Mild systemic disease
Severe systemic disease, not incapacitating
Severe systemic disease that is a constant threat to life
A moribund person who is not expected to survive without operation
A declared brain-dead person whose organs are being removed for transplantation
Child-Turgcotte-Pugh classification (CTP) (Table 31.2): The significance of the Child-Pugh classification was heavily debated. However, the classification has been shown to correlate with mortality in patients with liver dysfunction who underwent different types of surgery. Thus, it still might serve as additional information for the risk and risk-management of these patients [1, 15–17]. In this respect, patients with a CTP < 8 seem relatively save for most types of surgery .
Child-Turcotte-Pugh’s classification (CTP)
Total bilirubin (mg/dL)
Prothrombin time (s. prolonged)
Prothrombin time (INR)
Hepatic encephalopathy (grade)
Model of end-stage liver disease ( MELD , Table 31.3): MELD scores correlate with mortality in patients with liver cirrhosis subjected to different types of surgery [19–22]. In liver diseased nontransplanted or post-LT patients, an increased MELD additionally hints towards cardiac or renal malfunction [23, 24]. A range between 8 and 14 points were suggested, below which anesthesia and surgery should be relatively safe [18, 20, 21, 25]. In my opinion, the wide range of MELD score proposed would suggest that no clear MELD score cut-off exists that would reliably predict the patients’ individual risk for a certain anesthetic or surgical procedure. Certainly, the type of surgery and experience of the medical team are of great importance.
Model of end-stage liver disease score (MELD) : calculation
MELD = [0.957 × (log s-creatinine) + 0.378 × (log s-bilirubin) + 1.120 × (log INR) + 0.643] × 10
Patients with suspected liver dysfunction scheduled for anesthesia and surgery need to receive a thorough medical history and physical examination in order to detect preexisting liver disease and related problems [1, 26, 27]. Fatigue, nausea and vomiting, hematemesis, pruritus, jaundice, hemorrhagic diathesis, abdominal distension, or altered mental status can represent clinical signs of liver dysfunction . Additionally, taking a drug history is essential in order to uncover drug-induced liver failure . In particular paracetamol or antimicrobial drugs represent potential candidates for drug induced liver dysfunction [30, 31].
Hepatic encephalopathy exemplifies one of the main neurological complications in liver disease. Ammonia is thought to be of particular importance in its pathophysiology. Typical symptoms are ranging from apraxia and behavioral changes to decerebrate posturing and coma. Several aggravating and reversible factors should be avoided or minimized during anesthesia, such as: hypokalemia, alkalemia, hypoglycemia, hypovolemia, and administration of benzodiazepines [1, 6, 28].
See also Chap. 33
It is interesting to note that pulmonary symptoms might be the first signs of liver dysfunction which may occur even before liver disease is diagnosed . Pulmonary complications include lung restriction, pulmonary shunting, and portopulmonary hypertension:
Lung volume restriction can develop due to the presence of ascites and pleural effusion [32, 33]. To determine the quantity of pleural effusion and whether it needs preoperative drainage, pleural sonography is easier to perform and more specific as compared to chest X-ray [32, 34].
The hepatopulmonary syndrome predicates at least in part on imbalanced nitric oxide and endothelin production and endothelin receptors. Dilatation of pulmonary vessels in low ventilated areas results in a right to left shunt. The anesthesiologist must bear in mind that oxygen can improve hypoxemia, but mechanical ventilation during general anesthesia can even aggravate intrapulmonary shunting .
Portopulmonary hypertension develops due to a decreased clearance of vascular regulating mediators, e.g., serotonin, bradykinine, thromboxane, or neuropeptides. These mediators can activate vascular constriction, remodeling, and thrombosis in lung vessels . Portopulmonary hypertension should be ruled out prior to anesthesia and surgery, because it is associated with increased mortality . While mild forms of pulmonary hypertension might not be diagnosed, echocardiography can detect moderate to severe pulmonary hypertension . As potential treatment, prostacyclin analogues or endothelin receptor antagonist have been proposed recently [39–41].
