CHAPTER 19

V O L U M E

T W E N T Y - N I N E

ANESTHETIC CONCERNS FOR THE PATIENT WITH RENAL OR HEPATIC DISEASE ROBERT N. SLADEN, M.B.CH.B., M.R.C.P.(UK), F.R.C.P.(C) PROFESSOR AND VICE CHAIR DEPARTMENT OF ANESTHESIOLOGY COLLEGE OF PHYSICIANS AND SURGEONS OF COLUMBIA UNIVERSITY DIRECTOR CARDIOTHORACIC AND SURGICAL INTENSIVE CARE UNITS COLUMBIA PRESBYTERIAN MEDICAL CENTER NEW YORK, NEW YORK

EDITOR: ALAN JAY SCHWARTZ, M.D., M.S.ED. ASSOCIATE EDITORS: M. JANE MATJASKO, M.D. CHARLES W. OTTO, M.D.

The American Society of Anesthesiologists, Inc.

© 2001

The American Society of Anesthesiologists, Inc. ISSN 0363-471X ISBN 078-171-9593 An educational service to the profession under the auspices of The American Society of Anesthesiologists, Inc. Published for The Society by Lippincott Williams & Wilkins, Inc. 530 Walnut Street Philadelphia, Pennsylvania 19106-3621 Library of Congress Catalog Number 74-18961.

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Robert N. Sladen, M.B.Ch.B., M.R.C.P.(UK), F.R.C.P.(C) Professor and Vice Chair Department of Anesthesiology College of Physicians and Surgeons of Columbia University Director Cardiothoracic and Surgical Intensive Care Units Columbia Presbyterian Medical Center New York, New York

Advanced renal or hepatic disease should really be considered systemic disease processes, affecting multiple organ systems. They both reflect a fundamental defect in protein metabolism, i.e., nitrogen elimination after deamination of amino acids (Fig. 1). In liver failure, the arginine cycle fails to convert ammonia to urea, so that ammonia accumulates and blood urea nitrogen (BUN) remains very low. In renal failure, ammonia is converted to urea, which accumulates. In fact, hyperammonemia or elevated BUN are markers for other circulating byproducts of protein metabolism that cause defective ion transport across cell membranes, resulting in intracellular sodium and water accumulation. Every organ system is affected. Patients with renal or hepatic disease present a challenge to anesthesiologists because these conditions imply abnormal handling of anesthetic agents, as well as multiorgan system dysfunction, general debility, and specific problems associated with replacement therapy and transplantation. Moreover, in situations of hepatic or renal insufficiency, anesthesia and surgery may themselves precipitate acute failure. This refresher course highlights the similarities and differences between renal and hepatic disease with regard to the manifestations of organ dysfunction, pharmacology of anesthetic agents, and selected aspects of anesthetic preparation and perioperative management.

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FIG. 1. Nitrogen metabolism in liver or renal failure. The dotted lines represent a block in metabolism, so that in liver failure ammonia (NH3) accumulates but urea remains low. In renal failure, urea accumulates and ammonia remains normal. For further details, see text.

Electrolyte Imbalance. Extracellular potassium is normally maintained in a narrow range (3.5 to 5.0 mEq/l). This reflects active intracellular transport against a large concentration gradient by a sodium adenosine triphosphatase pump situated at the cell membrane (Fig. 2). In dialyzed patients, the serum potassium concentration may vary from 2.5 to 6.0 mEq/l and changes approximately 0.5 mEq/l for each 0.1 change in pH. Clinical and electrocardiograph manifestations of hyperkalemia (or hypokalemia) depend on potassium flux (i.e., changes in the intracellular to extracellular gradient) rather than the serum concentration per se.

