REVIEW

Hernofiltration: treating and preventing infection

Paul C. Turner' and Hilary Humphreys2

'Public Health Laboratory and 'Division of Microbiology, University Hospital, Queen's Medical Centre, Nottingham, UK

Key words: Hernofiltration, infection, intensive care, kidney failure, catheterization

GENERAL PRINCIPLES OF HEMOFILTRATION development. Furthermore, fluid balance can be accurately controlled and regulated, allowing other Renal failure is a recognized feature of the acutely ill, support measures such as total parenteral nutrition to intensive care patient, often in association with multi- be used [3]. Unlike CH, peritoneal is less suited organ failure. Henlofiltration is now routinely used for to the ICU as there is a delay before beneficial effects treating acute renal failure in the intensive care unit are seen and it cannot be used in the presence of intra- (ICU). Unlike and peritoneal dialysis, abdominal wounds, infection, ileus, or with a vascular both of which rely upon diffusion of molecules prosthesis [4]. across a concentration gradient, hemofiltration utilizes Although the underlying principle remains the convective solute transport (known as solvent drag) same, several modifications of hernofiltration are in whereby molecules are swept along by a moving stream use [5]. The two commonest variations are continuous of solvent [l]. This is analogous to the filtration that venovenous hernofiltration (CVVH) and continuous occurs naturally through the glomerulus. A special arteriovenous hemofiltration (CAVH). CAVH, which filter is used to remove plasma water and unbound requires arterial access, is circulation driven, resulting in particles weighing between 500 and 10 000 Da. The lower flow rates and filtrate volumes than CVHH. For nitrogenous substances traditionally associated with it to be effective, a mean arterial pressure of 60 mmHg uremia are removed, although urea itself is not is required, making it less useful in the septic, hypo- efficiently filtered. The process results in the produc- tensive patient. CAVH has now been supplanted tion of a large volume of filtrate containing an excess by CVVH, which is pump driven, achieving both of waste particles. The deficit of water and electrolytes higher flow rates and filtrate volumes, resulting in are made good by infusing fluid back into the patient's better clearance of waste products. CH can also be blood, usually after it has passed through the filter supplemented by hemodialysis, particularly in the (Figure 1). presence of a hypercatabolic state, to give continuous Continuous hemofiltration (CH) was first used or intermittent hemodiafiltration [5-71. CVVH is to treat a patient with renal failure in 1977 [2]. The performed via a dual lumen catheter inserted centrally, shortage of technical equipment and specialist staff preferably into the jugular or subclavian , but required to provide hemodialysis, combined with femoral catheterization may be necessary when access excellent tolerance even in hemodynanlically compro- at other sites is compromised [7]. mised patients, have been the main reasons for its Kierdorf has reviewed the advantages and dis- advantages of CH versus intermittent dialysis treatment Corresponding author and reprint requests: and the problems that accompany hemodialysis in the Dr Hilary Humphreys ICU patient [XI. CH decreases APACHE I1 scores, Division of Microbiology, Department of Clinical Laboratory significantly increases arterial blood pressure, avoids Sciences, University Hospital, Queen's Medical Centre, major fluctuations in electrolyte imbalances (which Nottingham NG7 2UH, UK. may improve cerebral function), and increases the Tel: +44 (0)115-9709162 Fax: t44 (0)115-9709233 survival rate for patients with multiple organ failure. Email [email protected] These benefits are partly offset by the requirement Accepted 30 June 1996 for continuous anticoagulation, hyperlactatemia and