See also Chap. 35
Severe liver disease can be associated with a hyperdynamic circulation, increased cardiac output, and reduced systemic vascular resistance. Furthermore, patients with CLD and ESLD show a high incidence of cardiac comorbidities:
Cirrhotic cardiomyopathy is defined as decreased cardiac contractility in hepatic patients [9, 23]. As a consequence during general anesthesia, the compensatory inotropic and chronotropic response to surgical stress is impaired. Thus, intraoperative hemorrhage, hypoxemia, or hypotension exacerbate hemodynamic instability and increase the risk of intra- and postoperative liver dysfunction.
Coronary artery disease is more prevalent in patients with ESLD . A 12-lead electrocardiogram should be routinely performed if not assessed recently. Furthermore, ECG-monitoring during anesthesia can detect intraoperative ischemic events.
See also Chap. 34
Hypoperfusion and/or ischemia play an important role in the development of the hepatorenal syndrome. It correlates with poor prognosis. Loop diuretics, aldosterone antagonists, and the use of vasoconstrictors appear to be important in these patients . In this regard, dopamine is not beneficial. As a first line therapy, vasopressin analogues, e.g., terlipressin, are recommended .
See also Chap. 36
The liver produces most coagulation factors. As a result of liver dysfunction or even liver failure, coagulation is impaired. In addition, splenic congestion as well as a decreased hepatic release of thrombopoietin can lead to low and dysfunctional platelets. Low preoperative platelet count reflects an independent risk factor on perioperative complications in liver surgery . Therefore, a thoroughly bleeding history should be taken prior to anesthesia and surgery. In case of intraoperative suspicion of diffuse bleeding, application of desmopressin before transfusion of thrombocytes should be considered .
Routine liver enzyme testing of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in CLD or ESDL patients is of little value and therefore not recommended, and should better depend on clinical suspicion of liver dysfunction . ALT as well as AST are markers of hepatocellular integrity and do not reflect hepatic function. Moreover, the remaining intact hepatocytes in severe liver cell damage can be low and result in a reduced release of cytosolic transaminases.
Albumin (half-life of 2–3 weeks) is probably a better marker of impaired liver function as compared to ALT or AST. To detect more acute alterations in hepatic function, prealbumin (half-life 2 days) can be of value.
Not only but especially when a history of bleeding exists, coagulation status should be assessed. Prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT) are of value. In addition, a complete blood count serves to determine possible thrombocytopenia and anemia .
Finally, testing electrolytes seems important, because imbalances are common in hepatic disease and need to be corrected in order to prevent cardiac arrhythmias, worsening of hepatic encephalopathy, or coagulation disorders.
Other than the above mentioned, markers of liver disease should be addressed according to the medical history and physical examination.
Alterations in hepatic blood flow, hypoalbuminaemia, volume of distribution, and changes in pharmacokinetics as well as pharmacodynamics are often seen in ESLD. Many anesthetics are metabolized in the liver. Liver dysfunction or liver insufficiency therefore impairs their metabolization. Combined with a higher susceptibility to narcotic drugs of the patient with ESLD, the requirement of anesthetics is lower [46–48]. In order not to overdose drugs or to risk awareness, the use of bispectral index monitoring to monitor depth of anesthesia in hepatic patients might be beneficial [49–51]. The metabolization and course of action of anesthetics might differ significantly in ESLD:
Opioids need dose adjustment and titration if applied continuously or repetitively. These drugs have prolonged half-lives in liver dysfunction. Single doses of fentanyl or sufentanil and continuous application of remifentanil is regarded safe in the hepatic patient.
With the exception of oxazepam and temazepam, benzodiazepines should be used with great caution. A decreased hepatic clearance for these drugs, lead to a longer elimination half-life and a prolonged recovery . Another disadvantage of benzodiazepines is reflected by the fact that stimulation of central GABA-receptors can worsen preexisting hepatic encephalopathy.
At the moment, propofol represents the best choice of intravenous narcotics. Its usage for sedation as well as induction of anesthesia seems save. It displays no significant pharmacokinetic alteration in cirrhosis, a normal recovery time, and minimal effects on preexisting encephalopathy [52–54].
Volatile anesthetics can be applied in order to maintain anesthesia. The use of halothane is discouraged, because of known hepatotoxic effects. If inhalational induction of anesthesia is necessary, sevoflurane should be used. Based on existing knowledge of modern volatile anesthetics, there is no major advantage or disadvantage between the different substances [55, 56]. Whether volatile anesthetics are a useful tool to especially sedate hepatic patients in the intensive care setting remains to be investigated .
