absorptive function retained, and oral rehy- dration or replacement can be effective in them. Because n utrient absorption is coupled with sodium absorption, glu- cose or amino acids in combination with sodium can enhance the absorption of electrolytes and water.It is impor- tant to remember that standard ORSs are primarily designed to increase electrolyte and fluid absorption and may not reduce stool output , and, in fact, stool output may increase. The World Health Organization’s (WHO) ORS recommendation con- tains sodium (90 mmol/L), potassium (20 mmol/L), chlo- ride (80 mmol/L), citrate (30 mmol/L), and glucose (111 mmol/L). This is prepared by adding 3.5 g of sodium chlo- ride, 1.5 g of potassium chloride, 2.9 g of trisodium citrate dihydrate, and 20 g of glucose per liter of water. Rice-based ORSs have been shown to not only increase absorption but also to decrease stool volume. Most sport drinks, such as Gatorade, are designed to replenish electrolytes primarily lost from sweat and do not have enough sodium to fully replace diarrheal sodium loss. Commercial solutions avail- able that approximate the WHO’s ORS include Resol, Ricalyte, Ceralyte, Pedialyte, and Rehydralyte. INTRAVENOUS REPLACEMENT In patients with severe diarrhea, such as frequently occurs with VIPomas, with the need to adequately correct the dehy- dration, hypokalemia, and metabolic alkalosis, the fluid and electrolyte replacement needs to be given intravenously.This can be accomplished by using parenteral hyperalimentation or administration of saline solutions supplemented with potassium and sodium bicarbonate. Restoration of hydra- tion and electrolytes can best be monitored by serial assess- me nt o f serum electrolytes and urine output. Pharmacologic Control of SD A number of different agents are used to control acute and long-term chronic diarrhea. As pointed out above, defini- tive treatment requires a correct diagnosis. In this section, the general use of pharmacologic agents in SD is dealt with, and in the following section, specific comments on some of the specific diseases are made. Opiates and synthetic long-acting somatostatin analogues (octreotide, lanreotide) are the most commonly used. Other agents that may be helpful are ␣ 2 -adrenergic agonists, corticosteroids, absorbent agents, prostaglandin synthetase inhibitors, cal- cium channel blockers, and phenothiazines. The use of each is briefly discussed below. Opiates Opiates are usually the first-line therapy for most mild to moderate diarrheas. Commonly used preparations include paregoric, tincture of opium, codeine, Lomotil (diphenoxylate with atropine), Imodium (loperamide), and difenoxin with atropine. These agents inhibit transit throughout the gas- trointestinal (GI) tract; therefore, they increase the contact t ime between intestinal luminal contents and the mucosa, increasing absorption. Experimentally, opiates have proab- sorptive and antisecretory effects, but it is unclear if these mechanisms are operative in humans. Synthetic opioids such as Lomotil (2.5 mg diphenoxylate plus 25 µg atropine per tablet) and loperamide (Imodium) (2 mg/tablet) have fewer central nervous system (CNS) side effects than morphine. The recommended doses are as follows: 1. Loperamide, 2 to 4 mg 4 times daily 2. Diphenyloxylate plus atropine, 1 to 2 tablets 4 times daily 3. Codeine, 30 to 60 mg 4 times daily 4. Paregoric (0.4 mg morphine/mL), 5 to 10 mL 4 times daily 5. Tincture of opium (10 mg morphine/mL), 5 to 20 drops 4 times daily All of these drugs except loperamide are controlled substances because of their potential for misuse or addiction. At high doses, Lomotil can also cause CNS side effects, whereas lop- eramide, because it does not cross the blood-brain barrier as efficiently, has fewer side effects at higher doses. The main side effects from the use of opiates are abdom- inal discomfort, constipation, nausea, vomiting, and CNS symptoms (drowsiness, respiratory depression, and altered mental status). Lomotil, because of the presence of atropine, can cause anticholinergic side effects. Physical dependence can occur with prolonged use, although it is reduced with Lomotil by combining the diphenoxylate with atropine. Long-Acting Somatostatin Analogues Octreotide and lanreotide are synthetic analogues of somato- statin that, because they are much more resistant to degra- dation than native somatostatin, have a much longer duration of action than native somatostatin and therefore can be used by intermittent subcutaneous injection. Like native somatostatin, these synthetic analogues suppress most intesti- nal secretions (gastric, pancreatic, biliary, intestinal), inhibit release of most GI hormones and neurotransmitters, and can inhibit GI motility. At present, only octreotide is available in the United States. Octreotide is the drug of choice for most large-volume, severe diarrheas. Numerous studies have demonstrated its effectiveness in VIPomas and diarrhea cause d by car cinoid syndrome . These somatostatin analogues inhibit both the ectopic release of hormones and neuro- transmitters by these tumors and secretion from the large and smal l intestine stimulated by a number of agents (prostaglandin E 1 , serotonin, VIP); they also stimulate sodium chloride absorption in animal studies. Because of these a ctions, somatostatin analogues have been used to treat Secretory Diarrhea / 427 a number of secretory and nonsecretory diarrheal condi- tions, both hormonally and nonhormonally mediated. These include, in addition to VIPomas, carcinoid syndrome, medullary thyroid carcinomas, glucagonomas, diarrhea asso- c iated with acquired i mmune deficiency syndrome (A IDS ) , diarrhea owing to short bowel syndrome, diarrhea owing to dumping syndrome, and diarrhea owing to chemotherapy or bone marrow transplantation treatments. The specific use of octreotide in the various secretory hormonal diarrheas is discussed in the following section on these specific diseases. Octreotide use is also discussed in the chapters on AIDS (see Chapter 46,“Gastrointestinal and Nutritional Complications of HIV Infection”), short bowel syndrome (see Chapter 64, “Short Bowel Syndrome”), and stem cell transplantation (see Chapter 48,“Gastrointestinal and Hepatic Complications of Stem Cell Transplantation”). O CTREOTIDE Treatment with somatostatin analogues