Best Practice & Research Clinical Anaesthesiology Vol. 18, No. 1, pp.

129 144, 2004

doi:10.1016/S1521-6896(03)00067-3, available online at http://www.sciencedirect.com

8 Perioperative management of patients with chronic kidney disease or ESRD

Paul M. Palevsky*
MD

Chief Renal Section, VA Pittsburgh Healthcare System Professor of Medicine University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

The perioperative management of patients with chronic kidney disease (CKD) or dialysisdependent end-stage renal disease (ESRD) is complicated by both the underlying renal dysfunction, with associated disturbances of uid and electrolyte homeostasis and altered drug clearance, and the presence of associated co-morbid conditions, including diabetes mellitus, chronic hypertension and cardiovascular and cerebrovascular disease. The impact of CKD on uid and electrolyte management, haematological and cardiovascular complications and drug management in the perioperative period are reviewed. Special issues related to the management of haemodialysis and peritoneal dialysis patients in the perioperative period are also reviewed. Key words: chronic kidney disease; end-stage renal disease; dialysis; haemodialysis; peritoneal dialysis; water-electrolyte imbalance; hyperkalaemia; anaesthesia; opioid analgesics; neuromuscular blocking agents; post-operative complications.

The perioperative management of patients with chronic kidney disease (CKD) or dialysis-dependent end-stage renal disease (ESRD) is complicated by both the underlying renal disease, with associated disturbances of uid and electrolyte homeostasis and altered drug clearance, and the presence of associated co-morbid conditions, including diabetes mellitus, chronic hypertension and cardiovascular and cerebrovascular disease. The perioperative and anaesthesia management of these patients must therefore take into account the specic changes related to renal dysfunction as well as the increased anaesthesia and operative risks associated with these comorbidities.

STRATIFICATION AND EPIDEMIOLOGY OF CHRONIC KIDNEY DISEASE The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKFK/DOQI), has recently proposed a standardized classication scheme for patients with
* Tel.: 1-412-688-6000; Fax: 412-688-6908. E-mail address: palevsky@pitt.edu (P. M. Palevsky). 1521-6896/$ - see front matter Published by Elsevier Ltd.

130 P. M. Palevsky

Table 1. Stages of CKD. Stage 1 2 3 4 5

a

Denition GFR GFR GFR GFR GFR $90 ml/minute/1.73 m2 with evidence of kidney damagea 6089 ml/minute/1.73 m2 with evidence of kidney damagea 3059 ml/minute/1.73 m2 1529 ml/minute/1.73 m2 ,15 ml/minute/1.73 m2 or dialysis-dependent

Kidney damage dened as pathological abnormalities or markers of damage, including abnormalities of blood or urine tests or imaging studies.

CKD.1 This classication scheme straties CKD into ve stages based on estimation of glomerular ltration rate (GFR) and documentation of renal injury (Table 1). All individuals with a GFR of less than 60 ml/minute/1.73 m2 for more than 3 months are classied as having CKD, irrespective of other evidence of kidney damage. Because GFR declines with ageing, other evidence of renal disease, such as pathological or anatomical abnormalities, or markers of kidney damage such as proteinuria or haematuria, must be present to dene CKD in patients with a GFR $ 60 ml/minute/1.73 m2. Reductions in GFR below this level represent a loss of more than half of the normal adult renal function and are associated with increased risk of progressive disease and associated co-morbidities. Although serum creatinine is the most widely utilized index of renal function in clinical practice, it is a relatively insensitive marker of renal function. Serum creatinine concentration is a function of both creatinine generation, primarily from muscle creatine metabolism, and renal and extra-renal creatinine excretion. Creatinine generation is proportional to muscle mass and is generally higher in men than in women, and in individuals of African descent as compared to other racial groups. In addition, creatinine generation tends to decline with increasing age and will also be decreased in individuals with muscle wasting or malnutrition. Although creatinine excretion occurs primarily through glomerular ltration, a small percentage of creatinine is normally excreted by renal tubular secretion and in the stool. The percentage of creatinine excretion occurring via these non-glomerular routes increases with impaired renal function. As a consequence of these factors, serum creatinine concentration, particularly in elderly or chronically ill patients may be normal or only minimally elevated despite signicant reduction in GFR. In order to improve the assessment of renal function from readily available clinical data, multiple prediction equations to estimate creatinine clearance or GFR have been developed. The two most widely utilized equations are the Cockroft Gault equation for estimation of creatinine clearance2 and the MDRD study equation for calculation of estimated GFR.1,3,4 These equations are Cockroft Gault equation

