Continuing Education Activity

With the increasing number of organ procurement and transplantation, it is essential to know the needs of this patient population's pathophysiology and administer anesthesia to improve graft survival and functioning. This activity will focus on anesthesia for kidney, pancreas, and liver transplant surgery—the role of the interprofessional team in the evaluation and management of recipient and donor.

Objectives:

• Review the indications and contraindications of kidney, pancreas, and liver transplants.
• Outline the anesthesia monitoring devices used during kidney, pancreas, and liver transplant surgeries.
• Ex[plain pre-transplant screening and optimization in kidney, pancreas, and liver transplant surgery.
• Summarize anesthesia, intraoperative complication, and management in kidney, pancreas, and liver transplantation by an interprofessional team.

Introduction

As per the Organ Procurement and Transplantation Network (OPTN) registry, the total number of people on the waitlist is 107,485 (as of 5/19/2021). United Network for Organ Sharing (UNOS) is a non-profit organization that functions with local organ procurement organizations to match the donor with the recipient. Hence, it becomes essential to register a patient early, evaluate and optimize them. So, whenever an appropriately matched organ is available, the patient can be scheduled for surgery.

Indications

The main indication of an organ transplant is an irreversible failure. The reason for organ failure can be an organ disease or secondary to systemic disease. Various bridge therapy is used till the organ transplantation is achieved to maintain that organ function.

Kidney Transplant

In kidney transplantation, a person becomes a candidate of organ recipient when there is an irreversible decrease in glomerular filtration rate (GFR) < 20 ml/min/1.73 m^2.[1]

The various causes of kidney failure are as follows:

Living donor kidney transplant (LDKT): In the case of a living donor transplant, the recipient can be in the early stages of ESRD and not started on dialysis. LDKT has shown better graft survival and function.  

Pancreas Transplant   

The causes of pancreatic failure are diabetes mellites type I and II, chronic pancreatitis, pancreatic cancer, biliary duct cancer, and graft failure.  

It can be performed alone, simultaneous pancreatic and kidney (SKP) transplantation, or pancreas after kidney (PAK) transplantation.    

Liver Transplant   

The various causes of liver failure:

MELD (model for end-stage liver disease) score determines the priority in transplant. There are a few exceptions to the standard MELD score. Those are hepatic cellular carcinoma, hepatopulmonary syndrome, Porto-pulmonary syndrome, familial amyloid polyneuropathy, cystic fibrosis, hilar cholangiocarcinoma, and acute liver failure with UNOS status 1A/1B.[2]

For hepatocellular carcinoma, the Milan criteria are used. It includes the liver tumor with a single lesion <5 cm or 2 to 3 lesions of 1 to 3 cm.[3]

Contraindications

The major contraindications for organ transplantation are active infection, active malignancy, active drug abuse, reversible organ failure, uncontrollable psychiatry condition, non-compliance to treatment, severe systemic condition with poor graft or patient survival. The recipient should wait for an organ transplant till infection or malignancy has been treated. For graft survival, it is essential to keep follow-up with the transplant team, regular clinic visits, blood work, and compliance to transplant medications. Hence, careful candidate selection becomes of utmost importance.[4][5]

Equipment

The standard ASA (American Society of Anesthesiology) monitoring tools intra-operatively is five leads ECG (electrocardiogram), pulse oximeter, non-invasive blood pressure, and temperature. In addition to the standard tools, other invasive and non-invasive monitoring devices are used as per the surgery. Major hemodynamic variation is anticipated in transplant surgeries, and invasive arterial blood pressure shows real-time values. Liver transplant patients are prone to severe hemodynamic fluctuation.

Stroke volume variation and pulse pressure variation are dynamic metrics to assist the volume status of the patient. Depending on institution protocol, the patient can have one or two arterial lines (one radial and other brachial or femoral). A central line is inserted for central venous pressure monitoring, vasopressor, and inotropes administration. In some cases, when there is severe pulmonary hypertension, portopulmonary shunts, or diminished right heart function, a pulmonary artery (PA) catheter is inserted for pulmonary pressure monitoring. TEE (Transesophageal echocardiogram) is used in some cases of liver transplantation for monitoring of right and left heart function, diagnosing volume status of the patient, early diagnosis of cardiac clots, and guiding placement of PA catheter. TEE is contraindicated in grade III and IV esophageal varices.  

Intra-operative arterial blood gas analysis and thromboelastographic studies (TEG) are beneficial in liver transplant surgeries. The arterial gas analysis provides information on acid-base and electrolytes in the body. TEG studies help to understand the coagulation cascade and which hemostatic component deficiency is contributing to coagulopathy. Therefore, assisting in the repletion.

