The first description of anesthesia for kidney transplantation (KTx) appeared in the early 1960s. It details the pioneering efforts in Boston with living related KTx between identical twins. The only monitors used in the 17 initial recipient cases described were a blood pressure cuff and an electrocardiogram (ECG). All recipients received neuraxial anesthesia. Within a few years, general anesthesia had become the norm and the first generation of immunosuppressants emerged, providing better deceased donor graft survival. As a result, the number of kidney transplants performed increased significantly.
Today, KTx is performed in most countries in the world, with the most active ones being the US, Canada, Australia, and most European countries, where the rate is greater than 35 per million citizens. Worldwide more than 79,000 KTxs were performed in 2014. The kidney remains the most commonly transplanted solid organ. Nevertheless, the need for KTx far outnumbers the transplantation rate. In the US in 2016, there were more than 19,000 KTxs performed but more than 96,000 patients remained on the waitlist. In fact, the active waitlist grew 27% from 10 years prior.
Despite much progress and advancement, kidney transplant patients continue to be a challenge during the perioperative period. End-stage renal disease (ESRD) itself frequently results in the dysfunction of other major organ systems. In addition, the underlying cause of renal disease may be associated with other important comorbidities. These patients are often at high risk for cardiac and other perioperative complications. Kidney transplantation remains the standard of care in patients with ESRD, imparting a significant survival advantage. After undergoing renal transplantation, patients are 10 times less likely to die of cardiovascular disease than patients on hemodialysis.
Comorbidities in End-Stage Renal Disease
The two main cardiovascular complications of chronic renal failure are arterial hypertension and atherosclerosis, both of which predispose the patient to ischemic heart disease. The prevalence of preoperative hypertension in patients undergoing renal transplantation ranges from 50% to 80%. Hypertension in chronic renal disease develops as a consequence of volume expansion secondary to salt and water retention. Other factors that contribute to the pathophysiology of hypertension in chronic kidney disease include dysregulation of the renin-angiotensin-aldosterone system, sympathetic overactivity, imbalance of endothelium-derived vasoactive substances (endothelin-1 and nitric oxide), erythropoietin replacement therapy, and secondary hyperparathyroidism. If untreated, elevated systemic pressure within the kidney can cause sclerotic changes in the renal vasculature that further contribute to a vicious cycle of increasing hypertension and accelerated kidney injury.
The combination of fluid overload and increased systemic vascular resistance leads to increased myocardial afterload and wall stress. The heart is able to partially compensate with left ventricular (LV) hypertrophy. However, LV hypertrophy and elevated wall stress result in increased myocardial oxygen requirements. At the same time, a rise in LV end-diastolic pressure reduces subendocardial coronary perfusion, reducing myocardial oxygen supply. Together, these forces increase the risk of myocardial ischemia.
Cardiac dysfunction may improve with the initiation of dialysis and the appropriate antihypertensive therapy. In patients in whom the hypertension cannot be controlled by dialysis alone, an abnormal relationship may exist among plasma renin activity, intravascular fluid volume, blood pressure, and inappropriate levels of sympathetic activity. Patients needing antihypertensive therapy in addition to dialysis are often refractory to single antihypertensive drug regimens and require a combination of antihypertensive drugs, which can have significant implications for the perioperative period. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) are two of the most commonly used antihypertensive agents in renal disease. Other commonly used antihypertensives include loop and thiazide diuretics, dihydropyridine calcium channel blockers, beta blockers, and hydralazine. A prospective study by Sear et al. demonstrated no difference in hemodynamic response to the induction of anesthesia and laryngoscopy between patients with mild to moderate hypertension on different single antihypertensive drug regimens. However, more recent studies have shown an increase in the incidence of intraoperative hypotension in patients taking ACE inhibitors or ARBs. Furthermore, patients with poorly controlled hypertension or requiring several antihypertensive agents often experience significant hemodynamic lability during general anesthesia.
Chronic kidney disease can accelerate the progression of atherosclerosis, including coronary artery disease (CAD), likely via modulation of lipid metabolism, which leads to dyslipidemia and accumulation of atherogenic particles. Cardiac disease is particularly prominent in ESRD patients with diabetes mellitus (DM). DM type 2 is the cause of ESRD in nearly 40% of patients. Patients with ESRD and DM have higher cardiovascular risk than do patients with uremia alone because of the acceleration of small-vessel atherosclerosis associated with DM and the frequently concomitant metabolic syndrome.
The prevalence of CAD in patients with ESRD has been reported in the range of 42% to 80%. Acute myocardial infarction (MI), cardiac arrest of unknown etiology, cardiac arrhythmia, and cardiomyopathy account for over 50% of deaths in patients maintained on dialysis. Cardiac mortality in dialysis patients increases with age. It is approximately two times higher for 45-to 64-year-olds and four times higher in patients older than 65 compared with younger patients in the 20-to 44-year-old range.
