Anesthesia for the patient with liver disease

Anesthesia for the Patient With Liver Disease Michelle Y. Braunfeld

LINICAL LIVER disease can be divided into acute and chronic processes. Chronic liver disease can either be parenchymal or cholestatic, but both eventually lead to cirrhosis. Acute disease can range from subclinical liver enzyme elevations to the extreme manifestation of fulminant hepatic failure (FHF). F H F is a condition with unique care and monitoring needs that will not be addressed in this article. Several studies have attempted to quantify surgical risk for patients with chronic liver disease. Perhaps the most enduring and easiest to use was originally developed in the 1960s to study risk for portocaval shunt, and is called Child's classification.l Over the years subsequent studies have shown the Child's classification (or elements of it) to correlate with rates of morbidity and mortality in intra-abdominal and especially biliary tract surgery in the cirrhotic patient.~4 The original Child's classification used five easily assessed components and divided patients into classes A, B, or C on the basis of their degrees of abnormality (Table 1). The appearance of a single abnormal factor was considered sufficient to place the patient in that class. Thus a serum albumin <3.0 classified a patient as a class C designation. However, not all clinicians adhered to this view, some required 3 or more class criteria to be fulfilled by patients before labeling them as such. In an effort to gain consistency, the Pugh modification weighted the variables and classified risk according to an added score (Table 2). The Pugh modification also notably substituted prothrombin time (PT) abnormality for nutritional status in the Child's classification. 5 Later studies support this variable, too, as a factor predicting perioperative morbidity and mortality in cirrhotic patients. 3,4,6 Surgical risk for the patient with acute disease is less circumscribed because of differences in the cause of the disease, the natural history of the disease process, the significance o f laboratory values, etc. Mortality for patients with acute hepatitis undergoing laparotomy varies from 9.5%

C

tO 58% depending on the cause and severity of the underlying disease. 7-9 Several studies describe subgroups of patients with alcoholic or viral hepatitis as having the highest mortality, even up to 100% in one study. 9 Although it is clear that laparotomy in the setting of acute hepatitis is a risky procedure to be avoided, the same is not so clear about peripheral surgery. A study by Zinn et al of patients with mild alcoholic hepatitis having a range of surgeries under both general and regional anesthesia showed no changes in transaminase or bilirubin studies up to 3 days postoperatively.~~ Nonetheless, prudence suggests that unless there is a compelling medical reason for immediate surgery, procedures are best delayed until resolution of the acute episode. Among the potential causes of postoperative hepatic dysfunction, hypoxic injury from compromise of the hepatic blood flow is far and away the biggest threat. Moreover, it is one of the few cause that the anesthesiologist may influence in any, albeit small, way. Hepatic blood supply comes roughly 20% to 30% from the hepatic artery and 70% to 80% from the portal vein. ~ All other factors held constant, these sources interact in such a way as to preserve hepatic flow ie, a fall in portal flow causes an increase in hepatic arterial flow, and vice versa. This relationship can be modified by systemic hemodynamics--decreased blood volume, cardiac output, and peripheral resistance, local sympathetic tone; and humorial mechanisms-gut-derived peptides, surgical stress response. Both regional and general anesthetics decrease hepatic blood flow via a combination

From the Department of Anesthesiology, UCLA School of Medicine, Los Angeles, CA. Address reprint requests to Michelle Y. Braunfeld, MD, Department of Anesthesiology, UCLA School of Medicine, 10833 Le Conte Avenue, BH-612 CHS, Los Angeles', CA 90024-1778. Copyright 9 1995 by W.B. Saunders Company 0277-0326/95/1403-000555.00/0

Seminars in Anesthesia, Vo114, No 3 (September), 1995: pp 193-203

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MICHELLE Y. BRAUNFELD Table 1.

Clinical and Laboratory Classification of Patients With Cirrhosis in Terms of Hepatic Functional Reserve

Group Designation

A Minimal

B Moderate

C Advanced

Serum bilirubin* (mg %) Serum albumin (gm %) Ascites Neurological disorder Nutrition

Below 2.0 Over 3.5 None None Excellent

2.0-3.0 3.0-3.5 Easily controlled Minimal Good

Over 3.0 Under 3.0 Poorly controlled Advanced, "coma" Poor, "wasting"

* Equivocal in biliary cirrhosis. (Reprinted with permission. 5)

of baseline under general anesthesia. 16 This decreased to 76% during peripheral procedures, and dropped dramatically to 42% during upper abdominal procedures. Thus it seems that surgical intervention and laparotomy per se are associated with a severe decrement in total hepatic flow. Nevertheless, although the main determinant of blood flow compromise is the surgical procedure, anesthetic management may attenuate that effect and possibly improve patient outcome.

