Anesthesia For Liver Transplantatin

Speaker:DR. UDAY PRATAP SINGHCo-ordinator:Dr. ROOPESH KUMAR

INTRODUCTION• In 2006, the number of liver transplantations performed in the United States

6650,LT decreased slightly to 6494 in 2007.

• As of early 2008, approximately 17,200 patients were on the waiting list for liver transplantation in the United States; approximately 1600 to 1800 patients die each year while awaiting liver transplantation.

• Nationwide, the 3-year patient survival rate after transplantation is greater than 75%.

• cirrhosis is likely to develop in 25% to 30% of the more than 4 million Americans with hepatitis C.

• Recurrent disease, especially with hepatitis C, necessitates retransplantation in future years, which aggravates the acute organ shortage problem further.

• Chronic liver failure is infrequently associated with cerebral edema; however, the encephalopathy found in chronic liver disease may represent a common underlying pathophysiology.

• The failure of hepatic clearance leads to the accumulation of toxins such as ammonia and manganese, and to alterations in endogenous transmitters and messengers, including g-aminobutyric acid (GABA), glutamate and nitric oxide.

PATHOPHYSIOLOGY OF END STAGE LIVER DISEASE

CNS

CVS

• A hyperdynamic state, characterized by an elevated cardiac output and arteriolar vasodilatation, occurs in up to 70% of patients with end-stage liver disease.

• The clinical improvement seen after total hepatectomy in patients with acute liver failure suggests that toxic substances released from the necrotic liver may be involved.

• As the criteria for transplantation is expanded, upper age limits for recipients have been liberalized, making an evaluation for ischemic heart disease part of the routine preoperative assessment.

• Dobutamine stress echocardiography (DSE) is used in many centers to risk stratify patients preoperatively. The advantages of DSE include the ability to diagnose pulmonary hypertension and valvular heart disease.

• The hyperdynamic circulatory state may resolve after transplant, though it has persisted for several years. A recent study supports earlier work indicating that cardiovascular risk is significantly elevated post transplant.

PULMONARY SYSTEM• The pulmonary complications associated with liver disease include restrictive lung

disease,intrapulmonary shunts, ventilation-perfusion abnormalities and pulmonary hypertension.

• The restrictive disease results from ascites and/or pleural effusions and frequently responds to fluid removal. Hypoxemia occurring in the absence of ascites or intrinsic lung disease is referred to as hepatopulmonary syndrome.

• This syndrome has been ascribed to shunting, ventilation-perfusion mismatch and/or diffusion defects.

• A contrast (bubble) echocardiograph is useful for defining the cause of room air hypoxemia. In the presence of intrapulmonary shunting, microbubbles appear five or six beats after injection, while in the presence of V/Q defects the bubbles are absorbed in the lung.

• Pulmonary hypertension, defined as a mean pulmonary artery pressure > 25 mmHg in the presence of a normal wedge pressure, occurs in up to 2% of patients with chronic liver disease.

• Mild (mean PAP 25-35 mmHg) or moderate (mean PAP 35-45 mmHg) pulmonary hypertension does not contraindicate transplantation, particularly in situations in which the pulmonary arterial pressures are responsive to a pharmacologic trial of vasodilators.

• Successful transplantation has been performed in patients with severe pulmonary hypertension after long-term vasodilator therapy.Pulmonary hypertension has been reported to improve, persist and even develop following liver transplantation.

RENAL SYSTEM• The identification of patients with advanced renal disease needing combined liver-

kidney transplants (approx 5% of liver transplant recipients in 2004) is important preoperatively, as is the treatment of preexisting acidbase abnormalities and plasma volume defects, which might worsen less advanced renal disease in the perioperative period.

• The predominant functional cause of renal failure in patients with hepatic failure is hepatorenal syndrome (HRS). The diagnosis requires the absence of primary renal disease, proteinuria, hypovolemia and hemodynamic causes of renal hypoperfusion. A urinary sodium < 10 mEq/L and/or a fractional excretion of sodium < 1% is typical.

• The syndrome has been treated with success with vasoconstrictors, which improve splanchnic vasodilatation, decrease endogenous vasoconstrictor levels and improve renal blood flow. Caution should be used in patients with acute hepatic necrosis, as cerebral blood flow has been shown to be adversely effected by terlipressin.

• Nephrotoxic antibiotics and contrast used for diagnostic studies should be avoided if possible.

• Cyclosporine adversely affects renal function postoperatively, typically decreasing GFR by 30-50%.

