Anesthetic considerations for patients post-organ transplantation

Anesthetic Considerations for Patients Post-Organ Transplantation Son B. Tran

cording to the United Network for Organ Sharing, in the year 2000, over 22,000 solid organ transplantations were performed in the United States. Thanks to better immunosuppression, improved patient care, and refined surgical skills, the survival rates of the transplanted patients have improved. Survival rates vary from 50% to 95%, depending upon the type of organ transplanted (Table 1). As the number of organ transplant increases, more and more transplanted patients are returning to the operating room for non-transplant surgeries. Although transplanted patients may return for any type of surgery, certain operations are more likely in previously transplanted patients. For example, because of immunosuppression, these patients may develop abscesses that require incision and drainage. Long-term corticosteroid use may lead to avascular necroses of the femoral head that require total hip replacement or fractures that require reduction. Post-transplant lymphoproliferative disease may bring the patients back for lymph node biopsy. Development of intraperitoneal adhesions that cause small bowel obstruction may require celiotomy and adhesiolysis. Women of childbearing age who were previously transplanted may return for childbirth labor and delivery or cesarean section. Kidney transplant patients may need removal of ureteral stents or parathyroidectomy after their transplants. If these patients develop rejection, transplant nephrectomy may be necessary. Liver transplant patients may sustain bile duct injury that warrants cholangiogram or bile duct repair. Heart transplant patients may develop coronary artery disease that requires coronary angiogram or heart block that necessitates pacemaker implantation. Lung transplant patients may need bronchoscopy, lung biopsy, and bronchoalveolar lavage to differentiate infection from rejection. For the sake of discussion, suppose that you work at a hospital where organ transplants are being performed and you find that you have been scheduled to provide anesthesia to a previously transplanted patient. What will be your anesthetic

A

approach to this patient? What do you have to tal~e into consideration? Will you have to change your routine practice? A well thought-out anesthetic plan that takes into consideration the patient's medical history, previous anesthetic experiences, allergies, physical examination, and laboratory findings is a must for any patient. Of additional importance in a previously transplanted patient, you must assess the functional integrity of the transplanted organ, rule out rejection, identify drug toxicity, and search for infection. Let us first examine how the functionality of different transplanted organs affects anesthesia. HEART

During heart transplantation, the autonomic innervation to the heart becomes interrupted.' Fortunately for these patients, the intrinsic cardiac control system suffices for cardiac work. However, any increases in cardiac output in these patients are met by increases in stroke volume, not heart rate. As a result, myocardial depressant drugs like halothane should be avoided, cardiac preload should be optimized, and anesthetic-induced vasodilation should be treated promptly due to the lack of a compensating tachycardia. While a central neuroaxial blockade may cause profound hypotension if the preload is inadequate, a peripheral nerve block may help avoid some of the aforementioned hemodynamic changes. The transplanted heart is paced by the atrium from the donor. Normal electrical conduction from the atrium to the ventricle is often present. However, heart block such as sinus node dysfunction or atrioventricular block may sometimes develop and necessitate permanent pacing in 11% of patients.'From the Department of Anesthesiology, David L Geffen, University of California Los Angeles School of Medicine, Los Angeles. CA . Address reprint requests to Son B. Tran, M.D.. Department of Anesthesiology, David L. Geffen, UCLA School of Medicine, PO Box 951778, Los Angeles, CA 90095-1778. © 2003 Elsevier Inc. All rights reserved. 0277-0326/03/2202-$30.00/0 doi: 10.10l 6/S0277-0326(03)00004- 7

Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 22, No 2 (June), 2003: pp 119-124

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Table 1. Adult Transplanted Patient Survival Rates

Organ Transplanted

1-year

Kidney Kidney-pancreas Pancreas Heart Liver Lung Heart-lung

96 95 94 85 86 76 63

Intestine

50

3-year 91 90 88 77 ,, 76 56 55 49

Values are expressedas percentages. 1-year survival from 1/1/97 to 12/31/98 with follow-up through 12/31/99 3-year survival from 1/1/95 to 12/31/96 with bllow-up through 12/31/99