Creatinine clearance ml=minute

140 2 age weightkg 0:85 if female 72 serum creatinine

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Abbreviated MDRD study equation eGFRml=minute=1:73 m2 186 serum creatinine21:154 age20:203 0:742 if female 1:210 if of African descent Accurate data regarding the prevalence of CKD are not available. Using data from the US Third National Health and Nutrition Examination Survey (NHANES III) it has been estimated that approximately 3% of the adult population in the USA, or 5.3 million patients, have stage 2 CKD as dened by persistent albuminuria and an estimated GFR of 60 84 ml/minute/1.73 m2.1 An additional 4.7% of the population, or 8.3 million patients, have more advanced renal disease, with a GFR of less than 60 ml/minute.1 In contrast to the paucity of data on the number of patients with early stages of CKD, detailed data are available from the United States Renal Data System (USRDS) on the incidence and prevalence of ESRD.5 In 2000 there were approximately 270 000 ESRD patients receiving chronic dialysis in the USA, with the population of dialysis patients increasing by 3 5% per year.5 The most common aetiology of renal failure is diabetes mellitus, accounting for over 40% of these patients, with an additional 27% having ESRD as the result of hypertensive renal disease.5 This population is also elderly; 45.6% of chronic dialysis patients are aged 65 or older. The proportion of elderly patients is also increasing, with this age group accounting for 51% of incident patients.5 Based on these epidemiological data it is clear that CKD is a common disease. In addition, given the increased representation of CKD and ESRD in the elderly population, and the high rate of co-morbid conditions, the management of patients with CKD is an important issue for anaesthesiologists.

FLUID AND ELECTROLYTE MANAGEMENT The capacity of the kidneys to maintain the volume and content of the extracellular compartment is normally preserved well into the course of chronic renal insufciency. In the majority of medically stable patients, extracellular uid volume and electrolyte composition remain normal until the development of dialysis-dependent end-stage kidney disease.6 This capacity of the failing kidney to maintain volume and electrolyte homeostasis is achieved, however, through adaptive processes which are limited in their capacity to respond to physiological stress. Thus, the patient with chronic renal disease who is well compensated in the pre-morbid state is at high risk for the development of uid and electrolyte disturbances during the perioperative period. Volume homeostasis The patients with chronic renal insufciency can usually maintain sodium balance on a xed sodium intake until end-stage kidney disease is reached.6 8 The ability of the chronically injured kidney to respond to extremes of sodium intake or to sudden changes in sodium balance is, however, markedly impaired. Maximal sodium excretion decreases as a function of the decline in GFR.8 10 Patients with mild chronic renal insufciency are generally able to excrete a sodium load and usually do not develop clinical volume overload unless other conditions which independently inhibit renal sodium excretion (e.g. heart failure, cirrhosis or nephrotic

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syndrome) are present.8,9 Volume overload may develop, however, if large volumes of saline solutions are rapidly administered. In advanced chronic renal insufciency, the ability to excrete even a modest sodium load is impaired and volume overload can rapidly develop following the administration of only modest quantities of enteral or intravenous uids. The administration of large volumes of intravenous uids to patients with CKD should be avoided. If volume overload develops, intravenous uids should be discontinued and diuretic therapy initiated. Diuretics inhibiting sodium transport in the thick ascending limb of the loop of Henle, such as furosemide and bumetanide, are the most effective agents. Sequential nephron blockade using a combination of a loopacting diuretic and oral metolazone or an intravenous thiazide diuretic may signicantly increase the diuresis in patients resistant to a loop-acting diuretic alone.11 In patients with ESRD, volume overload may precipitate the need for urgent dialysis. Paradoxically, patients with mild to moderate chronic renal insufciency are also at increased risk for the development of extracellular uid volume depletion. The chronically injured kidney maintains sodium balance at the expense of an increased fractional excretion of sodium; when challenged with sudden sodium restriction, maximal sodium conservation cannot be rapidly achieved.8 A sudden decrease in sodium intake or increased extrarenal losses due to diarrhoea, nasogastric suction, vomiting, enterocutaneous stulas, burns or fever may therefore be associated with relative renal salt-wasting and clinically signicant volume depletion. This volume depletion may be further exacerbated by the injudicious use of diuretics. Volume depletion in the patient with chronic renal insufciency is frequently not recognized until signicant complications, including pre-renal azotaemia and systemic hypotension, develop. The prescription of intra- and perioperative uids must therefore take this increased risk for volume depletion into consideration. Sufcient uids need to be provided to replace obligate renal and extrarenal losses while avoiding volume overload. Central haemodynamic monitoring is frequently necessary to guide uid management, especially in patients with concomitant cardiac or hepatic dysfunction. Tonicity homeostasis The ability to conserve or excrete free water in CKD is limited and patients are predisposed to the development of disturbances of body uid tonicity. Although patients with advanced renal insufciency usually retain the ability to dilute their urine, maximal free water clearance is reduced in proportion to the decrease in GFR.8 10 Thus, while a normal individual may have a maximal free water excretion in excess of 20 l per day, a patient with a GFR of 15 ml/minute is limited to a free water excretion of approximately 2 3 l per day. While this is sufcient to prevent water intoxication and hypotonicity in the medically stable patient, excessive free-water administration to patients with chronic renal insufciency may result in signicant hypotonicity. In contrast, renal concentrating ability is lost relatively early in the course of renal disease, primarily due to impairment of the generation and maintenance of the medullary solute gradient.8 10 The inability to elaborate a concentrated urine is not, however, generally associated with the development of hypertonicity as water intake is independently modulated by thirst in response to changes in plasma tonicity. During the perioperative period, when access to water is restricted, the risk of developing hypertonicity is increased.12 Adequate free water must therefore be prescribed to replace insensible, gastrointestinal and renal water losses.

