The Anesthetic Management of Adult Patients with Organ Transplants Undergoing Nontransplant Surgery
The United Network for Organ Sharing reports that in 2008 and 2009 there were more than 54,000 organs transplanted in the United States. Survival rates have continued to increase in the past several decades as surgical techniques, immunosuppressive therapy, and infection prophylaxis have improved. On October 31, 2009 there were nearly 280,000 surviving organ recipients who underwent transplantation between 1987 and 2009 (Table 1). Several organ types now have 1-year survival rates of 85% or greater, with some approaching 95%, and 3-year survival rates of 80% or better. Living donor kidney transplants, for example, have 1-year survival rates of 95% and 10-year survival rates greater than 75% [1]. As the number of people surviving organ transplant steadily increases, more of these patients are likely to present for nontransplant-related surgery, either elective or emergent, in centers that are not normally involved in transplant procedures. This population may be more likely to present for surgery than those without previous transplant for many reasons. Laparotomy for small bowel obstruction, hip arthroplasty given the increased risk of fracture and avascular necrosis as a result of chronic steroid use, lymph node excision and biopsy because of increased risk of lymphoproliferative disease, ureteral stent placement and removal and native nephrectomy in kidney transplant recipients, bronchoscopy in lung recipients, and biliary tract interventions in liver recipients are just a few of the increased surgical needs in this population. Incisional hernias rates are increased because of the effects of immunosuppressive drugs on wound healing and, abscess drainage because of increased risk of infection are additional problems requiring surgical intervention [2,3].
Table 1 United Network for Organ Sharing: patients transplanted in the United States,a 1 October 1987 to 31 October 2009 by organ received and most recent statusb
Many transplant recipients live relatively normal and productive lives, but often have limited physical reserves. A successful transplant abolishes the symptoms and replaces function of the failed organ, but often there are persistent abnormalities from the underlying or preexisting illness that may have caused the organ failure or chronic physiologic abnormalities resulting from the organ failure itself [4]. Kidney recipients whose renal failure was caused by diabetic nephropathy and pancreas recipients still have persistent complications of diabetes such as gastropathy and neuropathy. Heart recipients whose heart failure resulted from ischemic cardiomyopathy often have extracardiac vascular disease. Cardiovascular disease is also frequently present in patients with chronic kidney disease and those with previous kidney transplant [5,6]. In addition, although immunosuppressive drug use is essential in this population to prevent allograft rejection and protect its function, these drugs have many adverse effects and can lead to renal dysfunction, bone marrow suppression, increased risk of infection, lymphoproliferative disorders, adrenal insufficiency, and pharmacologic interactions. Graft function can deteriorate with time because of chronic rejection and vasculopathy, but at any time graft function can be compromised or suboptimal as a result of acute rejection.
General considerations for preanesthetic evaluation
When a patient with a previous transplant presents for nontransplant surgery, a comprehensive evaluation and survey by the anesthesiologist should include the following key factors: evaluation of the graft function, health and function of other organ systems or the presence of concomitant diseases, presence of infection, and performance or functional status, during the preanesthetic evaluation. Adherence to the fundamental principles of preoperative evaluation along with a high level of vigilance is required [4,7,8]. Information and medical history should be gathered from the medical record, interview with the patient, next of kin or guardian. If medical information is unavailable locally, attempts should be made to contact the transplant center for pertinent history, especially with regard to previous anesthetics. Other useful information from the transplant center includes their most recent evaluations and recent data on graft function and general health of the patient. Close communication with the transplant team may be the single most important step in preparing the patient for surgery and developing a perioperative anesthetic plan [7].
Preoperative laboratory testing in this population should include evaluation of renal function with electrolytes and creatinine, as well as a complete blood count given the adverse effects immune-suppressant medications may have on these organ systems. Serum glucose should also be considered in those patients on corticosteroids or with diabetes mellitus. If neuraxial anesthesia is planned, consideration should be given to obtaining coagulation studies. Focused and functional testing of the transplanted organ is an important part of the preanesthetic evaluation to assess graft function and exclude active rejection. Table 2 suggests tests that may be required to optimize the safe delivery of anesthesia, although preoperative testing need not be limited to these guidelines. Each preoperative evaluation and testing should be considered individually based on the target organ system(s) to be evaluated, the patient’s medical history, and the inherent risks of the upcoming surgical procedure.