Cardiovascular disease remains one of the largest causes of death even after successful KTx, accounting for 17% to 50% of deaths in KTx recipients. Humar and colleagues reported a 6.1% overall perioperative cardiac complication rate among 2694 KTx recipients. Another large study by Gill and Pereira reported a 4.6% first-year all-cause mortality rate in 23,546 adult KTx patients, with greater than 25% of these being secondary to cardiac causes. The main predictors of adverse outcome were a history of pretransplant cardiac disease or MI within the previous 6 months and age older than 40 years.
When echocardiography is performed on dialysis patients as a screening tool, a high incidence of abnormalities is found. In one study, left or right ventricular hypertrophy or pericarditis was detected in 60% of autopsies performed on dialysis patients. Both dilated cardiomyopathy and concentric hypertrophy are seen in dialysis patients. The accumulation of uremic toxins and metabolic acids also contributes to poor myocardial performance. Fluid overload and congestive heart failure occur when the kidneys cannot excrete the daily fluid. Other cardiac conditions, such as pericardial disease and arrhythmia, may be encountered in patients with ESRD. Pericarditis, which may coexist with hemorrhagic pericardial effusion, may reverse with dialysis. Arrhythmias may result from electrolyte abnormalities or MI.
Patients in renal failure most often have normochromic, normocytic anemia due to decreased erythropoietin synthesis and release. Other factors contributing to anemia in renal failure include a decreased red blood cell lifespan, increased hemolysis and bleeding, repeated blood loss during hemodialysis, aluminum toxicity, uremia-induced bone marrow suppression, and iron, folate, and vitamin B 6 and B 12 deficiencies. Treatment with recombinant erythropoietin can frequently raise hemoglobin levels to 10 to 13 g/dL, which reduces symptoms of fatigue and improves cerebral and cardiac function. Pretransplant treatment with recombinant erythropoietin in anemic patients improves long-term graft survival compared with blood transfusion, which causes allostimulation. However, preexisting hypertension can worsen with erythropoietin therapy in some patients.
An association between renal failure and bleeding tendency has long been recognized. Uremia produces a qualitative defect in platelet function wherein decreased levels of platelet factor III impair platelet adhesion. A prolonged bleeding time is seen (although with poor clinical utility), although prothrombin and partial thromboplastin time are usually normal. Treatments for uremic coagulopathy include dialysis, platelet transfusion, cryoprecipitate, and desmopressin (0.3 mcg/kg). Recent studies suggest a prothrombotic state may in fact exist with uremia. A thromboelastographic study of whole blood clotting found increased coagulability and decreased fibrinolysis in uremic patients versus controls. Platelet-derived procoagulant microparticles may be involved in clinical thrombogenesis.
Uremia can cause central nervous system disturbances ranging from drowsiness, memory loss, and decreased concentration to myoclonus, seizures, stupor, and coma. However, severe uremic central nervous system disturbances are rarely seen in patients when appropriately dialyzed. Chronic uremia may also cause delayed gastric emptying. Although the mechanism is not understood, gastric dysrhythmia with discoordinated myoelectrical activity has been found in uremic patients on maintenance hemodialysis. In addition, renal failure patients have an increase in acidity and gastric volume unrelated to Helicobacter pylori infection. There appears to be no difference in gastric emptying time between patients undergoing peritoneal dialysis and hemodialysis.
Preoperative evaluation begins with assessing medical suitability before listing for transplantation. Careful assessment of cardiorespiratory function is critical. In particular, patients must be screened for CAD, congestive heart failure, and autonomic dysfunction before listing. Once the transplant is scheduled, history and physical evaluation should focus on cardiorespiratory complications and comorbidities, volume status, electrolyte derangements, and any recent infections. With the benefit of advanced planning, living donor kidney transplant recipients have enough time to be medically optimized before surgery. Although deceased donor kidney transplants are often scheduled as urgent or emergency cases, prolonged cold preservation of the kidney is well tolerated, and recipients should have sufficient time to be dialyzed and to address other preoperative issues.
Almost all patients receiving an organ from a deceased organ donor receive some form of dialysis before transplantation. When possible, living donation is planned before initiation of dialysis. History of long-term chronic hemodialysis decreases graft function, but less than 6 months of dialysis was not found to decrease patient or graft survival. Patients maintained on hemodialysis usually undergo a dialysis session during the 24- to 36-hour period before transplantation to correct electrolyte imbalances and optimize volume status before surgery. Patients maintained on continuous ambulatory peritoneal dialysis often have more stable volume status and electrolytes.
Determination of volume status should include an assessment for dyspnea, orthopnea, and lower extremity edema. Patients should be questioned about how much urine volume they produce, and dry weight should be compared with current weight. Removing fluid with hemodialysis before surgery facilitates perioperative fluid management, as 40 to 50 mL/kg of crystalloid is often given intraoperatively. Nevertheless, overly aggressive removal of fluid during preoperative dialysis may make patients hypovolemic and put them at risk for significant intraoperative hypotension, especially during induction of anesthesia. The production of urine may be delayed if the new graft does not begin functioning immediately. These patients may require hemodialysis postoperatively until the new graft begins functioning. When patients without hemodialysis access are to receive potentially marginal grafts, plans can be made for the placement of hemodialysis lines intraoperatively.