of these modifiers, plus some direct effects on splanchnic vasculature. A comparison of the inhalational anesthetics shows that all decrease portal blood flow, but that hepatic arterial flow is preserved or increased to varying degrees.~3 This accounts for the differences in "liver friendliness" among agents. Evidence from several studies suggests that isoflurane preserves hepatic oxygen supply better than enflurane, which in turn performs better than halothane. ~4,15 Other conditions c o m m o n to general anesthesia that are associated with decreased hepatic blood flow are: positive pressure ventilation (especially with positive end-expiratory pressure), hypocarbia, and metabolic acidosis. ~3 It is also worth noting that hemodilution, by decreasing blood oxygen content, may also contribute to hepatic ischemia. Unfortunately, although careful anesthetic management can make a difference in hepatic blood flow, it cannot fully compensate for the insult of surgery. A study by Gelman in 1976 showed reduction of hepatic blood flow to 84%

Table 2.

PREOPERATIVE EVALUATION

Liver disease affects every major organ system in the body. A thorough and aggressive preoperative evaluation provides the opportunity to address these derangements and their underlying causes with the goal of improving patient outcome. Remember that Child's classification quantifies risk on the basis of the patient's condition at the time of surgery, not admission. CENTRAL NERVOUS SYSTEM

Encephalopathy associated with hepatic disease can be divided into two groups according to

Grading of Severity of Liver Disease

Clinical and Biochemical Measurements Encephalopathy (grade)* Ascites Bilirubin (mg per 100 mL) Albumin (mg per 100 mL) Prothrambin time (sec. prolonged) For primary biliary cirrhosis Bilirubin (mg per t00 mL)

Points Scored For Increasing Abnormality 1

2

3

None Absent

1 and 2 Slight

3 and 4 Moderate >3

1-2

2-3

3.5

2.8-3.5

1-4

4.6

1-4

4-10

<2.8 >6

>10

* According to grading of Trey, Burns, and Saunders (1966). (Reprinted with permissionfl)

ANESTHESIA FOR THE PATIENT WITH LIVER DISEASE

cause. True hepatic encephalopathy results from the failure of the liver to clear certain gut-generated substances, particularly ammonia, that have central nervous system activity. However, a frequently encountered change in mental status is nonhepatic in origin, resulting from oversedation, dehydration, occult infection, etc. While the role of ammonia in hepatic encephalopathy has long been debated, it is clear that properly collected arterial specimens show correlation between ammonia levels and mental status within a single patient.17 That is, although an ammonia level >x may not produce encephalopathy in every patient it may in some patients, and it can be relied on to correlate with encephalopathy in those patients. Other substances such as mercaptans, short-chain fatty acids, aromatic amino acids, and gamma-aminobutyric acid (GABA) have also been implicated in causing hepatic encephalopathy.~8 Therapy is first aimed at identifying and treating the underlying cause of encephalopathy, eg, gastrointestinal bleeding, dietary indiscretion, oversedation, etc. The final common toxin of most causes of true hepatic encephalopathy is ammonia and so the goal of further therapy is to decrease production and increase elimination of this substance. Other measures to be considered include correcting electrolyte imbalances (especially hypokalemia), replacing dietary deficiencies (eg, vitamin B and zinc), and ruling out hypoglycemia and hypoxemia. A more recent therapy is the use of the benzodiazepine antagonist flumazenil. Remember that GABA is one of the substances thought to contribute to hepatic coma, and is the major inhibitory neurotransmitter in humans. The rationale for using flumazenil is that the GABA receptor is not a discrete entity but actually part of a receptor complex that includes the receptor for benzodiazepines. This complex can be activated by either GABA or a benzodiazepine, and is inhibited by flumazenil. Indeed, studies have shown clinical improvement in hepatic coma in patients who have received flumazenil) 9'2~ PULMONARY

Chronic liver disease is associated with a variety of pulmonary disorders that may cause hypoxemia. Many are not unique to the liver pa-

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tient, such as bronchitis, chronic obstructive pulmonary disease, atelectasis, pleural effusions, pneumonia, etc, and their management is relatively straightforward. There is additionally a set of pulmonary vascular pathologies that may produce severe hypoxemia. They may coexist with the other, garden-variety pulmonary conditions and their diagnoses should be sought because they have different implications. The term "hepatopulmonary syndrome" encompasses two types of these vascular abnormalities. Their common anatomic lesion is arteriovenous dilations, but their size and location is what differentiates them. One type occurs at the precapillary.level near where gas exchange takes place. 2~ Here the vessels may be dilated to several times their normal diameter. This together with the usually increased cardiac output of the cirrhotic leads to inadequate opportunity for diffusion of oxygen through the entire stream of blood (Fig 1). Indeed on standard pulmonary function studies the only abnormality seen may be a decrease in diffusion capacity (DLCO). Of interest is that this lesion is easily correctable with increased inspired oxygen. Furthermore, oxygenation improves in the supine position (orthodeoxia) because of redistribution of blood flow away from the bases where these intra-pulmonary vascular dilations (IPVDs) predominate, and toward the apical, better ventilated areas of the lung. As long as the patient oxygen-