Table 2 Preoperative tests on transplant patients
| Test target | Essential tests | Consider also |
|---|---|---|
| Blood | Total cell count Hemoglobin | Hematocrit |
| Kidney | Creatinine Urine analysis | Urea Creatinine clearance |
| Blood electrolytes | Na+, K+, Mg2+, Ca2+ | |
| Liver | Prothrombin time Partial thromboplastin time Bilirubins Aminotransferases Alkaline phosphatase | Full coagulation status Ammonia Albumin Prealbumin Cholesterol Lactate dehydrogenase Galactose elimination capacity |
| Pancreas | Amylase | Lipase |
| Lung | Radiography Spirometry for lung and marrow transplant patients | Spirometry Sputum microbiology Blood gas analysis |
| Heart | Electrocardiography | Echocardiography Coronary angiography |
| Drugs | Cyclosporine or tacrolimus concentration, if applicable | |
| Infections | C-reactive protein Targeted samples | |
| Other | Blood glucose Blood pressure Pulse Temperature Respiratory rate |
Data from Toivonen HJ. Anaesthesia for patients with a transplanted organ. Acta Anaesthiol Scand 2000;44:819.
Cardiovascular disease is a major cause of mortality and morbidity among organ transplant recipients, especially in those with chronic kidney disease or previous heart transplant, making the risk of a perioperative cardiovascular event a legitimate concern [6,7,9]. After kidney transplantation, a progressive increase in the incidence of ischemic cardiovascular, cerebrovascular, and peripheral vascular events has been documented in epidemiologic studies [5]. Many transplant recipients have undergone complete cardiac testing and in some cases, interventions, before their transplant surgery. Records of the testing and interventions can be easily obtained from the transplant center to be used for comparison and consideration before the upcoming surgery. The question that remains is how long a time period may be allowed to pass before additional cardiac testing should be performed before an upcoming elective surgery. There is, unfortunately, no clear or easy single answer or guideline. Each evaluation should proceed on an individual basis with thorough documentation of the patient’s exercise capacity and functional status along with an electrocardiogram (ECG), taking into consideration any changes, as well as the inherent risk of the surgery itself and the patient’s known cardiovascular history, keeping in mind that many of these patients may have asymptomatic coronary disease as a result of diabetes or the transplant itself. It may be prudent to discuss the upcoming surgery, need for testing, and perioperative optimization, such as initiation of beta-blocker therapy, with the patient’s transplant team or cardiologist, especially if there is documented cardiovascular disease or previous cardiac intervention.
Posttransplantation diabetes mellitus (PTDM) is a common metabolic consequence of the agents of immunosuppressive therapy. PTDM is defined as sustained hyperglycemia that meets the diagnostic criteria of the American Diabetic Association (ADA) in any posttransplant patient who was not previously diabetic [10,11]. PTDM is generally assigned to the classification of type 2 diabetes because its pathophysiology is a combination of insulin resistance and insulin secretion defects. Risk factors for PTDM include age, nonwhite ethnicity, increased body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), chronic hepatitis C infection, pretransplant glucose intolerance, and use of glucocorticoids and calcineurin inhibitors. The incidence of PTDM is reported to be as high as 25% and possibly higher in patients with hepatitis C [4,11]. Unfortunately, PTDM has a negative effect on graft survival. Preexisting diabetes has implications for perioperative complications and morbidity, especially increased infection risk and poor wound healing. It is imperative to institute a plan of glycemic control before surgery with close attention to intraoperative and postoperative glucose management. Hyperglycemia suppresses various aspects of immune function, causes endothelial dysfunction and altered vascular reactivity, increases circulating inflammatory mediators, and is associated with a procoagulant state. If hyperglycemia is identified during the preoperative evaluation, the patient’s primary care provider may be contacted to assist in the effort to achieve glycemic control before elective surgery. It is not within the scope of this document to debate the literature and the issues surrounding intensive glycemic control. Most of the information gathered is taken from studies of glycemic control in the intensive care unit and has been extrapolated to the perioperative period. The actual level of hyperglycemia that is predictive of adverse outcome is debated, but perioperative serum glucose levels greater than 200 mg/dL seem to be consistently associated with adverse outcomes including stroke, myocardial infarction, poor wound healing, infection, and death [12,13]. Maintaining perioperative glucose between 120 and 180 mg/dL is a conservative approach that might avoid the perils of intensive glucose control yet control hyperglycemia. If the patient has a serum glucose level of greater than 300 mg/dL documented on 2 or more consecutive checks, consideration should be given to postponing elective surgery until adequate glycemia is achieved.
