DRUG THERAPY: SPECIAL CONSIDERATIONS IN DIALYSIS PATIENTS

Perioperative Pharmacologic Management of Patients with End Stage Renal Disease Ameet Karambelkar,* Riyaj Kasekar,* and Paul M. Palevsky*† *Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and †Renal Section, Medical Service, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania

ABSTRACT The pharmacokinetics of numerous medications used in the perioperative period are altered in patients with endstage renal disease. Clearance of drugs, or their metabolites, that are normally excreted by the kidney is markedly reduced in ESRD. In addition, patients with ESRD may also have alterations in gastrointestinal absorption, volume of distribution, protein binding, and metabolic

clearance of pharmacologic agents. Finally, drug removal may be augmented during dialysis. All of these factors contribute to the need for dose adjustment of medications, including analgesics, anesthetics, neuromuscular blockers, and antimicrobial agents, which may be used in the perioperative management of the ESRD patient.

The altered pharmacokinetics associated with end-stage renal disease (ESRD) poses particular challenges in the perioperative management of patients with ESRD. Decreased renal excretion of drugs, or their metabolites, and the potential for augmented removal during dialysis, often mandate adjustments in drug dosing. In addition, patients with ESRD display alterations in gastrointestinal absorption, drug metabolism, protein binding, and volume of distribution. In this review, we consider some of the medications commonly used in the perioperative period, including analgesics, anesthetics, and antimicrobials, and provide recommendations for the pharmacologic management of the ESRD patient in the perioperative period.

of distribution of opioids but also have impaired renal clearance of the parent opioid drug and metabolites. Orally administered opioids typically undergo extensive first-pass metabolism in the liver before entering the systemic circulation and thus require little dose adjustment in renal failure (2). Commonly used opioids are metabolized by cytochrome P450 (CYP) enzymes; fentanyl and oxycodone primarily by CYP3A4, hydrocodone, and codeine by CYP2D6 and methadone by CYP3A4 and CYP2B6. These opioids can potentially have drug–drug interactions with other CYP inhibitors and inducers. In contrast, morphine, hydromorphone, and oxymorphone are glucuronidated by uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7) and have little potential for metabolically based drug–drug interactions. Morphine is primarily glucuronidated to two metabolites, morphine-3-glucuronide (M3G; 55%) and morphine-6-glucuronide (M6G; 10%), both of which are normally renally excreted. Hasselstrom and Sawe found that renal clearance of morphine and M6G in healthy individuals exceeded creatinine clearance, suggesting an active secretion process by the kidney (3). Like morphine, M6G is a l-opioid receptor agonist with potent analgesic activity. Due to its reduced action at the l2-opioid receptor, it tends to have less unwanted adverse effects such as respiratory depression, gastrointestinal effects, and sedation in patients with normal renal function (4,5). However, due to decreased renal excretion, this metabolite can rapidly accumulate in ESRD patients and reach high serum levels, subsequently crossing the blood–brain barrier and causing prolonged CNS effects, including respiratory

Opioid Analgesics Although current guidelines encourage an opioid sparing and multimodal approach to pain management in the perioperative setting, opioid analgesics remain the cornerstone of postoperative pain management (1). It is therefore important to accurately understand fundamentals of opioid metabolism and clearance in patients with renal impairment. Patients with ESRD not only have variations in the volume Address correspondence to: Paul M. Palevsky, MD, Room 7E123 (111F-U), VA Pittsburgh Healthcare System, University Drive, Pittsburgh, Pennsylvania 15240, Tel.: 412-360-3932, Fax: 412-360-6130, or e-mail: [email protected]. Seminars in Dialysis—Vol 28, No 4 (July–August) 2015 pp. 392–396 DOI: 10.1111/sdi.12384 © 2015 Wiley Periodicals, Inc. 392