is usually lim- ited to severe diarrheas or those refractory to other treat- ments because of its cost and because parenteral administration is required (Farthing, 2002). The usual starting dose of octreotide, which is the only synthetic analogue available in the United States, is 50 to 100 µg 2 to 4 times a day administered subcutaneously. The dose and frequency can then be titrated to control the symp- toms. Doses as high as 750 µg 3 times daily have been used. The half-life of octreotide is 100 minutes compared with 2 to 3 minutes for native somatostatin, and octreotide has been shown to be 70-fold more potent than native somatostatin at inhibiting growth hormone release and 80-fold more potent at inhibiting acid secre- tion. There have been a small number of reports of cases in w hic h intermittent subcutaneous administration is not effective and a continuous infusion of octreotide is more effective. With continued treatment, octreotide may become less effective and increased dosage is fre- quently required (Fried, 1999). Recently, a long-acting formulation of octreotide (octreotide-LAR [long-acting release]) has become avail- able. This formulation is administered once per month intramuscularly. Three dosage forms are available, includ- ing 10, 20, and 30 mg formulations.We usually begin with the 20 mg formulation in a patient in whom extended con- trol of the SD will be required and who responds to the subcutaneous formulation. It is important to continue the subcutaneous formulation for at least 2 weeks after start- ing the o ctreotide-LAR because it takes that long to reach appropriate blood levels with the long-acting form. In patients with carcinoid syndrome or VIPomas, even after octreotide-LAR has been given for a number of months, it may have to be supplemented with subcutaneous octreotide periodically for acceptable symptom control (Szilagyi and Shrier, 2001). The side effects of treatment with synthetic somato- statin analogues include cramping or nausea, which usu- ally resolve with continued treatment, and pain at the subcutaneous injection site, which may be reduced by slow i njection and warming the vial. Worsening of glucose tol- erance develops in some patients, and it is advisable to obtain a serum glucose determination when beginning the medication. A small percentage of patients may develop fat malabsorption. Long term, the principal side effect is the development of biliary sludge or gallstones, thought to be due to the ability of somatostatin to inhibit gallbladder emptying. In various studies with long-term treatment, 10 to 50% of patients have developed biliary sludge or gall- stones, but in only 1 to 10% is it symptomatic. With long- term treatment, an ultrasound examination of the gallbladder before the treatment and every 6 to 12 months should be considered (Redfern and Fortuner, 1995). ␣ 2 -Adrenergic Agents CLONIDINE These agents slow GI transit as well as promote absorption. Clonidine is the frequently used drug in this class and has been recommended particularly for diabetic diarrhea based on a small number of reports. It also has been used to treat diarrhea associated with short bowel syndrome, usually in combination with opiates. Clonidine is usually started at 0.1 mg/d and increased slowly to 0.1 to 0.3 mg 3 times a day. A major limitation to the use of clonidine is its anti- hypertensive effect mediated centrally, resulting in postural hypotension. Clonidine should be reserved for patients with SDs that are refractory to opiates. When clonidine is discontinued, the dose should be tapered slowly over 3 to 5 da y s to avoid rebound symptoms (hypertension, nausea, vomiting, headache). This agent is discussed in the chap- ter on diabetic diarrhea (Chapter 71, “Management of Diabetic Diarrhea”). Glucocorticoids Glucocorticoids stimulate absorption of water and elec- trolytes and have been used in refractory patients with VIPomas. The recommended dose is 60 mg of prednisone per day. If it is effective, the dosage can be decreased to the lowest level controlling the diarrhea. Glucocorticoids are now rarely needed with the availability of the somato- statin analogues, which are effective acutely and long term in most patients with VIPomas. Prost aglandin Synthetase Inhibitors T hese agents have been used in a number of SDs because prostaglandins stimulate water and electrolyte secretion. Indomethacin has been reported to be effective in a small n umber of patients with SDs. 428 / Advanced Therapy in Gastroenterology and Liver Disease Other Agents A bsorbent agents such as psyllium husk, kaolin, methyl- cellulose, and cholestyramine are frequently used in mild to moderate diarrheas. Cholestyramine and other binding resins are principally used in diarrheas for which binding bile acids may be helpful, such as after cholecystectomy or ileal resection. Some series, but not others, report that patients with chronic diarrhea have idiopathic bile acid mal- absorption, and cholestyramine could reduce stool weight. It is important to remember that these agents may inter- fere with absorption of other drugs; therefore, the timing of their use needs to be carefully considered. Bismuth-containing compounds such as Pepto-Bismol are used primarily for the prophylaxis and treatment of infectious diarrheas. They may have effects on toxin pro- duction or action as well as antibacterial effects. Calcium channel blockers (verapamil) can inhibit GI motility and have an antidiarrheal effect. Hypotension may limit their usefulness. Trifluoroperazine and chlorpromazine act to decrease intestinal secretion by inhibiting the calcium-calmodulin complex. They have been occasionally used in patients with VIPomas or other SDs and have been largely replaced by somatostatin analogues. Specific Conditions VIPomas Almost all patients with VIPomas have large-volume diar- rhea frequently resulting in hypokalemia and dehydra- tion—hence the acronym WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria), which is also used to name this syndrome in addition to Verner-Morrison syndrome. Diarrhea occurs in 100% of these patients and is due to the net secretion of fluid and electrolytes, pri- marily in the jejunum, caused by ectopic release of VIP by the tumor. In adults, 90% of these patients have a pancre- atic endocrine tumor, which is usually