Recent electrolyte concentrations, particularly K + and HCO 3 − , should be reviewed preoperatively. Patients receiving hemodialysis may experience significant swings in K + and HCO 3 − levels. Therefore, patients who are hemodialysis-dependent may require serum potassium levels checked on the day of surgery. Potassium concentrations greater than 6.0 mEq/L may require a delay in surgery to correct potassium levels. Chronic hyperkalemia is less likely to cause arrhythmia than acute hyperkalemia, thus evaluating trends in potassium levels is useful.
Cardiac risk assessment is an important component of the preoperative evaluation and is dictated by the underlying renal disease, its duration, and attendant comorbidities. National organizations have published guidelines and position papers to inform cardiac evaluation practices; however, discrepancies exist among the guidelines and most do not consider the unique clinical characteristics of patients with ESRD. Not surprisingly, there is no absolute consensus on the optimal cardiac workup for ESRD patients being evaluated for KTx, and cardiac evaluation practices vary across the US.
Several noninvasive screening tests for CAD diagnosis have been studied in this patient population. However, the optimal noninvasive test for kidney transplant candidates has yet to be determined. In a prospective study, Herzog and colleagues performed dobutamine stress echocardiography (DSE) before quantitative coronary angiography in a mixed population of ESRD patients who were candidates for transplantation. More than 50% of patients had some degree of CAD (defined as coronary stenosis >50%). However, the DSE displayed a sensitivity of only 52% to 75% and a specificity of 74% to 76% for identifying patients with CAD. These patients were monitored for up to 2 years. During this time, 20% of those with a negative DSE suffered cardiac death or MI or underwent coronary revascularization. The authors concluded that DSE was a useful but imperfect tool for identifying patients needing further cardiac workup. In a subsequent study, Sharma and colleagues performed DSE and baseline troponin measurements in 118 ESRD patients referred for KTx and found significant CAD (>70% stenosis on angiography) in 30% of patients, abnormal DSE in 35%, and elevated troponin in 26%. DSE had a sensitivity and specificity of 88% and 94%, respectively, for detecting significant CAD, whereas an elevated troponin had a sensitivity and specificity of 54% and 62%, respectively.
A Cochrane Review meta-analysis investigated the accuracy of DSE and myocardial perfusion scintigraphy (MPS) compared with coronary angiography to detect CAD in kidney transplant candidates. These authors identified 13 studies in which DSE was the screening test and nine studies in which MPS was the screening test for CAD. They reported that DSE had an aggregate sensitivity and specificity for detecting CAD of 79% and 89% whereas MPS had a sensitivity and specificity of 74% and 70%. Pooled sensitivity and specificity of each screening test changed only marginally when the authors limited their analysis to studies that defined CAD as >70% stenosis on angiography. DSE showed improved accuracy over MPS for detecting CAD ( P = 0.02) when all 22 studies were included in the analysis; however, this difference became insignificant when the authors excluded studies that did not use a reference threshold of ≥70% stenosis on coronary angiography.
Although noninvasive testing for CAD in ESRD is certainly imperfect, abnormal MPS and DSE test results have been associated with prognostic value for major adverse cardiac events (MACE) in this patient population. In a study of 126 patients with ESRD who underwent technetium-99m MPS as part of their pretransplantation assessment, a reversible defect was associated with three times the risk of posttransplantation cardiac events and nearly twice the risk of death compared with normal test results. A meta-analysis of 12 studies involving either thallium-201 scintigraphy or DSE demonstrated that ESRD patients with inducible ischemia had six times the risk of MI and four times the risk of cardiac death as patients without inducible defects, whereas patients with fixed defects had nearly five times the risk of cardiac death.
Other studies suggest that cardiac risk assessment should begin with the analysis of easily obtainable clinical variables rather than with the wide pursuit of expensive tests with limited sensitivity and specificity. For example, a history of chest pain is a helpful starting point in detecting CAD in these patients because it has a sensitivity and specificity of 65% for CAD. A more comprehensive system, the revised cardiac risk index (RCRI), was originally derived from retrospective data and shown in a prospective population to predict cardiac risk for nonrenal failure patients undergoing noncardiac surgery. It focuses on the presence or absence of six variables: (1) high-risk surgical procedure; (2) history of ischemic heart disease (excluding previous coronary revascularization); (3) history of heart failure; (4) history of stroke or transient ischemic attacks; (5) preoperative insulin therapy; and (6) preoperative creatinine levels higher than 2 mg/dL (152.5 μmol/L). With zero or one risk factor, the rate of a major perioperative cardiac event is quite low; however, the rates rise rapidly to 6.6% and 11.0% when two or at least three of these risk factors are present. Although the RCRI was not designed specifically for patients with ESRD, a study by Hoftman et al. found this risk index to be an effective tool for predicting perioperative cardiovascular complications in patients undergoing KTx. Of the 325 patients included in the study, 7.1% suffered cardiac complications. An increasing number of RCRI risk factors was significantly associated with a higher rate of perioperative cardiac morbidity (receiver operating characteristic area, 0.77; P < 0.0001).