Normal vessels

Dilated vessels

(Room air)

8-15,u

Dilated vessels

(Room air),

(100% 02) _

90 ,o-lO0/t )

~ P.O2< 60

Ox > 500

( Fig 1. Schematic of pulmonary vascular abnormality suspected in hepatopulmonary syndrome. Schematic presumes that abnormal vessels are present at precapillary level and exist close to gas exchange units in the lung, thereby participating in diffusion of oxygen molecules from alveolus. Some vascular dilatations or communications may be larger, not in proximity to gas exchange units or have vascular walls that preclude transfer of oxygen molecules into venous blood flow. (Reprinted with permission. 64)

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ates easily and the need for supplemental oxygen recognized, there should be no significant increase in operative risk in a patient with a pure lesion of precapillary IPVD. The second type of abnormal arteriovenous communication are larger, and usually not closely associated with the alveoli. In particular, variations of porto-pulmonary anastomoses have been found in these patients. 22 These can be considered true anatomic shunts because supplemental oxygen produces minimal improvement to oxygenation. Fortunately, these shunts aie not considered an important cause of hypoxemia in liver disease. 22 The cause of hepatopulmonary syndrome is not clear. Certainly it can be supposed that the pulmonary circulation mirrors the widely dilated systemic circulation of the cirrhotic in response to the same stimuli. These may include any of several vasodilators that have been found to be elevated in end-stage liver disease such as vasoactive intestinal peptide (VIP), substance P, glucagon, endotoxin, prostaglandins,!etc. Alternatively, the pulmonary circulation rhay simply be responding to the primary development o f a hyperdynamic circulation in the cirehotic patient. Nevertheless, demonstrations of reversibility of hypoxemia caused by IPVD after orthotopic liver transplantation (OLT) suggest that this lesion has a functional component. 23'24 Equally unclear is the cause o f the third type o f pulmonary vascular lesion, which is pulmonary hypertension. Popular theories include repeat embolization of the p u l m o n a r y arterial tree by microthrombi, or failure of the liver to clear vasoconstrictor substances. A recent prospective study including over 500 patients with known portal hypertension reported a 2% incidence of p u l m o n a r y hypertension in that population. 25 This compares with a 0.13% incidence in an unselected population. 26 There was no correlation between p u l m o n a r y artery pressures and degree of liver failure (as assessed by Pugh's score) or portal pressures. However other signs consistent with p u l m o n a r y hypertension may be present, such as a p r o n o u n c e d P2 heart sound, right ventricular heave, large P-waves inferiorly on electrocardiogram, large R-waves in V1-3, and prominent p u l m o n a r y arteries on a chest radiograph.

MICHELLE Y. BRAUNFELD

A practical approach to the hypoxemic patient with liver disease would be to first look for and treat the c o m m o n pulmonary maladies mentioned earlier. A directed history and exam can suggest a need for further work-up. The findings of digital clubbing on exam and/or a history of worsening dyspnea on standing suggest a pup monary vascular lesion. As described earlier, findings consistent with fight ventricular hypertrophy or tricuspid disease point to possible pulmonary hypertension. Occasionally the fluffy appearance of a profusion of basilar IPVDs on a chest radiograph can be mistaken for an interstitial process. A simple first step to distinguish IPVD from true anatomic shunt is to measure the p02 on 100% oxygen. Minimal improvement suggests true shunt, although it does not distinguish intracardiac from other shunting. A normal response (partial pressure of oxygen > 500 m m Hg) essentially rules out shunt. A result somewhere in between cannot rule out shunt, and the next step to consider is contrast enhanced echocardiography (CE). Based on the time to appearance in the left heart of microbubbles from peripherally injected indocyanine green, the CE echo can differentiate between intracardiac shunt, IPVD, and a normal pulmonary circulation. 27 Although signs consistent with pulmonary hypertension can be found on routine preoperative studies, patients are frequently asymptomatic or have nonspecific symptoms such as dyspnea that can be attributed to other more obvious causes (ascites, pleural effusions, etc.). All too often the diagnosis is made only on fight heart eatherization at the time of surgery, if such was indicated. Once the diagnosis is established, whether preoperatively or intra-operatively, several issues need to be considered before proceeding with surgery: 1) How elevated are the pulmonary artery pressures (PAP)? 2) Are there associated cardiac lesions? 3) What is the nature of the surgery? Will there be large shifts in preload such as those that might occur with clamping and unclamping of large vessels? 4) How fixed is the disease? Does the PAP respond to oxygen and/or pharmacological therapy?