malignant, whereas in children and a small percentage of adults, it is due to neural (ganglioneuroma) or adrenal tumors. These patients can have very large daily losses exceeding 400 mmol of potassium and 700 mmol of sodium and, therefore, require vigorous rehydration. Octreotide is the agent of choice to control the diarrhea in these patients. In addition to controlling the diarrhea and rehydration, tumor localization studies using computed tomography (CT) and somatostatin receptor scintigraphy to define the location and extent of the tumor are indicated. In addition to medical treatment of the diarrhea, treatment directed against the tumor, including surgical debulking, and chemoembolization or chemotherapy for metastatic tumors are recommended. Carcinoid Syndrome I n the 32 to 84% of patients with carcinoid syndrome with diarrhea, similar to patients with medullary thyroid can- cer or thyrotoxicosis, the diarrhea is primarily caused by increased intestinal motility and increased fluid and elec- trolyte secretion. These actions are mediated in part by sero- tonin secretion and possibly ectopic release of tachykinins (substance P, substance K, neuropeptide K), motilin, and prostaglandins. Almost all patients with carcinoid syndrome have metastatic disease in the liver, usually from a midgut carcinoid (75 to 87%), foregut (2 to 9%), or hindgut (1 to 8%) tumor or from a carcinoid tumor of unknown loca- tion (2 to 15%). The treatment for the diarrhea is similar to that for VIPomas with somatostatin analogues. Octreotide controls the diarrhea in > 80% of patients by decreasing release of serotonin (5-hydroxytryptamine [HT]) and other mediators and is reported to decrease their synthe- sis by the tumors (O’Toole et al, 2000). Other agents that are effective are 5-HT 1 and 5-HT 2 receptor antagonists,such as methylsergide, cyproheptadine, and ketanserin. 5-HT 3 receptor antagonists (ondansetron, tropisetron, alosetron) are now increasingly being used to control the diarrhea and also help control the nausea and occasionally the flushing. In carcinoid syndrome caused by a foregut carcinoid tumor of the gastric mucosa, frequently a combination of H 1 and H 2 receptor antagonists is effective. The carcinoid tumors causing carcinoid syndrome are usually unresectable because of diffuse hepatic metastases, and treatment needs to be directed against the tumor itself. The primary anti- tumor treatments are chemoembolization, use of interferon alone or in combination with somatostatin analogues, or somatostatin analogues alone (Jensen and Doherty, 2001). Systemic Mastocy tosis In the 23 to 43% of patients with systemic mastocytosis, the diarrhea is mild to moderate in the majority, with > 90% having a stool volume < 1 L/d. In systemic mastocytosis, the primary cause of the most troubling diarrhea is gastric hypersecretion owing to hyperhistaminemia; therefore, it has a pathogenesis similar to that seen in patients with Zollinger-Ellison syndrome. However, villous atrophy and a secretory component, perhaps owing to prostaglandins,may be important diarrheal factors in some patients with sys- temic mastocytosis. The diarrhea in these patients is usu- ally controlled by a combination of H 1 and H 2 receptor antagonists. The mast cell membrane-stabilizing drug cro- molyn sodium (disodium chromoglycate) has been reported to be useful to treat diarrhea and other GI symptoms in a smal l number of patients with systemic mastocytosis. In patients with the malignant forms of mastocytosis, treat- ment with interferon alpha-2b, as well as chemotherapy and c orticosteroids , has been used (Jensen, 2000). Secretory Diarrhea / 429 Surreptitious Use of Laxatives or Diuretics P atients with a f actitious cause f requently have large-volume diarrhea (> 1 L/d). It should be remembered that this con- dition is not infrequent, occurring in 15 to 20% of patients referred to a referral center with chronic diarrhea. The pri- mary treatment of these patients is having a high suspicion for the diagnosis because no clinical feature except for a his- tory of psychiatric illness or macroscopic melanosis coli on sigmoidoscopy assists in the diagnosis. Some patients have a medical or veterinary background. Some laxatives increased the osmotic gap in the stool (magnesium), and its detection will help lead to the diagnosis (Phillips et al, 1995). However, with others, the osmotic gap is not increased, and only screening for laxatives in the stool or urine will establish the diagnosis. There is a chapter on man- aging patients with factitious or exaggerated illnesses (see Chapter 42,“Exaggerated and Factitious Disease”). Supplemental Reading Farthing MJ. Novel targets for the control of secretory diarrhea. Gut 2002;50:III15–8. F ried M. Octreotide in the treatment of refractory diarrhea. Digestion 1999;60:42–6. Jensen RT. Overview of chronic diarrhea caused by functional neu- roendocrine neoplasms. Semin Gastrointest Dis 1999;10:156–72. J ensen RT. Gastrointestinal abnormalities and involvement in sys- t emic mastocytosis. Oncol Hematol Clin North Am 2000;14:579–623. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syn- drome. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. C ancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 1813–33. O’Toole D, Ducreux M, Bommelaer G, et al. Treatment of carci- noid syndrome: a prospective crossover evaluation of lan- reotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer 2000;88:770–6. Phillips S, Donaldson L, Geisler K, et al. Stool composition in fac- titial diarrhea. Ann Intern Med 1995;123:97–100. Redfern JS, Fortuner WJ II. Octreotide-associated biliary tract dysfunction and gallstone formation: pathophysiology and manag ement. Am J Gastroenterol 1995;90:1042–52. Szilagyi A, Shrier I. Systematic review: the use of somatostatin or octreotide in refractory diarrhoea. Aliment Pharmacol Ther 2001;15:1889–97. 