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depression. M3G on the other hand lacks analgesic activity and exhibits neuroexcitatory effects in animal studies. It has also been proposed as a cause of allodynia, myoclonus, and seizures in humans (6). Hence, morphine use is best avoided in dialysis patients due to potential toxicity from accumulation of these metabolites. In cases of accidental overdose, morphine and its active metabolites can be removed by dialysis (4). Morphine has low protein binding which is reduced in uremic states and moderate water solubility, although removal may be limited by a large volume of distribution (7–9). M6G is also removed by hemodialysis but it slowly reequilibrates across the blood–brain barrier into the systemic circulation causing delayed CNS effects (4). Hydromorphone is glucuronidated to form hydromorphone-3-glucuronide (36.8%), which is also renally excreted. This metabolite has potential neuroexcitatory effects, but has not been well studied in the clinical setting. There is general consensus that hydromorphone is safer than morphine in dialysis patients, however this is based on limited data (10). Durnin et al. studied hydromorphone pharmacokinetics in subjects with varying degrees of renal function and recommended lower starting doses with increased dosing intervals in patients with moderate to severe renal failure (11). Fentanyl is primarily hepatically metabolized to nontoxic and inactive norfentanyl (>99%) (12). From limited data available, it appears that fentanyl can be safely used in patients with advanced renal failure, including patients on dialysis, with close monitoring for signs of gradual accumulation of the parent drug. As a result of its high protein binding, low water solubility, large volume of distribution, and moderately high molecular weight, fentanyl is not effectively dialyzable (13). Oxycodone is metabolized in the liver into largely inactive metabolites and some negligible amounts of active oxymorphone. This active metabolite exerts no effect in patients with normal renal function but can potentially accumulate in patients with renal failure (14). Codeine is not commonly used for perioperative pain management. It is a prodrug and exerts it analgesic affects after metabolism to morphine. Like morphine, its use is also contraindicated in patients with renal failure due to similar concerns mentioned above (2). Methadone is not routinely used in the perioperative setting due to its prolonged half-life and time to peak analgesic effect. It is metabolized by CYP enzymes to the pharmacologically inactive pyrrolidine and pyrroline. These metabolites, including a small fraction of the parent drug, are mostly eliminated by fecal excretion in oliguric and anuric patients (15). Consequently, some have deemed it safe to be used in patients with renal failure (2,14). Due to its high protein binding and high volume of distribution, methadone is not effectively dialyzed (16). Meperidine is metabolized through the hepatic microsomal hydroxylation system into normeperidine which is a renally excreted,

nonopioid, neuroexcitatory active metabolite (17). Elimination of normeperidine is significantly prolonged in renal failure and can precipitate anxiety, hyperreflexia, myoclonus, and even seizures (17,18). For this reason, meperideine should not be used in patients with severe kidney disease. On the basis of the available data, we recommend (Table 1) that morphine, meperidine, and codeine be avoided in ESRD patients, while hydromorphone and oxycodone should be used with caution and close monitoring. Methadone and fentanyl appear to be safe in dialysis, though they remain the least dialyzable of the opioid analgesics. Nonopioid Analgesics Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used as nonopioid analgesics in patients with ESRD. However, caution must be given regarding effects on residual renal function and increased risk of NSAID-induced gastrointestinal (GI) bleeding in ESRD patients. Residual renal function correlates with survival in patients on peritoneal dialysis, but there is no such well-known correlation in patients on hemodialysis (19). Therefore, NSAIDs and COX2 inhibitor use should be preferably avoided in the peritoneal dialysis population. One study describing analgesic prescription patterns in patients enrolled in the DOPPS trial, failed to demonstrate any effect of NSAID use on residual renal function (20). There are limited and conflicting data, regarding the risk of NSAID-induced GI bleeding in the ESRD population. The evidence available is largely observational and retrospective. Wasse et al. did not find any significant association between upper GI bleeding and aspirin or NSAID use in patients with ESRD after adjustment for confounding variables (21). Similarly, an observational study by Ethier et al. conducted on >28,000 ESRD patients from the DOPPS I and DOPPS II cohorts failed to find an association between chronic aspirin use and hemorrhagic complications (22). However, a subsequent study demonstrated that chronic NSAID use was associated with a significant risk of GI bleeding in ESRD patients on hemodialysis (23). Chronic use of NSAIDs in ESRD patients could potentially have increased risk of GI bleeding in some high-risk TABLE 1. Opioids and their active metabolites—safety profile in ESRD patients Opioid Morphine Hydromorphone Codeine Meperidine Oxycodone Fentanyl Methadone

Active metabolite/s

Use in ESRD

Morphine-6-glucuronide Hydromorphone-3glucuronide Hydrocodone, Morphine Normeperidine Noroxymorphone None None