Atrial arrythmias are common and occur in up to 50% of patients. 3 Thus, a preoperative 12-lead electrocardiogram is required for all these patients. Interestingly, due to the considerable electrical stability of the denervated heart, ventricular arrythmias are unlikely to occur, t Because of the autonomic denervation, neuralmediated cardiac reflexes such as the baroreceptor reflex, carotid sinus massage, and Valsalva maneuver are absent. The heart responds to endogenous catecholamines and direct-acting drugs, but not to indirect acting drugs. 4 Hence any bradycardia that occurs perioperatively should be treated with isoproterenol or epinephrine, instead of atropine or glycopyrrolate. The use of anticholinesterase drugs to reverse the effects of non-depolarizing muscle relaxant is questionable. Although studies have shown that anticholinesterase drugs provoke bradycardia, clinical experience has proven that these drugs can be safely administered to heart transplant patients if accompanied by antimuscarinic drugs. 5 Coronary blood flow has also been shown to be commensurate with myocardial oxygen requirement. However, accelerated coronary graft atherosclerosis occurs in 10-20% of patients at l-year and up to 50% of patients at 5-year post-transplant. 6 Thus a recent cardiac stress test may be indicated to detect coronary artery disease that would then require coronary angiography. LUNGS Several respiratory changes occur as a result of lung transplantation. Some functions deteriorate, others stay the same, while some improve after

transplantation. A consistent finding is a decrease in mucociliary cle,'u-ance. 7 Additionally, while the carinal innervation may be preserved during single-lung transplantation, it becomes ablated during double-lung transplantation. 8 This absence of carinal cough reflex will increase the risks of silent aspiration, retention of secretions, and development of infection. Thus, endotracheal extubation should only be undertaken when these patients are awake and able to cough. Studies have shown that respiratory rate, rhythm, and sleep respiratory pattern are unaffected by lung transplantation. 9 Similarly, airway tone and function are also unaffected. Improvements in respiratory function may be observed soon after transplantation. Normalization of the fractional expiratory volume at 1 second (FEVI) has been observed at one week after transplantation. At one month post-transplant, the arterial carbon dioxide partial pressure and the ventilatory response to carbon dioxide improve. "~ At 10 months post-transplant, the patients" ventilatory responses to exercise normalize, tL Between 12 to 18 months after transplant, double lung transplant patients have only mildly restrictive pulmonary function tests, while single lung transplant patients continue to have impaired puhnonary function tests because of the native lung. j2 When these patients return for non-transplant surgery, laboratory testing such as arterial blood gas, chest x-ray, and pulmonary function testing may be helpful tools to assess the functional integrity of the respiratory system. Endotracheal intubation must be performed carefully to avoid trauma to previous surgical anastomosis. Because disruption of lymphatic drainage and vascular permeability may have occurred as a result of lung transplant, administration of excessive intravenous fluid should be avoided to reduce the risk of pulmonary edema. Cun'ently, there are no data to support routine use of air filters and sterile equipment such as laryngoscopes or breathing circuits. LIVER Initially after liver transplantation, patients have hemodilution due to the large amount of intravascular resuscitation during surgery. This produces relative leukopenia, anemia, and thrombocytopenia. The thrombocytopenia is worsened by the vascular endothelial injury that occurs over the first five d~iys after transplantation. ~3 However, as a