80 Turner and Hurnphreys: Hernofiltration and Infection 81 reduced efficiency in the control of azoteniia per unit catheter-related infections include the distinction tinie [S]. Indications for CH include an increasing between colonizationhfection and contamination by variety of other conditions (Table 1) [9-111. Although semiquantitation of catheter tip cultures, or defining there are no absolute contraindications to hemo- catheter-related bactereniia as organisni(s) recovered filtration, extra care is needed for patients at increased from a catheter segment or tip with the same organ- risk of hemorrhage (e.g. in severe thrombocyto- ism(s) recovered froin blood cultures without clinical penia), when the anticoagulation required may be evidence of another source of infection [14-161. As problematic [9]. patients on CH are likely to have more than one catheter, confirming a diagnosis of catheter-related bacteremia and determining its source is more difficult PREVENTION AND DIAGNOSIS OF than in other patient groups. Diagnostic options HEMOFILTRATION-RELATED INFECTION include semiquantitative blood cultures taken through the hemofiltration catheter. However, this is tinie- As the procedure involves cannulation of a large consuming and cumbersome to perform. Alternatively, vein, and with CAVH an artery, insertion should be removal of the catheter for culture of the tip may be regarded as a sterile procedure and subject to the same performed, but this is usually a difficult decision in precautions as central venous catheters. This has been patients with limited [17,1X]. Further- reviewed recently and recommendations emphasize more, patients on CH may already be receiving that insertion should be considered a minor operation, treatment with multiple antimicrobial agents, reducing but because of the condition of patients requiring CH the chance of successfully culturing the organism(s) and the need for other organ support (e.g. ventilation), responsible. it is rarely possible to perform the procedure in In a series of 17 patients receiving continuous an operating theater [12]. As with central venous arteriovenous hemodiafiltration (CAVHD) for renal catheters, it is difficult to justify the routine use of prophylactic antibiotics to reduce the risk of infection. Handling of the cannulae should be kept to a mini- Venous (afferent) Venous (efferent) mum, apart from during use and flushing with . circuit circuit It is advisable not to use the catheter for obtaining routine blood samples unless there is limited vascular access or infection at that site is suspected. Unfortunately, there are no generally agreed clinical or microbiological definitions for diagnosing heniofiltration-related infections. Furthermore, infec- tive coniplications vary from center to center according to the techniques used for catheter insertion, culture protocols, type of patient and duration of treatment. Attempts to define hemofiltration-related infection should be based on guidelines similar to those of tliiid catheter-related infection [13-151. This would allow a Heparin 1 (infusate) more accurate assessment of infection risk among different patient groups. Definitions used to diagnose