The guidelines for perioperative cardiovascular evaluation and management for noncardiac surgery published by the American College of Cardiology (ACC) and the American Heart Association (AHA) do not take into consideration the unique clinical characteristics of patients with ESRD. Additionally, cardiovascular screening and treatment practices vary widely across transplant programs and are often inconsistent with published guidelines. In response, the ACC and AHA worked with the American Society of Transplant Surgeons, the American Society of Transplantation, and the National Kidney Foundation to develop the expert consensus document entitled “Cardiac Disease Evaluation and Management Among Kidney and Liver Transplantation Candidates.” This document provides recommendations for appropriate cardiovascular screening and management of kidney transplantation candidates, as well as ongoing surveillance. A summary of these recommendations can be found in Table 13.1 . Overall, these guidelines have a lower threshold for formal cardiac testing. For example, the guidelines recommend that providers consider noninvasive stress testing in kidney transplantation candidates with no active cardiac conditions based on the presence of multiple CAD risk factors regardless of functional status. Relevant risk factors in this population include DM, prior cardiovascular disease, more than 1 year on dialysis, LV hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia.
|Evaluation and Management Categories||ACA/AHA Recommendations|
|Determining active cardiac conditions||Perform a thorough history and physical examination to identify active cardiac conditions before solid-organ transplantation.|
|Noninvasive stress testing in KTx candidates without active cardiac conditions||Consider noninvasive stress testing in KTx candidates with no active cardiac conditions based on the presence of multiple CAD risk factors regardless of functional status. Relevant risk factors among transplantation candidates include DM, prior cardiovascular disease, more than 1 year on dialysis, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia.|
|Cardiac surveillance after listing for transplantation||The usefulness of periodically screening asymptomatic KTx candidates for myocardial ischemia while on the transplant waiting list to reduce the risk of MACE is uncertain.|
|Resting echocardiography in KTx candidates||It is reasonable to perform preoperative assessment of left ventricular function by echocardiography in potential KTx candidates. There is no evidence for or against surveillance by repeated left ventricular function tests after listing for kidney transplantation.|
|Echocardiographic surveillance for ESRD patients with moderate aortic stenosis (AS)||It may be reasonable to consider ESRD patients with moderate AS to be equivalent to “rapid progressors” who warrant a yearly echocardiogram.|
|Evaluation and management of KTx candidates with echocardiographic evidence of significant pulmonary hypertension (pHTN)||It is reasonable to evaluate KTx candidates with echocardiographic evidence of significant pHTN. |
It may be reasonable to confirm echocardiographic evidence of elevated pulmonary arterial pressures in KTx candidates by right heart catheterization.
If right heart catheterization confirms the presence of significant pulmonary arterial hypertension, referral to an expert consultant and advanced vasodilator therapies is reasonable.
|Preoperative 12-lead ECG in KTx candidates||A preoperative resting 12-lead ECG is recommended for potential KTx candidates with CAD, peripheral arterial disease, or any cardiovascular symptoms. |
A preoperative resting 12-lead ECG is reasonable in potential KTx candidates without known cardiovascular disease.
Annual 12-lead ECG after listing for KTx may be reasonable.
|Biomarkers for cardiac evaluation in KTx candidates||Cardiac troponin level at the time of evaluation for KTx may be considered as an additional prognostic marker.|
|Cardiac computed tomography (CT) in KTx candidates||The usefulness of noncontrast CT calcium scoring and cardiac CT angiography is uncertain for the assessment of pretransplantation cardiovascular risk.|
|Referral to a cardiologist||KTx candidates who have an LVEF <50%, evidence of ischemic left ventricular dilation, exercise-induced hypotension, angina, or ischemia in the distribution of multiple coronary arteries should be referred to a cardiologist for evaluation and management according to ACC/AHA guidelines for the general population.|
|Coronary revascularization and related care before KTx||Coronary revascularization before KTx should be considered in patients who meet the criteria outlined in the “2011 ACCF/AHA Guidelines for Coronary Artery Bypass Graft Surgery.” In some asymptomatic KTx candidates, the risk of coronary revascularization may outweigh the risk of transplantation and these risks must be weighed by the transplantation team on a case-by-case basis until further studies are performed in this population. |
CABG is probably recommended over PCI to improve survival in patients with multivessel CAD and DM.
CABG may be reasonable for patients with ESRD with significant (>50%) left main stenosis or significant (>70%) stenoses in three major vessels or in the proximal LAD artery plus one other major vessel, regardless of left ventricular systolic function.