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Intraoperative and perioperative uid management in the patient with renal insufciency must therefore take into account the reduced capacity for both water excretion and conservation. Excessive free water administration must be avoided to prevent iatrogenic hypotonicity, while providing sufcient free-water to prevent hypertonicity. Electrolyte status should be monitored frequently and water administration adjusted if hypo- or hypernatraemia ensue. Potassium homeostasis Maintenance of the extracellular potassium concentration is dependent upon both total body potassium balance and on the distribution of potassium between the extracellular and intracellular compartments.13,14 Renal potassium excretion is primarily dependent upon potassium secretion in the collecting duct and is not directly impaired by reductions in GFR. In the absence of disease directly involving the distal nephron or associated with mineralocorticoid deciency, renal potassium excretion is maintained until late in the course of CKD and hyperkalaemia usually does not ensue until the onset of ESRD.6 The ability to tolerate an acute potassium load is, however, markedly impaired in patients with CKD. During the perioperative period, patients with CKD are therefore susceptible to the development of hyperkalaemia from either exogenous administration of potassium or from sudden shifts of potassium from the intracellular into the extracellular space. Excessive administration of potassium must therefore be avoided, with particular attention paid to the potassium content of intravenous uids. Routine prescription of potassium-containing uids, such as lactated Ringers solution, should be avoided. Other sources of exogenous potassium administration include blood transfusions and medications administered as potassium salts (e.g. antibiotics). Preservative solutions for kidney transplants and cardioplegia solutions may also provide substantial potassium loads. A variety of renal and systemic diseases are associated with tubular defects in potassium secretion, and predispose to the development of hyperkalaemia at lesser degrees of renal insufciency. These include systemic lupus erythematosus15, sickle-cell disease16, obstructive uropathy17, chronic interstitial nephritis18 and renal transplantation.19 Mineralocorticoid deciency may also impair renal potassium excretion in association with a wide variety of diseases, including diabetes mellitus20, chronic interstitial nephritis20, systemic lupus erythematosus21, acquired immune deciency syndrome22, and sickle-cell disease.20 Inhibitors of aldosterone secretion, such as angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, betaadrenergic receptor blockers, non-steroidal anti-inammatory drugs (both nonselective COX-1/COX-2 inhibitors and selective COX-2 inhibitors) and heparin, impair potassium tolerance and may also contribute to the development of hyperkalaemia.13,23,24 The potassium-sparing diuretics amiloride, triamterene and spironolactone inhibit tubular potassium secretion amiloride and trimethoprim through inhibition of the epithelial sodium channel (ENaC) and spironolactone through antagonism of the intracellular mineralocorticoid receptor.13,24 Trimethoprim also contributes to hyperkalaemia through inhibition of the epithelial sodium channel.25 A combination of mechanisms underlies the hyperkalaemia associated with cyclosporin A and tacrolimus.26,27 Patients with chronic renal insufciency are also more susceptible to the development of hyperkalaemia from transcellular potassium shifts. Factors that may produce transcellular potassium shifts and precipitate hyperkalaemia include

