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 dialysis-dependent end-stage renal disease (ESRD) is complicated by both the underlying renaldysfunction, with associated disturbances of fluid and electrolyte homeostasis and altered drugclearance, and the presence of associated co-morbid conditions, including diabetes mellitus,chronic hypertension and cardiovascular and cerebrovascular disease. The impact of CKD onfluid and electrolyte management, haematological and cardiovascular complications and drugmanagement in the perioperative period are reviewed. Special issues related to the managementof haemodialysis and peritoneal dialysis patients in the perioperative period are also reviewed.

Key words: chronic kidney disease; end-stage renal disease; dialysis; haemodialysis; peritonealdialysis; water-electrolyte imbalance; hyperkalaemia; anaesthesia; opioid analgesics; neuromus-cular blocking agents; post-operative complications.

The perioperative management of patients with chronic kidney disease (CKD) ordialysis-dependent end-stage renal disease (ESRD) is complicated by both the underlyingrenal disease, with associated disturbances of fluid and electrolyte homeostasis andaltered drug clearance, and the presence of associated co-morbid conditions, includingdiabetes mellitus, chronic hypertension and cardiovascular and cerebrovascular disease.The perioperative and anaesthesia management of these patients must therefore takeinto account the specific changes related to renal dysfunction as well as the increasedanaesthesia and operative risks associated with these comorbidities.

STRATIFICATION AND EPIDEMIOLOGY OF CHRONICKIDNEY DISEASE

The National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI), has recently proposed a standardized classification scheme for patients with

1521-6896/$ - see front matter Published by Elsevier Ltd.

Best Practice & Research Clinical AnaesthesiologyVol. 18, No. 1, pp. 129–144, 2004doi:10.1016/S1521-6896(03)00067-3, available online at http://www.sciencedirect.com

* Tel.: þ1-412-688-6000; Fax: þ412-688-6908.E-mail address: palevsky@pitt.edu (P. M. Palevsky).

CKD.1 This classification scheme stratifies CKD into five stages based on estimation ofglomerular filtration rate (GFR) and documentation of renal injury (Table 1). Allindividuals with a GFR of less than 60 ml/minute/1.73 m2 for more than 3 months areclassified as having CKD, irrespective of other evidence of kidney damage. Because GFRdeclines with ageing, other evidence of renal disease, such as pathological or anatomicalabnormalities, or markers of kidney damage such as proteinuria or haematuria, must bepresent to define CKD in patients with a GFR $60 ml/minute/1.73 m2. Reductions inGFR below this level represent a loss of more than half of the normal adult renalfunction and are associated with increased risk of progressive disease and associatedco-morbidities.

Although serum creatinine is the most widely utilized index of renal function inclinical practice, it is a relatively insensitive marker of renal function. Serum creatinineconcentration is a function of both creatinine generation, primarily from musclecreatine metabolism, and renal and extra-renal creatinine excretion. Creatininegeneration is proportional to muscle mass and is generally higher in men than inwomen, and in individuals of African descent as compared to other racial groups. Inaddition, creatinine generation tends to decline with increasing age and will also bedecreased in individuals with muscle wasting or malnutrition. Although creatinineexcretion occurs primarily through glomerular filtration, a small percentage ofcreatinine is normally excreted by renal tubular secretion and in the stool. Thepercentage of creatinine excretion occurring via these non-glomerular routes increaseswith impaired renal function. As a consequence of these factors, serum creatinineconcentration, particularly in elderly or chronically ill patients may be normal or onlyminimally elevated despite significant reduction in GFR.

In order to improve the assessment of renal function from readily available clinicaldata, multiple prediction equations to estimate creatinine clearance or GFR have beendeveloped. The two most widely utilized equations are the Cockroft–Gault equationfor estimation of creatinine clearance2 and the MDRD study equation for calculation ofestimated GFR.1,3,4 These equations are

Cockroft–Gault equation

Creatinine clearance ðml=minuteÞ ¼ð140 2 ageÞ £ weightðkgÞ

ð72 £ serum creatinineÞ£ ð0:85 if femaleÞ

Table 1. Stages of CKD.

Stage Definition

1 GFR $90 ml/minute/1.73 m2 with evidence of kidney damagea

2 GFR 60–89 ml/minute/1.73 m2 with evidence of kidney damagea

3 GFR 30–59 ml/minute/1.73 m2

4 GFR 15–29 ml/minute/1.73 m2

5 GFR ,15 ml/minute/1.73 m2 or dialysis-dependent

a Kidney damage defined as pathological abnormalities or markers of damage, including abnormalities of

blood or urine tests or imaging studies.