GASTROINTESTINAL SYSTEM

• Esophageal varices, portal hypertension and ascites are common. Sclerotherapy and/or portosystemic shunts may be required.

• Gastric emptying is delayed

• Drug metabolism is affected.

• End-stage liver disease patients tend to be sensitive to drugs, though they may be resistant to some drugs (e.g., pancuronium) due to increased binding to globulin.

• The action of many drugs (such as opioids, lidocaine and propranolol) is prolonged due to an increased volume of distribution and/or decreased metabolism

HEMATOLOGICAL AND COAGULATION SYSTEM

• Anemia, due to chronic disease, malnutrition and/or bleeding, is common.

• Coagulation defects result from the decreased synthesis of all clotting factors except fibrinogen and factor VIII.

• Splenic sequestration of platelets reduces the number of circulating platelets, while a functional defect also occurs.

• Ongoing fibrinolysis may occur due to low levels of antiplasmin and inadequate clearance of tissue plasminogen activators.

COAGULATION DISORDERS

• Levels of procoagulant factors (II, V, VII, IX, X) and anticoagulant factors (protein C and S, antithrombin III) are frequently decreased in patients with end-stage liver disease

• Thrombocytopenia as a result of hypersplenism, qualitative platelet dysfunction, and disorders of the fibrinolytic system (reduced levels of plasminogen, α2 -antiplasmin, and factor XIII and increased plasma tissue-type plasminogen activator levels) is often encountered during the perioperative period

ADULTS % CHILDREN %Noncholestatic cirrhosis 65 Biliary atresia 58

 Viral hepatitis B and C Inborn errors of metabolism 11

 Alcoholic[*] Cholestatic 9 Cryptogenic    Primary sclerosing cholangitis  

Cholestatic 14  Alagille's syndrome

 Primary biliary cirrhosis   Autoimmune 4

 Primary sclerosing cholangitis   Viral hepatitis 2

Autoimmune 5 Miscellaneous 16Malignant neoplasm 2

Miscellaneous 14

 Indications for Liver Transplantation

ANESTHESIA MANAGEMENT

• Manipulation of the liver can impede venous return and result in hypotension. Similarly, acute decompression of ascites early during the dissection phase can result in hypotension.

• During this phase, adequate fluid replacement is crucial, and colloids are frequently used.

• Diuresis should be established early during the procedure to facilitate fluid management, and it may produce some renal protection in anticipation of relative renal ischemia during the anhepatic period .

PRE-ANESTHETIC EVALUATION

• pre-operative evaluation differ for an LT patient and a routine patient.

• Pre-operative evaluation is performed in two stages. In the early first stage all LT candidates are examined by anesthesiologists; the later, second-stage evaluation is performed immediately before surgery.

• One should plan for an operating room time of 8 to 20 hours , with an average total time of 8.5 hours for anesthesia, 7 of which are devoted to surgery .

• Acessing any neurologic deterioration since the initial first-stage evaluation is necessary, and signs of progressive metabolic acidosis,infection or sepsids,Cardiovascular instability, pulmonary infection and severe coagulopathy should be corrected and treated.

• Ideally, ascites should be controlled and nutrition improved, with prothrombin time showing a return toward normal.

PRE-ANESTHETIC EVALUATION

• Coagulation status should be determined, and parenteral vitamin K should be given at least 3 days pre-operatively if possible, although it is not always possible to anticipate and schedule the operation (i.e., using cadaveric transplants).

• Vitamin K administration corrects coagulation defects within 24±36 hours, unless liver function is so poor that vitamin K-dependent proteins such as Factor V and prothrombin can not be synthesized.

• Albumin, fresh-frozen plasma, and cryoprecipitate can be given immediately before surgery;

• platelets can be infused (if the count is < 50,000/mm3) immediately after induction .

PREOP INVESTIGATIONS

• Hematological –Hb , Platelet count,WBC Coagulation profile

• Metabolic – glucose ,urea ,creatinine electrolytes

• Cardio respiratory – chest x-ray,ECG ,PFT, ABG

• Liver function – sr.bilirubin,albumin,liver enzymes

Monitoring• Monitoring of temperature • Coagulation status should be monitored –platelet count ,fibrin degradation

products , prothrombin time , activated clotting time, partial thromboplastin time

Thromboelastography has been used as a tool in liver transplantation.

• Repeated BP cuff inflation –may lead to bruising in patients with altered haemostatic function.