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hypertonicity (most commonly due to hyperglycaemia), insulin deciency, betaadrenergic receptor blockade and acidaemia. Of particular concern in perioperative management, the use of intravenous beta-adrenergic receptor blockers for the acute management of hypertension has been associated with the development of severe hyperkalaemia in patients with advanced CKD.28,29 For this reason, these agents, and in particular intravenous labetalol, should be used with great caution in the management of intraoperative and post-operative hypertension in patients with advanced renal failure. The depolarizing muscle relaxant succinylcholine has also been associated with acute hyperkalaemia.30,31 Use of this agent in normal individuals is associated with a transient increase in serum potassium concentration of between 0.5 and 1.0 mmol/l within 3 5 minutes and lasting 10 15 minutes.32 The mechanism for the hyperkalaemia is believed to be related directly to muscle depolarization at the neuromuscular junction. In patients with trauma, burns or neuromuscular disorders, this hyperkalaemic response may be exaggerated. Case reports of severe hyperkalaemia associated with succinylcholine use in patients with CKD has lead to the recommendation that it not be used in this population.30,31 In an extensive review of the literature, however, Thapa and Brull conclude that succinylcholine is not associated with an excess risk of hyperkalaemia in CKD and that its use in patients with advanced renal disease is safe, so long as there is no pre-operative hyperkalaemia, repeated doses are not administered and other conditions that predispose to hyperkalaemia (e.g. trauma, burns, neuromuscular disorders) are not present.31 Acute hyperkalaemia must be promptly treated.33 If cardiac toxicity is present, intravenous calcium should be administered to antagonize the membrane effects of hyperkalaemia, normalizing the associated EKG changes. The use of intravenous calcium has no effect on the serum potassium concentration and must be followed immediately by interventions to shift potassium from the extracellular uids into the intracellular compartment. Intravenous insulin (accompanied by glucose infusion to prevent hypoglycaemia in non-hyperglycaemic patients), and intravenous or inhaled beta-adrenergic agonists are the most effective agents, with an onset of action within 10 20 minutes and durations of action of 1 2 hours.33 Sodium bicarbonate, which previously had been recommended for the treatment of hyperkalaemia, has now been shown to be a relatively ineffective agent, with little utility in the acute treatment of hyperkalaemia, particularly in ESRD patients.33 35 Its use should be reserved for patients with concomitant metabolic acidosis. Decreasing total body potassium is the nal step in the treatment of hyperkalaemia. In non-oliguric patients, renal potassium excretion may be enhanced with loop-acting diuretics. Sodium polystyrene sulphonate (Kayexalatew) may be used as an exchange resin in the gastrointestinal tract; when given orally in sufcient sorbitol to promote elimination, each gram binds approximately one millimole of potassium. Although less effective, sodium polystyrene sulphonate may also be administered as a rectal retention enema. If treatment with sodium polystyrene sulphonate is ineffective or cannot be employed due to gastrointestinal disease, acute haemodialysis should be performed. Although continuous renal replacement therapy is highly effective for the control of hyperkalaemia over a course of hours, potassium removal is not sufciently rapid for this modality to be used for acute treatment. Many patients with advanced CKD or ESRD are chronically hyperkalaemic. The need for pre-operative normalization of serum potassium in these patients has not been rigorously evaluated. Anecdotal experience suggests that these patients are not at signicantly increased risk for hyperkalaemic arrhythmias if the serum potassium is

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stable and is less than 6.0 6.5 mmol/l. This is of particular importance in chronic dialysis patients who may require semi-emergent operative procedures to re-establish patency of malfunctioning or thrombosed vascular accesses. In these patients, the risk of inserting a temporary dialysis catheter may be greater than the risk of proceeding with anaesthesia and surgery despite modest hyperkalaemia. Acid base homeostasis Medically stable patients with chronic renal insufciency will generally not develop metabolic acidosis until the GFR falls below 20 30 ml/minute.8,9,36 Initially, the acidosis of CKD is hyperchloraemic; with more severe renal insufciency phosphates, sulphates and organic anions accumulate and the anion gap increases. The acidosis of chronic renal failure is generally mild, with the serum bicarbonate concentration rarely falling below 15 18 mmol/l until the onset of ESRD. Correspondingly, arterial pH is usually greater than 7.30 unless intercurrent respiratory or diarrhoeal disease is present. With the development of superimposed acute illness, patients with CKD are at increased risk for acute worsening of their acid base status. Their ability to maintain blood pH following an acute hydrogen ion load is reduced and severe acidaemia may develop due to a combination of reduced renal hydrogen ion excretory capacity, diminished blood-buffering capacity (due to pre-existent metabolic acidosis), and decreased capacity for further respiratory compensation. Similarly, the capacity to compensate for respiratory acidosis is reduced and a modest reduction in minute ventilation may result in severe acidaemia. Alkali supplementation should therefore be provided to maintain the serum bicarbonate concentration at a value greater than 18 20 mmol/l. Fluid losses from diarrhoea, and from enteric, biliary and pancreatic stulae should be minimized, if possible, and replaced with appropriate alkali-containing uids. Bicarbonate-wasting diuretics (e.g. acetazolamide) should be avoided. Although protein restriction may reduce the daily acid load, its appropriateness in the acutely ill patient is questionable. Mineral homeostasis Although disorders of calcium, phosphate and magnesium homeostasis are common in patients with CKD, they generally do not result in specic complications in the perioperative period. The most common of these disturbances is hyperphosphataemia, resulting from decreased renal phosphate excretion.37 Acutely, hyperphosphataemia may be controlled using aluminium hydroxide containing-antacids as oral phosphate binders. Chronic use of aluminium-containing binders may result in aluminium intoxication and should be avoided. Calcium salts (calcium carbonate, calcium acetate) are also effective as phosphate binders but do not achieve as rapid a lowering of serum phosphate as do the aluminium-based binders. Newer non-aluminium, non-calcium binders are also available, but are of limited efcacy in the treatment of acute hyperphosphataemia. Dietary phosphate should be restricted, and phosphate should be removed from hyperalimentation solutions. In severe hyperphosphataemia, emergency haemodialysis is effective at lowering the serum levels. Phosphate-containing cathartics (e.g. Fleetsw enema) have been associated with life-threatening hyperphosphataemia and should never be used in patients with renal insufciency.38 Mild hypocalcaemia is the most frequent disturbance of calcium homeostasis associated with CKD.37 Infrequently, symptomatic hypocalcaemia may develop in