ANESTHESIA FOR THE PATIENT WITH LIVER DISEASE

If time permits one would ideally like to see improvement on a trial of oral vasodilators, such as hydralazine or nifedipine. Failing that, one may consider parenteral nitroglycerin, nitroprusside, dobutamine, amrinone, and prostaglandin E1 alone or in combination. The factor limiting therapy is systemic hypotension because none of these drugs selectively affect the pulmonary arteries. For this reason, the use of nitric oxide which experimentally can selectively decrease pulmonary vascular resistance without decreasing systemic vascular resistance, may be an attractive future option. 28 CARDIAC

The cardiovascular system can be involved in two major ways. First, there may be intrinsic cardiac disease associated with the underlying cause of the liver disease. Second, there may be a typical hyperdynamic circulatory pattern with high cardiac output and low peripheral resistance. Alcohol abuse is associated with a dilated cardiomyopathy and dysrhythmias. However, c o m m o n wisdom maintains that patients will develop cirrhosis or cardiomyopathy, but rarely both. 29'3~Generalized inflammatory and deposition processes that produce cirrhosis may also affect the myocardium, such as systemic lupus erythematosis, sarcoidosis, amyloidosis, hemochromatosis, etc. Between 30% and 60% of all patients with cirrhosis develop a hyperdynamic circulation. 3~ Typically the cardiac index is elevated to 4 to 6 L / m i n / m 2 with an systemic vascular resistance < 700 dyne/cm/sec-5. 32 Extremities are well perfused, warm, and dry in contrast to the clinical picture of septic shock that may have similar indices. Although overt cardiomyopathy with congestive failure is u n c o m m o n in cirrhosis, some patients will manifest ventricular dysfunction when faced with volume or pressure overload. 3~ Thus, even in the apparently compensated cirrhotic the threshold for instituting Swan-Ganz monitoring should be low. RENAL

The sine qua non of renal dysfunction in cirrhosis is inappropriate avid salt and water retention. The signs of this may range from a little peripheral edema to the extreme condition of he-

197

patorenal syndrome. Several mediators play on this field, some only enter the picture in the decompensated cirrhotic with chronic ascites. These include anti-diuretic hormone, the renin-angiotensin-aldosterone system, prostaglandins, and the sympathetic nervous system. The event initiating sodium and water retention is controversial. The "underfilling" theory proposed that the kidneys saved salt and water in response to a decrease in central volume by the formation ofascites. When it was shown that in fact an increase in central volume preceded ascites formation in experimental animals, the "overfilling" theory was put forth. This claimed that the kidneys primarily saved salt and water in response to some hormone or reflex, probably gut-induced, that appeared in cirrhosis and superseded the usual homeostatic mechanisms. In the late 1980s, Schrier et al produced yet a third hypothesis that was perhaps most consistent with the observed phenomena. 33 This was that the primary event is peripheral vasodilation caused by failure of the liver to clear any of a number of vasoactive endogenous substances. Putative culprits included those mentioned earlier as possible causes of IPVDs, ie, glucagon, substance P, endotoxin, prostaglandins, etc. The kidney perceives this decrease in SVR as a decrease in central blood volume and responds by saving sodium and water. When presented with an olioguric patient with liver disease, the first step should be to rule out treatable disease, most often hypovolemia and sepsis. Early and aggressive central monitoring as opposed to empiric therapy is indicated in this fragile patient population. Diuretics should not be administered without first assuring adequate central volume. Although the hemodynamic pattern of high cardiac output and low SVR is c o m m o n to both sepsis and end-stage liver disease, further work-up with appropriate cultures should delineate sepsis. Particularly ]n hospitalized patients, nephrotoxic drugs should be sought and discontinued if possible. These include aminoglycosides, ibuprofen (and probably all non-steroidal anti-inflammatory drugs), and intravenous contrast. The serum creatinine measurement notoriously underestimates renal function in the cirrhotic. In one study of nonazotemic cirrhotic patients, a serum creatinine

198

of 1.1 mg/dL correlated with a GFR of 66 mL/ min. 34 Furthermore, hyperbilirubinemia may artifactually lower measured serum creatinine. 35 Hepatorenal syndrome (HRS) is a diagnosis of exclusion given to renal insufficiency in the setting of liver disease. The renal lesion is profound vasoconstriction causing reduced GFR. 36The lesion is not fixed, and histologically the kidneys show no specific abnormality.3v Therapy is primarily supportive and aimed at increasing renal perfusion via pharmacological or mechanical means. These may include the administration of diuretics, PGE1 (a vasodilator), large volume paracentesis with albumin replacement, LeVeen shunt, and possibly the placement of a transjugular intrahepatic porto-caval stent (TIPS). Dialysis is reserved for the rare patient who is expected to recover hepatic function or while awaiting orthotopic liver transplantation (OLT). Without improvement in hepatic function either by healing or by OLT, cure of HRS is unlikely and the clinical course often progresses rapidly downhill. Anesthetic interventions should be mindful of maintaining renal perfusion and avoiding nephro- and hepatotoxic drugs. Adequate central volumes must be maintained and hypotension, obviously, avoided. Although there is one intriguing study showing increased renal perfusion and natriuresis from unilateral lumbar sympathetic block in HRS patients, 38 the severe complex coagulopathy present in these patients makes major conductive block inadvisable. Anesthetic choices are essentially limited to general anesthesia, peripheral blocks, and local anesthesia. Ideally the method should be used that affects the least number of major organ systems. Among general anesthetics, inhalational agents are preferable to fixed agents because of the unpredictability of disposition in the patient with renal and hepatic failure, and the amplified central nervous system effect of drugs in the patient with any encephalopathy. Isoflurane, being the least metabolized and best preserving of hepatic blood flow seems to be the inhalational agent of choice. Although the enzyme that degrades succinylcholine, pseudocholinesterase, is synthesized by the liver, there is no evidence that a single dose for intubation produces clinically significant prolongation of neuromuscular blockade in liver