Table 1 Indications for hemofiltration

Acute renal failure Fluid and electrolyte imbalancc ____- Myoglobinuric acute renal failure r- --1 Total parenteral nutrition with fluid restriction I Filter I Ccrcbral edema and increased intracranial pressure Severe burns Septic shock with multiple organ failure - - - r]Ultrafiltrate - - - Hepatorenal syndrome (waste products)5- Hepatic encephalopathy Cori-ection of acid-base dmturbancet Figure 1 Schematic representation of continuouz Pulmonary edema venovenous hernofiltration (CWH). 82 Clinical Microbiology and Infection, Volume 2 Number 2, October 1996 failure (mean duration 15 days), 35% of the catheters on , it seems likely that CH will remain the removed for suspected infection were colonized, but treatment of choice for renal support in the ICU catheter-related infection was confirmed in only one patient with severe hemodynamic instability, particu- patient [6]. No mention of the criteria used to larly in the absence of local facilities for hemodialysis distinguish colonization from infection was made. [33,34]. Yet another dificulty that may obscure clinical diagnosis, although less common with modern systems, is the effect of hemofiltration on core temperature, CLEARANCE OF ANTIMICROBIAL AGENTS which may mask a pyrexial response. The reduction in core temperature observed can be explained in The effect of hemofiltration on the clearance of drugs part by the extracorporeal circulation required for will influence the dose, dosage interval and require- hernofiltration and the removal of pyrogens in the ment for measurement of antimicrobial agents. The filtrate [19]. efficiency of antimicrobial removal or filtration is related to the sieving coefficient (SC), which is a mathematical expression of the ability of a solute to THERAPEUTIC POTENTIAL OF HEMOFllTRATlON cross a membrane by convection. The SC is also FOR SEPSIS dependent on the degree of protein binding. An SC of close to 1 (e.g. amikacin, imipenem, ciprofloxacin, Hemofiltration has been advocated as a useful adjunct vancomycin) implies the agent crosses the membrane in the treatment of the sepsis syndrome both with easily, whereas when the SC approaches zero (e.g. and without multiple organ failure [20]. Experimental amphotericin B, oxacillin), there will be little removal studies in animals have shown increased survival times [35]. For small molecules that pass freely into the in Staphylococcus aureus induced septicemia in immature filtrate, the filtration rate may be considered equivalent swine, and beneficial effects on pulmonary artery to the glomerular filtration rate in patients with normal wedge pressure and systemic vascular resistance in renal function. swine injected with Eschevichia coli endotoxin [21-231. Several agents have been studied in a handful of A beneficial effect on ventricular contractility in dogs patients, resulting in guidelines that often conflict [36]. with induced E. coli septicemia has been demonstrated Furthermore, clearance of antimicrobial agents will [24]. However, no increase in survival was seen in vary with the hernofiltration modality used, type and induced E. coli septicemia in dogs without renal failure make of filter, filtration rate, volume of ultrafiltrate [25]. Hemofiltration with dialysis has been shown to produced, underlying renal function and general con- remove cytokines such as TNF-a, IL-IP, IL-6 and It- dition of the patient. Any treatment with antimicrobials 8, important in the cytokine cascade leading to septic must allow for all of these variables. shock and multiple organ failure, from the circulation Antimicrobial dosing of severely immuno- of septic patients with acute renal failure [19,26,27]. suppressed patients requiring hemofiltration is Extrapolating the results of animal studies to humans especially difficult, as they often receive treatment with is, however, difficult. A prospective multicenter, con- several antimicrobial agents and require adequate serum trolled trial recruiting large numbers of patients with and tissue cidal levels to achieve a successful outcome. septic shock and multiple organ failure would be Vos and colleagues have assessed the drug clearance of required to demonstrate a therapeutic effect [28]. As seven antibiotics by continuous hemodiafiltration in mortality in this group is already over 60%, distinguish- anuric patients and found that the dosages required for ing death directly attributable to sepsis from that some patients were higher than expected [37]. A recent occurring in association with sepsis would be difficult review with recommendations for antimicrobial pre- [29,30]. scribing in patients on hemofiltration has emphasized A recent report of the successful use of hemo- the enhanced clearance compared to hemodialysis with diafiltration in the management of severe meningo- the risk of underdosing resulting, e.g. with vancomycin coccal septicemia in four children has stimulated much [38]. These guidelines are primarily based on educated interest in the UK [31]. Although more formal trials are guesswork, rather than documented experience, and awaited, it has been suggested that the removal of originate from recommendations in the USA which are cytokines and the entrapment of polymorph neutro- issued annually [39]. phils in the filter may partly explain the beneficial As a general rule and until further information effects [32]. Replacement of the extracorporeal circuit becomes