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the acutely ill patient with chronic renal injury, most often in association with severe hyperphosphataemia. Treatment includes control of the serum phosphate concentration using oral binders, calcium supplementation and the administration of 1,25dihydroxy vitamin D analogues. The administration of intravenous calcium salts should be avoided in patients with severe hyperphosphataemia. Less commonly, hypercalcaemia may develop in the setting of severe secondary hyperparathyroidism or aluminiumdeposition bone disease. Magnesium excretion is reduced in CKD.37 Excessive magnesium intake in the form of antacids and cathartics, or from excessive supplementation in parenteral nutrition, may result in signicant hypermagnesaemia. Magnesium restriction is usually sufcient therapy for control of moderate hypermagnesaemia. In severe hypermagnesaemia, intravenous calcium infusion may be necessary to treat hypotension, bradyarrhythmias and muscle weakness. Emergency haemodialysis is effective at rapidly lowering the serum magnesium concentration, although it is rarely necessary.

HAEMATOLOGICAL ABNORMALITIES Anaemia Anaemia is a common feature of patients with CKD. Erythropoietin deciency is the predominant cause, however, hyperparathyroidism, aluminium toxicity, iron deciency and decreased red blood cell survival also contribute to its development.39 Prior to the introduction of replacement therapy with recombinant human erythropoietin (rHuEPO), haemoglobin concentrations of less than 80 g/l (8 g/dl) were common, although remarkably well tolerated. Many patients were, however, transfusiondependent and iron overload was not uncommon. The introduction of replacement therapy with rHuEPO and newer analogues has markedly altered this aspect of CKD.39 41 Therapy with rHuEPO allows maintenance of haemoglobin concentrations above 110 g/l (11 g/dl) and has eliminated the need for transfusion in the majority of patients with CKD or ESRD. The response to rHuEPO takes 2 6 weeks.40 As a result, although it is highly effective in the chronic management of anaemia of renal disease, it is of little value in the acute management of anaemia. Furthermore, the response to rHuEPO is diminished in acute inammatory states and other acute illnesses.42 Acute blood loss or severe anaemia in the acutely ill patient with CKD should therefore be treated with blood transfusion following the same criteria used for patients without renal disease. Careful monitoring of volume status and blood chemistry is required, however, as many patients with chronic renal disease are at increased risk for volume overload and hyperkalaemia following blood transfusion. Bleeding diathesis Patients with chronic renal disease may have an increased risk of bleeding complications. In a retrospective analysis of more than 3900 patients undergoing coronary artery bypass grafting, bleeding complications were signicantly more common in patients with mild to moderate elevations in serum creatinine (130 270 mmol/l; 1.5 3.0 mg/dl) as compared to patients with a baseline serum creatinine of less than 130 mmol/l (1.5 mg/dl) and was associated with increased transfusion requirement.43 Similarly,