MICHELLE Y. BRAUNFELD

disease. 39 Should continued muscle relaxation be necessary, atracurium, which is dependent on neither the liver nor the kidney for clearance, is probably the drug of choice.4~ Additionally, administering low dose dopamine (2 to 3 t~g/kg/ min) in attempt to increase renal plasma flow may be considered. GASTROINTESTINAL Most patients with chronic liver disease can be considered to have full stomachs for a variety of reasons. In addition to the idiopathic nausea and vomiting associated with cirrhosis, gastritis and a congestive gastropathy associated with portal hypertension are common lesions and predispose the patient to gastrointestinal bleeding. For mechanical reasons, all patients with ascites, especially tense ascites, should also be considered to have a full stomach. A controversial issue is the use of esophageal stethoscopes in the patient with esophageal varices. A study of patients undergoing OLT at the Mayo Clinic showed no significant incidence of variceal bleed in patients with a history of varices.4~ It should be added that this does not apply to patients with recent or active bleeds. Furthermore, caution should also be exercised in patients who have had sclerotherapy who have had strictures and scarring and may be at risk for perforation. In the patient with ascites, laparotomy with loss of ascitic fluid should be followed with aggressive albumin replacement. It should be kept in mind that tense ascites causes artificial elevation of cardiac filling pressures by transmission of abdominal pressures. 42 Release, especially of tense ascites may initially increase cardiac output by increasing venous return. 43 However, ascites reaccumulates rapidly. The continued fall in central pressures may cause a deterioration in hemodynamics and should be treated in an anticipatory manner. HEMOSTASIS The coagulation system consists of three interactive processes. The first is the local reaction to a vessel injury that includes vasoconstriction and platelet adherence and aggregation at the site. The second involves activation of the clotting cascade that ends in fibrin deposition to form a

ANESTHESIA FOR THE PATIENT WITH LIVER DISEASE fibrin plug. The third is modulation of the clotting process both by revision of the formed fibrin clot and by inhibition and clearance of activated clotting cascade factors. The liver is the site of not only the synthesis of most of the important factors in the coagulation cascade but also for those that limit and revise clot formation. Further, it is where activated coagulation factors are cleared. Liver disease renders a complex coagulopathy by interfering with synthetic and clearance functions as well as affecting platelet number and function. Although procoagulant and anticoagulant factors may both be decreased in liver disease, the net result clinically is a bleeding rather than thrombotic diathesis. Portal hypertension with splenic congestion leads to platelet sequestration and a low circulating platelet count. The underlying cause of the liver disease may contribute to the thrombocytopenia, eg, alcohol-induced bone marrow suppression or immune-mediated platelet destruction in chronic hepatitis. Furthermore, there may be qualitative defects in the platelets that are available. Platelet transfusions are given with the aim of keeping counts above 50,000/mm 2, but continued sequestration or antibody activity may occasionally make this difficult. Coagulation factors may be decreased both in a m o u n t and function. The vitamin Kdependent factors (II, VII, IX, and X) require adequate amounts of vitamin K to be made functional. In malabsorptive states where the fat-soluble vitamin K is poorly absorbed, a correctable functional defect occurs. This means, for example, that in cholestatic disease although coagulation factor levels may even be elevated, 44 tests of function (prothrombin time) may still be abnormal and could be expected to respond to vitamin K. On the other hand, the patient with hepatocellular liver disease who has lost synthetic function will be found to have depressed levels of coagulation factors and an abnormal PT. Although vitamin K administration may help, his overwhelming problem is that he needs coagulation factor supplementation. Fresh-frozen plasma should be administered with the goal of keeping PT at an international normalized ratio <1.5. Although fresh-frozen plasma contains fibrinogen