130 P. M. Palevsky

Abbreviated MDRD study equation

eGFRðml=minute=1:73 m2Þ ¼186 £ ðserum creatinineÞ21:154

£ ðageÞ20:203 £ ð0:742 if femaleÞ

£ ð1:210 if of African descentÞ

Accurate data regarding the prevalence of CKD are not available. Using data fromthe US Third National Health and Nutrition Examination Survey (NHANES III) it hasbeen estimated that approximately 3% of the adult population in the USA, or 5.3 millionpatients, have stage 2 CKD as defined by persistent albuminuria and an estimated GFRof 60–84 ml/minute/1.73 m2.1 An additional 4.7% of the population, or 8.3 millionpatients, 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 ofCKD, detailed data are available from the United States Renal Data System (USRDS) onthe incidence and prevalence of ESRD.5 In 2000 there were approximately 270 000ESRD patients receiving chronic dialysis in the USA, with the population of dialysispatients increasing by 3–5% per year.5 The most common aetiology of renal failure isdiabetes 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 elderlypatients 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. Inaddition, given the increased representation of CKD and ESRD in the elderlypopulation, and the high rate of co-morbid conditions, the management of patients withCKD is an important issue for anaesthesiologists.

FLUID AND ELECTROLYTE MANAGEMENT

The capacity of the kidneys to maintain the volume and content of the extracellularcompartment is normally preserved well into the course of chronic renal insufficiency.In the majority of medically stable patients, extracellular fluid volume and electrolytecomposition remain normal until the development of dialysis-dependent end-stagekidney disease.6 This capacity of the failing kidney to maintain volume and electrolytehomeostasis is achieved, however, through adaptive processes which are limited in theircapacity to respond to physiological stress. Thus, the patient with chronic renal diseasewho is well compensated in the pre-morbid state is at high risk for the development offluid and electrolyte disturbances during the perioperative period.

Volume homeostasis

The patients with chronic renal insufficiency can usually maintain sodium balance on afixed sodium intake until end-stage kidney disease is reached.6–8 The ability of thechronically injured kidney to respond to extremes of sodium intake or to suddenchanges 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 insufficiency are generally able to excrete a sodium loadand usually do not develop clinical volume overload unless other conditions whichindependently inhibit renal sodium excretion (e.g. heart failure, cirrhosis or nephrotic

Perioperative management of ESRD 131

syndrome) are present.8,9 Volume overload may develop, however, if large volumes ofsaline solutions are rapidly administered. In advanced chronic renal insufficiency, theability to excrete even a modest sodium load is impaired and volume overload canrapidly develop following the administration of only modest quantities of enteral orintravenous fluids.

The administration of large volumes of intravenous fluids to patients with CKDshould be avoided. If volume overload develops, intravenous fluids should bediscontinued and diuretic therapy initiated. Diuretics inhibiting sodium transport inthe thick ascending limb of the loop of Henle, such as furosemide and bumetanide, arethe most effective agents. Sequential nephron blockade using a combination of a loop-acting diuretic and oral metolazone or an intravenous thiazide diuretic may significantlyincrease the diuresis in patients resistant to a loop-acting diuretic alone.11 In patientswith ESRD, volume overload may precipitate the need for urgent dialysis.

Paradoxically, patients with mild to moderate chronic renal insufficiency are also atincreased risk for the development of extracellular fluid volume depletion. Thechronically injured kidney maintains sodium balance at the expense of an increasedfractional excretion of sodium; when challenged with sudden sodium restriction,maximal sodium conservation cannot be rapidly achieved.8 A sudden decrease insodium intake or increased extrarenal losses due to diarrhoea, nasogastric suction,vomiting, enterocutaneous fistulas, burns or fever may therefore be associated withrelative renal ‘salt-wasting’ and clinically significant volume depletion. This volumedepletion may be further exacerbated by the injudicious use of diuretics.

Volume depletion in the patient with chronic renal insufficiency is frequently notrecognized until significant complications, including pre-renal azotaemia and systemichypotension, develop. The prescription of intra- and perioperative fluids musttherefore take this increased risk for volume depletion into consideration. Sufficientfluids need to be provided to replace obligate renal and extrarenal losses while avoidingvolume overload. Central haemodynamic monitoring is frequently necessary to guidefluid management, especially in patients with concomitant cardiac or hepaticdysfunction.