Hepatic metabolized muscular blocking agents should be avoided. Because of extra-hepatic and extra-renal elimination, cis-atracurium seems best.
The possibility of employing regional anesthesia as an anesthetic technique in hepatic patients has been reviewed recently . Regional anesthesia might be applied under certain circumstances. However, up to date no evidence exist supporting better survival in this population with regional anesthesia.
Standardization of monitoring has not been fully established for ESLD or liver failure patients undergoing anesthesia. The decision for invasive monitoring should depend on the general constitution of the patient and the planned extend of surgery. In expectation of increased blood loss, large bore venous access is mandatory. The placement of arterial lines, central venous lines, or pulmonary artery catheters has not yet proven to count for improved outcome. During major surgery, monitoring of pH, lactate, glucose, sodium, potassium, calcium, and urine output is helpful.
Recovery from Anesthesia
Whether a patient with ESLD needs to be transferred to an intensive care unit depends on the type of surgery, risk of postoperative bleeding, and comorbidities of the patient.
In the recovery room and as mentioned above, benzodiazepines should be avoided and opioids for pain management should be titrated to effect.
General Anesthesia for the Patient Post Liver Transplantation
Patients who have undergone liver transplantation in the past often display symptoms related to the transplant operation or to immunosuppressive therapy on presentation in the emergency department. Hepatic, biliary and intestinal disorders, infections, or rejection are common diagnosis . Given the increasing survival and age of transplant recipients, this population might also develop diseases not related to liver transplantation. Taken together, a large proportion of patients post LT undergo some type of nontransplant surgery in the following years . While in the early posttransplant-stage abdominal surgery is needed, ENT, urology, gynecology, orthopedic, cardiac, and many other operations are scheduled later after LT [60–62].
With sufficient graft function, elective procedures including major cardiac surgery seem quite safe, and a higher incidence of complications are unlikely [59, 62]. However, in emergency operations, complication rate rises as compared to the nontransplanted population . Depending on the type of operation and the number of reoperations, the anesthesiologist should keep in mind that a difficult surgical approach could occur and that abdominal surgery is associated with increased blood loss and longer duration of operation .
See also Chap. 26
In the preoperative evaluation of post-LT patients several issues should be considered:
Preexisting diseases initiated by liver dysfunction might still be evident despite LT, e.g., left ventricular outflow obstruction, renal impairment, pulmonary affections, etc. .
The underlying disease that led to LT might reoccur, e.g., autoimmune disease, hepatitis, primary biliary cirrhosis, sclerosis, alcohol consumption, etc. [65, 66].
Perioperative complications and immunosuppression-related disorders might have developed, e.g., infection, rejection, vasculopathy, renal impairment, diabetes, systemic hypertension, neurotoxicity, malignancies, etc. .
The increase in survival of liver graft recipients has resulted in greater prevalence of complications. Most important with respect to post-LT morbidity and mortality are posttransplant cardiovascular and chronic kidney diseases, but also include diabetes, metabolic syndrome, systemic hypertension, and many others [70, 71]. Therefore, the focus during the preoperative evaluation should not be restricted to liver graft function, but must be expanded to all possible complications by thoroughly taking the medical history and evaluating the physical capacity of the patient. The preoperative assessment must include questions regarding recent changes in weight, fever, malaise, etc. The following most important issues should be ruled out prior to anesthesia and surgery:
Graft function and potential rejection
Organ systems, that might have been influenced by the underlying disease as well as the potential complication after liver transplantation
State of immunosuppression
Likewise, preoperative evaluation of pediatric liver transplant recipients should focus on side effects of immunosuppressive therapy, risk of infection, and the potential of rejection . Especially in children, but also to a lesser extend in adults, the anesthesiologist should carefully assess the airway. Post-LT lymphoproliferative diseases might have developed, affecting the tonsils, and complicating airway management [73, 74].