430 CHAPTER 73 REDUCING CARDIOVASCULAR RISK WITH MAJOR SURGERY MICHAEL Y. CHAN,MD,AND STEPHEN C. ACHUFF,MD Similarly, patients who are asymptomatic with one or more coronary risk factors but who do not have established CAD also have been shown to be at very low risk. The excep- tion is diabetic patients; those with long standing diabetes are at particularly higher risk (Eagle et al, 2002). Clinical predictors can be classified as major, intermediate, or minor. High risk clinical predictors include the following: 1. Unstable coronary syndromes 2. Recent MI (> 7 days but < 1 month before surgery) 3. Severe angina 4. Decompensated congestive heart failure (CHF) 5. High grade atrioventricular block 6. Symptomatic ventricular arrhythmias in the pres- ence of underlying heart disease 7. Supraventricular arrhythmias with uncontrolled ventricular rate 8. Severe valvular disease If any of these major indicators are present, considera- tion should be given to delaying or canceling nonemergent surgery until medical stabilization can be achieved. Background Of the 27 million people undergoing surgery in the United States each year, approximately one-third have coronary artery disease (CAD) or significant risk factors for cardio- vascular disease (Mangano and Goldman, 1995; Grayburn and Hillis, 2003). Thus it is not surprising that myocardial events are the most common serious complication of surgery. An estimated 50,000 patients per year will have perioperative myocardial infarctions (MI) with a periop- erative mortality rate of approximately 20% (Fleisher and Eagle, 2001; Sprung et al, 2000; Badner et al, 1998). Most cases occur within the first 3 days after surgery with atypical symptoms being the norm. Another 1 million patients annually will have perioperative cardiac complica- tions with a concomitant $20 billion per year in hospital and long term care costs (Fleisher and Eagle, 2001). The purpose of preoperative cardiovascular evaluation is more than simply “giving clearance for surgery.” The goals are (1) to assess clinically the patient’s current med- ical status and estimate a cardiac risk profile, (2) to iden- tify patients who would benefit from further noninvasive or invasive testing, (3) to make recommendations for peri- o p erative management that reduces risk for cardiac com- plications, and (4) to identify those patients who would benefit from postoperative risk stratification and modifi- cation (Cohn and Goldman, 2003). American College of Cardiology/ American Heart Association Guidelines The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for perioperative cardiovas- cular evaluation for noncardiac surgery were initially pub- lished in 1996 and subsequently revised in 2002 (Eagle et al, 2002). The strategy is based on the following five factors: 1. Clinical risk predictors 2. Functional capacity of the patient 3. History of previous cardiac evaluation or treatment 4. Urgency of the surgery 5. Surgery-specific risks Patients with no cardiac risk factors are generally at very low risk for perioperative cardiac complications and require no further evaluation or therapy (Eagle et al, 2002). TABLE 73-1. Factors that Increase the Risk of Perioperative Cardiac Complications in Patients Underg oing Noncardiac Surgery and Indications for Use of P erioperative β β -Blocker Therapy Odds Ratio Perioperative Risk Factor (95% CI)* β-Blocker Indicated Ischemic heart disease † 2.4 (1.3 to 4.2) Yes CHF 1.9 (1.1 to 3.5) Yes High risk sur ger y ‡ 2.8 (1.6 to 4.9) Uncer tain, but pr obably Diabetes mellitus 3.0 (1.3 to 7.1) Yes (especially insulin-requiring) Renal insufficiency 3.0 (1.4 to 6.8) Uncertain, but probably if renal insufficiency is due to diabetes or vascular disease Poor function status § 1.8 (0.9 to 3.5) Yes, if poor status is thought to be due to CAD or heart failur e From Fleisher and Eagle, 2001. *Data from Lee et al, 1999 and Reilly et al, 1999. CAD = coronary artery disease; CHF = congestive heart failure; CI = confidence interval. † Ischemic hear t disease includes angina and prior myocar dial infar ction. ‡ High risk surgery includes intraperitoneal, intrathoracic, and supra-inguinal vascular procedures. § Poor functional status is defined as the inability to walk four blocks or climb two flights of stairs. Reducing Cardiovascular Risk with Major Surgery / 431 The patient’s functional status prior to surgery has been shown to be a strong predictor of perioperative risk. Functional status can be expressed in metabolic equivalent (MET) levels. Both perioperative and long term risks are s ignificantly increased in those patients who are unable to achieve a 4-MET demand during most normal daily activities (Reilly et al, 1999; Older et al, 1999; Bartels et al, 1997). As a comparison, 4-METs is approximated by climb- ing 1 flight of stairs carrying a bag of groceries or walking on level ground at 3 to 4 mph (Cohn and Goldman, 2003). Surgery-specific risk, grouped into high, intermediate, or minor risk procedures, is defined by the type of surgery and the associated hemodynamic stress. High risk proce- dures, associated with a cardiac risk of > 5%, include emer- gent major operations, particularly in the elderly, and prolonged operations associated with large fluid shifts and/or blood loss. Intermediate risk procedures with a car- diac complication rate of 1 to 5% include most routine intraperitoneal and intrathoracic operations. Low risk surgeries include endoscopic procedures and superficial procedures; these are associated with a cardiac risk < 1%. Step-Wise Approach to Risk Stratification Step 1: How urgent is the surgery? If surgery is deemed emergent, then the patient should proceed to the oper- ating room without further assessment. Step 2: Has the patient undergone coronary revasculariza- tion (coronary artery bypass grafting or percutaneous coronary intervention) within the past 5 years? If so, and the patient is without recurrent signs or symptoms, the patient can also proceed to the operating room directly without further cardiac testing. Step 3: Has the patient had a coronary evaluation (cardiac st r ess test or coronary angiogram) in the past 2 years? If a sufficient evaluation with favorable results was per- formed within the past 2 years and the patient has not experienced a change or new cardiac symptoms, then no further testing is necessary. Step 4: Does the patient have an unstable coronary syn- drome or high risk features? In the setting of non- emergent surgery, any of the major clinical predictors reviewed above usually leads to cancellation or delay of surgery until correction and treatment of the prob- lem. Step 5: Does the patient have intermediate predictors of risk? Intermediate clinical predictors include mild angina pectoris, history of remote MI (> 1 month