Tonicity homeostasis

The ability to conserve or excrete free water in CKD is limited and patients arepredisposed to the development of disturbances of body fluid tonicity. Althoughpatients with advanced renal insufficiency 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 of20 l per day, a patient with a GFR of 15 ml/minute is limited to a free water excretion ofapproximately 2–3 l per day. While this is sufficient to prevent water intoxication andhypotonicity in the medically stable patient, excessive free-water administration topatients with chronic renal insufficiency may result in significant hypotonicity.

In contrast, renal concentrating ability is lost relatively early in the course of renaldisease, primarily due to impairment of the generation and maintenance of themedullary solute gradient.8–10 The inability to elaborate a concentrated urine is not,however, generally associated with the development of hypertonicity as water intake isindependently modulated by thirst in response to changes in plasma tonicity. During theperioperative period, when access to water is restricted, the risk of developinghypertonicity is increased.12 Adequate free water must therefore be prescribed toreplace insensible, gastrointestinal and renal water losses.

132 P. M. Palevsky

Intraoperative and perioperative fluid management in the patient with renalinsufficiency must therefore take into account the reduced capacity for both waterexcretion and conservation. Excessive free water administration must be avoided toprevent iatrogenic hypotonicity, while providing sufficient free-water to preventhypertonicity. Electrolyte status should be monitored frequently and water adminis-tration adjusted if hypo- or hypernatraemia ensue.

Potassium homeostasis

Maintenance of the extracellular potassium concentration is dependent upon both totalbody potassium balance and on the distribution of potassium between the extracellularand intracellular compartments.13,14 Renal potassium excretion is primarily dependentupon potassium secretion in the collecting duct and is not directly impaired byreductions in GFR. In the absence of disease directly involving the distal nephron orassociated with mineralocorticoid deficiency, renal potassium excretion is maintaineduntil late in the course of CKD and hyperkalaemia usually does not ensue until theonset of ESRD.6

The ability to tolerate an acute potassium load is, however, markedly impaired inpatients with CKD. During the perioperative period, patients with CKD are thereforesusceptible to the development of hyperkalaemia from either exogenous administrationof potassium or from sudden shifts of potassium from the intracellular into theextracellular space. Excessive administration of potassium must therefore be avoided,with particular attention paid to the potassium content of intravenous fluids. Routineprescription of potassium-containing fluids, such as lactated Ringer’s solution, should beavoided. Other sources of exogenous potassium administration include bloodtransfusions and medications administered as potassium salts (e.g. antibiotics).Preservative solutions for kidney transplants and cardioplegia solutions may alsoprovide substantial potassium loads.

A variety of renal and systemic diseases are associated with tubular defects inpotassium secretion, and predispose to the development of hyperkalaemia at lesserdegrees of renal insufficiency. These include systemic lupus erythematosus15, sickle-celldisease16, obstructive uropathy17, chronic interstitial nephritis18 and renal transplan-tation.19 Mineralocorticoid deficiency may also impair renal potassium excretion inassociation with a wide variety of diseases, including diabetes mellitus20, chronicinterstitial nephritis20, systemic lupus erythematosus21, acquired immune deficiencysyndrome22, and sickle-cell disease.20 Inhibitors of aldosterone secretion, such asangiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, beta-adrenergic receptor blockers, non-steroidal anti-inflammatory drugs (both non-selective COX-1/COX-2 inhibitors and selective COX-2 inhibitors) and heparin,impair potassium tolerance and may also contribute to the development ofhyperkalaemia.13,23,24 The potassium-sparing diuretics amiloride, triamterene andspironolactone inhibit tubular potassium secretion–amiloride and trimethoprimthrough inhibition of the epithelial sodium channel (ENaC) and spironolactone throughantagonism of the intracellular mineralocorticoid receptor.13,24 Trimethoprim alsocontributes to hyperkalaemia through inhibition of the epithelial sodium channel.25 Acombination of mechanisms underlies the hyperkalaemia associated with cyclosporin Aand tacrolimus.26,27

Patients with chronic renal insufficiency are also more susceptible to thedevelopment of hyperkalaemia from transcellular potassium shifts. Factors that mayproduce transcellular potassium shifts and precipitate hyperkalaemia include

Perioperative management of ESRD 133

hypertonicity (most commonly due to hyperglycaemia), insulin deficiency, beta-adrenergic receptor blockade and acidaemia. Of particular concern in perioperativemanagement, the use of intravenous beta-adrenergic receptor blockers for the acutemanagement of hypertension has been associated with the development of severehyperkalaemia in patients with advanced CKD.28,29 For this reason, these agents, and inparticular intravenous labetalol, should be used with great caution in the managementof intraoperative and post-operative hypertension in patients with advanced renalfailure.