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increased bleeding complications have been observed following general surgical procedures44 and lower extremity vascular surgery.45 Renal failure per se is not associated with abnormalities of clotting factors or of altered platelet number but is associated with platelet dysfunction.46 This abnormality is multifactorial: retained uraemic toxins, abnormal binding of von Willebrand factor, abnormal platelet arachidonic acid metabolism and excess vascular prostacyclin and nitric oxide production have all been implicated in its pathogenesis.46 In addition, anaemia may exacerbate the platelet dysfunction by altering the rheological properties of the circulation, thereby decreasing contact between platelets and the endothelium.47 The bleeding time provides the best correlation with risk of clinical bleeding in patients with CKD.48 In patients with clinical bleeding associated with a prolonged bleeding time due to renal failure, several therapeutic strategies may be employed. Pre-operative initiation of dialysis in patients who have not yet been dialysed, or intensication of the dialysis prescription, may shorten the bleeding time49 but is frequently not effective, particularly in patients who had previously been adequately dialysed. Anaemic patients should be transfused to maintain a haemoglobin concentration of at least 100 g/l (10 g/dl) in order to optimize the rheologic conditions for haemostasis.47 A variety of pharmacological agents have also been demonstrated to reduce the bleeding time in patients with chronic renal disease. Intravenous desmopressin (dDAVP; 0.3 mg/kg of body weight) has a rapid onset of action and is effective for approximately 6 8 hours; however, tachyphylaxis may develop with repeated doses.50 Oestrogens are also effective at reducing the bleeding time and may be administered intravenously, orally or transcutaneously.51 53 When administered intravenously at a dose of 0.6 mg/kg of body weight administered daily for 5 days, conjugated oestrogen shortens the bleeding time within 24 48 hours and has a duration of action of approximately 14 days.51 Cryoprecipitate has also been demonstrated to improve the bleeding time and reduce haemorrhagic complications, but as a pooled blood product it carries an increased risk of transmitting viral agents.54

CARDIOVASCULAR RISK Cardiovascular disease is the major cause of death in patients with ESRD, with cardiovascular mortality rates 10 20 times higher than in the general population even after stratication for age, gender and race.55,56 The prevalence of coronary artery disease in patients on chronic haemodialysis or peritoneal dialysis is approximately 40%, with a prevalence of left ventricular hypertrophy (LVH) of approximately 75%.55 Conventional risk factors contributing to this high rate of cardiovascular disease include high prevalence rates for hypertension, diabetes mellitus and hyperlipidaemia in this population. Other factors include chronic anaemia and elevated homocysteine levels. Even after controlling for these factors, patients with ESRD are more prone to the development of cardiovascular disease than is the general population.55,56 In fact, a reverse epidemiological association has been observed between several traditional cardiovascular risk factors, including obesity, hypercholesterolaemia and hypertension and mortality in ESRD patients.57 Although there are multiple explanations for this observation, an important factor is the high prevalence of malnutrition and chronic inammation in chronic dialysis patients. This condition, which has been termed

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the malnutrition-inammation complex syndrome, is associated with increased mortality, including adverse cardiovascular outcomes, despite decreased body mass index, hypoalbuminaemia and low serum cholesterol levels.57 In the pre-operative evaluation of ESRD patients, it is therefore important to recognize that they are at increased risk for perioperative cardiovascular events even in the absence of traditional cardiovascular risk factors. The increased prevalence of cardiovascular disease is also observed in patients with earlier stages of CKD.58 60 Even minimal decreases in GFR below 90 ml/minute/ 1.73 m2 are associated with an increased adjusted risk of atherosclerotic cardiovascular disease (ASCVD) as compared to individuals with normal renal function. Each 10 ml/ minute/1.73 m2 reduction in GFR was associated with an adjusted hazard ratio of 1.05 (95% CI:1.02 1.09) for ASCVD events in patients aged 45 64 years.58 Similar results have also been observed in an elderly population.59,60 For example, minimal elevations of serum creatinine, in the range of 115 130 mmol/l (1.3 1.5 mg/dl) were associated with an approximately 40% increase in the risk of cardiovascular disease as compared to patients with a serum creatinine of less than 100 mmol/l (1.1 mg/dl).59 In patients undergoing surgery, the presence of renal dysfunction is associated with increased cardiac morbidity and mortality.43 45,61 In a retrospective analysis of noncardiac surgery, a pre-operative serum creatinine level of $ 177 mmol/l (2 mg/dl) was associated with an almost seven-fold increase in hospital mortality.61 In patients undergoing major general surgery, 30-day post-operative mortality was increased by approximately 40% in patients with a serum creatinine of 130 270 mmol/l (1.5 3.0 mg/ dl) and by approximately 90% in patients with a serum creatinine greater than 270 mmol/l (3 mg/dl) as compared to patients with a pre-operative serum creatinine , 130 mmol/l (1.5 mg/dl).44 Elevations in pre-operative serum creatinine above 130 mmol/l (1.5 mg/dl) were also signicantly associated with post-operative cardiac morbidity, including cardiac arrest.44 Similar results have also been observed in patients undergoing lower extremity re-vascularization in whom stage 3 CKD (GFR 30 19 ml/ minute/1.73 m2) was associated with an increased risks of cardiac arrest and myocardial infarction as compared to patients with a pre-operative GFR $ 60 ml/minute/1.73 m2.45 Based on these data, it is clear that patients with even mild CKD are at substantially increased risk of perioperative cardiac morbidity and mortality. Careful pre-operative evaluation for cardiac risk and intraoperative and post-operative monitoring for cardiac events is therefore necessary in this population.