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result of the effectiveness of the new liver, the previously diminished procoagulant factors achieve normal activity by postoperative day 1 to 2, the diminished fibrinolytic activity normalizes by postoperative day 4 to 7, and the previously low anticoagulant factors reach normal activity by postoperative day 7 to 14.14 By the second week after transplantation, hepatic synthetic activity is effectively normal.15 Over the first 3 months posttransplant, the hyperbilirubinemia will improve. ~6 However, the aminotransferase enzymes and alkaline phosphatase may continue to stay above normal in most patients.17 Thus liver function testing remains a very important tool in assessing the functional status of the transplanted liver. Persistent elevation of bilirubin and alkaline phosphatase may suggest bile duct obstruction. Elevated aspartate aminotransferase is the most sensitive test to detect rejection. Studies have shown that volatile anesthetics and drugs that are metabolized by the liver can be safely administered to these patients. 17-as In addition, there is no evidence to support the avoidance of drugs that decrease hepatic blood flow such as propanolol or cimetidine.19

mia exists, neuroaxial blockade should be avoided due to platelet dysfunction. Repeated dosing of morphine can lead to a dangerous accumulation of its active metabolite, morphine-6-glucuronide. 23 Meperidine should also be avoided because its metabolite normeperidine may lower seizure threshold. 24 Furthermore, drugs that are excreted' unchanged by the kidney must be used with caution because of impaired clearance during renal failurefl5

Control of blood glucose concentration by the pancreas occurs immediately after reperfusion of the transplanted organ. 12 However, because of the stress of the surgery and the administration of corticosteroid, additional doses of insulin may be needed to regulate blood glucose level. Later on, exogenous insulin usually becomes unnecessary. The major problem with pancreas transplantation is the high risk of surgical complications. Common problems include intra-abdominal infection and abscess, vascular graft thrombosis, and anastomotic leaks. 26 Patients may also have increased risks of major bleeding and postoperative sepsis.

KIDNEY

INTESTINE

Studies have shown that although the kidney is denervated during transplantation, renal plasma flow and urinary potassium excretion remain intact. 2° In contrast, urinary sodium and bicarbonate excretion are elevated. Serum erythropoietin level may increase immediately after surgery, but will gradually return to normal. 2~ With time, the anemia of chronic renal failure will resolve. Most patients experience a 20% reduction in the function of the transplanted kidney as a result of either cyclosporin-induced nephropathy or chronic rejection. ~2 Although survival rates are high, preexisting cardiovascular disease remains the leading cause of death among these patients. ~2 Patients may have hypertension that pre-dated their transplantation or develop hypertension as a result of rejection, drug toxicity, or vascular stenosis of the transplanted kidney. 22 Hyperlipidemia is also common. Electrolyte disorders including renal tubular acidosis, hyperkalemia, hypercalemia, hypophosphatemia, hypomagnesemia, and hyperglycemia can often be seen. When anesthetizing these patients, the assessment of kidney function is very important. If ure-

After intestine transplant, bowel motility usually returns by postoperative day 7 to 15. ~2 Gastric emptying may take longer to return. Although the absorption of dietary sugar occurs shortly after motility is resumed, tat malabsorption may occur for a more prolonged period. Diarrhea and dehydration are common due to short native or transplant colon, fat malabsorption, rejection, or infection. Preoperative testing must include serum electrolytes. Of note, graft versus host disease (GVHD) may occur in post-intestine transplanted patients. 27 Migration of lymphocytes between graft and host may occur even in th~ absence of rejection. Unexplained hemolysis, pancytopenia, pneumonitis, diarrhea, altered mental status, and skin rash should arouse suspicion of GVHD.

PANCREAS

REJECTION Once the functional integrity of the transplanted organ has been assessed, rejection must be ruled out. There are 3 major types of rejection: hyperacute, acute, and chronic. The acuity of the episode and the type of immunologic cells involved determine the type of rejection. Of more importance to