199

(factor I) cryoprecipitate is better source and should be used to treat levels <100 mg/dL. Even replacement ofplatelets and coagulation factors may not produce normal hemostasis in the patient with liver disease. Primary firbrinolysis associated with increased levels of tissue plasminogen activator (TPA), and possibly DIC (disseminated intravascular coagulation) with secondary fibrinolysis are both thought to contribute to reduced hemostasis. 45 The issue of whether or not DIC is part of the coagulopathy of liver disease is controversial. Many of the laboratory abnormalities present in severe liver disease are consistent with a diagnosis of DIC, but may also be attributable to liver failure per se. Nonetheless, it is certainly possible for the cirrhotic to present with a superimposed DIC from a classically recognized cause such as LeVeen shunting or sepsis. 45,46 Antifibrinolytics such as epsilonaminocaproic acid (EACA or Amicar) or tranexamic acid are effective therapy for primary fibrinolysis. Both work by inhibiting plasminogen activation. Because EACA has a short half-life it may be preferable to tranexamic acid in the operating room. Caution must be exercised in the patient with suspected superimposed DIC as antifibrinolytics in this setting may produce life-threatening thrombosis. ELECTROLYTES

Sodium As previously discussed, the hallmark effect of cirrhosis on renal function is avid salt and water retention. Cirrhotics have elevated levels of aldosterone and antidiuretic hormone, both of which lead to hyponatremia. This, coupled with the fact that many of these patients are on diuretics but not fluid restriction, can easily set the stage for severe hyponatremia. Particularly in the setting of liver disease, large acute increases in sodium are associated with ceritral pontine myelinolysis, a devastating neurological complication. 47,48Correction of serum sodium should ideally be made before surgery using the most reasonably conservative means. 49 If this is not possible, limitation of perioperative increase in serum sodium is important. Although the data is far from satisfying, a 1989 study of liver transplant patients suggests an allowable increase of

200

MICHELLE Y. BRAUNFELD

up to 16 meq/L over an 8-day perioperative period. 5~Measures to limit sodium increase include avoidance of normal saline intravenous fluids (Plasmalyte [Baxter, Deerfield, IL], Lactated Ringer's, and half-normal saline all have less sodium), using salt-poor or 25% albumin, and the use of THAM (Abbott Labs, Chicago, IL), a nonsodium buffer, instead of sodium bicarbonate to treat acidosis. Potassium The combination of gastrointestinal losses, poor nutrition, and diuretics are the most common causes of hypokalemia in the cirrhotic patient. Less-common causes include hyperaldosteronism and renal tubular acidosis (particularly in autoimmune liver disease). Cirrhotic patients are particularly sensitive to hypokalemia. The associated metabolic alkalosis favors the intracellular movement of ammonia in the central nervous system, leading to encephalopathy) ~ Calcium All banked-blood products contain citrate as part of the preservative. The cirrhotic liver may have a diminished capacity for metabolizing citrate, which binds ionized calcium and may produce clinically significant hypocalcemia. 5z'53 Fresh-frozen plasma is the worst offender, having more citrate than any other banked product. During procedures that require blood product administration, serial ionized calcium measurements should be monitored and supplemental calcium administered as needed. PHARMACOLOGY Liver disease affects not only the number of cells available to metabolize a drug, but also the blood flow to those cells, the volume of distribution of drug, and drug protein binding. Furthermore, there may be changes in end-organ effects of a drug, especially in the CNS. Because there are different phases of dysfunction in liver disease, the patient's reaction to a drug is frequently unpredictable. For example, early in the course of alcoholic liver disease the patient may have CNS tolerance of sedatives and increased metabolism because of induction of microsomal enzymes. 54 Later, when significant hepatocellular damage has supervened with por-

tal-systemic shunting, the patient may show extreme sensitivity and prolonged effect of those same drugs. 55'56 A useful way to consider drug disposition is by the degree of extraction from blood by the liver. One may describe the extraction ration (ER) of a drug as (Ci-Co/Ci where Ci = drug concentration in blood entering the liver and Co = drug concentration leaving the liver. If a drug is highly extracted, then the Co is very small and ER approaches Ci/Ci or 1. If a drug is poorly extracted, then Co is close to Ci and ER approaches 0. Drug availability for pharmacological effect or bioavailability (B) can be expressed as a percentage of the whole B = 1-ER. Thus, a highly extracted drug with an ER close to 1 has a small fraction of the total dose available fo/pharmacological effect and a poorly extracted drug has a large percentage of the dose available. Clearance of highly extracted drugs is theoretically not limited by the intrinsic ability of the liver to metabolized them (hepatocellular function) but by the rate that the drug can be presented to be metabolized, ie, hepatic blood flow. Predictably, in cirrhosis clearance is prolonged. If porto-systemic shunting also exists or if there is severe hepatocellular dysfunction, these drugs no longer behave like highly extracted drugs, but more like poorly extracted drugs. 57 Among other things this means a significant increase in bioavailability because even a small drop in ER from say 95% to 90% means a 100% increase in bioavailability from 5% to 10%. Decreases in protein binding of highly extracted drugs do not alter their already efficient clearance but do increase the amount of unbound drug and thus pharmacological effect of a dose. In contrast, clearance of a poorly extracted drug is subject to the degree of protein binding and by the liver's intrinsic ability to eliminate that drug. Because these variables do not always change in concert, it is generally more difficult to predict the disposition of poorly extracted drugs in liver disease. However, unlike highly extracted drugs, decreased protein binding does not increase bioavailability, but may increase clearance. Volume of distribution for drugs may be increased or decreased. When it is decreased, loading doses should be decreased accordingly. When