The depolarizing muscle relaxant succinylcholine has also been associated with acutehyperkalaemia.30,31 Use of this agent in normal individuals is associated with a transientincrease 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 isbelieved to be related directly to muscle depolarization at the neuromuscular junction.In patients with trauma, burns or neuromuscular disorders, this hyperkalaemicresponse may be exaggerated. Case reports of severe hyperkalaemia associated withsuccinylcholine use in patients with CKD has lead to the recommendation that it not beused in this population.30,31 In an extensive review of the literature, however, Thapa andBrull conclude that succinylcholine is not associated with an excess risk ofhyperkalaemia in CKD and that its use in patients with advanced renal disease issafe, so long as there is no pre-operative hyperkalaemia, repeated doses are notadministered 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 ofhyperkalaemia, normalizing the associated EKG changes. The use of intravenouscalcium has no effect on the serum potassium concentration and must be followedimmediately by interventions to shift potassium from the extracellular fluids into theintracellular compartment. Intravenous insulin (accompanied by glucose infusion toprevent hypoglycaemia in non-hyperglycaemic patients), and intravenous or inhaledbeta-adrenergic agonists are the most effective agents, with an onset of action within10–20 minutes and durations of action of 1–2 hours.33 Sodium bicarbonate, whichpreviously had been recommended for the treatment of hyperkalaemia, has now beenshown to be a relatively ineffective agent, with little utility in the acute treatment ofhyperkalaemia, particularly in ESRD patients.33–35 Its use should be reserved forpatients with concomitant metabolic acidosis.

Decreasing total body potassium is the final step in the treatment of hyperkalaemia.In non-oliguric patients, renal potassium excretion may be enhanced with loop-actingdiuretics. Sodium polystyrene sulphonate (Kayexalatew) may be used as an exchangeresin in the gastrointestinal tract; when given orally in sufficient sorbitol to promoteelimination, each gram binds approximately one millimole of potassium. Although lesseffective, sodium polystyrene sulphonate may also be administered as a rectal retentionenema. If treatment with sodium polystyrene sulphonate is ineffective or cannot beemployed due to gastrointestinal disease, acute haemodialysis should be performed.Although continuous renal replacement therapy is highly effective for the control ofhyperkalaemia over a course of hours, potassium removal is not sufficiently rapid forthis modality to be used for acute treatment.

Many patients with advanced CKD or ESRD are chronically hyperkalaemic. The needfor pre-operative normalization of serum potassium in these patients has not beenrigorously evaluated. Anecdotal experience suggests that these patients are not atsignificantly increased risk for hyperkalaemic arrhythmias if the serum potassium is

134 P. M. Palevsky

stable and is less than 6.0–6.5 mmol/l. This is of particular importance in chronicdialysis patients who may require semi-emergent operative procedures to re-establishpatency of malfunctioning or thrombosed vascular accesses. In these patients, the riskof inserting a temporary dialysis catheter may be greater than the risk of proceedingwith anaesthesia and surgery despite modest hyperkalaemia.

Acid–base homeostasis

Medically stable patients with chronic renal insufficiency will generally not developmetabolic acidosis until the GFR falls below 20–30 ml/minute.8,9,36 Initially, theacidosis of CKD is hyperchloraemic; with more severe renal insufficiency phosphates,sulphates and organic anions accumulate and the anion gap increases. The acidosis ofchronic renal failure is generally mild, with the serum bicarbonate concentrationrarely falling below 15–18 mmol/l until the onset of ESRD. Correspondingly, arterialpH is usually greater than 7.30 unless intercurrent respiratory or diarrhoeal disease ispresent.