DRUG DOSING IN CKD The pharmacokinetics of many drugs is altered in CKD. While the most notable impact of CKD on drug disposition is decreased renal excretion, CKD may also be associated with changes in plasma protein binding, alterations in volume of distribution and altered drug metabolism.62,63 Changes in metabolic clearance are affected by both decreased metabolic clearance by the kidney and alterations in the activity of hepatic metabolic pathways.64 Although a detailed discussion of the alterations in drug pharmacokinetics in CKD and ESRD is beyond the scope of this chapter, and has been reviewed elsewhere62,63, the effect of renal failure on the disposition of analgesics and neuromuscular blocking agents is of critical importance in the perioperative management of CKD patients. Table 2 lists analgesic and neuromuscular blocking agents of particular concern in patients with renal insufciency.

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Table 2. Opioid analgesics and neuromuscular blockers with altered pharmacokinetics in renal failure. Drug Opioid analgesics Morphine Meperidine Neuromuscular blockers Gallamine Metocurine Mivacurium Pancuronium Pipecuronium Tubocurarine Vecuronium Alteration of pharmacokinetics

Accumulation of active metabolite (morphine-6-glucuronide) Accumulation of neuroexcitatory metabolite (normeperidine) Decreased renal clearance; recurarization may develop Decreased renal clearance Prolonged half-life due to decreased cholinesterase activity in renal failure Decreased renal clearance; recurarization may develop Decreased renal clearance Decreased clearance; recurarization may develop Accumulation of active metabolites

Most analgesics are eliminated from the body through hepatic biotransformation and thus require little dose adjustment in renal failure. Patients with renal failure may, however, be more susceptible to prolonged sedation and other adverse events with use of these agents as the result of alterations in the volume of distribution or impaired clearance of active metabolites. Of particular concern are the opioid analgesics meperidine and morphine. Meperidine is metabolized to normeperidine, a seizureinducing metabolite cleared by renal excretion. Patients with renal failure are at increased risk of seizures when treated with meperidine, especially if therapy is prolonged.65,66 Morphine-6-glucuronide, a highly active metabolite of morphine, is excreted primarily by the kidney. Prolonged therapy with morphine can lead to intoxication from the accumulation of this metabolite.67,68 Meperidine and morphine should therefore be avoided in patients with CKD or ESRD, particularly if repeated, or prolonged dosing will be required. The preferred opioid analgesics in this setting include hydromorphone and fentanyl. Non-steroidal anti-inammatory drugs (NSAIDs) may be used as non-opioid analgesics in patients with ESRD; however, these patients are at increased risk of NSAID-induced gastrointestinal bleeding. Both non-specic COX-1/COX-2 inhibitors and specic COX-2 inhibitors should be avoided in patients with earlier stages of CKD as these patients are at increased risk of acute renal failure from both classes of NSAID. The pharmacokinetics of neuromuscular blocking agents may be signicantly altered in patients with renal failure. Renal failure prolongs the half-life of many of the non-depolarizing muscle relaxants either by directly decreasing their elimination or indirectly through reduction in the activity of enzymes required for metabolic inactivation.63 Gallamine, metocurine, pancuronium, pipecuronium and tubocurarine are predominantly or partially dependent upon renal elimination. Vecuronium is metabolized by the liver to active metabolites that are renally excreted. Use of these agents in patients with renal failure may be associated with sustained muscle weakness or re-curarization.69 72 In contrast, mivacurium is metabolized by plasma pseudocholinesterases. In renal failure, the activity of cholinesterases are reduced, leading to a prolonged drug half-life.73 Because atracuronium and cisatracuronium

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are cleared predominantly by ester hydrolysis, their half-lives are unchanged in renal failure, making them the neuromuscular blocking agents of choice in renal failure.74