available, serum monitoring of antimicrobials may be required due to rapid accumulation of insoluble is recommended, wherever possible. Dosage adjust- deposits in the air trap and filter. Whatever the impact ments should then be made accordingly. Unfortunately, Turner and Humphreys: Hernofiltration and Infection 83 referral to a national reference center, which is Other antibacterials necessary for some agents, will result in a delay before Dosage guidelines for ciprofloxacin in patients dose adjustment can occur. In order to avoid errors in undergoing hemofiltration are similar to those in dose calculations, it is important to emphasize that patients with normal renal function. Recommen- the clearance of antimicrobials by hemofiltration is not dations in adults undergoing treatment with CAVH, equivalent to that following hemodialysis [36]. and CAVHD/CVVHD are 400 to 800mg/day and 200 mg 8- to 12-hourly, respectively [52,531. The Beta-lactam agents increased clearance of ciprofloxacin is likely to be In spite of the widespread use of cephalosporins for related not only to increased extracorporeal clearance patients receiving CH, the data available on their use but also to the altered pharmacokinetics of this drug in are limited and often conflicting. Cefuroxime was seriously ill patients [53]. studied in three adult patients on CAVH and the The trimethoprim component of co-trimoxazole authors suggested an initial dose of 1.5 g followed by has a large volume of distribution, and is unlikely to be 750 mg every 24 h [40]. They also recommended removed by hemofiltration, whereas sulfamethoxazole serum drug monitoring if continued beyond 72 h. For is, leading to a selective accumulation of trimethoprim patients undergoing CAVHD, 500 to 750 mg cefu- [54]. Clear guidelines are not available but it may be roxime 12-hourly and 500 mg ceftazidime 12-hourly appropriate to reduce the trimethoprim component have been suggested [41]. For cefotaxime, one study alone or in combination with the sulfonamide, based which measured both cefotaxime and its active on renal function. Measurement of serum concen- metabolite desacetylcefotaxime in eight patients with trations of sulfamethoxazole and trimethoprim should renal failure on CAVH, a dose of 1 g every 24 h was ideally be performed on all patients with severe renal recommended [42]. Andrassy suggested that dosage impairment. adjustments for cefotaxime should be based on renal function with no adjustments during CH [43] . Antifungal agents The clearance of imipenem/cilastatin was assessed There is little or no information on the clearance of in 10 patients undergoing treatment with CAVH, amphotericin B by hemofiltration 1551. Liposomal following which a recommendation was made to amphotericin B was not detected in ultrafiltrate in one modifi dosage on the basis of renal dysfunction [44]. report and subsequently suggestions were made to give Other workers have concluded that a fixed-dose a standard dose initially, with a reduction if treatment combination of 500 mg twice a day is preferred with is continued beyond 2 weeks [56]. Standard or higher no further dosage adjustment considered necessary - on doses of fluconazole are recommended, as this agent is the basis that elimination of inlipenem by CAVH is low cleared more efficiently by hernofiltration than by compared to cilastatin (7% versus 30% of dose normal renal function [57]. Flucytosine is also removed respectively) [45]. Information on the clearance of by CH, and, following measurement in one patient, meropenem by hemofiltration is awaited. regular serum monitoring was recommended to guide dosage [%I. Aminoglycosides and glycopeptides Aminoglycosides are cleared in part by hemofiltration; Antiviral agents regular serum monitoring, which is available in most Limited guidelines for antiviral agents are available centers, is required before the next dose is given [59,60]. The clearance of acyclovir by CAVHD is [46,47]. Vancomycin is cleared better by hemofiltration similar to that of CAPD (5.5 mL/min) which is than hemodialysis alone. Slugg and colleagues studied considerably lower than clearance by conventional 18 patients with acute renal failure receiving either hemodialysis (82 mL/min). The dose therefore does intermittent hemodialysis or CAVH/CAVHD and not need to be increased for patients receiving found that the latter group required larger doses of hemofiltration [59]. Suggestions for a starting dose of vancomycin at shorter intervals [48]. High clearance of ganciclovir are available from the manufacturer and vancomycin was also described in six patients requiring are based on calculating the creatinine clearance by CAVH for renal failure [49]. In another study, clear- hemofiltration and following data sheet guidelines [60]. ance of vancomycin on CAVHD was found to be A dosage of 5 mg/kg/48 h has also been recommended approximately double that on CAVH [SO]. Regular based on three patients undergoing CVVHD, with serum monitoring (e.g. daily) is therefore required for adjustments made according to monitoring of plasma patients undergoing hemofiltration, to determine the drug levels [61]. Foscarnet is not recommended optimal dose in the individual patient [Sl]. for patients with a serum creatinine greater than 250 pmol/L, and should therefore be avoided [62]. 84 Clinical Microbiology and Infection, Volume 2 Number 2, October 1996

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