• Insertion of Intra arterial line – care to prevent haematoma .

• Jugular route is preferred in CVP monitoring.

• Oximetry

• Urine output

• Blood loss

PREMEDICATION

• Since coagulation may be abnormal pre-operatively, intramuscular premedication is not advised.

• Hepatic encephalopathy is another contraindication . If coagulation and level of consciousness are normal, standard medications are not contraindicated.

• The dose is usually adjusted downward because of reduced hepatic function, including drug elimination. Premedication is frequently reduced or even omitted.

• Pre- operative counseling for the patient's preparation and allows family interaction with an alert individual before surgery.

• However, if a patient so desires, short-acting benzo- diazepines are often appropriate.

ANESTHETIC INDUCTION

• Rapid-sequence induction is performed because many of these patients have ascites and, perhaps, the equivalent of a full stomach.

• Delayed gastric emptying often exists in patients taking cyclosporine orally.

• Thiopental 4 mg/kg, propofol 1-2 mg/kg, or etomidate 0.3-0.5 mg/kg, is used.

• Succinylcholine 1-2 mg/kg is added to facilitate tracheal intubation while cricoid pressure is maintained.

• The induction agents are protein bound, and the free drug fraction is increased in liver disease

• when serum albumin is low, leading to an enhanced effect.

• Thiopental and etomidate are metabolized in the liver but their activity is terminated by redistribution. Hence, their duration of action is normal unless the doses are large or repeated.

ANESTHETIC MANAGEMENT

• NARCOTICS• Anesthetic maintenance is largely similar to that in other major abdominal

surgery. A narcotic can be successfully used in patients with hepatic disease despite the pharmacologic consequences of decreased clearance and prolonged half-life

• Fentanyl, sufentanil and alfentanil are suitable opioid analgesic agents because they have short half-lives and inactive metabolites.

• fentanyl does not decrease hepatic oxygen and blood supply or prevent increases in demand when used in moderate doses (50 mg/ kg bolus and 0.5 mg/kg/min infusions)

• INHALATION AGENTS• Halothane is avoided in favor of isoflurane for LT.

• Halothane,enflurane and isoflurane all reduce liver blood flow, but halothane reduces hepatic arterial flow to a greater extent .

• The use of halothane is not advised because of its potenial to cause hepatic damage. Nitrous oxide has been used for many years without increased anesthesia-related postoperative hepatic complications.

• However, it is often considered counterproductive because of its sympathomimetic effect and accumulation in the intestinal lumen.

• Another reason to avoid nitrous oxide is that potenial air emboli created during the vascular anastomosis .

ANESTHETIC MANAGEMENT

ABNORMALITIES IN ELECTROLYTE LEVELS

• Hyponatremia • Hypernatremia• Hyperkalemia • Hypokalemia• Hypomagnesemia

VITAL ORGAN

• Encephalopathy• Increased Intracranial Pressure (ICP) • Decreased SVR• Increased CO, HR• Cirrhotic Cardiomyopathy • Alcoholic Cardiomyopathy

INTRAOPERATIVE MANAGEMENT, PREANHEPATIC STAGE

• This stage begins with surgical incision and ends with the occlusion of flow through the portal vein, inferior vena cava and hepatic artery.

• This phase involves dissection and mobilization of the liver.

• With abdominal incision and drainage of ascites, hypovolemia typically occurs. This should be treated with colloid containing fluid to minimize preload changes. In the presence of preexisting coagulopathy, fresh frozen plasma is indicated soon after incision.

• Thromboelastography (TEG) or standard laboratory tests (prothrombin time, fibrinogen and platelet count) are used to guide the correction of coagulopathy.

• Citrate intoxication, ionized hypocalcemia resulting from the infusion of citrate-rich blood products in the absence of hepatic function, is avoided by the administration of calcium chloride.

• Ionized hypomagnesemia also results from citrate infusion.

• Aggressive treatment of hypokalemia is best avoided, particularly in preparation for reperfusion and the associated rise in potassium.

• Supplemental glucose is usually not required, except in patients with severe disease or those in fulminant hepatic failure.

• The maintenance of urine output is desirable; however, the use of lowdose dopamine for this reason is unproven.

• Avoidance of hypothermia is important. Heated venovenous bypass during the anhepatic phase permits core temperature control.

INTRAOPERATIVE MANAGEMENT, ANHEPATIC STAGE

• This stage begins with the occlusion of vascular inflow to the liver and ends with graft reperfusion. Occlusion of the vena cava reduces venous return by as much as 50%.