With the development of superimposed acute illness, patients with CKD are atincreased risk for acute worsening of their acid–base status. Their ability to maintainblood pH following an acute hydrogen ion load is reduced and severe acidaemia maydevelop due to a combination of reduced renal hydrogen ion excretory capacity,diminished blood-buffering capacity (due to pre-existent metabolic acidosis), anddecreased capacity for further respiratory compensation. Similarly, the capacity tocompensate for respiratory acidosis is reduced and a modest reduction in minuteventilation may result in severe acidaemia. Alkali supplementation should therefore beprovided 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 fistulaeshould be minimized, if possible, and replaced with appropriate alkali-containing fluids.Bicarbonate-wasting diuretics (e.g. acetazolamide) should be avoided. Although proteinrestriction may reduce the daily acid load, its appropriateness in the acutely ill patient isquestionable.

Mineral homeostasis

Although disorders of calcium, phosphate and magnesium homeostasis are common inpatients with CKD, they generally do not result in specific complications in theperioperative period. The most common of these disturbances is hyperphosphataemia,resulting from decreased renal phosphate excretion.37 Acutely, hyperphosphataemiamay be controlled using aluminium hydroxide containing-antacids as oral phosphatebinders. Chronic use of aluminium-containing binders may result in aluminiumintoxication 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 serumphosphate as do the aluminium-based binders. Newer non-aluminium, non-calciumbinders are also available, but are of limited efficacy in the treatment of acutehyperphosphataemia. Dietary phosphate should be restricted, and phosphate should beremoved from hyperalimentation solutions. In severe hyperphosphataemia, emergencyhaemodialysis is effective at lowering the serum levels. Phosphate-containing cathartics(e.g. Fleetsw enema) have been associated with life-threatening hyperphosphataemiaand should never be used in patients with renal insufficiency.38

Mild hypocalcaemia is the most frequent disturbance of calcium homeostasisassociated with CKD.37 Infrequently, symptomatic hypocalcaemia may develop in

Perioperative management of ESRD 135

the acutely ill patient with chronic renal injury, most often in association with severehyperphosphataemia. Treatment includes control of the serum phosphate concen-tration using oral binders, calcium supplementation and the administration of 1,25-dihydroxy vitamin D analogues. The administration of intravenous calcium salts shouldbe avoided in patients with severe hyperphosphataemia. Less commonly, hypercalcae-mia may develop in the setting of severe secondary hyperparathyroidism or aluminium-deposition bone disease.

Magnesium excretion is reduced in CKD.37 Excessive magnesium intake in the formof antacids and cathartics, or from excessive supplementation in parenteral nutrition,may result in significant hypermagnesaemia. Magnesium restriction is usually sufficienttherapy for control of moderate hypermagnesaemia. In severe hypermagnesaemia,intravenous calcium infusion may be necessary to treat hypotension, bradyarrhythmiasand muscle weakness. Emergency haemodialysis is effective at rapidly lowering theserum magnesium concentration, although it is rarely necessary.

HAEMATOLOGICAL ABNORMALITIES

Anaemia

Anaemia is a common feature of patients with CKD. Erythropoietin deficiency is thepredominant cause, however, hyperparathyroidism, aluminium toxicity, iron deficiencyand decreased red blood cell survival also contribute to its development.39 Prior to theintroduction 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, transfusion-dependent and iron overload was not uncommon. The introduction of replacementtherapy with rHuEPO and newer analogues has markedly altered this aspect ofCKD.39–41 Therapy with rHuEPO allows maintenance of haemoglobin concentrationsabove 110 g/l (11 g/dl) and has eliminated the need for transfusion in the majority ofpatients with CKD or ESRD.

The response to rHuEPO takes 2–6 weeks.40 As a result, although it is highlyeffective in the chronic management of anaemia of renal disease, it is of little value in theacute management of anaemia. Furthermore, the response to rHuEPO is diminished inacute inflammatory states and other acute illnesses.42 Acute blood loss or severeanaemia in the acutely ill patient with CKD should therefore be treated with bloodtransfusion following the same criteria used for patients without renal disease. Carefulmonitoring of volume status and blood chemistry is required, however, as manypatients with chronic renal disease are at increased risk for volume overload andhyperkalaemia 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 arterybypass grafting, bleeding complications were significantly more common in patients withmild to moderate elevations in serum creatinine (130–270 mmol/l; 1.5–3.0 mg/dl) ascompared 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,

136 P. M. Palevsky

increased bleeding complications have been observed following general surgicalprocedures44 and lower extremity vascular surgery.45