b efore surgery), compensated or prior CHF, renal insufficiency (as defined by a serum creatinine ≥ 2.0 mg/dL), and diabetes mellitus. The presence of an intermediate clinical predictor,in addition to either a high risk surgery or low patient functional capacity, would warrant noninvasive testing for further risk stratification prior to surgery. Step 6: Patients with intermediate predictors of risk and m oderate to excellent functional capacity can gener- ally undergo intermediate-risk surgery with low like- lihood of perioperative death or MI. On the other hand, further cardiac testing is often necessary in patients with low functional capacity or those under- going high risk procedures. Step 7: Noncardiac surgery is generally safe for patients with low risk predictors (ie, advanced age, abnormal electrocardiogram [eg, left ventricular hypertrophy (LVH), left bundle branch block (LBBB), or ST-T changes], rhythm other than sinus [eg, atrial fibrilla- tion], history of stroke, or uncontrolled systemic hypertension) with moderate to high functional capac- ity ( ≥ 4 METs). Step 8: The results of noninvasive testing can be used to determine the need for additional evaluation and treat- ment. In some patients with documented CAD, the risk of PCI or CABG may even exceed the risk of the pro- posed noncardiac surgery. This approach may be appropriate, however, if it increases the long term prog- nosis of the patient. Noninvasive Testing Although a careful history and physical examination are the most crucial component of any preoperative evalua- tion, exercise or pharmacologic stress testing can con- tribute significantly to a patient’s risk stratification prior to surgery. Exercise ECG Stress Testing Exercise stress testing with or without imaging remains the test of first choice in those patients who can exercise. It pro- vides a functional estimate of the patient’s overall car- diopulmonary system and yields helpful prognostic information. The main limitation of ECG exercise testing is that only about half of the patients tested achieve peak exercise heart rates > 75% of the age-predicted maximum (Cohn and Goldman, 2003). Ischemia induced by low level exercise identifies a subset of patients at particularly high r isk. H o w ever, a negative test in a patient who achieves the target blood pressure–heart rate product ratio predicts a low risk for perioperative complications. Pharm acologic Stress T esting Pharmacologic stress testing with imaging, primarily dobu- tamine st r ess echocardiography (DSE) and dipyridamole/ exercise thallium, are excellent predictors of cardiac risk. Numerous studies have demonstrated a high negative pre- dictive value (93 to 100%) of both thallium and DSE. The p osit i v e predictive value for thallium (4 to 67%) and DSE (7 t o 23%) are much lower. The choice of the optimal test 432 / Advanced Therapy in Gastroenterology and Liver Disease in the patient who cannot exercise depends on institutional expertise and physician comfort in interpreting results. Specific Preoperative Cardiovascular Conditions Hypertension Despite earlier concerns, it is now abundantly clear that stable and reasonably well-controlled hypertension, and the drugs used to maintain this control, should not present an important risk for patients undergoing surgery. Antihypertensive medications should not be discontinued, tapered, or omitted prior to surgery because of concern over interaction with anesthetic agents. Stage 3 hyperten- sion (systolic blood pressure ≥ to 180 mm Hg and dias- tolic blood pressure ≥ 100 mm Hg) should be controlled before surgery (Eagle et al, 2002). Most patients can be ade- quately controlled by titrating antihypertensives over days to weeks in the outpatient setting. β-Blockers are a par- ticularly attractive choice given their perioperative protec- tive effects (as will be discussed later). We strongly recommend preoperative antihypertensive medications be continued throughout the perioperative period to prevent a hypertensive crisis. Valvular Heart Disease The major complication one faces in dealing with patients with significant valvular heart disease is the potential for CHF. The indications for evaluation and treatment of valvular heart disease are identical to those in the nonpre- operative setting. Symptomatic stenotic lesions are associ- ated with substantial risk of perioperative heart failure or sho c k and often require percutaneous valvulotomy or valve replacement prior to surgery (Reyes et al, 1994; Raymer and Yung, 1998; Torsher et al, 1998). In contrast, sympto- matic regurgitant lesions are better tolerated periopera- tively and may be stabilized with intensive medical therapy and monitoring. An exception occurs when severe regur- gitation exists with reduced ventricular function in which myocardial reserve is so limited that destabilization dur- ing perioperative stresses is likely. In such cases, consider- ation should be given to valve repair prior to nonemergent noncardiac surgery. Two other problems should be mentioned that are nearly unique to the patient with valvular heart disease. First is the potential risk of endocarditis, which is partic- ular ly important in patients with prosthetic heart valves. Antibiotic prophylaxis should be given prior to any surgery with even the slightest risk of bacteremia. The second area of specific concern is the management of anticoagulation therapy. This applies primarily to patients with mechani- cal prosthetic valves. Thomboembolic complications are an inescapable hazard of artificial heart valves, even when anticoagulation is rigorously monitored and controlled. The potential is substantially greater when normal clotting status is maintained for more than 5 to 7 days. Fortunately, the risk is relatively low if this time range is respected. T he simplest strategy for managing warfarin in the face of upcoming surgery is to discontinue the drug 2 or 3 days preoperatively, then restart it the second or third postop- erative day, assuming the risk of surgical bleeding has sub- sided (Tinker and Tarhan, 1978). A more conservative approach from the standpoint of preventing prosthetic valve thromboembolic complications is to give heparin or low molecular weight heparin up to 6 hours preoperatively, and then again beginning 18 to 24 hours postoperatively until warfarin levels