Differences Between Transplanted and Normal Liver
Some physiological responses relevant to anesthesia change with a transplanted liver as compared to a normal liver. Most importantly, the transplanted liver is denervated, thus, physiological responses of the liver might be blunted [60, 75]. For instance, patients are unable to feel liver capsule pain and typical clinical symptoms of liver pathologies may be absent. Another issue regards autonomic regulation. At least within the first year, it seems unlikely that sympathetic denervation is restored by re-innervation post LT, and catecholamine levels in the liver remain lower than normal . Soon after LT, total liver blood flow is elevated, firstly, due to the lack of vasomotor control and secondly, due to continued preexisting and abnormal splanchnic hemodynamics that might last for several months [76, 77]. Later after LT, liver allograft function and liver blood flow do not appear to be significantly impaired as a result of denervation under physiological conditions . Nevertheless, two points should be considered by the anesthesia care giver:
Experimental data suggest that catecholamine treatment , i.e., epinephrine and norepinephrine, act different in the transplanted liver as compared to normal liver. Here, macro- and microcirculation seems to be more decreased after LT in response to catecholamine therapy . Some authors recommend continuous administration of prostaglandin E to maintain sufficient hepatic perfusion in the allograft .
Most regulations of metabolism, metabolization, and protein synthesis seem to recover post-LT . Glucose metabolism and insulin resistance can be affected especially during the first months after LT. Immunosuppressive therapy appears to play a major role. Despite reduction of immunosuppressive drug dosing over time and the potential of normalization in glucose metabolism, post-LT diabetes represents a common side effect (see below) [81, 82].
The transplantation itself, the sometimes poor clinical condition of patients, and immunosuppressive therapy compromise the immune function of post-LT patients. Even if the immunosuppressive therapy can be reduced over time, most patients have to continue some form of immunosuppression lifelong . The choice of drugs for immunosuppressive therapy after liver transplantation varies between centers. Despite standardization, immunosuppressive regimens are additionally tailored to patients’ individual risk characteristics and primary indication for liver transplantation. Furthermore, the course of immunosuppressive therapy might change over time, including dose modification as well as switch of drugs according to side effect profile or allograft rejection [71, 83]. Commonly used immunosuppressive therapy after liver transplantation includes:
Calcineurin inhibitors (e.g., cyclosporine A, tacrolimus)
Antimetabolites (e.g., mycophenolate mofetil, mycophenolate sodium, azathioprine)
Mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus)
Anti-body based drugs (e.g., anti-thymocyte globulin, anti-lymphocyte globulin, muromonab-CD3 antibody, basiliximab, daclizumab)
The combination of these drugs aim to target different sites of the T-cell activation cascade and to minimize side effects . Stopping immunosuppression might result in fatal rejection of the transplanted organ . Therefore, it is more than important to continue immunosuppressive therapy in post-LT patients during the perioperative period of subsequent surgery or even pregnancy [4, 85]. The dose, schedule, and route of administration should be continued as before surgery and no dose should be withheld . If possible, a switch from oral administration to an intravenous route should be avoided. In case that oral intake cannot be continued, the transplantation center or the transplant team should be contacted regarding dosage advice [69, 84]. This is especially true, when sepsis or other severe disease might impact the gastrointestinal uptake of the drug .
Whether corticosteroid therapy needs additional intraoperative substitution, remains a matter of debate [60, 61]. Minor surgery after LT without signs of allograft rejection, most likely does not require additional cortisone applications. A routine use of stress dose has not been recommended [60, 84]. However, in major surgery and with a high degree of stress estimated for the patient, cortisone substitution might be considered.
Some immunosuppressive drugs are administered according to their blood concentration (e.g., cyclosporine A or tacrolimus) . Because of bleeding-induced hemodilution during post-LT operations and drug–drug interactions, these concentrations may vary. Therefore, daily monitoring of blood levels through the perioperative period and adjustment of dose are recommended [72, 85, 86].
The immunosuppressive therapy can exert significant side effects including neurotoxicity, nephrotoxicity, hyperkalemia, hypertension, diabetes, thrombocytopenia, leucopenia, etc. In the pediatric post-LT population, immunosuppression might further lead to growth retardation, hirsutism, serum electrolyte abnormalities, Cushing, obesity, pathological fractures, malignancies, and rarely hypertrophic obstructive cardiomyopathy . As mentioned above, the preoperative anesthesia evaluation needs to rule out all potential side effects of immunosuppressive therapy.