Avoid Use with caution Avoid Avoid Use with caution Safe Safe

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patients. The short-term use of NSAIDs in the perioperative period, however, is not well studied and the risk of bleeding should be evaluated on an individual basis. Anesthetic Agents Propofol is an intravenous agent often used for induction and maintenance of anesthesia and for sedation in postoperative state. Propofol is primarily metabolized in the liver and the pharmacokinetics of propofol infusion are similar in well-dialyzed ESRD patients and those with normal renal function (24). Goyal et al. reported that ESRD patients required higher doses of propofol compared to those with normal renal function to achieve similar degree of hypnosis (25). The kidney, however, does not seem to play a significant role in the extra hepatic metabolism of propofol. Fluoride-based inhaled anesthetic agents like sevoflurane, enflurane, and isoflurane are widely used for general anesthesia. Although sevoflurane is thought to release potentially nephrotoxic inorganic fluoride ions, it has been extensively used in patients with renal disease and ESRD and appears to be safe (26). The serum levels of the inorganic fluoride ions and their elimination rate in dialysis-dependent patients was no different than in healthy controls (27). Enflurane and halothane were also found suitable for use in patients with mild to moderate renal insufficiency (28), although there are limited data relevant to ESRD patients. Neuromuscular Blocking Agents Succinylcholine is a neuromuscular blocker that acts as an agonist at the acetylcholine receptor, resulting in depolarization of the neuromuscular junction and paralysis. Its rapid onset of action and short half-life makes it an ideal agent for rapid induction of paralysis during endotracheal intuba-

tion. In normal individuals, succinylcholine is associated with a 0.5–1.0 mEq/l increase in serum potassium, which occurs within 3–5 minutes and lasts for 10–15 minutes (29). This transient rise in potassium occurs as a result of potassium efflux from intracellular stores during depolarization. In conditions such as burns, trauma, and variety of neuromuscular disorders, there can be an exaggerated increase in serum potassium that is thought to be due to the up-regulation of acetylcholine receptors (30). Several case reports have described acute hyperkalemia causing arrhythmias in patients with renal failure after the administration of succinylcholine (31,32) and has raised concern about its safety in patients with renal impairment (Table 2). However, after an extensive review of the literature, Thapa and Brull determined that available evidence demonstrated that succinylcholine can be used safely in patients with advanced renal disease who do not have preexistent hyperkalemia (33). In four controlled studies and two cases series, administration of succinylcholine was not associated with excessive hyperkalemia in patients with renal failure. There is, however, a paucity of controlled data on succinylcholine use patients with ESRD in the presence of preoperative hyperkalemia. Hence, caution should be used in this situation. In addition, the use of repeated doses of succinylcholine in ESRD patients should be avoided. Lastly, succinylcholine should be avoided in patients with concomitant renal failure and burns, trauma, or neuromuscular disorders given the propensity for an exaggerated increase in serum potassium. In these situations, a nondepolarizing neuromuscular blocker such as cisatracurium should be used. The duration of action of certain neuromuscular blockers can be prolonged in patients with renal failure as the result of reduced renal elimination of the drug or active metabolites and reduced acetylcholinesterase activity, which accompanies renal failure. Gallamine, metocurine, pancuronium, rocuronium, pipecuronium, doxacurium, and d-tubocurarine are

TABLE 2. Neuromuscular blockers and pharmacokinetic alterations in renal failure—safety profile in ESRD patients Neuromuscular Blocker

Pharmacokinetics in renal failure

Succinylcholine

Unchanged

Gallamine Metocurine Pancuronium Rocuronium Pipecuronium Doxacurium d-Tubocurarine Mivacuronium

Decreased renal clearance Decreased renal clearance Decreased renal clearance Decreased renal clearance Decreased renal clearance Decreased renal clearance Decreased renal clearance Decreased metabolism by acetylcholinesterases Decreased renal clearance of active metabolite, 3-desacetylvecuronium Unchanged Unchanged

Vecuronium Atracurium Cisatracurium

Use in ESRD Increased risk of serious hyperkalemia; avoid in patients with elevated serum potassium; avoid repeated doses Avoid Avoid Avoid Avoid Avoid Avoid Avoid Avoid Avoid Safe Safe