FIG. 2. Intracellular potassium (K) flux. The 401 ratio between intracellular K concentration (160 mEq/l) and extracellular K concentration (4 mEq/l) is maintained by an active sodium (Na) adenosine triphosphatase (ATPase) pump at the cell membrane. β-adrenergic (β) agonists stimulate the Na ATPase pump and enhance K uptake into the cell; β-adrenergic antagonists have the opposite effect. The lower section of the figure illustrates the effect of extracellular acidosis, i.e., an increase in hydrogen ion (H+) concentration causes H+ to move into the cell along its concentration gradient. To maintain electrical neutrality, K moves out of the cell and causes extracellular hyperkalemia. A change (∆) of 0.1 in pH results in a change of approximately 0.5 mEq/l in serum potassium concentration. For example, a decrease in pH from 7.4 to 7.2 could result in an increase in serum potassium of 1.0 mEq/l, e.g., from 5.0 to 6.0 mEq/l. (Reprinted with permission from Sladen RN: Anesthetic considerations in the patient with renal failure. Anesth Clin North Am 2000; 8:866.)

Rapid, life-threatening hyperkalemia may be caused by catabolic stress, acidosis potassium-sparing diuretics, or erythrocyte transfusion. Although total body potassium may be depleted, potassium replacement may easily induce acute hyperkalemia. Hypermagnesemia causes muscle weakness and increased susceptibility to muscle relaxants. Hypomagnesemia is usually associated with hypokalemia and may predispose to ventricular irritability. Hyperphosphatemia results in increased bone deposition of calcium and hypocalcemia. If the calcium:phosphate product (serum calcium times serum phosphate) exceeds 60 mg/dl, metastatic calcification may occur. Decreased renal synthesis of dihydrocholecalciferol (vitamin D) contributes to hypocalcemia and stimulates secondary hyperparathyroidism and bone resorption. These metabolic abnormalities culminate in the syndrome of renal osteodystrophy, with joint deformity, osteoporosis, osteomalacia, and the potential for spontaneous fractures. Treatment consists of administration of vitamin D, calcium salts, and phosphate binders such as aluminum hydroxide, together with dietary phosphate restriction. However, aggressive dialysis, aluminum hydroxide therapy, or total parenteral nutrition may result in hypophosphatemia (120 mg/dl) is well tolerated, but major surgery, gastrointestinal bleeding, or infection may precipitate acute encephalopathy. Lifetime hospital dependence may lead patients to become passive–aggressive, depressed, manipulative, and churlish. Uremic distal sensorimotor neuropathy is an important indication for dialysis and is a marker for autonomic neuropathy, which may manifest as orthostatic hypotension, impaired circulatory response to anesthesia, and delayed gastric emptying. Myocardial ischemia may be silent (i.e., occur without angina).

Chronic Liver Disease Ascites, Fluid, and Electrolyte Imbalance. Hypoalbuminemia and portal hypertension combine to induce ascites and intravascular hypovolemia. This triggers secondary hyperaldosteronism, with sodium and water retention and potassium excretion. The result is hypokalemic metabolic alkalosis, generalized edema (anasarca), and progressive ascites. Ascites elevates the diaphragms and decreases functional residual capacity, resulting in basal atelectasis and hypoxemia. Tense ascites may increase intraabdominal pressure to the extent that venous return and renal blood flow are decreased. Spontaneous bacterial peritonitis occurs in approximately 10% of patients. It is important to distinguish this from surgical peritonitis and avoid unnecessary (and potentially devastating) exploratory laparotomy.