Renal failure per se is not associated with abnormalities of clotting factors or ofaltered platelet number but is associated with platelet dysfunction.46 This abnormalityis multifactorial: retained uraemic toxins, abnormal binding of von Willebrand factor,abnormal platelet arachidonic acid metabolism and excess vascular prostacyclin andnitric oxide production have all been implicated in its pathogenesis.46 In addition,anaemia may exacerbate the platelet dysfunction by altering the rheological propertiesof the circulation, thereby decreasing contact between platelets and the endo-thelium.47

The bleeding time provides the best correlation with risk of clinical bleeding inpatients with CKD.48 In patients with clinical bleeding associated with a prolongedbleeding time due to renal failure, several therapeutic strategies may be employed.Pre-operative initiation of dialysis in patients who have not yet been dialysed, orintensification of the dialysis prescription, may shorten the bleeding time49 but isfrequently not effective, particularly in patients who had previously been adequatelydialysed. Anaemic patients should be transfused to maintain a haemoglobinconcentration of at least 100 g/l (10 g/dl) in order to optimize the rheologicconditions for haemostasis.47 A variety of pharmacological agents have also beendemonstrated 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 ofaction and is effective for approximately 6–8 hours; however, tachyphylaxis maydevelop with repeated doses.50 Oestrogens are also effective at reducing the bleedingtime and may be administered intravenously, orally or transcutaneously.51–53 Whenadministered intravenously at a dose of 0.6 mg/kg of body weight administered dailyfor 5 days, conjugated oestrogen shortens the bleeding time within 24–48 hours andhas a duration of action of approximately 14 days.51 Cryoprecipitate has also beendemonstrated to improve the bleeding time and reduce haemorrhagic complications,but as a pooled blood product it carries an increased risk of transmitting viralagents.54

CARDIOVASCULAR RISK

Cardiovascular disease is the major cause of death in patients with ESRD, withcardiovascular mortality rates 10–20 times higher than in the general population evenafter stratification for age, gender and race.55,56 The prevalence of coronary arterydisease in patients on chronic haemodialysis or peritoneal dialysis is approximately40%, with a prevalence of left ventricular hypertrophy (LVH) of approximately 75%.55

Conventional risk factors contributing to this high rate of cardiovascular diseaseinclude high prevalence rates for hypertension, diabetes mellitus and hyperlipidaemiain this population. Other factors include chronic anaemia and elevated homocysteinelevels.

Even after controlling for these factors, patients with ESRD are more prone to thedevelopment of cardiovascular disease than is the general population.55,56 In fact, areverse epidemiological association has been observed between several ‘traditional’cardiovascular risk factors, including obesity, hypercholesterolaemia and hypertensionand mortality in ESRD patients.57 Although there are multiple explanations for thisobservation, an important factor is the high prevalence of malnutrition and chronicinflammation in chronic dialysis patients. This condition, which has been termed

Perioperative management of ESRD 137

the ‘malnutrition-inflammation complex syndrome’, is associated with increasedmortality, including adverse cardiovascular outcomes, despite decreased body massindex, hypoalbuminaemia and low serum cholesterol levels.57 In the pre-operativeevaluation of ESRD patients, it is therefore important to recognize that they are atincreased risk for perioperative cardiovascular events even in the absence of traditionalcardiovascular risk factors.

The increased prevalence of cardiovascular disease is also observed in patients withearlier 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 cardiovasculardisease (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 resultshave also been observed in an elderly population.59,60 For example, minimal elevationsof serum creatinine, in the range of 115–130 mmol/l (1.3–1.5 mg/dl) were associatedwith an approximately 40% increase in the risk of cardiovascular disease as compared topatients 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 withincreased cardiac morbidity and mortality.43–45,61 In a retrospective analysis of non-cardiac surgery, a pre-operative serum creatinine level of $177 mmol/l (2 mg/dl) wasassociated with an almost seven-fold increase in hospital mortality.61 In patientsundergoing major general surgery, 30-day post-operative mortality was increased byapproximately 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 than270 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 above130 mmol/l (1.5 mg/dl) were also significantly associated with post-operative cardiacmorbidity, including cardiac arrest.44 Similar results have also been observed in patientsundergoing 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 myocardialinfarction 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 substantiallyincreased risk of perioperative cardiac morbidity and mortality. Careful pre-operativeevaluation for cardiac risk and intraoperative and post-operative monitoring for cardiacevents is therefore necessary in this population.

