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 [75]. 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 [75]. Nevertheless, two points should be considered by the anesthesia care giver:

Most regulations of metabolism, metabolization, and protein synthesis seem to recover post-LT [75]. 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 [83]. 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:

The combination of these drugs aim to target different sites of the T-cell activation cascade and to minimize side effects [83]. Stopping immunosuppression might result in fatal rejection of the transplanted organ [84]. 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 [59]. 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 [59].

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) [69]. 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 [72]. 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 [84]. 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 [84].

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 [79].

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 [79]. 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 [79].

The risk of allograft dysfunction in nontransplant surgery following LT remains low [59]. But a potential rejection of the transplanted liver should always be ruled out prior to elective surgery and anesthesia [79]. 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 [72]. 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 [92]. The prevalence of neurological symptoms or disorders after LT ranges from 11 to 42 % [93]. Remarkably, patients diagnosed with hepatic encephalopathy before transplantation are at high risk developing neurological symptoms post-LT [94].

Most neurological complications occur in the early phase after LT [95]. 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 [92]. Cerebrovascular events, particularly in the early phase after LT, represent most severe complications that are associated with high mortality [97].

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 [93]. 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.