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The edema and ascites are resistant to loop diuretics, which exacerbate intravascular hypovolemia and hypokalemia and worsen hepatic perfusion. The specific aldosterone antagonist spironolactone is most effective in maintaining a modest potassium-sparing diuresis. However, its onset and offset are very slow (2 to 3 days), and its potassiumsparing effect in acute renal insufficiency can provoke acute hyperkalemia. Metabolic alkalosis worsens hepatic encephalopathy by nonionic diffusion trapping. With a decrease in extracellular hydrogen ion concentration, ammonium (NH +4 ), which is polarized and lipid insoluble, is converted to ammonia (NH3), which is nonionic and crosses lipid membranes. Treatment consists of administration of potassium chloride with careful volume repletion. Refractory alkalosis has been corrected by the central venous administration of dilute (0.1N) hydrochloric acid. Gastrointestinal Dysfunction. All patients have the potential for active viral hepatitis (A, C, D). Hepatic encephalopathy is associated with anorexia, hiccups, nausea, and vomiting. As in uremia, gastric emptying is delayed and increases the risk of regurgitation and aspiration during anesthetic induction. This risk is exacerbated by severe ascites with increased abdominal pressure. Patients with portal hypertension are at constant risk of massive hemorrhage from esophageal or gastric varices. However, there is also an increased risk of peptic ulcer disease, which must be considered as a potential source when gastrointestinal bleeding occurs. Hepatorenal Syndrome. The term hepatorenal syndrome is often used to refer to any degree of renal insufficiency that occurs in the presence of liver failure. It is, in fact, a specific form of vasomotor nephropathy, characterized by severe prerenal oliguria, low urine sodium (≤10 mEq/l), and progressive azotemia. The syndrome is seen with severe obstructive jaundice (total bilirubin concentration >8 mg/dl) or hepatic failure. Bile salts bind endotoxin in the gut, and their absence allows access of endotoxin into the portal circulation. Endotoxin enters the systemic circulation because of Kupffer cell failure in the liver and via portasystemic shunting. At the kidney, endotoxin induces renal vasoconstriction; as a consequence there is intense activation of renal tubular salt and water retention. Acute tubular necrosis may complicate liver failure independently of, or concomitant to, the hepatorenal syndrome. Endotoxin also has direct nephrotoxic effects. Tense ascites exacerbates renal dysfunction by increasing renal vein pressure, which impairs glomerular filtration. Variceal bleeding with hemorrhagic shock is one of several insults that may induce ischemic acute tubular necrosis. In advanced liver failure, BUN remains low ( control) CNS (coma grade) Ascites Nutrition

0–10% 3.5 1–4 Normal None Excellent

4–31% 2–3 3–3.5 4–6 Confused (1–2) Easily controlled Good

19–76% >3 6 Coma (3–4) Poorly controlled Poor

ascites must be performed with caution because of the risk of inducing acute intravascular hypovolemia, hypotension, and further liver injury. Many patients take the aldosterone antagonist spironolactone, which promotes sodium excretion and potassium retention. It is long-acting and could exacerbate hyperkalemia in the presence of acute renal insufficiency or failure. If possible, spironolactone therapy should be discontinued 3 to 4 days before surgery. An attempt to correct factor VII deficiency and prolonged prothrombin time should be made with parenteral vitamin K or fresh frozen plasma. However, these may be largely ineffective in patients with severe liver damage, and administration of several units of fresh frozen plasma represents a substantial volume load. Precipitating factors of encephalopathy should be treated or removed by protein restriction, lactulose, or neomycin. Patients with end-stage liver disease have a very high incidence of hepatorenal syndrome and are exquisitely sensitive to small decreases in intravascular volume. Steps should be taken to ensure adequate preoperative hydration in these patients, such as through maintenance saline infusion during preoperative fasting. Pharmacologic renal protection (low-dose dopamine, furosemide infusion, fenoldopam) is used frequently during orthotopic liver transplantation. Although these agents are effective at inducing diuresis, few if any prospective data suggest that they decrease the risk for perioperative renal injury. TRANSJUGULAR INTRAHEPATIC PORTASYSTEMIC SHUNT. The transjugular intrahepatic portasystemic shunt procedure is being used with increasing frequency, especially in patients who are candidates for orthotopic liver transplantation. It decompresses the portal system, relieves severe ascites, decreases the risk for variceal bleeding, and,

TABLE 5.

High Risk Procedures in Cirrhotic Patients Independent of Child-Pugh Classification

Procedure

Risks and Complications

Emergency surgery (laparotomy) Prior abdominal surgery Cardiopulmonary bypass Ileostomy, colostomy Cholecystectomy

Liver failure, 25% mortality rate Neovascularization: bleeding Severe coagulopathy and bleeding, high mortality rate High incidence of ascitic leaks Portal hypertension, coagulopathy: bleeding from gallbladder bed Bleeding, liver failure