ANESTHESIA FOR THE PATIENT WITH LIVER DISEASE it is increased, it does not necessarily follow that loading doses should be increased. Decreased protein binding may cause an unanticipated greater pharmacological effect if this is done. Nor can it be assumed that a greater than usual initial dose to reach a desired effect means that the patient will continue to have an increased dosing need. It may simply be, as with some neuromuscular blockers, that an increase in Va does necessitate a greater loading dose to reach a therapeutic end point. However, clearance of the drug is impaired so that subsequent doses are smaller or spread further than usual. In general, the safest approach, as with any other ill patient, is to start conservatively with a low dose of drug and titrate slowly. This is particularly true for drugs with a high first pass m e t a b o l i s m (highly extracted) and for drugs with CNS activity. While certain metabolic functions are better preserved t h a n others (eg, Phase II glucuronidation is better m a i n t a i n e d t h a n Phase I r e a c t i o n s - - o x i d a t i o n , reduction, hydrolysis), 5a in end stage liver disease all pathways are impaired. Drugs such as l o r a z e p a m and m o r p h i n e that are eliminated by glucuronidation m a y not require dosage a d j u s t m e n t in well-compensated cirrhosis but will in the dec o m p e n s a t e d patient. Another consideration is to avoid fixed agents as m u c h as possible, relying instead on inhalational agents. If fixed agents are necessary, drugs that require the least a m o u n t of hepatic metabolism m a y be favored. A m o n g the neuromuscular blockers, a t r a c u r i u m m a y be the drug of choice for reasons discussed earlier. Vecuronium, despite a significant c o m p o n e n t o f hepatic m e t a b o l i s m behaves in a dose-dependent manner, with doses _<0.15 m g / k g exhibiting a similar duration of action in cirrhotic and normal patients. 59 A m o n g the m e d i u m duration narcotics, m o r p h i n e emerges as the drug of choice for two reasons. First, its metabolism is by glucuronidation, a function that is well-preserved. Second, studies suggest the existence of extra-hepatic m o r p h i n e m e t a b o lism and maintenance of normal clearance even in cirrhosis. 6~ A m o n g short acting narcotics, clearance of fentany162 and sufentani163 r e m a i n unchanged in cirrhosis, whereas clearance of alfentanil is markedly prolonged.

201 SUMMARY

Patients with liver disease are at increased risk for complications after surgery. 14 In those patients with chronic disease, risk correlates with Child's or Pugh's class and the location of surgery. In those patients with acute disease (excluding FHF), risk is less quantified but prudence dictates a conservative approach to proceeding with surgery. Careful anesthetic m a n a g e m e n t may make a difference in patient outcome. This includes optimizing the patient preoperatively, appropriate invasive monitoring, meticulous attention to metabolic and electrolyte abnormalities, rational selection of agents, and careful titration of drugs to clinical effect. End organ disease associated with liver disease affects every major organ system and may be as important or even more so than the liver disease per se. An index of suspicion must be kept for these disease processes during preoperative evaluation and appropriate work-up sought. A low threshold for invasive monitoring should be adopted particularly for the patient with end-stage disease. Successful care of these patients demands that the anesthesiologist accommodate a large group of medical needs when forming his or her anesthetic plan. REFERENCES 1. Child CG III: The liver and portal hypertension, in Dunphy JE, (ed): Major Problems in Clinical Surgery, Philadelphia PA, Saunders, 1964, p 24 2. Block RS, Allaben RD, Walt AJ: Cholecystectomyin patients with cirrhosis. Arch Surg 120:669, 1985 3. Doberneck RC, Sterling WA, Allison DC: Morbidity and mortality after operation in non-bleeding cirrhotic patients. Am J Surg 146:306, 1983 4. GarrisonRN, CryerHM, HowardDA, et al: Clarification of risk factorsfor abdominaloperationsin patientswith hepatic cirrhosis. Ann Surg 199:648, 1984 5. Pugh RNH, Murray-Lyon IM, Dawson J, et al: Transection of the oesophagus for bleeding oesophageal vafices. Br J Surg 60:646, 1973 6. Aranha GV, Greenlee HB: lntra-abdominal surgery in patients with advanced cirrhosis. Arch Surg 121:275, 1986 7. Greenwood SM, LeltlerG, Minkowitz S: The increased mortality rate of open liver biopsy in alcoholichepatitis. Surg Gynecol Obst 134:600, 1972 8. Harville DD, SummerskillWHJ: Surgeryin acute hepatitis, JAMA 184:257, 1963 9. Powell-JacksonP, Greeway B, Williams R: Adverseeffects of exploratory laparotomy in patients with unsuspected liver disease. Br J Surg 69:449, 1982