It is not recommended that routine prophylactic coronary revascularization be performed in patients with stable CAD, absent symptomatic or survival indications, before transplantation surgery.
|Perioperative medical management of cardiovascular risk before KTx||Among patients already taking beta-blockers before KTx, continuing the medication perioperatively and postoperatively is recommended to prevent rebound hypertension and tachycardia. |
Among potential KTx candidates with clinical markers of cardiac risk (DM, prior known CAD, prior heart failure, extracardiac atherosclerosis) and those with unequivocal myocardial ischemia on preoperative stress testing, it is reasonable to initiate beta blockers preoperatively and to continue them postoperatively provided that dose titration is done carefully to avoid bradycardia and hypotension.
Perioperative initiation of beta blockers in beta blocker–naïve patients may be considered in KTx candidates with established CAD or two or more cardiovascular risk markers to protect against perioperative cardiovascular events if dosing is titrated and monitored.
Initiating beta blocker therapy in beta blocker–naïve patients the night before and/or the morning of noncardiac surgery is not recommended.
Depending on risk factors and the results of screening tests, patients may require medical management or a revascularization procedure. The benefit of revascularization is controversial. Data from the CARP trial, where revascularization was performed before vascular surgery, showed no benefit of revascularization compared with medical management. In the COURAGE trial, an examination of the subgroup of patients with chronic kidney disease found no benefit of percutaneous coronary intervention versus medical management.
Medical management for these patients at high perioperative cardiac risk often includes beta-blockade. Several studies throughout the late 1990s established that perioperative beta-blockade provides significant protection from major cardiac events in high-risk, nontransplant patients, although the efficacy of perioperative beta-blockade in patients undergoing noncardiac surgery remains controversial. In 2009 the DECREASE-IV trial demonstrated a safe and effective way to provide perioperative beta-blockade to patients with an estimated risk of MI or cardiovascular death greater than 1%. However, no prospective randomized trials have been conducted with perioperative beta-blockade in the ESRD or kidney transplant population. Currently it is unknown whether such treatment can be applied safely to these patients, especially those with DM.
No existing guidelines specifically address the evaluation and management of pulmonary function in KTx candidates. However, a thorough pulmonary history and physical examination should be performed before transplantation, with additional studies pursued when deemed appropriate. Patients with severe pulmonary limitations, such as a baseline oxygen requirement, uncontrolled asthma, cor pulmonale, or severe obstructive or restrictive disease may be too high risk to undergo KTx surgery. Active smokers should be encouraged to quit preoperatively.
Coagulation status, as reflected by the prothrombin time, international normalized ratio, partial thromboplastin time, fibrinogen, and platelet count, is routinely assessed before surgery. The bleeding time is not a useful screening test to predict intraoperative bleeding. Patients who are on anticoagulants or antiplatelet agents as maintenance medications to prevent thrombosis of their dialysis access or because of cardiovascular pathology should discontinue these medications and potentially receive a reversal agent as soon as they are notified of a transplant. However, because deceased organ transplants are scheduled for surgery urgently with minimal advanced notice, anticoagulation and antiplatelet therapy often cannot be discontinued sufficiently early. One center’s review of 105 patients on a variety of anticoagulants and antiplatelet medications before KTx found no difference in reoperation rates and transfusion utilization compared with a control group of transplant patients not on these medications. Despite these potential coagulation problems, blood loss during renal transplantation is normally less than 250 mL in experienced centers. Patients should be typed and crossed for blood. It is usually appropriate to have at least two units of packed red blood cells available given the risk of major vascular bleeding. More blood products may be ordered in anemic patients and those taking antiplatelet and anticoagulant agents.
Another preoperative consideration is pregnancy testing in female patients. The American Society of Anesthesiologists recommends offering pregnancy testing with informed consent to female patients of childbearing age for whom the result would alter management. In some institutions, preoperative pregnancy testing is performed routinely. Although fertility is decreased in patients with ESRD, irregular menses can make pregnancy testing especially important. Serum beta-HCG can be falsely elevated due to ESRD. Urine HCG is the recommended confirmatory test in such cases, but it is often not possible to obtain due to anuria. For patients on the transplant list, serial serum beta-HCG testing can be helpful to establish an elevated baseline value that can be distinguished from the rapid rise in HCG characteristic of pregnancy.
Patients with DM presenting for KTx can be considered to have full stomachs despite preoperative fasting. Gastric volumes greater than 0.4 mL/kg were seen in 50% of diabetic uremic patients but in only 17% of nondiabetic uremics. The routine prophylactic administration of antacids may be advocated for patients with symptoms of esophageal reflux; a single dose of sodium citrate (30 mL) immediately before surgery is appropriate. Histamine H 2 -receptor antagonists can be given to reduce gastric hyper-acidity (e.g., ranitidine 150 mg orally 2 hours before the procedure or ranitidine 50 mg IV 30 minutes before surgery). Phenothiazine antiemetics and metoclopramide should be administered with care because they may cause prolonged sedation and extrapyramidal side effects in patients with renal failure.