are therapeutic (Katholi et al, 1978). The latter approach may be preferable in patients with mechanical mitral valves, which are at higher risk for clot- ting than valves in the aortic position. Cardiac Arrhythmias One of the most frequent reasons for preoperative cardi- ology consultation is the discovery of an arrhythmia on routine ECG or the detection of some pulse irregularity on examination. This should prompt a careful search for underlying cardiopulmonary disease, drug toxicity, or metabolic abnormality (Eagle et al, 2002). In the majority of patients, these abnormalities are either intrinsically benign or are a marker of a correctable problem such as diuretic-induced hypokalemia or a relative excess of an antiarrhythmic agent (eg, digoxin). Therapy is indicated for symptomatic or hemodynamically significant arrhyth- mias (Eagle et al, 2002). Patients already on chronic oral antiarrhythmics should be maintained on their usual dosages that give standardized therapeutic blood levels up t o the t ime of surgery and then have them reinstituted as promptly as possible postoperatively. Several studies have demonstrated that frequent pre- mature ventricular contractions or nonsustained ventric- ular tachycardia do not increase the risk for nonfatal MI or cardiac death in the perioperative period; therefore, aggres- sive monitoring or treatment is not recommended (O’Kelly et al, 1992; Mahla et al, 1998; Eagle et al, 2002). In the set- ting of a patient with an implantable cardiac defibrillator, the device should be programmed off immediately before surgery and reprogrammed on postoperatively (Eagle et al, 2002). Perioperative Management β β -Blockers S everal recent trials have evaluated the benefit of medical therapy initiated in the preoperative setting in reducing cardiac events. Mangano and colleagues (1995) conducted a r andomized controlled trial of atenolol versus placebo in Reducing Cardiovascular Risk with Major Surgery / 433 200 patients with or at risk for CAD undergoing noncar- diac surgery and followed them for 2 years. They found that, although there was no difference in perioperative MI or death during initial hospitalization, ischemic episodes w ere significantly lower in the atenolol group (24% vs 39%). In addition, mortality at 2 years was 10% in the atenolol group versus 21% in controls (p = .019). The prin- cipal effect of atenolol was a decrease in mortality during the first 6 to 8 months. Of note, there was no difference in β-blocker use between groups over the follow-up period (approximately 15% in each treatment group). Poldermans and colleagues (1999) randomized 173 patients undergoing major vascular surgery who had pos- itive DSE on preoperative testing to bisoprolol versus stan- dard care. Patients were excluded if (1) they had extensive wall motion abnormalities at rest or with dobutamine or (2) they were already on β-blocker therapy. Patients in the treatment group received bisoprolol for at least 1 week pre- operatively (mean 37 days) and were continued on biso- prolol for 30 days. The primary endpoints of cardiac death and nonfatal MI occurred in only 3.4% of patients in the bisoprolol group versus 34% in the standard care group (p < .001). The majority of events occurred during the first 7 days after surgery. The study was subsequently extended to follow long term outcomes in 101 of 112 surviving patients remaining on bisoprolol compared with those receiving standard care (Poldermans et al, 2001). During a median follow-up period of 22 months, the bisoprolol group had a markedly decreased risk of MI and cardiac death versus standard care group (12% vs 32%). Current recommendations suggest starting oral β-blocker therapy days to weeks before elective surgery and continuing for a week to a month postoperatively (Eagle et al, 2002). The dose should be titrated to achieve a rest- ing heart rate of 50 to 60 bpm. There may even be benefit to starting therapy intraoperatively if it has not been ini- tiated beforehand; evidence comes from a small study showing a decreased incidence and duration of ischemic events with intraoperative esmolol followed by postoper- ative metoprolol in patients undergoing total knee artho- plasty (Urban et al, 2000). α α -2 Agonist Several trials have evaluated the use of clonidine in reduc- ing cardiac event rates in subsets of patients with known CAD undergoing vascular surgery. Clonidine has been shown to decrease the incidence of ischemia in a study of 297 pat ients undergoing vascular surgery (24% vs 39%) (Stuhmeier et al, 1996). In the European Mivazerol Trial (EMIT), mivazerol, an α-2 agonist not currently available in the United States, was studied perioperatively in 2,854 patients with known CAD or significant CAD risk factors undergoing noncardiac surgery (Oliver et al, 1999). No effect was found on the rate of perioperative MI; however, a statistically significant reduced rate of cardiac death was seen in patients undergoing both general and vascular surgery. Overall, perioperative clonidine may have a similar effect o n myocardial ischemia, infarction, and cardiac death as peri- operative β-blockers, but further research is needed before its role in perioperative management can be fully elucidated. Summary In summary, preoperative risk stratification should be undertaken with consideration of the patient’s clinical markers, functional status, and surgery-specific risks. Cardiac stress tests are helpful in predicting risk but there is no clear-cut evidence they improve perioperative care. Current guidelines suggest their use in patients undergoing nonemergent surgery with two of the following three fea- tures: (1) intermediate risk profile, (2) low functional capac- ity, or (3) high risk surgery. The indications for coronary revascularization are the same as in the nonpreoperative setting. Lastly, perioperative β-blockers should be used in all patients with intermediate or high risk of cardiac com- plications in whom they are not absolutely contraindicated. Supplemental Reading Badner NH, Knill RL, Brown JE, et al. Myocardial infarction after noncardiac surgery.Anesthesiology 1998; 88:572–8. Bartels C, Bechtel JF, Hossmann V,Horsch S.Cardiac risk stratification for high-risk vascular surgery. Circulation 1997;95:2473–5. Cohn SL, Goldman L. Preoperative risk evaluation and perioperative management of patients with coronary artery disease. Med Clin North Am 2003;87:111–36. Eagle KA, Berger PB, Calkins H, et al. ACC/AHA Guideline Update f o r Perioperative Cardiovascular Evaluation for Noncardiac S urg e ry—Executive Summary. A report of the American C ol lege of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for N o ncardiac Surgery). Circulation 2002;12;105:1257–67. Fleisher LA, Eagle KA. Lowering cardiac risk in noncardiac s urge ry. N Engl J Med 2001;345:1677–82. Grayburn P, Hillis LD. Cardiac events in patients undergoing noncardiac surgery: shifting the paradigm from noninvasive risk stratification to therapy.Ann Intern Med 2003 Mar 18;138:506–11. K atholi RE, N olan SP , McGuire LB. The management of anticoagulation during noncardiac operations in patients with prosthetic heart disease. A prosthetic study. Am Heart J 1978; 96:163–5. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and p r ospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999 Sep 7;100:1043–9. Mahla E, Rotman B, Rehak P, et al. Perioperative ventricular d y sr h ythmias in patients with structural heart disease undergoing no ncardiac surgery. Anesth Analg 1998;86:16–21. 434 / Advanced Therapy in Gastroenterology and Liver Disease M angano DT, Goldman L. Preoperative assessment of patients with known or suspected coronary disease. N Engl J Med 1995; 333:1750–6. O’Kelly B, Browner WS, Massie B, et al. Ventricular arrhythmias in p atients undergoing noncardiac surgery. The Study of P erioperative Ischemia Research Group.JAMA 1992;268:217–21. Older P, Hall A, Hader R. Cardiopulmonary exercise testing as a screening test for perioperative management of major surgery in the elderly. Chest 1999;116:355–62. O liver MF, Goldman L, Julian DG, Holme I. Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease: the European Mivazerol Trial (EMIT). Anesthesiology 1999;91:951–61. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery.Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999;34124:1789–94. Poldermans D, Boersma E, Bax JJ, et al. Dutch Echocardiographic C ardiac Risk Evaluation Applying Stress Echocardiography Study Group. Bisoprolol reduces cardiac death and myocardial infarction in high-risk patients as long as 2 years after successful major vascular surgery. Eur Heart J 2001;22:1353–8. Raymer K,Yang H. Patients with aortic stenosis: cardiac complications in non-cardiac surgery. Can J Anaesth 1998;45:855–9. R eilly DF, McNeely MJ, Doerner D, et al. Self-reported exercise tolerance and the risk of serious perioperative complications. Arch Intern Med 1999;159:2185–92. Reyes VP,Raju BS,Wynne J, et al. Percutaneous balloon valvuloplasty c ompared with open surgical commissurotomy for mitral s tenosis. N Engl J Med 1994;331:961–7. Sprung J, Abdelmalak B, Gottlieb A, et al. Analysis of risk factors for myocardial infarction and cardiac mortality after major vascular surgery. Anesthesiology 2000 Jul;93(1):129–40. S tuhmeier KD, Mainzer B, Cierpka J, et al. Small, oral dose of clonidine reduces the incidence of intraoperative myocardial ischemia in patients having vascular surgery. Anesthesiology 1996;85:706–12. Torsher LC, Shub C, Rettke SR, Brown DL. Risk of patients with severe aortic stenosis undergoing noncardiac surgery. Am J Cardiol 1998;81:448–52. Tinker JH, Tarhan S. Discontinuing anticoagulant therapy in surgical patients with cardiac valve prosthesis. Observation in 180 operations. JAMA 1978;239:738–9. U rban MK, Markowitz SM, Gordon MA, et al. Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia. Anesth Analg 2000;90:1257–61. 435 CHAPTER 74 ACUTE APPENDICITIS DORRY SEGEV,MD,AND PAUL COLOMBANI,MD,FACS On physical examination, there is usually focal tender- ness and localized peritoneal irritation in the right lower quadrant of the abdomen, over the appendix.Although the appendix is classically located at McBurney’s point (two- thirds the distance from the umbilicus to the right anterior superior iliac spine), anatomic variations are common and include retrocecal, intrapelvic, left lower quadrant, or right upper quadrant positions. A number of clinical signs can be used to discern local- ized peritonitis. Tenderness to percussion over the appen- dix is more sensitive, more specific, and certainly more kind to the patient being examined than rebound tenderness. The unsolicited complaint of pain in the right lower quad- rant with maneuvers such as palpation of the left lower quadrant (Rovsing sign), cough (Dunphy sign), internal rotation of the flexed right thigh (obturator sign), or exten- sion of the right hip (iliopsoas sign) all indicate an inflam- matory process in the right lower quadrant. Laboratory values can be notoriously misleading, but the classic patient has a mild leukocytosis with a left shift of neutrophils to immature forms. Urinalysis should be negative, although pyuria without bacteria can occur in the setting of appendicitis from periureteral inflammation. Differential Diagnosis The diagnosis can be even more difficult in a number of clinical settings. Patients who are immunocompromised, through diseases or medications, and patients at both extremes of age commonly have atypical histories and phys- ical findings. Radiographic studies can be helpful in these patients. Gynecological conditions can be distracting in female patients. A pelvic examination, if not a pelvic ultra- sound, is always warranted in this population. Young patients with conditions such as otitis media, streptococcal pharyngitis, meningitis, and mesenteric lymphadenitis may have abdominal complaints which can masquerade as ap pendicitis. Inflammatory bowel disease should always be considered in a patient with right lower quadrant abdom- inal pain. A final important consideration is the differen- t ial diagnosis of t yphlitis, or neutropenic enterocolitis, in neutropenic patients undergoing chemotherapy for onco- logic conditions. Acute appendicitis continues to be one of the most com- mon causes of abdominal pain in both the adult and pedi- atric populations, with a lifetime risk of about 6%. It is the most common surgical emergency in the child. The etiology of appendicitis varies from lymphoid hyperpla- sia in children and teenagers to appendicolith or tumor in adults, but the common pathophysiology is thought to consist of appendiceal outlet