Neuromuscular block monitoring is done with a train of four studies. It also guides with reversal and extubation of patient, especially in kidney and liver transplants where metabolism of drugs is prolonged due to suppress organ function. The bispectral index aids in decreasing awareness during anesthesia and assists in titrating drugs. Jugular venous oxygen saturation is used to monitor cerebral blood flow and oxygen consumption, especially in the anhepatic and neohepatic phases of liver transplantation. There is a significant fluctuation of cardiac output, leading to impaired cerebral blood flow.[6][7][8][9]

Preparation

The preoperative evaluation and optimization should begin as soon as a person becomes a candidate for being an organ recipient. It plays a very crucial role in minimizing perioperative complications, improved graft, and recipient survival. 

The recipient is screened for malignancy, active infection, and other viral infections. The common screening includes HIV (Human Immunodeficiency Virus), Hepatitis panel, EBV (Epstein-Barr virus), and CMV (Cytomegalovirus). They are tested accordingly depending on the comorbidities such as coronary artery disease, peripheral artery disease, and cerebrovascular accidents. It is crucial to document allergies, prior solid organ transplantation, prior blood transfusions, and previous pregnancies. It assists in determining the antibody load in the recipient and guiding the immunosuppression regimen. Rabbit allergy is important to note as thymoglobulin is obtained from rabbit serum. Additional testing is done as per institutional protocol. 

Repeat evaluation every two years after the initial evaluation is required and sooner if the clinical situation changes.  

If the patient has to undergo coronary revascularization, then a multidisciplinary team evaluation is required. This team aids in determining the time and type of intervention required. The duration of the dual antiplatelet regimen is a minimum of 4 weeks for balloon angioplasty, three months for a bare-metal stent, and 6-12 months for a drug-eluting stent. There are no guidelines for pulmonary function testing. However, patients with uncontrolled COPD (chronic obstructive pulmonary disease), asthma, ILD (interstitial lung disease) should not undergo organ transplantation. Pancreatic transplantation patients are younger with fewer comorbidities. However, they may be at a greater risk of micro and macrovascular complications due to diabetes mellites.[10][11][12][13][14]

If the patient continues to be eligible for transplantation and an organ is available, surgery is planned. 

It is crucial to thoroughly examine the airway before surgery, inquire about bleeding or clotting disorder, previous anesthesia exposure, type of anesthesia, any complication associated with previous exposure, and family history of anesthesia complication. Drug allergies are an important aspect of the pre-operative evaluation to avoid any adverse reaction intra-operatively. An anesthesiologist should note consent for blood and blood product transfusion, history of previous blood transfusion, and adverse reaction. The device should be interrogated before surgery by the company representative in patients with a permanent pacemaker or defibrillator. Qualified personnel should be present in the OR throughout the procedure to manage the device and revert its settings to baseline at the end. With all the above information and utmost diligence, anesthesia-related complications can be minimized intra-operatively.

The following tests are done on the day of surgery:

• CBC (complete blood count) with differentials  
• Complete metabolic panel 
• Coagulation panel (PT/INR/APTT) 
• Blood group and HLA crossmatch and typing 
• 12 lead ECG 
• Chest X-ray
• Covid nasopharyngeal antigen and antibody testing 
• Thorough airway examination

Technique or Treatment

General: Antibiotics and immunosuppression regimens based on transplant physician recommendations are administered during the day of surgery. The surgeon will perform back-table preparation of the donor organ.   

Kidney Transplant

Dialysis   

The patient may or may not be dialysis-dependent. An anesthesiologist should evaluate the patient's volume, electrolytes, and uremia status on the day of surgery. Initially, hemodialysis was avoided 24 hours before transplant to decrease heparin in circulation. However, with the evolution of anesthesia care, point-of-care diagnostic test, and technique, it is no longer required.[15][16][17]

Intra-operative

1. Maintain normothermia, position the patient, and secure the dialysis access site   
2. Induction, muscle relaxants and inhalational agent:    

Induction agents: The nephrotoxic drugs and opioids (morphine, meperidine, and codeine) are avoided. The opioids, as mentioned above, have active metabolites excreted by the kidney, which can accumulate.  