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the anesthesiologist are the questions of how to detect rejection in the perioperative period and what to do in that circumstance. Rejection usually presents as a functional deterioration of the transplanted organ. Constitutional signs and symptoms may include fever, chills, fatigue, and leukocytosis. Definitive diagnosis requires a tissue biopsy./ Heart transplant patients may present with dyspnea, decreased exercise tolerance, and angina. Endomyocardial biopsy provides the definitive diagnosis. Lung transplant patients may have dyspnea and hypoxemia. Diagnostic tests include bronchoscopy, lung biopsy, and bronchoalveolar lavage. When chronic rejection occurs, these patients may have bronchiolitis obliterans, a condition that presents as dry coughing and dyspnea at 8 to 12 months post-transplant and progresses to chronic obstructive pulmonary disease. Liver transplant patients may present with jaundice, changes in the color of urine and stool, pruritus, and weight gain. Physical examination will reveal peripheral edema, ascites, and asterixis. Elevation of aspartate aminotransferase, serum bilirubin, prothrombin time, and decrease in albumin may suggest rejection. Kidney transplant patients may have progressive azotemia, proteinuria, hypertension, recent weight gain, and edema. Pancreas transplant patients may present with epigastric tenderness. Elevated serum glucose, amylase, and lipase may occur. If patients have bladder-drained pancreatic transplant, a decrease in urinary amylase may be noted. Intestine transplant patients may have diarrhea, blood in stool, nausea, vomiting, and abdominal pain. Endoscopy-guided mucosal biopsy is needed to confirm the diagnosis. When rejection is suspected, elective surgery should be canceled and the transplant team contacted for further evaluation and treatment.

IMMUNOSUPPRESSION As previously mentioned, immunosuppression plays a key role in improving the survival of both transplanted organs and transplant patients. It does so by reducing the incidence and severity of rejectionl and thus ensuring a high level of the transplanted organ's functional integrity. There are several classes of immunosuppressive drugs. They include calcineurin inhibitors, rapamycin, antimetabolites, corticosteroids, and antibodies. While effective, these drugs also have toxicity that may adversely affect patients and their anesthetic care.

Calcineurin is a phosphatase enzyme that plays a significant role in the transcription of messenger RNA for cytokines (interleukin-2) and clonal expression of alloreactive T lymphocyte cells. Cyclosporin and tacrolimus are examples of drugs that inhibit calcineurin after binding to different intracellular proteins. Both drugs are metabolized by the hepatic cytochrome P-450 system. Adverse effects of cyclosporin include nephrotoxicity, hepatoxicity, neurotoxicity, electrolyte disturbances, gingival hypertrophy, and lymphoproliferative disease. Studies have shown that isoflurane anesthesia may reduce the absorption of oral cyclosporin by delaying gastric emptying and reducing small bowel absorption, resulting in subtherapeutic levels of cyclosporin when administered less than 4 hours before surgery. '829 However, once a steady state therapeutic level of cyclosporin has been reached, isoflurane anesthesia does not alter the pharmacokinetics of cyclosporin.3° Cyclosporin has been shown to potentiate or prolong neuromuscular blockade by vecuronium, pancuronium, and atracurium. 31-33 Although recently introduced, tacrolimus also has many adverse effects such as nausea, vomiting, flushing, nephrotoxicity, hyperkalemia, post-transplant diabetes mellitus, psychological disturbances, headache, and tremor. Rapamycin is a new immunosuppressive drug that acts on calcineurin. However, instead of inhibiting the enzyme as tacrolimus does, rapamycin actually inhibits cellular signaling events. Adverse effects such as nephrotoxicity, hypertension, and hyperlipidemia have been reported for rapamycin. Antimetabolite drugs such as azathioprine work by inhibiting the synthesis of purine nucleotides necessary for DNA synthesis. Adverse effects of azathioprine include nausea, vomiting, diarrhea, hepatotoxicity, pancreatitis, and bone marrow suppression. Mycophenolate mofetil is a new prodrug that breaks down to form the active agent, mycophenolic acid. Mycophenolic acid works by inhibiting synthesis of purine nucleotides. However, mycophenolic acid is more selective against stimulated lymphocytes than resting lymphocytes. Adverse effects from this drug include vomiting, diarrhea, neutropenia, lymphoma, and lymphoproliferative disease. Corticosteroids act by interfering with the presentation of antigen by disrupting interleukin-l metabolism or preventing a nuclear binding protein required for expression of cytokines from reaching

ANESTHETIC CONSIDERATIONS FOR PATIENTS POSTI'RANSPtANTATION

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Table 2. Pathogens Infecting Transplanted Patients