General considerations of anesthetic management
There is no ideal or generic anesthetic plan that can be used for all transplant recipients undergoing nontransplant surgery. There are no prospective studies comparing anesthesia techniques, but most anesthetics have been used with success including general (inhalational, balanced, and total intravenous), neuraxial, regional, and monitored anesthesia. A successful anesthetic plan requires a clear understanding of the medical and pharmacologic problems that accompany this population, the function and physiology of the allograft, functionality and general health of the patient, the underlying surgical condition, and proposed surgical procedure [4,14].
Monitoring
As a general rule, special equipment is not needed and anesthesia should be performed using standard American Society of Anesthesiology’s monitoring guidelines. The decision to use invasive hemodynamic monitors, placement of central venous access, pulmonary artery catheters or other procedures such as transesophageal echocardiography should be made on a case by case basis. This decision should be guided by consideration of the patient’s comorbidities, hemodynamic stability, the expertise of the anesthesiologist in placing the invasive device and interpreting the data, the inherent risk of the surgery, and the overall risk to benefit ratio of the proposed monitor [15]. It is important to consider that central venous access may be difficult as many of these patients have had long-standing illnesses with the need for central venous catheters for parenteral nutrition, hemodialysis, esophageal variceal hemorrhage, sepsis, and other clinical problems that required central venous access. These may have been complicated by thrombosis, stenosis, and infection making reaccessing these veins difficult or impossible [14]. Meticulous hygiene practice and aseptic technique are of utmost importance to minimize exposure to infectious organisms and bacteremia when attempting any invasive procedures in this population [4,8,16].
Airway Management
Airway management of transplant patients may pose a concern for several reasons. Many patients may have preexisting diabetes mellitus before transplant or acquire diabetes after transplant (PTDM). Diabetic patients can develop limitations in joint mobility caused by glycosylation of the connective tissue within their joints. Several retrospective and prospective evaluations performed at transplant institutions in patients with diabetes mellitus undergoing kidney and/or pancreas transplantation report increased rates of difficult laryngoscopy, including a retrospective analysis from our institution [17,19]. The airway management plan should be formulated after careful airway examination and review of previous anesthetic records. If recent records are not available locally, they may be obtained from the transplant center keeping in mind that if extended time has elapsed since the last anesthetic, the ongoing effects of diabetes on the mandibular and atlanto-occipital joints may result in a difficult intubation not previously reported. Graft-versus-host disease can also create limited joint mobility creating a similar scenario. This population is also at increased risk for lymphoproliferative disorders secondary to immune-suppressant drugs, and lymphoproliferative growth may compromise any part of the airway or mediastinum and cause life-threatening airway obstruction during sedation and anesthesia. Aspiration risk may be increased in transplanted patients as a result of delayed gastric emptying and gastropathy [4,8]. These potential problems should all be taken into consideration when constructing the anesthetic plan for airway management.
Antibiotic Prophylaxis
Antibiotic prophylaxis has not been studied extensively in transplant recipients undergoing nontransplant surgery. Although transplant patients are considered at-risk hosts for infection because of their immune status, there is no evidence to suggest different bacteriology of surgical site infections than for the general population. However, the use of prophylaxis even for clean cases in this higher risk population is advocated and has some supporting evidence [20,21]. It is recommended that the guidelines for surgical antibiotic prophylaxis from the National Surgical Infection Project be followed and should be given before incision.(Table 3). Antimicrobial coverage need not be expanded to include atypical or opportunistic organisms as long as active infection with such an organism is not present or suspected [7,21,22].