Muscle relaxant and reversal agents: succinylcholine can cause an increase in serum potassium level, which can be detrimental in ESRD patients. Cisatracurium is metabolized by Hofmann elimination and can be used in renal failure patients. Laudanosine is one of the breakdown products of atracurium and cisatracurium. Kidneys eliminate it. Cisatracurium is more potent than atracurium. Hence the amount of laudanosine generated is significantly less and below the toxic amount. The kidney partially excretes rocuronium. Sugammadex is cleared from the kidney. However, it is found to have a complete reversal in kidney failure. Though clearance of sugammadex rocuronium complex takes time, no rebound muscle weakness is observed.[18][19][20]

Inhalational agents: Oxygen and air or oxygen and nitrous oxide combination are routinely used with the inhalational agent. Sevoflurane administration can lead to the accumulation of inorganic fluoride ions and compound A in patients with renal insufficiency. However, the FDA (Food and drug administration) has approved safe sevoflurane administration with fresh gas flows > 1 liter/minute. Isoflurane and desflurane can be used as an alternative to sevoflurane. 

Fluid Status 

Depending on the volume status of the patient pre-operatively, volume replacement is performed. Using the acetated or lactated solution can lead to an increase in potassium levels in ESRD patients. Normal saline causes hyperchloremic acidosis, taking longer to normalize the acid-base status. Adequate graft perfusion is vital to avoid delayed graft function or ischemia-perfusion injury. The auto-regulatory mechanism is not present in the transplanted kidney. Colloids are not the preferred choice for volume replacement.     

Depending on the volume status of the patient pre-operatively, replace volume. There were concerns regarding using acetated or lactated solution, causing an increase in potassium level in ESRD patients. Normal saline causes hyperchloremic acidosis, taking longer to clear acid. Adequate graft perfusion is vital to avoid delayed graft function or ischemia-perfusion injury. The auto-regulatory mechanism is not present in the transplanted kidney. Colloids are not the preferred choice for volume replacement.  Dynamic blood pressure monitoring with stroke volume variation and pulse pressure variation assists in maintaining adequate volume resuscitation. Vasopressors like norepinephrine with alpha and beta-blocker activity have shown decreased elevation in the renal resistive indices. Previously, low-dose dopamine was preferred. However, it has shown to be harmful to renal graft and is no longer used.[21]

Immunosuppression

Mycophenolate and methyl-prednisolone are given before surgery. Thymoglobulin is given intra-operatively. The rate is adjusted based on the blood pressure of the patient. If the initial dose causes hypotension, the rate is reduced to half.    

Pancreatic Transplant

1. Thorough airway examination becomes vital in a diabetic patient as there is an increased incidence of the stiffness of the atlantoaxial joint.  
2. Pancreatic transplant surgery is done under general anesthesia with an inducing agent, muscle relaxant, and opioids. If there are concerns for cardiovascular instability, etomidate is preferred for induction. Diabetic patients can have gastroparesis; if it is present, rapid sequence induction is done. After pancreas transplantation, the pancreas starts functioning within 5 minutes. Strict glucose monitoring is required to avoid pancreatic cell dysfunction. Frequent glucose level tests every 15 minutes for an hour followed by every 30 minutes. No major fluid shift is anticipated in pancreatic transplant surgery. The blood pressure goal is to maintain baseline to a little high after transplant to maintain adequate blood flow to graft.[22][23]

Liver Transplant  

1. Induction, muscle relaxant and inhalational agents:  

Induction: Rapid sequence induction is preferred if there is a concern for aspiration, especially if the recipient is not fasting, has gastroparesis or ascites. Pharmacodynamics and pharmacokinetics of drugs are altered in liver transplant recipients due to decreased serum albumin, increase in the volume of distribution of drugs, changes in the metabolization of drugs via the liver. The inducing agent should be carefully administered as they impact systemic blood pressure and hepatic blood flow. Etomidate has been shown to decrease hepatic blood flow with unpredictable clinical recovery. Propofol is a vasodilator with a moderate decrease in hepatic blood flow.  

Muscle relaxants: Atracurium and cisatracurium are used as they are metabolized via Hofmann degradation. Rocuronium can be used if sugammadex is unavailable.  

Inhalational agents: Desflurane and sevoflurane do not affect hepatic blood flow.  

      2. Vasopressors and inotropes:

They should be kept available as hemodynamic fluctuations are anticipated. Common reasons being coagulopathy, extensive blood, decrease in preload, third space loss, and reperfusion syndrome. Epinephrine, norepinephrine, and dopamine are used first. Vasopressin is used in refractory hypotension.   

      3. Intravenous volume resuscitation:    

Albumin synthesis is affected in end-stage liver disease. Albumin has shown decreased mortality, crystalloids requirements, the need for vasoactive drugs, the incidence of pulmonary edema, and post-reperfusion syndrome. With hydroxyethyl starch, there is an increase in coagulopathy, decreases platelet aggregation, and factor VIII level. Isotonic K crystalloid is preferred. Normal saline used in large volumes can cause a rapid rise in sodium level, which increases the incidence of central pontine myelinolysis. Lactated ringers in liver failure can lead to the accumulation of lactate, leading to lactic acidosis. Cell savers are used for autologous blood transfusion; however, their use is contraindicated in infection and neoplasia.[24][25]

     4. Different phases in liver transplantation are prehepatic, anhepatic, and neohepatic phases. Each phase is associated with its own set of pathophysiological changes. It is essential to recognize it and anticipate complications with a plan in place.   

