Diagnosis
Screening method
Perioperative consequences
Cirrhotic cardiomyopathy (CCM)
Echocardiography assessment of LV diastolic function
Congestive heart failurea
Hepatopulmonary syndrome (HPS)
Room air hypoxemia (PaO2 <70 mmHg) in the absence of other causes; confirmed by bubble echo
Although hypoxemia is typically responsive to supplemental oxygen, HPS is associated with increased infectious risk and perioperative mortality during liver transplantationb
Portopulmonary hypertension (POPH)
Echocardiographic estimate of RVSP; confirmed by right heart catheterization
Moderate to severe POPH associated with right heart failure and perioperative mortality during liver transplantationc
Medical management to optimize cirrhotic patients undergoing surgery should be directed toward treating active infection, optimizing central blood volume and renal status while minimizing ascites and improving encephalopathy. However, there is little evidence to support specific goal-directed targets for preoperative care in any of these areas. In particular, preoperative INR correction has little support. Evidence suggests that transfusion of plasma in the absence of bleeding increases central blood volume and worsens portal hypertension, which can lead to an increased risk of variceal bleeding [18]. Recent reviews argue against prophylactic plasma administration [19]. In an observational study of over 1200 patients with preoperative INR > 1.5 undergoing noncardiac surgery, 11% received preoperative plasma transfusion. Despite this, WHO grade 3 bleeding occurred in 53% of those receiving plasma compared to 32% in those who did not (OR 2.35, 95% CI 1.65–3.36) [20]. Standard doses of plasma rarely correct the coagulopathy of cirrhosis and, by worsening portal hypertension, can be harmful [21]. The INR has been recognized as an inadequate indicator of preoperative bleeding risk since PT/INR values depend upon the levels of procoagulants (factors I, II, V, VII and X) without accounting for low levels of endogenous anticoagulant factors. Due to elevated levels of endothelial-derived factor VIII and low levels of protein C, chronic liver disease patients often generate normal or high levels of thrombin [22]. Chronic liver disease patients are often in a delicate balance between inadequate hemostasis and excessive coagulation [23]. With bleeding, fibrinogen levels should be maintained >150–200 mg/dL with transfusion of cryoprecipitate or if available, human fibrinogen concentrate [19].
Perioperative risk depends more on the operative site and the degree of liver impairment than the anesthetic technique [24]. In a retrospective study of 733 cirrhotic patients, mortality was associated with the Child score (ascites, elevated creatinine), male gender, cryptogenic cirrhosis (vs. other etiologies), preoperative infection, higher ASA physical status, and surgery on the respiratory system. One-year mortality in patients with six risk factors was over 80%; mortality with two risk factors was 30% [4].
In addition to optimizing medical management, minimizing surgical risk should be considered. Gallstones are twice as common in cirrhotic patients as in patients without cirrhosis [8]. Laparoscopic surgery is safe in patients with Child A and B cirrhosis [25]. However, Child C patients may benefit from percutaneous drainage of the gallbladder over cholecystectomy [26]. In a series of over 4200 laparoscopic cholecystectomies, cirrhotics (n = 226) had a mortality of approximately 1/100, compared to 1/2000 without [27]. Preoperative decompression of portal hypertension by TIPS may improve outcomes in patients with severe portal hypertension [28].
Intraoperative Management
Monitoring and Vascular Access
In addition to standard noninvasive monitors, arterial pressure monitoring should be considered for patients with ESLD. The decision is based on preoperative hypotension due to vasodilatation, anticipated blood loss, the need for intraoperative laboratory studies, coexisting disease, and age. The usefulness of CVP monitoring to predict fluid responsiveness is debatable [29]. Many have abandoned CVP monitoring in the setting of liver resection [30–32]. In our practice, we do not place a central venous catheter exclusively for CVP monitoring. Pulmonary artery catheterization is used for patients with known or suspected pulmonary artery hypertension and/or low cardiac ejection fraction. Transesophageal echocardiography (TEE) is a sensitive monitor for the assessment of preload, contractility (including regional wall motion), ejection fraction, static and dynamic valvular abnormalities, emboli, and pericardial fluid. In a small series of patients with esophageal varices, TEE universally aided in diagnosis and was not associated with bleeding complications, although transgastric views were avoided to minimize esophageal manipulation [33]. Other authors have confirmed the safety of TEE in this population [34, 35].
Coagulation Management
Viscoelastic coagulation testing using thromboelastography or thromboelastometry may be a useful guide, more accurately reflecting the overall effects of altered levels of endogenous pro- and anticoagulant factors [36]. Abnormalities in platelet number and function are in part compensated for by increased levels of von Willebrand factor (VWF), a platelet adhesive protein, and by decreased levels of ADAMTS13, the VWF cleaving protease. Thrombin generation is preserved with platelet counts exceeding 50 × 109 / L, making this value a practical target in the setting of active bleeding [37].