• Venovenous bypass, which diverts inferior vena cava and portal venous flow to the axillary vein, attenuates the decrease in preload, improves renal perfusion pressure, lessens splanchnic congestion and delays the development of metabolic acidosis. The use of venovenous bypass is not without risk.

• Air embolism, thromboembolism and inadvertent decannulation may be fatal or result in significant morbidity. Venovenous bypass is not uniformly used at all centers.

• Hepatectomy is followed by vascular anastomoses of the supra- and infra-hepatic IVC and the portal vein.

• Fibrinolysis may begin during this stage due to an absence of liver produced plasminogen activator inhibitor resulting in the unopposed action of tissue plasminogen activator.

INTRAOPERATIVE MANAGEMENT, NEOHEPATIC STAGE

• The reperfusion of the graft begins the neohepatic stage. Reperfusion is typically via the portal vein, though the sequence of revascularization may have implications.

• Reperfusion is associated with abrupt elevations in potassium and hydrogen ion concentrations, an increase in preload and a decrease in systemic vascular resistance and blood pressure.

• Hypothermia, monitored via blood Temperature, is a marker for the presence of graft outflow into the central circulation.

• Potentially life-threatening hyperkalemia requires calcium chloride and possibly bicarbonate administration. However, even in the absence of treatment, elevated potassium levels fall spontaneously within minutes due to redistribution. The presence of EKG changes suggestive of hyperkalemia requires prompt treatment.

• Fibrinolysis is most severe after reperfusion. Antifibrinolytics and cryoprecipitate may be required.

• The hepatic arterial anastomosis and biliary reconstruction are generally performed after venous reperfusion.

• Signs of graft function that may be observed in the operating room include decreased calcium requirements, improvement in acidosis, increased urine output, a rising core temperature and bile output from the graft.

PEDIATRIC TRANSPLANTATION

• Biliary atresia is the most common primary diagnosis in pediatric liver transplant recipients, while metabolic liver disease represents the second largest group.

• Bleeding may not be severe in these patients because synthetic function is usually preserved.

• The risk of hepatic artery thrombosis in children leads to less vigorous correction of any clotting defects. Fresh frozen plasma is used sparingly and antifibrinolytics are typically avoided.

Donor Assessment • A major limitation to clinical transplantation is the availability of organ donors.

• Avoidance of damage to the graft during the procedure are essential in securing optimal function of the transplant.

• aggressive donor management protocols to minimize the adverse physiologic consequences of brain death. These protocols include respiratory and hemodynamic support, adequate fluid resuscitation, and the initiation of hormone replacement.

• Brain death is associated with significant instability, and minute-to-minute management by experienced personnel in the intensive care unit (ICU) is necessary to ensure adequate perfusion of all organs.

• the donor's liver function must be determined. Rapid screening and serial follow-up of liver enzymes and synthetic function are performed to determine the degree of liver injury and predict the potential for recovery.

• Routine assessment for diseases that might be transmitted by the liver graft must include hepatitis screening, as well as any history of the use of toxic substances such as long-standing alcohol consumption.

• Although donor age has been shown to have an adverse impact on outcome, most programs now consider the use of donors up to 75 or 80 years of age. This approach has been necessary because of the desperate need for lifesaving organs and is supported by scientific evidence of a relatively slow aging process occurring within the liver parenchyma.

• It also appears that grafts from donors with serology positive for a pathogen present in the recipient (i.e., hepatitis B or C) can be used with results equal to those of transplantation with uninfected grafts, as long as the liver does not have established severe hepatitis or fibrosis.

• Donor and recipient matching are based on ABO blood group compatibility and size. However, these barriers may be crossed when transplantation is urgent.

• Most surgeons try to match donor-recipient age for pediatric recipients because variation may have an impact on long-term graft survival.

LIVING DONOR TRANSPLANTATION

• Initial reports about LDLT in the early twentieth century established technical feasibility of the procedure .

• The donor hepatectomy can include left lobes, left lateral segments , or extended right lobe. LDLT has some advantages for the pediatric recipient and the transplant population as a whole.

• These include increased graft availability and survival, and decreased morbidity, mortality, rejections, and cost.

• Potential donor evaluation should include bedside ABO blood type compatibility with the recipient (the only need in a cadaveric donor). Also necessary is the exclusion of acute, chronic or viral illness, and liver/biliary system function and anatomy assessment, as well as psychological assessment.