Spinal anesthesia was used in the first reports of anesthesia for KTx performed in Boston. Today, the vast majority of transplant centers use general endotracheal anesthesia; however, neuraxial anesthesia can provide adequate surgical conditions and excellent postoperative analgesia. Intraoperative management should focus on tailoring the anesthetic to the patient’s medical status rather than on the type of anesthesia used. Patients presenting for kidney transplant range from the young and otherwise healthy with IgA nephropathy to the elderly with severe hypertension, DM, and CAD. Anesthetic depth and pharmacologic interventions need to be tailored to two different biological systems—the transplant recipient and the allograft—with sometimes conflicting management needs. For example, maintenance of adequate anesthetic depth to avoid intraoperative awareness may also reduce blood pressure and perfusion pressure to the newly reperfused graft. Aggressive fluid loading to optimize graft perfusion may be dangerous in patients with a low ejection fraction and a history of congestive heart failure.
Intraoperative monitoring includes standard monitors as recommended by the American Society of Anesthesiologists for all patients. Patients with advanced cardiac disease, such as CAD or heart failure, may require additional invasive monitoring, such as continuous arterial pressure or central venous pressure (CVP) monitoring, or both. Pulmonary artery catheters and transesophageal echocardiography are rarely indicated. Nevertheless, there is no consensus on appropriate intraoperative monitoring, and most protocols are based on institutional preference and experience.
Care must be taken when positioning these patients, with special attention to arteriovenous grafts or fistulae. Grafts and fistulae must be properly padded, and anesthesiologists should confirm appropriate thrill intermittently throughout the procedure. Venous and arterial lines and noninvasive blood pressure (NIBP) cuffs should not be placed on a limb with an AV graft or fistula. Occasionally, anesthesiologists will elect to place the NIBP cuff on a lower extremity to avoid interference with the flow of an intravenous line. Before placing a lower extremity NIBP cuff, the anesthesiologist must confirm with the surgeon that the kidney graft will not be transplanted on the same side as the NIBP cuff, as this could compromise blood flow to the new graft.
Significant acute changes in blood pressure may occur throughout the surgical procedure, with hypotension (50%) being more likely than hypertension (27%) in one series. Patients on multiple antihypertensive medications can have severe hypotension when volatile and intravenous anesthetic agents are administered, especially during induction of general anesthesia. Hypotension during KTx has been associated with delayed graft function, which, in turn, is associated with short- and long-term complications. Hypertension is commonly seen just before induction of anesthesia and during endotracheal intubation, during emergence from anesthesia, and in the postanesthesia care unit. Several methods have been used to achieve adequate heart rate and blood pressure control during the critical periods of induction and endotracheal intubation, including high potency opioids, beta blockers, and intravenous lidocaine. Fentanyl, with a time to peak effect of 3.6 minutes, can blunt the sympathetic response to laryngoscopy and tracheal intubation at doses of 2 to 6 mcg/kg. However, patients frequently experience hypotension immediately and well after induction with these moderate to large doses of fentanyl. Subsequently, they will often require vasoconstrictors to maintain adequate blood pressure, especially because there is little surgical stimulation once the fascia is dissected. The short-acting, potent opioid remifentanil, which is rapidly metabolized in the plasma, is an effective drug for heart rate control both during induction and maintenance of anesthesia. Remifentanil dosing can be titrated to rapidly adjust anesthetic depth. The short-acting β-adrenergic blocker, esmolol, is an excellent choice for blunting the hemodynamic response to endotracheal intubation and is well suited for kidney transplant patients with preserved ventricular function. Patients with long-standing severe hypertension often require high doses of esmolol, best given in increments. In a comparison study of hemodynamics with fentanyl, lidocaine and esmolol for intubation, esmolol at 2 mg/kg prevented tachycardia and hypertension with intubation, fentanyl (3 mcg/kg) blocked hypertension but not tachycardia, and lidocaine (2 mg/kg) was ineffective.
The single most common agent used for the induction of general anesthesia during KTx is propofol. Other hypnotics such as thiopental and etomidate have also been used successfully. Several studies have demonstrated that the induction dose of propofol needed to achieve clinical hypnosis and appropriate reduction of the bispectral index (a quantitative indicator of depth of anesthesia) was 40% to 60% higher in patients with ESKD compared with normal patients. In the study by Goyal and colleagues, 0.2 mg/kg of propofol was titrated every 15 seconds to predefined end points. The authors found a negative correlation between required propofol dose and preoperative hemoglobin level. However, caution is advised when considering these studies. Propofol is a vasodilator and larger induction doses can cause significant hypotension particularly in volume-depleted patients dialyzed immediately before surgery.
Neuromuscular blockade is useful for both endotracheal intubation and surgical muscle relaxation. The most common nondepolarizing neuromuscular blocking agents used today are rocuronium, vecuronium, atracurium, and cisatracurium. Vecuronium is primarily metabolized and eliminated by the liver, with up to 25% renally excreted. The principal metabolite is also a potent neuromuscular blocker and can cause prolonged effect in patients with renal failure. Rocuronium is also primarily eliminated in the liver, with 10% to 25% renal excretion, but with no active metabolites. Rocuronium at a bolus dose of 0.6 mg/kg also has a prolonged duration of action in patients with renal failure. Although many anesthesiologists will avoid these drugs in patients with ESRD, rocuronium and vecuronium can be safely used with appropriate clinical monitoring and understanding of their prolonged duration. Atracurium and cisatracurium are metabolized primarily by spontaneous Hofmann degradation, an organ-independent metabolism. The parent agent, atracurium, is associated with histamine release, but cisatracurium is not.