Bacteria

Viruses

Fungi

Protozoa

Parasites

Staphylococcus Streptococcus Enterococcus E. Coli H. Influenza Pseudomonas Klebsiella Serratia Proteus Syphillis Mycobacteria Legionella Mycoplasma Chlamydia Norcardia

Cytomegalovirus Epstein-Barr Herpes Simplex Hepatitis B Hepatitis C Papilloma HIV HTLV

Candida Aspergilus Pneumocystis Zygomycetes Cryptococcus Coccidomycosis Histoplasmosis Blastomycosis

Toxoplasmosis

Strongyloidis

the nucleus. Their adverse effects are well-known and include: inhibition of pituitary-adrenal function, infection, impaired wound healing, salt and water retention, hyperglycemia, hypertension, electrolyte abnormalities, peptic ulceration, osteoporosis, myopathy, psychological disturbances, cataracts, and Cushingoid features. Although important, the exact dose of corticosteroid supplementation remains controversial. Studies have shown that the pituitary-adrenal function in patients treated with corticosteroids cannot be reliably estimated from the dose or duration of therapy, or the basal plasma cortisol concentration. 34 Spontaneous recovery of the hypothalamic-pituitary-adrenal axis has been observed in patients taking low doses of corticosteroids. 35 Currently, supraphysiologic doses of supplemental corticosteroids are given to many patients in the perioperative period. Some experts have recommended lowdose supplementation, while others recommend administration of maintenance doses without perioperative stress dosing. 3638 Whatever the combination of drugs or the doses of drugs, it is important to continue immunosuppression up to the time of surgery. If the route of administration needs to change, you should consult with the transplant team. Serum levels of drugs should be checked before and after surgery to ensure adequate immunosuppresion and minimize toxicity.

INFECTION The last consideration that is important to these transplanted patients is the search for infection.

Infection can be caused by nosocomial spread, transmission from the transplanted organ to the patient, reactivation of a previous infection in the organ recipient, or acquisition from the community. Many bacteria, viruses, fungi, and protozoa can ~cause infection (Table 2). When taking care of these patients, you should provide prophylaxis against opportunistic and wound infection, avoid nasotracheal or nasogastric intubation that may cause bacteremia, monitor the intravenous line and Foley catheter meticulously and remove them as soon as possible, wear masks, isolate patients from other people with potentially contagious diseases, and most importantly, wash your hands. If an active infection is discovered, elective surgery should be cancelled until the infection is treated.

SUMMARY In summary, considerations should be paid to the functional status of the transplanted organ, rejection, infection, and drug toxicity when taking care of previously transplanted patients. These special concerns w~l be more relevant in the general practice of anesthesiology as the number of transplanted patients increase and their survival improves.