202 10. Zinn SE, Fairley HB, Glenn JD: Liver function in patients with mild alcoholic hepatitis after enflurane, N20-narcotic, and spinal anesthesia. Anesth Anal 64:487, 1985 11. Rappaport AM, Wanless IR: Physioanatomic considerations, in Scbiff LS, Schiff ER (eds): Diseases of the liver (ed 7). Philadelphia, PA, Lippincott, 1993 12. Ackroyd F, Mito M, McDermott N: Autonomic vasomotor controls in hepatic blood flow. Am J Surg 112:356, 1966 13. Gelman S: General anesthesia and hepatic circulation. Am J Phys Pharm 65:1762, 1986 14. Gelman S, Fowler K, Smith L: Liver circulation and function during isoflurane and halothane anesthesia. Anesthesiology 61:726, 1984 15. Goldfarb G, Debaene B, Ang E, et al: Hepatic blood flow in humans during isoflurane-N20 and halothane-N20 anesthesia. Anesth Analg 71:349, 1990 16. Gelman S: Disturbances in hepatic blood flow during anesthesia and surgery. Arch Surg 111:881, 1976 17. Hoyumpa AM, Desmond PV, Avant GR, et al: Hepatic encephalopathy. Gastroenterology 76:184, 1979 18. Schafer DF, Jones EA: Hepatic encephalopathy, in Zakin D and Boyer TD (eds): Hepatology, a textbook of liver disease (ed 2). Philadelphia, PA, Saunders, 1990 19. Gyr K, Meier R: Flumazenil in the treatment of portal systemic encephalopathy. Int Care Med 17:$39, 1991 (suppl) 20. Howard CD, Seifert CF: Flumazenil in the treatment of hepatic encephalopathy. Ann Pharmac 27:46, 1993 21. Krowka MJ, Cortese DA: Pulmonary aspects of liver disease and liver transplantation. Clin Chest Med 10:593, 1989 22. Krowka M J, Cortese DA: Hepatopulmonary syndrome: An evolving perspective in the era of liver transplantation. Hepatology 11 : 138, 1990 23. Eriksson L, Soderman C, et al: Normalization of V/Q relationships after transplantation in patients with decompensated cirrhosis. Hepatology 12:1350, 1990 24. Stoller JK, Moodie D, Schiavone WA, et al: Reduction of pulmonary shunt and resolution of digital clubbing associated with primary biliary cirrhosis after liver transplantation. Hepatology 11:54, 1990 25. Hadengue A, Benhayoun MK, et al: Pulmonary hypertension complicating portal hypertension. Gastroenterology 100:520, 1991 26. McDonnell PJ, Toye PA, Hutchins GM: Primary pulmonary hypertension and cirrhosis: Are they related? Am Rev Respir Dis 127:437, 1983 27. Krowka M J, Tajik AJ, Dickson ER, et al: Intrapulmonary vascular dilations (IPVD) in liver transplant candidates: Screening by two-dimensional contrast-enhanced echocardiography. Chest 96:164S, 1989 (suppl) 28. Pepke-Zaba J, Higenbottam TW, Dinh-Zuan AT, et ah Inhaled nitric oxide as a cause of selective vasodilation in pulmonary hypertension. Lancet 338:1173, 1991 29. Regan T J, Haider B: Ethanol abuse and heart disease. Circulation 64:14, 198 l (supp 3) 30. Lefkowitch JH, Fenoglio JS: Liver disease in alcoholic cardiomyopathy. Hum Pathol 14:457, 1983 31. Rakela J, Krowka M J: Cardiovascular and pulmonary complications of liver disease, in Zakim D, Boyer TD (eds):

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ANESTHESIA FOR THE PATIENT WITH LIVER DISEASE 51. Gabuzda GJ, Hall PW III: Relation of potassium depletion to renal ammonia metabolism and hepatic coma. Medicine 45:481, 1966 52. Washington DE, Prager MC, Kelley SD, et al: Ionized calcium levels during fresh frozen plasma administration in patients with end-stage liver disease. Anesthesiology 75:A277, 1991 (abstr) 53. Marquez J, Martin D, Virji AA, et al: Cardiovascular depression secondary to ionic hypocalcemia during hepatic transplantation in humans. Anesthesiology 65:457, 1986 54. Coudere E, Ferrier C, Haberer JP, et al: Thiopentone pharmacokinetics in patients with chronic alcoholism. Br J Anaesth 56:1393, 1984 55. MacGilchrist A, Birnic G, et al: Pharmacokineties and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 27:190, 1986 56. Neal E, Milfin P: Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 77:96, 1979 57. Williams RL: Drug administration in hepatic disease. New Engl J Med 309:1616, 1983

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