Pre Hepatic Phase  

It begins from the incision of the skin till the clamping of the inferior vena cava (IVC). Hypotension is expected in this phase. It can be due to sudden loss of ascitic fluid, portal hypertension, portopulmonary shunts, and bleeding from the surgical site, worsened by coagulopathy associated with end-stage liver disease. Mindful administration of fluids (choice of fluid as above) is essential. TEG studies are beneficial. Excessive volume resuscitation should also be avoided as it can lead to dilutional coagulopathy and thrombocytopenia. Octreotide infusion can be used in portal hypertension and requires careful monitoring. It reduces the need for blood transfusion and improves renal function. If, despite all these efforts, hypotension persists, consider veno-venous bypass.[26][27]

Anhepatic Phase 

It begins with the clamping of hepatic vein flow till vascular anastomosis is achieved. Hypotension is a common complication in this phase due to a decrease in preload, causing decreased cardiac output. In refractory hypotension, portosystemic shunt or veno-venous shunt should be considered. It is essential to ensure that cerebral blood flow is not compromised in this stage. Lactate, citrate, and other metabolites accumulate in the body, causing acidosis, hypocalcemia, and hyperkalemia. For hyperkalemia, insulin with dextrose, bicarbonate, loop diuretics, and tromethamine is administered. Renal replacement therapy should be considered as a last resort. Coagulopathy is not uncommon during this stage; TEG studies will assist in correction. Consider correction only if clinically indicated, as correction does occur in the neohepatic stage. In hepatitis B positive recipients, hepatitis B hyper immunoglobulin is administered in this stage. Monitor for allergic reactions to hepatitis B hyper immunoglobulin.[28][29]

Neohepatic Phase

It begins with reperfusion of the liver until blood flow resumes to the portal vein and IVC. It is preferred to keep mean arterial pressure between 80-100 mm Hg before revascularization is established. Post-reperfusion syndrome (PRS), worsening pulmonary hypertension, right heart failure, and malignant arrhythmia need to be monitored in this stage. Volume resuscitation, autologous blood transfusion (preferred overpacked red blood cells due to low potassium content), and inotropes are administered as clinically indicated. After re-establishing blood flow, a sudden release in metabolites and vasodilatory substances can occur, leading to a sudden fall in blood pressure and malignant arrhythmias. In case of hyperkalemia causing ECG changes, intravenous calcium chloride helps to stabilize the cardiac membrane. In the event of a cardiac arrest, an incision should be made in the diaphragm, and an internal cardiac massage should be delivered. TTE can assist in diagnosing volume status, cardiac clots, cardiac function and treat accordingly. If cardiac clots are detected, and concerns for pulmonary thromboembolism, heparin, and tissue plasminogen activator are administered.[30][31]

Complications

During organ transplant surgeries, complications are related to anesthetic agents, immunosuppression, organ dysfunction, acid-base and electrolyte imbalances, coagulopathy, and blood loss. These are further elaborated individually in different types of transplant surgeries.

Clinical Significance

Solid-organ transplantations involving the kidney, pancreas, and liver pose a unique challenge perioperatively. Thorough preoperative evaluation and preparedness for anticipated complications during the surgery can improve surgical outcomes associated with these complex procedures.

Enhancing Healthcare Team Outcomes

An interdisciplinary team is required for a successful transplant. The team includes organ donor, UNOS and local organ procurement organization, transportation team of an organ from donor to recipient, transplant anesthesiologists, transplant surgeons, operating room members, transplant pharmacists, transplant physicians, radiologist, physical therapist, occupational therapist, nutritionist, social worker, and strong social support.[32]

For a successful transplant surgery and survival of graft, it involves tremendous coordination between the team members due to the complexity of care involved, extending beyond the perioperative period. 

If the patient has to undergo coronary revascularization, then evaluation by a cardiology consultant is required. The consultant will determine the time and type of intervention required. [Level 1] [12] There are no guidelines for pulmonary function testing. However, patients with uncontrolled COPD (chronic obstructive pulmonary disease), asthma, ILD (interstitial lung disease) should be evaluated by a pulmonologist before being considered for organ donation. Hemodialysis can be performed 24 hours before kidney transplant and does not impact early graft function. Therefore, coordination with the nephrologist for evaluation for dialysis is recommended.[Level 1] [15]