DRUG DOSING IN CKD

The pharmacokinetics of many drugs is altered in CKD. While the most notable impactof CKD on drug disposition is decreased renal excretion, CKD may also be associatedwith changes in plasma protein binding, alterations in volume of distribution and altereddrug metabolism.62,63 Changes in metabolic clearance are affected by both decreasedmetabolic clearance by the kidney and alterations in the activity of hepatic metabolicpathways.64 Although a detailed discussion of the alterations in drug pharmacokineticsin CKD and ESRD is beyond the scope of this chapter, and has been reviewedelsewhere62,63, the effect of renal failure on the disposition of analgesics andneuromuscular blocking agents is of critical importance in the perioperative manage-ment of CKD patients. Table 2 lists analgesic and neuromuscular blocking agents ofparticular concern in patients with renal insufficiency.

138 P. M. Palevsky

Most analgesics are eliminated from the body through hepatic biotransformation andthus require little dose adjustment in renal failure. Patients with renal failure may,however, be more susceptible to prolonged sedation and other adverse events with useof these agents as the result of alterations in the volume of distribution or impairedclearance of active metabolites. Of particular concern are the opioid analgesicsmeperidine and morphine. Meperidine is metabolized to normeperidine, a seizure-inducing metabolite cleared by renal excretion. Patients with renal failure are atincreased risk of seizures when treated with meperidine, especially if therapy isprolonged.65,66 Morphine-6-glucuronide, a highly active metabolite of morphine, isexcreted primarily by the kidney. Prolonged therapy with morphine can lead tointoxication from the accumulation of this metabolite.67,68 Meperidine and morphineshould therefore be avoided in patients with CKD or ESRD, particularly if repeated, orprolonged dosing will be required. The preferred opioid analgesics in this settinginclude hydromorphone and fentanyl.

Non-steroidal anti-inflammatory drugs (NSAIDs) may be used as non-opioidanalgesics in patients with ESRD; however, these patients are at increased risk ofNSAID-induced gastrointestinal bleeding. Both non-specific COX-1/COX-2 inhibi-tors and specific COX-2 inhibitors should be avoided in patients with earlier stagesof CKD as these patients are at increased risk of acute renal failure from bothclasses of NSAID.

The pharmacokinetics of neuromuscular blocking agents may be significantlyaltered in patients with renal failure. Renal failure prolongs the half-life of many ofthe non-depolarizing muscle relaxants either by directly decreasing their eliminationor indirectly through reduction in the activity of enzymes required for metabolicinactivation.63 Gallamine, metocurine, pancuronium, pipecuronium and tubocurarineare predominantly or partially dependent upon renal elimination. Vecuronium ismetabolized by the liver to active metabolites that are renally excreted. Use ofthese agents in patients with renal failure may be associated with sustained muscleweakness or re-curarization.69–72 In contrast, mivacurium is metabolized by plasmapseudocholinesterases. In renal failure, the activity of cholinesterases are reduced,leading to a prolonged drug half-life.73 Because atracuronium and cisatracuronium

Table 2. Opioid analgesics and neuromuscular blockers with altered pharmacokinetics in renal failure.

Drug Alteration of pharmacokinetics

Opioid analgesics

Morphine Accumulation of active metabolite (morphine-6-glucuronide)

Meperidine Accumulation of neuroexcitatory metabolite (normeperidine)

Neuromuscular blockers

Gallamine Decreased renal clearance; recurarization may develop

Metocurine Decreased renal clearance

Mivacurium Prolonged half-life due to decreased cholinesterase activity in renal failure

Pancuronium Decreased renal clearance; recurarization may develop

Pipecuronium Decreased renal clearance

Tubocurarine Decreased clearance; recurarization may develop

Vecuronium Accumulation of active metabolites

Perioperative management of ESRD 139

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

DIALYSIS

Haemodialysis

The majority of patients with ESRD are maintained on haemodialysis, withtreatments provided on a thrice-weekly schedule. Additional dialysis treatments inthe pre-operative period are not usually necessary, although the dialysis schedule mayneed to be adjusted to accommodate the surgical schedule. Optimally, patientsscheduled for major surgical procedures should be dialysed on the day precedingsurgery. A longer interval between the dialysis procedure and surgery increases therisk 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 least4 hours should be permitted between the end of dialysis and the surgical procedureto permit reversal of anticoagulation. If a shorter interval is necessary, the dose ofanticoagulation should be minimized or the dialysis performed without antic-oagulation in order to decrease the risk of excessive intraoperative bleeding.Regional anticoagulation with citrate may be an alternative option. The use of thismodality of anticoagulation requires the use of calcium-free dialysate and may beassociated with significant hypocalcaemia. Frequent monitoring of ionized calciumlevels is therefore required.