Hepatic tumor resection

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high laudanosine concentrations are associated with electrical seizure activity, but these have never been encountered in humans or reported in patients. All volatile anesthetic agents decrease hepatic blood flow based on their effects on the central circulation, but this can be overcome by appropriate hemodynamic management. Hypercarbia (arterial carbon dioxide tension >45 mmHg) decreases portal flow and should be avoided. Opioids, with the notable exception of remifentanil, may accumulate, and delayed emergence should be anticipated if they are used. Remifentanil pharmacokinetics are unchanged even in the presence of severe liver disease, but patients are more sensitive to its pharmacodynamic effect in suppressing ventilatory drive.11 Propofol remains a relatively short-acting drug even in patients with advanced cirrhosis. However, this advantage may be offset by its effects on the circulation (myocardial depression, inhibition of reflex tachycardia, vasodilation) in patients who are usually hypotensive to begin with. The anesthesiologist should anticipate intraoperative hypoxemia (ascites, intrapulmonary shunting), bleeding (coagulopathy), and oliguria (vasomotor nephropathy). An important intraoperative consideration in the anesthetic management of partial hepatectomy or liver transplantation is the avoidance of excessive volume loading. Hepatic venous congestion increases venous oozing and markedly increases intraoperative blood loss, perhaps the most important determinant of outcome after hepatic resection. A fluid-restrictive approach during hepatic resection has been shown to decrease intraoperative blood loss.12 Hepatic swelling can also irreparably injure the newly transplanted liver. Although it is essential to maintain intravascular volume and hepatic perfusion, efforts should be made to keep the central venous pressure 10 mmHg or lower in patients with normal cardiac function. Postoperative Care. Anesthetic emergence may be delayed and complicated by vomiting and aspiration, hypotension, respiratory depression, and acute respiratory failure. Patients should have their trachea extubated only when they are fully awake to reduce the risk of aspiration. Similarly, a short period of postoperative mechanical ventilation allows controlled emergence, avoids reversal agents, and facilitates evaluation of neurologic and ventilatory function before extubation. Potential postoperative problems include bleeding, oliguria, encephalopathy, acute respiratory failure, sepsis, wound dehiscence, and acute hepatic failure.

References 1. Prough DS, Foreman AS: Anesthesia and the renal system, Clinical Anesthesia, 2nd edition. Edited by Barash PG, Cullen BF, Stoelting RK. Philadelphia, Lippincott, 1992, pp 1125–56. 2. Sear J: Effect of renal function and failure, Sedation and Anesthesia in the Critically Ill. Edited by Park GP, Sladen RN. Oxford, Blackwell Science, 1995, pp 108–129. 3. Conzen PF, Nuscheler M, Melotte A, et al: Renal function and serum fluoride concentrations in patients with stable renal insufficiency after anesthesia with sevoflurane or enflurane. Anesth Analg 1995; 81:569–75. 4. Mannucci PM, Remuzzi G, Pusineri F, et al: Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 1983; 308:8–12. 5. Miller RD, Way WL, Hamilton WK, et al: Succinylcholine-induced hyperkalemia in patients with renal failure? Anesthesiology 1972; 36:138–41. 6. Bion JF, Bowden MI, Chow B, et al: Atracurium infusions in patients with fulminant hepatic failure awaiting liver transplantation. Intensive Care Med 1993; 19(suppl 2):S94–8. 7. Conn M: Preoperative evaluation of the patient with liver disease. Mt Sinai J Med 1991; 58:75–80.

8. Gholson CF, Provenza JM, Bacon BR: Hepatologic considerations in patients with parenchymal liver disease undergoing surgery. Am J Gastroenterol 1990; 85:487–96. 9. Pugh PNH, Murray-Lyon IM, Dawson JL, et al: Transection of the oesophagus for bleeding varices. Br J Surg 1973; 160:646–9. 10. Khalil M, D’Honneur G, Duvaldestin P, et al: Pharmacokinetics and pharmacodynamics of rocuronium in patients with cirrhosis. Anesthesiology 1994; 80:1241–7. 11. Dershwitz M, Hoke JF, Rosow CE, et al: Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease. Anesthesiology 1996; 84: 812–20. 12. Melendez, JA, Arslan V, Fischer ME, et al: Perioperative outcomes of major hepatic resec-

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