Anesthetic Technique: Neuraxial Versus General Anesthesia
The effect of neuraxial or epidural anesthesia on hepatic blood flow appears related to alterations of systemic blood pressure [38, 39]. Standard contraindications to neuraxial blockade should be considered and weighed against the benefits on a case-by-case basis. Many patients with advanced hepatic disease may not be candidates for neuraxial techniques due to coagulopathy and/or thrombocytopenia. Nerve blockade may be appropriate even when neuraxial blockade is contraindicated. The transversus abdominal plane (TAP) block has been used successfully for abdominal surgery, including hepatobiliary procedures [40, 41]. However, the efficacy has been questioned and reported complications include abdominal wall hematoma.
Volatile Anesthetics
Volatile anesthetics decrease hepatic blood flow to varying degrees. Commonly used agents, isoflurane and sevoflurane, have less significant effects on hepatic blood flow than halothane [42]. Desflurane appears to more substantially decrease hepatic blood flow at one MAC, causing a 30% reduction [43]. At higher anesthetic concentrations, isoflurane causes a dose-dependent reduction in hepatic blood flow not seen with sevoflurane. In animal studies, both sevoflurane and isoflurane maintain the hepatic arterial buffer response, which increases hepatic arterial blood flow in the presence of reductions of portal blood flow [44, 45].
Concerns exist regarding the production of reactive intermediates during the metabolism of inhaled anesthetics. There is little evidence, however, to suggest that volatile anesthetics besides halothane are responsible for hepatic complications. Most volatile anesthetics undergo metabolism that yields reactive trifluoroacetylated (TFA) intermediates. These intermediates bind to hepatic proteins, producing an immunologic reaction leading to liver injury. The incidence of liver injury correlates to the extent to which inhaled anesthetics undergo this oxidative metabolism (halothane 20%, isoflurane 0.2%, desflurane 0.02%). Notably, sevoflurane metabolism does not result in TFA intermediates [46].
Nitrous Oxide
Nitrous oxide administration has not been shown to cause hepatocellular injury in the absence of hepatic hypoxemia [47]. Due to sympathomimetic effects, nitrous oxide can decrease hepatic blood flow, and inhibition of methionine synthase can occur after even brief exposures. However, the clinical significance of these effects is unclear [48].
Intravenous Anesthetics
Intravenous anesthetics and sedatives including propofol, etomidate, and midazolam do not appear to alter hepatic function when given for short durations. The effects of IV anesthetics after prolonged infusions in patients with advanced liver disease are not well studied. Propofol infusion syndrome (lactic acidosis, lipemia, rhabdomyolysis, hyperkalemia, and myocardial failure) has resulted in patient deaths [49]. Liver dysfunction resulting in altered lipid metabolism may predispose to cirrhotics to propofol infusion syndrome [50]. Patients on prolonged propofol infusions should be monitored for progressive lactic acidosis and escalating vasopressor requirements.
There is no evidence that opioids have an effect on hepatic function independent of hepatic blood flow. All opioids increase sphincter of Oddi pressure. Some authors have suggested that morphine causes spasm in the sphincter of Oddi, but a review failed to show a differential effect, concluding that morphine may be preferred over meperidine for the treatment of patients with acute pancreatitis due to less risk of seizures [51].
Pharmacokinetic and Pharmacodynamic Alterations
Decreased hepatocellular mass and portocaval shunts lead to reduced metabolism of drugs that rely on hepatic metabolism. Factors that affect hepatic clearance include blood flow to the liver, the fraction of the drug unbound to plasma proteins, and intrinsic clearance. Drugs with low extraction ratios < 0.3, have restrictive hepatic clearance. Clearance of drugs in this class is affected by protein binding, the induction or inhibition of hepatic enzymes, age, and hepatic pathology, but clearance is not significantly affected by hepatic blood flow. Drugs with high extraction ratios (> 0.7) undergo extensive first-pass metabolism, which alters their bioavailability after oral administration. Drugs with high extraction ratios are significantly affected by alteration in hepatic blood flow, which can occur with hemodynamic changes or hepatic inflow clamping during liver resection.
Benzodiazepines have a low extraction ratio and the elimination half-life can be prolonged (diazepam t 1/2 = 43 h). Studies have shown conflicting effects of cirrhosis on the metabolism of midazolam, possibly due to changes in protein binding [52, 53]. As hepatic protein synthesis declines, the drug fraction bound to protein decreases. While the pharmacokinetic implications of ESLD are complex, patients with encephalopathy display an increased sensitivity to sedatives and analgesics.
Opioid metabolism is reduced in patients with liver disease, so dosing intervals should be increased to avoid drug accumulation. The clearance of the meperidine metabolite normeperidine is reduced in liver disease, which can lead to neurotoxicity [54]. The elimination of a single IV opioid bolus is less affected than a continuous infusion through redistribution to storage sites. Opioid dosages in patients with advanced disease should be reduced to avoid precipitating or worsening encephalopathy.
The intermediate duration neuromuscular blocking agents vecuronium and rocuronium are metabolized by the liver and exhibit a prolonged duration of action [55, 56]. Despite this, a resistance to the initial dose of neuromuscular blocker typically occurs due to elevated γ-globulin concentrations and an increase in the volume of distribution (due to edema and/or ascites). Atracurium and cisatracurium undergo organ-independent elimination and their durations of action are not affected by liver disease. Succinylcholine metabolism is altered due to reduced plasma cholinesterase activity in cirrhotic patients, but the clinical impact is rarely significant.