Succinylcholine is a very short acting depolarizing neuromuscular blocker and is the drug of choice in rapid sequence intubations. Succinylcholine is known to cause an increase in extracellular potassium. The increase in serum potassium after an intubating dose of succinylcholine was found to be the same, approximately 0.6 mEq/L, for patients with and without ESRD. This increase can be tolerated without significant risk of arrhythmia even by patients with an initial serum K + concentration greater than 5 mEq/L. The use of succinylcholine therefore is not absolutely contraindicated in patients with ESRD.
As previously mentioned, rapid sequence intubation may be required to reduce the risk of aspiration during induction in ESRD patients with uremic or diabetic gastroparesis, or with other typical indications such as acid reflux or full stomach. If there is a contradiction to succinylcholine, high-dose rocuronium (1.2 mg/kg) can provide rapid intubating conditions. However, high-dose rocuronium in a patient with ESRD will likely have a significantly prolonged effect.
Sugammadex is a reversal agent for rocuronium, acting via selective binding to rocuronium. The rocuronium-sugammadex complex is then eliminated by the kidneys. Sugammadex is an effective reversal agent in patients with ESRD, however excretion of rocuronium and sugammadex is significantly slower in patients with ESRD. This complex will remain in the plasma for a prolonged period. The effects of prolonged exposure to the rocuronium-sugammadex complex is not clear. Therefore neostigmine is the preferred neuromuscular blocker reversal agent for patients with ESRD. It can be used for reversal of all of the nondepolarizing neuromuscular blockers. Of note, neostigmine is also partially eliminated in the kidneys, with an elimination half-life of 3 hours versus 1.3 hours in patients with normal renal function.
Overall, there is no evidence that the type of anesthetic used during KTx is associated with patient and graft outcomes. Most commonly, an inhaled volatile is used, either desflurane, isoflurane, or sevoflurane. All three of these volatile anesthetics have been reported to be safe during KTx. The metabolism of sevoflurane has been implicated in renal toxicity, but there are no controlled studies identifying safety concerns or harm associated with sevoflurane administration in the setting of a newly transplanted kidney. There are two elements of potential concern with regard to sevoflurane and renal toxicity: (1) production of fluoride ion from the metabolism of sevoflurane; and (2) generation of “compound A” from the breakdown of sevoflurane by sodium or barium hydroxide lime. Sevoflurane appears to have a very good safety record; it has been administered to millions of patients worldwide without conclusive evidence of renal toxicity. Two volunteer studies have found biochemical evidence of renal injury during sevoflurane anesthesia, whereas five other volunteer studies have not. Nevertheless, KTx may represent a period of increased risk for renal injury, as defined by Artru. One study found that exposure to sevoflurane or isoflurane had no significant effect on renal function parameters such as serum creatinine or creatinine clearance in patients with baseline renal insufficiency (Cr >1.5 mg/dL). Additionally, a study of 200 patients who underwent KTx reported no difference in postoperative creatinine, postoperative dialysis, and the incidence of rejection between patients who received sevoflurane and those who received isoflurane during transplantation.
Intraoperative management during KTx should primarily focus on hemodynamic stability with preservation of adequate perfusion pressure to the graft. KTx surgery often has prolonged periods of minimal stimulation. Blood loss rarely exceeds 300 mL and large fluid shifts are not common. Hypotension is frequently encountered during periods of minimal surgical stimulation and may be aggravated with unclamping of the iliac vessels and reperfusion of the graft. Individualized fluid management is the cornerstone of intraoperative hemodynamic management, whereas usage of vasoconstrictors with strong α-adrenergic effects, such as phenylephrine, is discouraged.
Maintenance of intravascular fluid status can be accomplished using natural colloids (albumin), synthetic colloids (hydroxyethyl starches, dextrans, gelatins), and crystalloids (normal saline, Ringer’s lactate, plasmalyte). Given the minimal blood loss and fluid shifts during KTx, crystalloids are sufficient for volume replacement and should be the preferred choice of fluid. Data for natural and synthetic colloids in KTx are sparse. Therefore the routine use of these fluids in KTx cannot be recommended.