obstruction leading to inflammation, venous congestion followed by ischemia, and necrosis. The natural history includes either local- ized perforation, in the form of phlegmon or abscess, or free perforation with peritonitis. Diagnosis remains a clinical one and treatment remains surgical, but the roles of computed tomography (CT), percutaneous drainage, interval appendectomy, and minimally invasive surgery are evolving. Diagnosis Even in the era of inexpensive and easily accessible radi- ography, acute appendicitis is a clinical diagnosis that can often be difficult and is made with the goal of minimizing negative appendectomies but avoiding perforation. It is a rare patient that embodies the textbook presentation of this dis- ease, but a combination of historical features, physical find- ings, laboratory values, and occasionally radiography, should reliably lead to a diagnosis and appropriate treat- ment. Classic Patient The classic patient with appendicitis complains of peri- umbilical pain 1 or 2 days prior to presentation that has subsequently migrated to the right lower quadrant. The patient has a low grade fever. The patient may have one or two episodes of vomiting, which are self-limiting, and is usually anorexic. Diarrhea, persistent vomiting, or a pat ient requesting food or drink would be unusual.A clin- ical course exceeding 2 or 3 days would also be unusual. A protracted course beyond 72 hours may indicate that the appendix has perforated, with the patient initially feeling better, and then worsening systemically as a phlegmon or abscess was being formed. [...]... Medical Therapy during Pregnancy and Nursing 5-ASA and corticosteroids are safe to use during pregnancy and during nursing There is reassuring retrospective data that AZA / 6- MP and cyclosporine are safe and do not need to be stopped if pregnancy occurs while on such therapy Nicotine should not be used during pregnancy and nursing There is a separate chapter (Chapter 84, “Pregnancy and In ammatory Bowel Disease )... in patients who were staying in remission on antibiotics patients with left-sided UC to try to reduce the symptoms of intestinal gas and some of the diarrhea.‡ Perineal dermatitis presents with perineal itching, pain, and occasionally bleeding The attempt to maintain perineal hygiene in the presence of diarrhea often leads to physical trauma of the perineal cleansing Patients should be instructed in. .. integrity of the anal sphincter complex Topical rectal therapy including mesalamine and/ or corti-foam can be initiated to control the tenesmus or antihistamines can be used to change the anorectal dynamics and improve this troublesome symptom Maintaining Remission Maintenance therapy with mesalamine prolongs the duration of remission and should be continued The role of maintenance therapy in ulcerative proctitis... constipation includes educating the patient and correcting any misconceptions as to the wide range of normal bowel habits Broad treatment principles include increasing fluid and fiber intake, and reducing excessive or incorrect use of laxatives and cathartics Taking advantage of normal postprandial increases in colonic motility, patients should attempt to defecate after meals, particularly in the morning when... occurred in the understanding and management of inflammatory bowel disease (IBD) over the past decade The interaction of luminal contents with the gastrointestinal (GI) immune system has enhanced our understanding of mucosal in ammation and has improved the focus of general management Biologic therapy is coming of age and dozens of new “silver bullet” compounds are being developed to treat both Crohn’s disease. .. with the dominant luminal substrate for oxidative phosphorylation being glutamine in the right colon and butyrate in the left colon In addition, there are differences in the distribution of in ammatory cells in the right and left colon, which may provide insight into the abrupt cessation of in ammation at the line of disease demarcation We histologically evaluated the “line of demarcation” in an attempt... use in inflammatory bowel disease (IBD) (Chapter 69 , “Monitoring of Azathioprine Metabolite Levels in Inflammatory Bowel Disease ) We continue prednisone for about 2 months after starting AZA / 6- MP to allow time for the drug to become effective Occasionally, we use nicotine patches for UC, in patients who have not responded to steroids, particularly in former smokers We start nicotine patches at an initial... eosinophils Eosinophils in the stool indicate migration of eosinophils Charcot-Layden crystals, which are related to the intracellular products of the eosinophil, reflect probable eosinophil-induced tissue injury and suggest the need for aggressive treatment of the increased number of eosinophils Anorectal Physiology in Health and with In ammation The complex physiology of the anorectum is adversely in uenced... also concerned about IAP anastomosis in patients with severe co-existent irritable bowel syndrome Note: AZA / 6- MP dosage variation based on TPMT and later 6- TG / 6- MMP levels can also be used There is a separate chapter on this approach 4 56 / Advanced Therapy in Gastroenterology and Liver Disease Asacol (available as 800 mg tablets), 1 g/d of olsalazine (Dipentum), or 6. 75 g/d of balsalazide (Colazal) Another... Consider colectomy and ileoproctostomy Indeterminate favor ulcerative colitis TPC and ileostomy FIGURE 7 9-1 Legend: Indications for surgery IPAA= ileal pouch-anal anastomosis; TPC= total proctocolectomy *Absence of perianal or small bowel disease **Presence of adverse/clinical/radiologic indicators 457 458 / Advanced Therapy in Gastroenterology and Liver Disease hospital stay and the 2-month normal recovery . caused by increased intestinal motility and increased fluid and elec- trolyte secretion. These actions are mediated in part by sero- tonin secretion and possibly ectopic release of tachykinins (substance. principles include increasing fluid and fiber intake, and reducing excessive or incorrect use of lax- atives and cathartics. Taking advantage of normal post- prandial increases in colonic motility,. difenoxin with atropine. These agents inhibit transit throughout the gas- trointestinal (GI) tract; therefore, they increase the contact t ime between intestinal luminal contents and the mucosa, increasing