Post-operatively, it is optimal if dialysis can be postponed for at least 24 hoursfollowing the completion of surgery. Anticoagulation should be minimized during post-operative dialysis, and performed without anticoagulation in patients at high risk forpost-operative bleeding complications (e.g. following neurosurgical and ophthalmo-logical procedures).

Intraoperative management of haemodialysis patients needs to include protection ofthe haemodialysis vascular access. No intravenous catheters, including central venouscatheters, should be placed on the same side as an arteriovenous access. Bloodpressure should be measured only in the contralateral arm. The limb with thearteriovenous access should be carefully positioned to ensure that inadvertentocclusion 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 theaccess arm. Access patency needs to be carefully monitored both intraoperatively andpost-operatively and any alteration in access function addressed promptly by a vascularsurgeon or an interventional radiologist or nephrologist.

If possible, cannulation of the subclavian veins should be avoided in all patients withCKD or ESRD. Cannulation of these vessels is associated with an increased risk for latestenosis or thrombosis, which may then preclude function of an arteriovenous accesson the same side.

All patients with a patent arteriovenous access, particularly patients with prostheticarteriovenous grafts, should receive prophylactic antibiotics before any procedure thatmay cause bacteraemia. In general, standard guidelines for antibiotic prophylaxis toprevent endocarditis may be used to guide antibiotic administration for the preventionof access infection.

140 P. M. Palevsky

Peritoneal dialysis

Patients receiving chronic peritoneal dialysis should have their abdomen drained of alldialysate, and the peritoneal catheter flushed with heparin-containing fluid and cappedprior to any procedure involving conscious sedation or general anaesthesia. Drainingthe peritoneal fluid decreases intra-abdominal pressure, allowing easier ventilation andreducing the risk of aspiration. In addition, draining the glucose-rich intra-abdominalfluid decreases the risk for peritonitis associated with transient bacteraemia during theprocedure. Peritoneal dialysis may be resumed in the immediate post-operative periodafter non-abdominal surgery, so long as the patient’s ventilatory status will tolerate theassociated abdominal distention. Following abdominal surgery, peritoneal dialysisshould be suspended and the patient maintained with haemodialysis to decrease therisks of anastomotic leaks, wound dehiscence, infection and late incisional herniaformation.

SUMMARY

Patients with CKD or ESRD pose special challenges for anaesthesia and perioperativemanagement. The prevalence of CKD is increasing, and these patients have many co-morbid conditions that need to be taken into account in planning their care. As aresult of their renal insufficiency, they are at increased risk for fluid and electrolytedisorders, anaemia and haemorrhagic complications. Patients with CKD are atincreased risk for cardiovascular disease, even in the absence of traditional riskfactors, and require careful pre-operative cardiac assessment and perioperativemonitoring. The pharmacokinetics of many drugs used in anaesthesia management arealtered in CKD. Specifically, the opioid analgesics morphine and meperidine should beavoided, as should many neuromuscular blocking agents whose half-lives areprolonged in renal failure. The preferred neuromuscular blockers include atracur-onium and cisatracuronium. Succinylcholine may also be used in renal failure, despiteconcerns regarding hyperkalaemia. Special attention needs to be paid to preservingarteriovenous access patency in the intraoperative management of patients onhaemodialysis.

Practice points

† CKD is a frequent disturbance among patients, especially in the elderlypopulation

† patients with CKD are at increased risk for CKD, even in the absence oftraditional risk factors

† the opioid analgesics morphine and meperidine should be avoided in patientswith advanced renal failure

† the preferred neuromuscular blocking agents in CKD include atracuronium andcisatracuronium; succinylcholine may also be used despite concerns regardinghyperkalaemia

† special attention must be provided to preserving arteriovenous access patencyduring intraoperative management

Perioperative management of ESRD 141

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Research agenda

† approaches to stratification of the risk for perioperative cardiac events inpatients with CKD need to be optimized

† the pharmacokinetics of drugs used in the perioperative period need to bebetter defined over a wide range of renal function in order to ensure greaterpatient safety

† strategies for minimizing the excess perioperative morbidity and mortality ofpatients with CKD need to be developed

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