Table 3 Antimicrobial prophylaxis for selected surgical procedures
| Operation | Recommended antibiotic prophylaxis | Comments |
|---|---|---|
| Cardiothoracic surgery | Cefazolin, cefuroxime, or cefamandole. If patient has a β-lactam allergy: vancomycin or clindamycin | Most of the guidelines agree that prophylaxis for cardiac surgery should be administered for >24 h after surgery. The ASHP suggests continuation of prophylaxis for cardiothoracic surgery up to 72 h; however, its authors suggest that prophylaxis for <24 h may be appropriate. Cefamandole is not available in the United States |
| Vascular surgery | Cefazolin or cefuroxime. If patient has a β-lactam allergy: vancomycin with or without gentamycin, or clindamycin | |
| Colon surgery | Oral: neomycin plus erythromycin base, or neomycin plus metronidazole. Parenteral: cefoxitin or cefotetan, or cefazolin plus metronidazole | Currently, none of the guidelines address antimicrobial prophylaxis for those patients with β-lactam allergy. Cefmetazole is not available in the United States. Although a recent study indicates that the combination of oral prophylaxis with parenteral antibiotics may result in lower wound infection rates, this is not specified in any of the published guidelines |
| Hip or knee arthroplasty | Cefazolin or cefuroxime. If the patient has a β-lactam allergy: vancomycin or clindamycin | Although not addressed in any of the published guidelines, the workgroup recommends that prophylactic antimicrobial be completely infused before inflation of the tourniquet. Cefuroxime is recommended as a choice for patients undergoing total hip arthroplasty |
| Vaginal or abdominal hysterectomy | Cefazolin, cefotetan, cefoxitin, or cefuroxime | Metronidazole monotherapy is recommended in the ACOG Practice Bulletin as an alternative to cephalosporin prophylaxis for patients undergoing hysterectomy. Trovafloxin, although still available in the United States, is recommended only for serious infections |
Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ASHP, American Society of Health-System Pharmacists.
Data from Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis 2004;38:1706–15.
Intravenous Anesthetics
The selection and administration of intravenous anesthetics should be guided by the patient’s hemodynamic status, the drug’s cardiovascular effects and pharmacokinetic properties, especially the biotransformation and elimination profiles of the drug. Drugs that undergo primarily hepatic metabolism, such as barbiturates, should be dose adjusted if administered to avoid prolonged effects in patients with hepatic insufficiency. Care should be taken when using barbiturates as cardiac output and mean arterial pressures can decrease precipitously as a result of venous pooling and loss of cardiac preload. Propofol is extensively metabolized by the liver to inactive glucuronic acid metabolites that are excreted by the kidneys. Despite the known mechanisms of biotransformation, there seems to be no need for dose adjustments in patients with hepatic or renal failure indicating an extrahepatic route of elimination as well [23]. Care should be used in patients with cardiovascular compromise as propofol can worsen cardiac contractility, compromise cardiac preload, cause bradycardia, and lower systemic vascular resistance culminating in diminished cardiac output and mean arterial pressure. Etomidate does not have the cardiac depressant effect of barbiturates and propofol. Etomidate is metabolized rapidly by hydrolysis within the liver and by plasma esterases, and also does not require dosage adjustment in renal or hepatic disease. One unique characteristic of etomidate is its ability to inhibit the 11-β-hydroxylase, an enzyme necessary for the synthesis of cortisol, for 5 to 8 hours after administration. The clinical significance in patients who already have adrenal suppression as a result of exogenous steroid use is unclear, but heightened attention should be paid to the need for perioperative stress-dose corticosteroids [23]. Ketamine is metabolized via the hepatic cytochrome P-450 system to norketamine, which has approximately one-third of the clinical activity of its parent and therefore the clinical effects of ketamine are prolonged in the presence of hepatic insufficiency. The metabolites of norketamine are excreted by the kidneys. The usual cardiac stimulating effects caused by central stimulation of the sympathetic system are not present in the denervated heart, but ketamine can still increase systemic vascular tone. Ketamine has neuroexcitatory effects and is known to cause myoclonic activity, although its ability to actually cause seizures is debated [23]. However, there are case reports of seizures after its administration in patients who have previously had liver transplant and in the presence of cyclosporine, an immunosuppressant drug with the potential for neurotoxicity [24]. Table 4 is an abbreviated list of drugs commonly used in the perioperative period that have active metabolites that require renal excretion and accumulate in patients with renal insufficiency.