Immunosuppressants are extensively metabolized by hepatic cytochrome P450. Thus, multiple drug–drug interactions might occur and become unpredictable when several medications are administered at the same time. Calcineurin and mTOR inhibitors are of special interest regarding potential drug–drug interactions . With respect to anesthetic drugs used for induction and maintenance of anesthesia, human data is very limited. However, the characteristics of drugs administered during anesthesia might be altered on one hand, and anesthetics might alter blood concentrations of immunosuppressants on the other hand [69, 85]. An updated extended list on several drug–drug interactions with immunosuppressants can be found online .
Calcium channel inhibitors , in particular diltiazem, can elevate cyclosporine levels. This becomes evident if these drugs are given repetitively over days. A single bolus administration has probably no effect .
Propofol does not seem to alter cyclosporine levels nor is its action being altered by immunosuppressants .
Recovery from neuromuscular relaxants , e.g., vecuronium and pancuronium might be prolonged in patients receiving cyclosporine, and lower does might be necessary [88, 89]. In contrast to cyclosporine, azathioprine seems not to interact with neuromuscular relaxants . It is highly recommended that neuromuscular monitoring is employed in all patients on an immunosuppressive regimen.
Blood concentrations of benzodiazepines can be moderately increased if coadministered with cyclosporine. Application to effect has been recommended .
Most anti-infectives increase either the immunosuppressant concentration or their toxic side effects .
Time after Liver Transplantation
After successful transplantation the function of the allograft and subsequently of extra hepatic organs normalizes with time. It has been proposed grouping the time course post-LT in stages: e.g., perioperative, mid-term, and long-term .
Shortly after transplantation , direct consequences of the transplantation might be most prominent: poor clinical condition of the patient, pulmonary infections and effusion, insufficient liver function, acid base imbalances, anemia, coagulation disorders, and others. During this period, abdominal surgery might occur more often, e.g., re-exploration, revision of the bile duct system, revision of vascular complications, drainage of abscess or hematoma . If the patient requires a reoperation, the anesthesiologist may be confronted with increased intraoperative blood loss and severe hypotension. The latter can impair graft function and should be avoided as good as possible. Therefore, blood pressure, acid base and coagulation imbalances must be tightly monitored and corrected.
Later after transplantation and with restored liver function, the side effects of immunosuppression are predominant. For instance, hyperglycemia or renal dysfunction can develop and need attention from the anesthesiologist .
Liver Graft Function
The risk of allograft dysfunction in nontransplant surgery following LT remains low . But a potential rejection of the transplanted liver should always be ruled out prior to elective surgery and anesthesia . Of note, routine operations during graft rejection increase perioperative morbidity. Clinical signs of acute rejection involve cholestatic jaundice, increased liver enzymes, failure of hepatic synthetic function, eosinophilia, lymphocytosis, and nonspecific symptoms, e.g., poor appetite, irritability, fatigue . If suspicious signs of rejection are discovered, the patient should first undergo diagnostic and appropriate treatment in cowork with the transplant team or transplant center, before being scheduled for elective surgery. Finally and in case of living-related liver transplantation, the “small for size” liver syndrome and related graft insufficiency needs to be assessed prior to surgery [90, 91].
The neurological status might be impaired post-LT and represents a significant risk for morbidity and mortality . The prevalence of neurological symptoms or disorders after LT ranges from 11 to 42 % . Remarkably, patients diagnosed with hepatic encephalopathy before transplantation are at high risk developing neurological symptoms post-LT .
Most neurological complications occur in the early phase after LT . Here, seizures, encephalopathy, and mental confusion are predominant [92, 95, 96]. Later in the course after transplantation, encephalopathy and mental confusion are still of major impact . Cerebrovascular events, particularly in the early phase after LT, represent most severe complications that are associated with high mortality .
It appears difficult or almost impossible to find specific causes for neurological dysfunction after LT. Preexisting alcoholism, hepatitis, or malnutrition add to post-LT neurological malfunction . Other peri- or postoperative factors comprise for instance infections, side effects of immunosuppressive therapy, electrolyte dysbalances, and many others [92, 96]. Most likely, the orchestration of several pre-, intra-, and postoperative factors leads to neurological dysfunction post-LT.
Why are neurological malfunctions important to the anesthesiologist? First, morbidity and mortality are increased in these patients. Second, patients might present with seizures, thus, anesthetics which lower the seizure threshold and intraoperative hyperventilation should be avoided in these patients. Third, patients might not be fully aware of the planned procedure and may be incompliant to preoperative orders or unable to give consent to the anesthesia procedure.