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124 4. Stinson EB: Hemodynamic observations one and two years after cardiac transplantation in man. Circulation 45: I 18394. 1972 5, Backman SB: Neostigmine decreases heart rate in heart transplant recipients. Can J Anaesth 43:373-8, 1996 6. Sharp MD: Anaesthesia and the transplanted heart. Can J Anaesth 43:R89-98. 1996 7. Helve P: Impairment of bronchial mucociliary clearance in/ long-term survivors of heart/lung and double-lung transplantation. Chest 103:59-63, 1993 8. Hatb~,way T: Pulmonary reflexes after human heart-lung transplantation. Respir Med 85:(Suppl A)17-21, 1991 9. Sanders MH: Breathing during wakefulness and sleep after human heart-lung transplantation. Ain Rev Respir Dis 140:4551, 1989 10. Trachiotis G: Respiratory responses to CO_~rebreathing in lung transplant recipients. Ann Thorac Surg 58:1709-17, 1994 I I. Grassi B: Ventilatory responses to exercise after heart and lung denervation in humans. Respir Physiol 92:289-304, 1993 12. Williams TJ: Early and long-term functional outcomes in unilateral, bilateral, and living-related transplant recipients. Clin Chest Med 18:245-57. 1997 13. Alhashemi JA: Anesthesia considerations related to tbe transplanted organ, in Sharp MD and Gelb AW (eds): Anesthesia and Transplantation. New York. Butterworth-Heinemann. 1999, pp 323-36 14. Stahl RL: A hypercoagulable state following orthotopic liver transplantation. Hepatology 12:553-8, 1990 15. Velasco F: Diminished anticoagulant and fibrinolytic activity following living transplantation. Transplantation 53: 1256-61. 1992 16. O'Grady J: Long-term management, complications, and disease recurrence, in Maddrey WC (ed]: Transplantation of the Liver. New York, Elsevier, 1988. pp 143-65 17. Essen P: Fluoride plasma concentration alter isoflurane anesthesia during and alter liver transplantation. Transplant Proc 21:3530, 1989 18. Fisher DM: Pharmacokinetics of rocuronium during the three stages of liver transplantation. Anesthesiology 86:130616, 1997 19. Puff MR: The effect of cimetidine on cyclosporine A levels in liver transplant recipients: a preliminary report. Am J Gastroenterol 87:827-91, 1992 20. Zincke H: The role of denervation in renal transplantation on renal function in the dog. Invest Urol 14:210-2. 1976 21. Sun CH: Serum erythropoietin levels after renal transplantation. NEJM 321 : 15 I-7. 1989

SON B. TRAN 22. Sears JW: Kidney Transplants: Induction and analgesic agents..in Royston D and Feeley TW (eds): Anesthesia for the patient with a transplanted organ. Boston, Little and Brown. 1995, pp. 45-68 23. Chauvin M: Morphine pharmacokinetic in renal failure. Anesthesiology 66:327-31, 1987 24. Armstrong PJ: Normeperidine toxicity. Anesth Analg 65:536-8, 1986 25. Linder R: Long-term renal allograft function under mainteuance immunosuppression with cyclosporine A or azathioprine. A single center, five-year follow-up study. Transpl Int 4:166-72. 1991 26. Gruesnner RW: The surgical risk of pancreas transplantation in the cyclosporine era: an overview. J Am Coil Surg 185:128'-44. 1997 27. Abu-Elmagd K: Rejection of human intestinal allografts: alone or in combination with the liver. Transplant Proc 26: 1430- I, 1994 28. Brown MR: Eflicacy of oral cyclosporine given prior to liver transplantation. Anesth Analg 69:773-5. 1989 29. Gelb AW: Isoflurane alters the kinetics of oral cyclosporinc. Ancsth Analg 72:801-4. 1991 30. Freeman D J: Effects of nitrous oxide/oxygen-isoflurane anesthesia on blood cyclosporine concentrations in the rabbit. Transplantation 58:640-2, 1994 31. Sidi A: Prolonged neuromuscular blockade and ventilatory failure after renal transplantation and cyclosporine. Can J Anaesth 37:543-8, 1990 32. Crosby E: Cyclosporine-pancuronium interaction in a patient with a renal allograft Can J Anaesth 35:300-2, 1988 33. Gramstad L: Interaction of cyclosporine and its solvent, Cremophor, with atracurium and vecuronium Br J Anaesth 58:1149-58, 1986 34. Schlagbecke R: The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone. NEJM 326:226-30, 1992 35. LaRochelle GE Jr: Recovery of the hypothalamic-pituitary-adrenal (HPAJ axis in patients with rheunmtic diseases receiving low-dose prednisonc. Am J Med 95:258-64, 1993 36. Bromberg JS: Stress steroids are not required for patients receiving a renal allograft and undergoing operation. J Am Coil Surg 180:532-6. 1995 37. Friedman RJ: Use of supplemental steroids in patients having orthopaedic operations. J Bone Joint Surg Am 77:1801-6, 1995 38. Symreng T: Physiological cortisol substitution of longtern1 steroid-treated patients undergoing major surgery. Br J Anaesth 53:949-54, 1981