Table 4 Drugs with renally excreted active metabolites and their actions
| Morphine | Morphine 6-glucuronide | Antianalgesic |
| Morphine 3-glucuronide | Potent sedative-analgesic | |
| Normorphine | Neuroexcitatory and seizures | |
| Meperidine | Normeperidine | Neuroexcitatory and seizures |
| Diazepam | Oxazepam | Sedative |
| Midazolam | 1-Hydroxymidazolam | Sedative |
| Vecuronium | Desacetyl-vecuronium | Neuromuscular blockade |
| Ketamine | Norketamine | Neuroexcitatory and psychomimmetic actions |
Data from Littlewood K. The immunocompromised adult and surgery. Best Pract Res Clin Anaesth 2008;22(3):585–609.
Inhalational Anesthetics
All inhaled anesthetics have been used in transplanted patients with success. Among the inhaled anesthetics currently used, only halothane requires a truly cautionary note given its potential for hepatotoxicity and direct cardiac depressant effects. Of the most commonly used volatile anesthetics in the United States today, isoflurane, desflurane, and sevoflurane, there does not seem to be a significant clinical advantage or disadvantage of one over the others. The choice of inhaled anesthetic can be dictated by the anesthesiologist’s preference, experiences, and comfort with the anesthetic [25]. The decision whether or not to use a volatile anesthetic need not be imposed by the presence of a transplanted organ, but should be guided by other patient factors, such as hemodynamic stability and history or risk of malignant hyperthermia. The theoretic risk of nephrotoxicity caused by the liberation of free fluoride and Compound A following sevoflurane metabolism does not seem to be a true clinical concern outside of laboratory animals [4,25]. The decision to use nitrous oxide (N2O) as part of the anesthetic should be considered with caution. Whether or not to use N2O as part of the anesthetic should be based on clinical findings of the patient and type of surgical procedure, such as the potential for postoperative nausea and for expanding air-filled cavities such as pneumothorax, intestinal obstruction, and tympanic membrane grafts. It is probably prudent to avoid prolonged use of N2O because of the potential risk of bone marrow suppression and the potential for altered immunologic response (impaired chemotaxis and motility of polymorphonuclear leukocytes) [25]. Although these effects were seen in laboratory animals receiving N2O for more than 24 hours, they may be potentiated in immune-compromised patients. N2O can also worsen preexisting pulmonary hypertension, which may be present in patients who have undergone lung, heart, or liver transplant, by increasing pulmonary vascular resistance and potentiating hypoxemia. N2O is best avoided in patients who have known or suspected pulmonary hypertension. Although there is little data on the use of N2O in the transplanted population, the brief use of N2O during induction or emergence is probably acceptable and without clinical consequence but may be best avoided if there are alternatives [25,26].
Neuromuscular Blockade
The decision to use neuromuscular blockade should be based on the type of surgery and actual need for muscle relaxation during the procedure or the need to optimize intubating conditions. The choice of specific neuromuscular blocking agent to be used should be dictated by length of surgery, underlying medical illnesses such as myasthenia or other neuromuscular disorders, history of malignant hyperthermia, and the functional state of the patient’s kidney and liver. Of the nondepolarizing agents, the metabolism and clearance of mivacurium, a short-acting agent, and cisatracurium and atracurium, intermediate-acting agents, are independent of kidney and liver function (Table 5). In the presence of a normally functioning kidney or liver graft, other nondepolarizing agents, such as vecuronium, rocuronium, and pancuronium, exhibit normal clinical activity, but can have prolonged effects in the face of hepatic or renal insufficiency and require dose adjustments and close neuromuscular monitoring and evidence of full reversal before extubation [27]. Some immune-suppressant drugs can have effects on neuromuscular blockade. Azathioprine can increase the dose required to achieve and maintain muscle relaxation and cyclosporine can prolong the action of the neuromuscular blocking agents [28]. Succinylcholine, the only depolarizing agent available in the United States currently, is used frequently in this population given the need for rapid sequence intubation and rapid airway control. There are no contraindications in patients who have undergone organ transplant with the possible exception of previous cardiac transplant, in which its actions can be complex. Otherwise, succinylcholine should be avoided only if there are other clinical reasons, such as hyperkalemia, muscular dystrophy, or history of malignant hyperthermia [27,28].