DIALYSIS Haemodialysis The majority of patients with ESRD are maintained on haemodialysis, with treatments provided on a thrice-weekly schedule. Additional dialysis treatments in the pre-operative period are not usually necessary, although the dialysis schedule may need to be adjusted to accommodate the surgical schedule. Optimally, patients scheduled for major surgical procedures should be dialysed on the day preceding surgery. A longer interval between the dialysis procedure and surgery increases the risk that the patient will develop volume overload, or be acidaemic or hyperkalaemic. If major surgery is scheduled for the same day as dialysis, an interval of at least 4 hours should be permitted between the end of dialysis and the surgical procedure to permit reversal of anticoagulation. If a shorter interval is necessary, the dose of anticoagulation should be minimized or the dialysis performed without anticoagulation in order to decrease the risk of excessive intraoperative bleeding. Regional anticoagulation with citrate may be an alternative option. The use of this modality of anticoagulation requires the use of calcium-free dialysate and may be associated with signicant hypocalcaemia. Frequent monitoring of ionized calcium levels is therefore required. Post-operatively, it is optimal if dialysis can be postponed for at least 24 hours following the completion of surgery. Anticoagulation should be minimized during postoperative dialysis, and performed without anticoagulation in patients at high risk for post-operative bleeding complications (e.g. following neurosurgical and ophthalmological procedures). Intraoperative management of haemodialysis patients needs to include protection of the haemodialysis vascular access. No intravenous catheters, including central venous catheters, should be placed on the same side as an arteriovenous access. Blood pressure should be measured only in the contralateral arm. The limb with the arteriovenous access should be carefully positioned to ensure that inadvertent occlusion of the arteriovenous access does not occur. It is important that armbands, which may migrate up the arm and occlude a forearm access, not be placed on the access arm. Access patency needs to be carefully monitored both intraoperatively and post-operatively and any alteration in access function addressed promptly by a vascular surgeon or an interventional radiologist or nephrologist. If possible, cannulation of the subclavian veins should be avoided in all patients with CKD or ESRD. Cannulation of these vessels is associated with an increased risk for late stenosis or thrombosis, which may then preclude function of an arteriovenous access on the same side. All patients with a patent arteriovenous access, particularly patients with prosthetic arteriovenous grafts, should receive prophylactic antibiotics before any procedure that may cause bacteraemia. In general, standard guidelines for antibiotic prophylaxis to prevent endocarditis may be used to guide antibiotic administration for the prevention of access infection.

Perioperative management of ESRD 141

Peritoneal dialysis Patients receiving chronic peritoneal dialysis should have their abdomen drained of all dialysate, and the peritoneal catheter ushed with heparin-containing uid and capped prior to any procedure involving conscious sedation or general anaesthesia. Draining the peritoneal uid decreases intra-abdominal pressure, allowing easier ventilation and reducing the risk of aspiration. In addition, draining the glucose-rich intra-abdominal uid decreases the risk for peritonitis associated with transient bacteraemia during the procedure. Peritoneal dialysis may be resumed in the immediate post-operative period after non-abdominal surgery, so long as the patients ventilatory status will tolerate the associated abdominal distention. Following abdominal surgery, peritoneal dialysis should be suspended and the patient maintained with haemodialysis to decrease the risks of anastomotic leaks, wound dehiscence, infection and late incisional hernia formation.

SUMMARY Patients with CKD or ESRD pose special challenges for anaesthesia and perioperative management. The prevalence of CKD is increasing, and these patients have many comorbid conditions that need to be taken into account in planning their care. As a result of their renal insufciency, they are at increased risk for uid and electrolyte disorders, anaemia and haemorrhagic complications. Patients with CKD are at increased risk for cardiovascular disease, even in the absence of traditional risk factors, and require careful pre-operative cardiac assessment and perioperative monitoring. The pharmacokinetics of many drugs used in anaesthesia management are altered in CKD. Specically, the opioid analgesics morphine and meperidine should be avoided, as should many neuromuscular blocking agents whose half-lives are prolonged in renal failure. The preferred neuromuscular blockers include atracuronium and cisatracuronium. Succinylcholine may also be used in renal failure, despite concerns regarding hyperkalaemia. Special attention needs to be paid to preserving arteriovenous access patency in the intraoperative management of patients on haemodialysis.

Practice points CKD is a frequent disturbance among patients, especially in the elderly population patients with CKD are at increased risk for CKD, even in the absence of traditional risk factors the opioid analgesics morphine and meperidine should be avoided in patients with advanced renal failure the preferred neuromuscular blocking agents in CKD include atracuronium and cisatracuronium; succinylcholine may also be used despite concerns regarding hyperkalaemia special attention must be provided to preserving arteriovenous access patency during intraoperative management

142 P. M. Palevsky

Research agenda approaches to stratication of the risk for perioperative cardiac events in patients with CKD need to be optimized the pharmacokinetics of drugs used in the perioperative period need to be better dened over a wide range of renal function in order to ensure greater patient safety strategies for minimizing the excess perioperative morbidity and mortality of patients with CKD need to be developed

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