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predominately eliminated by the kidney and have longer, more variable duration of action in patients with renal failure (34–39). Mivacuronium is metabolized by actelycholinesterases, which also results in a longer duration of action in renal failure (40). Although vecuronium is predominately metabolized by the liver, its active metabolite, 3-desacetylvecuronium, is renally excreted, which can result in prolonged duration of action in renal failure (41). Atracurium and cisatracurium are metabolized via ester hydrolysis and Hoffman elimination, respectively. Duration of action of these agents is not altered by renal function, making them preferred agents for neuromuscular blockade in the setting of ESRD (42,43). Antimicrobial Agents Antimicrobial agents are commonly used for infection prophylaxis prior to surgery and the treatment of postsurgical infectious complications. As a majority of antibiotics are renally excreted, dosing adjustments are often required. In addition, supplemental dosing after hemodialysis is often required in ESRD patients to ensure attainment of adequate therapeutic levels while minimizing toxicity. Clearance of antimicrobials with hemodialysis is dependent on several drug factors including molecular weight, protein binding, and volume of distribution. Dialysate and blood flow rates along with dialyzer characteristics also affect clearance of antimicrobials during hemodialysis. Despite being renally excreted, most penicillins can be safely used without dose adjustment in ESRD patients due to their short half-lives and wide therapeutic window. Ticarcillin and piperacillin, however, do require modest dose reduction (44). Although cephalosporins are predominately renal excreted, ceftriaxone and cefoperazone do not require dose adjustment in renal failure. Cefoxitin, cefazolin, cefepime, cefotaxime, cephalexin, and ceftazidime require dose reduction in ESRD patients to avoid neurotoxicity (45–48). Aminoglycosides such as gentamicin are commonly used for the treatment of gram negative infections in hemodialysis patients. Aminoglycosides are renally excreted and dialyzable, necessitating dose adjustments in patients with renal failure. Guidelines suggest giving 50% of the usual dose after hemodialysis (49). Although nephrotoxicity is not a consideration in ESRD patients with minimal residual renal function, it is a concern in patients with residual renal function. In addition, vestibular and ototoxicity are common complications of aminoglycoside therapy. The glycopeptide vancomycin is also predominantly renally excreted and requires substantial dose reduction in ESRD patients. Vancomycin is commonly used for treatment of gram positive infections in ESRD patients due to ease of administration, and is widely used for treatment of methi-

cillin-resistant Staphylococcal organisms. The usual loading dose is 20 mg/kg and subsequent doses of 15 mg/kg should be given at the end of each hemodialysis session with targeting of predialysis serum levels of 15–20 lg/ml (50). Giving a larger dose during the last dialysis session of the week to achieve therapeutic levels during the longer interdialytic period has been suggested (51), but is not necessarily required in patients with minimal residual kidney function. Both carbapenems and fluoroquinolones (with the exception of moxifloxacin) are renally excreted and require reduced dosing in patients with ESRD. Imipenem has been associated with seizures in the setting of renal failure and as a result, doripenem and meropenem may be preferred in the setting of renal failure (52,53). If oral fluoroquinolones are to be used, care must be taken to avoid administration with phosphate binders as they can interfere with absorption of fluoroquinolones (54). Conclusion As the prevalence of ESRD increases, more patients with renal impairment will be undergoing surgical procedures. Due to the variety of changes in pharmacokinetics in ESRD patients, drug dosing needs to be carefully considered in the perioperative period. Opioids such as morphine, hydromorphone, meperidine, and hydrocodone are renally excreted or have renally excreted metabolites and should be avoided in renal failure. Fentanyl appears to be safe for the treatment of severe pain in dialysis patients. NSAIDs may also be used for perioperative pain, though a careful assessment of bleeding risk and impact on residual kidney function should be undertaken prior to prescribing. Inhaled anesthetic agents undergo hepatic metabolism and do not require dose adjustment. Many of the nondepolarizing muscle relaxants exhibit increased duration of action in ESRD patients. However, atracurium and cisatracurium are not renally excreted and are preferred agents in patient with renal failure. While hyperkalemia has been reported with the use of succinylcholine in the setting of renal disease, several studies have demonstrated that it may be safely used in ESRD patients who are not hypokalemic. Many antimicrobial agents are renally excreted and dialyzable. Consequently, antibiotic dose adjustment is necessary in most cases, and levels should be monitored when appropriate.

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