• Although the procedure is relatively safe for the donor, over 10% of donors have presurgical complications . Surgical experience and technical modifications have resulted in significant reduction of these complications.

• The mortality risk of hepatic resection in non-cirrhotic individuals is extremely low when the operation is performed in an experienced center .

Conti..

SPLIT CADAVERIC-DONOR GRAFT

• LT in small children has been limited by the shortage of suitable cadaveric donor organs.

• The number of new transplant candidates under 5 years of age has increased by 5% annually since 1988, while the annual number of CD transplants performed in this age group has fallen

• The split is done between the adult recipient, (using the extended right lobe), and the pediatric recipient (using the left lobe) of the CD graft.

• Split CD graft was the obvious technical solution to this problem of pediatric graft availability.

• However, in high urgency patients where emergency OLT was needed, and the technique of emergency living donor liver transplant could not be applied or was not yet developed (i.e., prior to 1999) , split CD transplantation of two grafts was the only solution.

NEW IMMUNOSUPPRESSIVE DRUGS

• Cyclosporin is the most commonly used maintenance immunosuppressive drug.

• Steroids are almost invariably added .

• Azathioprine may be used as a third agent to reduce the dose of cyclosporine and, in some cases, may replace cyclosporine altogether when the latter is contraindicated or can no longer be used because of adverse side effects.

• Anti-lymphocyte globulin preparations, including the monoclonal antibody OKT-3 , have been given prophylactically and for specific indications to prevent rejection. OKT-3 reacts against all mature T lymphocytes.

• The most prominent is tacrolimus (FK506), which became an established immuno-suppressant agent for primary and rescue therapy (when experiencing rejection or poor tolerability to cyclosporin) in patients with liver, kidney and pancreas transplants.

FULMINANT HEPATIC FAILURE

• Fulminant hepatic failure is an uncommon entity with the potential for rapid progression to coma. Cerebral edema and elevated intracranial pressure occur in up to 80% of patients with acute liver failure. The combination of coagulopathy and altered mental status is ominous, particularly, when associated with a decrease of previously elevated liver enzyme values.

• In patients with stage III or IV coma, intracranial pressure monitoring should be considered. Fresh frozen plasma and platelet concentrates are indicated prior to ICP monitor placement when the INR is > 2 or the platelet count is < 50,000, or in the presence of clinically significant microvascular bleeding.

• The cerebral perfusion pressure should be maintained above 50 mmHg. Administration of diuretics, elevation of the patient’s head 10-20 degrees, maintenance of the arterial pressure and treatment of agitation are important in maintaining cerebral perfusion pressure.

Post oprative• Postsurgical pain control is not generally a problem. Several studies

have shown that analgesic requirements in patients with end-stage liver disease undergoing liver transplantation appear to be significantly decreased compared with other major abdominal surgery.

• In one study, the neuropeptide metenkephalin, which is involved in pain modulation, was shown to be significantly elevated in liver transplant patients compared with the control population.

• The exact mechanism of this clinical observation is unknown, and preoperative administration of large doses of steroids may play some role.

• Recovery can range from uncomplicated to extremely complex.• Frequent assessment of cardiac and pulmonary function, serum glucose

and electrolytes, renal and liver function, and coagulation and the blood count is crucial.

• Certain aspects require special attention, Patients occasionally need fresh frozen plasma therapy postoperatively to offset an initially low graft liver function.

• Fresh frozen plasma requirements also are considered an indirect measure of postoperative liver function.

• Leakage from vascular anastomosis sites, or “bleeders,” and diminished flow or thrombosis in the hepatic artery or portal vein should always be considered.

• Patients who have adequate postoperative liver function and have received steroids tend to be hyperglycemic, which may warrant an infusion of insulin.

OUTCOMES• The one-year patient and graft survival rates reported in the 2006 was 88% and 83%,

respectively. The three-year patient and graft survival rates were 80%and74%,respectively.

• Repeat transplantation is associated with a decrease in patient survival compared to primary transplants. Similarly, decreased survival is also seen in patients transplanted from the ICU.

• Patient survival after CD transplant is decreased compared to donation after brain death (DBD) transplants, though the difference in survival between the two groups appears to be diminishing.

THANK YOU

• The requirment of fresh frozen plasma 10unite, blood10unit , platelets, and cryoprecipitate remains the mainstay of therapy for blood loss and coagulopathy during liver transplantation.

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