Table 5 Drugs not solely dependent on renal and/or hepatic elimination
| Drug | Metabolism |
|---|---|
| Succinylcholine | Pseudocholinesterase |
| Propofol | Extrahepatic and hepatic metabolism |
| Esmolol | Red cell esterase |
| Remifentanil | Nonspecific esterases |
| Cisatracurium | Hofmann elimination |
| Mivacurium | Pseudocholinesterase |
| Atracurium | Non specific plasma esterase |
| Etomidate | Plasma esterases and hepatic metabolism |
Regional and Neuraxial Anesthesia
There are few contraindications to performing a regional or neuraxial anesthetic in previously transplanted patients. The consideration of spinal or epidural anesthesia is appropriate in this population as long as there is no increased risk for bleeding complications. There may be several advantages to choosing a neuraxial or regional technique in this population. Superior analgesia over systemic opioids, especially in patients who may have narcotics tolerance as a result of long-term opioid use, reduced pulmonary complications, decreased incidence of graft occlusion, and improved joint mobility are just a few of the benefits of regional and neuraxial anesthesia [29]. Clinically relevant doses of bupivicaine and ropiviciane, which are commonly used local anesthetics for neuraxial anesthesia, do not seem to result in toxic levels or increased risk of toxic effects in renal and liver transplant recipients [8,14]. However, it is important to be prepared for the risk of hypotension because of preexisting autonomic neuropathy and cardiac denervation in this population when performing a neuraxial anesthetic [9,29]. Concurrent hemodynamic monitoring is imperative during the procedure. Direct and indirect-acting adrenergic agonists should be readily available along with emergency airway supplies. Cautious correction of hypovolemia before epidural or spinal anesthesia may help to attenuate the hypotension.
Although the risk of epidural abscess complicating epidural anesthesia is low (about 1 in 2000 or less), there seems to be a very slight increase of the incidence in immunocompromised patients in many epidemiologic series. Staphylococcus aureus is isolated in approximately two-thirds of the epidural abscesses indicating infection from normal skin flora. Meningitis after spinal anesthesia seemingly does not have a greater disposition for immunocompromised hosts compared with healthy patients. When meningitis occurs after spinal anesthesia, the organism cultured is usually an oropharyngeal bacteria implying iatrogenic infection from the proceduralist [29,30]. Therefore, if a neuraxial block is included in the anesthetic plan, it is imperative that strict aseptic technique is practiced and a mask should be worn. Although the risk of infectious complications is very low, it is important to be highly vigilant when monitoring these patients after a neuraxial anesthetic as the attenuated inflammatory response may diminish the typical signs and symptoms of epidural abscess or meningitis [29].
There is limited information available on the incidence of infectious complications after peripheral nerve block procedures in immunocompromised patients, other than a few case reports and series. Overall, the incidence of infectious complications seems to be extremely low, even in immune-suppressed patients. When they do occur, the organisms cultured are similar to those found in infections after neuraxial anesthesia, Staphylococcus aureus and mouth organisms, indicating skin or mouth flora from the anesthesiologist or patient as the source [31]. Again, aseptic technique and a mask should be considered essential when performing these procedures.
There may be other, albeit less well understood benefits of using a neuraxial or regional anesthetic technique in this population. There is consistent evidence that surgical stress suppresses both cellular and humoral immune function for several days after surgery. This effect may be exaggerated or prolonged in patients with preexisting immune dysfunction. General anesthetics alone do not diminish the surgical stress response [20,29]. Neuraxial anesthesia and postoperative analgesia are associated with some preservation of cell-mediated immunity and attenuated inflammatory response. Local anesthetics themselves lessen the inflammatory response to stress and injury [20,32]. The risk to benefit ratio of neuraxial anesthesia or regional block may, therefore, be altered in previously transplanted patients. The decision to perform a regional or neuraxial anesthetic technique in a previously transplanted patient must be made on an individual basis. Anesthetic alternatives, the risks of the technique that may be increased, balanced with the potential for greater benefit should all be carefully considered when constructing the anesthetic plan in this population.