The contents of the crystalloid solution administered during KTx should be considered. In large amounts, normal saline can cause a hyperchloremic metabolic acidosis, whereas Ringer’s lactate and plasmalyte both contain potassium, which raises concern for hyperkalemia in the patient with ESRD. A prospective, randomized, double-blinded study compared normal saline to Ringer’s lactate for intraoperative intravenous fluid therapy during KTx. The study was terminated for safety reasons and interim analysis showed no difference in postoperative creatinine levels. However, it demonstrated higher rates of severe hyperkalemia and metabolic acidosis in the normal saline group. Most recently, a 2016 Cochrane Review meta-analysis investigated the effect of lower-chloride solutions versus normal saline on delayed graft function, hyperkalemia and acid–base status in kidney transplant recipients. The authors found no difference in the rates of delayed graft function or hyperkalemia, but showed that intraoperative balanced electrolyte solutions were associated with higher blood pH, higher serum bicarbonate and lower serum chloride.
The debate continues over whether CVP monitoring is required to guide fluid administration during KTx. When CVP monitoring is in place, most centers recommend maintaining the CVP at 10 to 15 mm Hg. The effect of timing and duration of fluid replacement during KTx were examined in a prospective randomized trial. Patients were randomized to a continuous crystalloid infusion or a CVP-targeted crystalloid infusion with a low CVP target of 5 mm Hg throughout most of the case and a CVP target of 15 mm Hg at the end of renal vascular anastomoses (achieved by rapid infusion). Primary endpoints were markers of allograft function within 5 postoperative days. Although both groups received equal total volumes of crystalloid, the CVP-targeted group had better early allograft function. However, several confounding factors in the study design warrant larger studies. A small prospective study by Hadimioglu et al. demonstrated a highly significant relationship between peripheral venous pressure (PVP) and CVP in patients undergoing kidney transplantation, suggesting that PVP may be a reasonable surrogate for CVP in patients without significant cardiac dysfunction.
Pharmacologic blood pressure support using α-agonist vasoconstrictors is usually discouraged based on some limited experimental animal data. Taken together, studies indicate that there is a substantial attenuation of renal hemodynamic responsiveness in transplanted kidney grafts with α-agonist administration. Furthermore, the studies suggest that the transplanted, denervated kidney loses its capacity for autoregulation and that the renal response to sympathomimetics is altered with a shift toward time-dependent flow reduction to the kidney. In one rat study, the response to sympathomimetics in the transplanted kidney was shifted toward renal blood flow reduction. The authors postulated enhanced vasoconstriction via stimulation of α-adrenoceptors and blunted vasodilatation via stimulation of β-adrenoceptors as a possible mechanism. However, the clinical significance of these findings in human kidney transplant recipients remains unclear. A retrospective study compared 75 renal transplant recipients who required phenylephrine intraoperatively to 75 matched controls who did not. The authors found no difference in rates of delayed graft function or in serum creatinine 30, 90, and 365 days after transplant.
Intraoperative urine production, a surrogate for allograft function, is frequently augmented with mannitol and loop diuretics. Mannitol is freely filtered and not reabsorbed by the nephron, causing osmotic expansion of urine volume. It may also have a protective effect on the cells lining the renal tubule. It is usually administered during the warm ischemia phase; thus mannitol may protect against ischemic injury, as well as induce osmotic diuresis in the newly transplanted kidney. In most centers, relatively low doses of mannitol are administered, ranging between 0.25 and 0.5 mg/kg. Some data have shown that delayed graft function of the deceased donor renal allograft can be prevented by intraoperative administration of mannitol.
Low-dose dopamine (2–3 μg/kg/min) is commonly used to stimulate DA 1 dopaminergic receptors in the kidney vasculature and thereby induce vasodilation and increase urine output. Some small trials have shown improved urine output and creatinine clearance with low-dose dopamine during KTx, whereas other larger studies have shown no significant improvement in either parameter. The utility of this approach has been questioned on the basis that a newly transplanted, denervated kidney may not respond to low-dose dopamine normally. Doppler ultrasound examination of newly transplanted kidneys found no significant change in blood flow with dopamine infusion rates of 1 to 5 μg/kg/min.
Pain associated with surgery is moderate and is typically managed in the immediate postoperative phase with intravenous opioids, often using patient-controlled analgesia. Patients are transitioned to oral opioids quickly. When continuous epidural is placed for intraoperative anesthesia, it can provide excellent postoperative analgesia as well, but it is typically not necessary. As shown in Table 13.2 , the opioids morphine, meperidine, and oxycodone should be used cautiously in patients with ESRD because they (or their active metabolites) are renally excreted and thus may accumulate in such patients. This risk of opioid accumulation persists in the period after transplantation when the allograft may suffer from delayed graft function. In contrast, the opioids fentanyl, sufentanil, alfentanil, and remifentanil have been shown to be safe alternatives, with fentanyl being the most commonly used. Ketamine is a nonopioid analgesic with the active metabolite norketamine, which is also metabolized by the kidney and can cause prolonged effect. The large dose of steroid (usually methylprednisolone) given intraoperatively for induction of immunosuppression contributes an important analgesic effect as well. Intrathecal opioid and transversus abdominis plane (TAP) blocks have been studied in kidney transplant patients as part of enhanced recovery pathways, with improved satisfaction and decreased hospital length of stay. Some institutions instead utilize TAP blocks as a rescue method for patients with severe pain postoperatively.