Vasopressors and Volume Resuscitation
In contrast to sedatives, patients with liver disease exhibit a reduced responsiveness to endogenous vasoconstrictors including angiotensin II, vasopressin, and norepinephrine [57]. Hyporesponsiveness to catecholamines may be modulated by the release of nitric oxide, prostacyclin, and other endothelial-derived factors in response to humoral and mechanical stimuli [58]. Many patients present with hyperdynamic circulation characterized by low systemic vascular resistance, borderline hypotension and elevated cardiac output. These patients frequently cannot tolerate induction or maintenance of anesthesia without vasopressor support. In patients undergoing abdominal surgery, fluids should be restricted (with or without CVP monitoring) in order to lower portal pressures.
When need for volume resuscitation arises, the fluid and blood products administered are similar in patients with and without liver disease, but with several notable exceptions. In ESLD, serum albumin function is quantitatively and qualitatively decreased [59]. Albumin has three major indications in the treatment of cirrhotic patients [60]:
In a randomized trial of terlipressin with and without albumin, a higher proportion (77%) of the group that received albumin showed a complete response compared to terlipressin alone (25%) [63]. In patients with hyponatremia, hypotonic sodium should be administered to avoid a rapid rise in serum sodium, which can be associated with central pontine demyelination and permanent neurologic injury.
Transjugular Intrahepatic Portosystemic Shunt (TIPS) Procedure
Sedation is commonly used to facilitate placement, although general anesthesia is preferred by some to limit patient movement, control diaphragmatic excursion, and reduce the risk of aspiration. Complications include pneumothorax or vascular injury during access to the jugular vein. Dysrhythmias can occur during catheter insertion and extrahepatic artery or portal vein puncture can result in significant hemorrhage [64].
Hepatic Resection
Hemorrhage remains a major complication in hepatic resections, although transfusion is necessary in less than 20% of cases [65, 66]. Newer transection techniques using ultrasonic dissectors, high-pressure water jets, and harmonic scalpels may be helpful, but they have not been proven to be superior to conventional clamp crush techniques [67–69]. Techniques to maintain CVP at normal or low (<5 cm H2O) levels have been suggested to limit blood loss [70]. In a single-center, uncontrolled series of nearly 500 hepatic resections managed with low CVP, no cases of renal failure were attributed to the technique [71]. There is conflicting data regarding the correlation between low CVP technique and blood loss. Two series of living liver donor surgeries concluded that CVP is not a predictor of blood loss during hepatic resection [72, 73]. A recent meta-analysis found that low CVP does not decrease morbidity, but does reduce blood loss [74]. Another recent study found that fluid restriction, confirmed by high stroke volume variation, resulted in less blood loss [75]. Aside from CVP, vasopressors can reduce splanchnic pressure and decrease blood loss through their direct effects on splanchnic vessels [76].
Even in patients with normal preoperative coagulation profiles, the INR and platelet count can be abnormal after liver resection. The severity of the derangement correlates with the extent of the resection, peaks postoperative day one to two, and takes up to five or more days to resolve [77, 78]. This postoperative coagulopathy may be a contraindication to continuous epidural analgesia, increasing the risk of epidural hematoma during catheter removal. Some authors advise against preoperative epidural catheter placement, while others recommend correcting coagulation abnormalities prior to catheter discontinuation [79]. Using viscoelastic testing, brief hypercoagulability after liver resection despite prolonged prothrombin times have been reported [80]. Alternatives that avoid epidural catheter placement include intrathecal opioid and local anesthesia infusion systems [81].
Conclusion
In general, contraindications to elective surgery in patients with ESLD include acute viral or alcoholic hepatitis, fulminant liver failure, Child’s class C cirrhosis, severe coagulopathy due to splenic sequestration of platelets or prolongation of the INR despite vitamin K repletion, and severe extrahepatic complications secondary to hepatopulmonary syndrome, portopulmonary hypertension, hepatorenal syndrome, or cardiomyopathy [7]. Elective surgery is considered relatively safe with MELD scores below 11 and contraindicated until after liver transplantation when MELD exceeds 20 [15].
Preoperative optimization includes effective control of ascites through diuretics or paracentesis to improve oxygenation and increase functional residual capacity. Elevated INR is not an independent risk factor for increased perioperative bleeding. When available, viscoelastic testing may be a more accurate reflection of coagulopathy to guide repletion of clotting factors, fibrinogen, and platelets.
In the absence of particular contraindications (primarily significant coagulapthy), neuraxial, regional, as well as general anesthesia have all been successful in ESLD patients. Because of decreased hepatic metabolism and increased volume of distribution, initial dosing and dosing intervals will have to be adjusted, particularly for opioids and intermediate-acting neuromuscular blockers.
Advances in surgery, anesthesia, and intensive care have led to improved outcomes in patients with significant liver disease. These advances are related to comprehensive preoperative screening and preparation that avoids further hepatic injury. However, when deterioration occurs, liver transplantation should be considered early as it is the only definitive treatment for irreversible hepatic failure.
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