Intensive Care Med (2007) 33:1503–1505DOI 10.1007/s00134-007-0755-3 E D I T O R I A L

Michael JoannidisLui G. Forni CRRT – still far from being a standardised

BEST treatment?

Received: 25 May 2007Accepted: 27 May 2007Published online: 27 June 2007© Springer-Verlag 2007

This editorial refers to the article available at:http://dx.doi.org/10.1007/s00134-007-0754-4.

M. Joannidis (�)Medical University Innsbruck, Medical Intensive Care Unit,Division of General Internal Medicine, Department of InternalMedicine,Anichstrasse 35, A-6020 Innsbruck, Austriae-mail: michael.joannidis@i-med.ac.at

L. G. ForniWorthing and Southlands Hospitals,West Sussex, UK

L. G. ForniUniversity of Sussex, Brighton and Sussex Medical School,Sussex, UK

Since the first description of an arteriovenous haemofil-tration technique by Kramer and co-workers in 1977,continuous renal replacement therapy (CRRT) has becomethe favoured treatment for acute renal failure in manyintensive care units (ICUs) throughout Europe and Aus-tralia [1]. Kramer and co-workers developed this systemfrom other ultrafiltration techniques using the systemicarteriovenous pressure difference in an extracorporealcircuit to generate the ultrafiltrate, providing an effectivemethod for the elimination of both fluid and solutes. This“new” technique was technically simpler and providedhaemodynamic stability in critically ill patients, provingadvantageous over the conventional haemodialysis avail-able at that time. However, limitations included reducedclearance capacity in the presence of a high catabolicrate, complications associated with arterial access and

reliance on the arterial pressure to pump blood throughthe circuit (often limited in the critically ill), which led tothe development of pump-driven venovenous techniques.Furthermore, the convection-based modality, continuousvenovenous haemofiltration (CVVH), was enhancedthrough the development of techniques based on diffu-sion, including continuous venovenous haemodialysis(CVVHD) and combinations of both (continuous veno-venous haemodiafiltration, CVVHDF). Modern devicesfor CRRT are now capable of providing all of thesetechniques at almost every dose desired. However, thelack of controlled studies showing any clear superiority ofany of these modalities results in the choice of techniquebeing influenced by personal preference and local habits.

The study by Uchino and co-workers [2] published inthis issue of Intensive Care Medicine reflects the existingspectrum and gives important insights into worldwidepreferences when using CRRT in critically ill patients.The B.E.S.T. Kidney (Beginning and Ending SupportiveTherapy for the Kidney) project prospectively collecteddata from September 2000 to December 2001 and con-tains one of the largest data sets from 54 ICUs in 23countries throughout the world. This database has alreadyserved as a source of important information for previouspublications on acute renal failure [3, 4] and has nowbeen analysed with regard to several aspects of CRRT.In that article [2], the data of 1006 ICU patients treatedwith CRRT were analysed, leading to some interestingresults.

Firstly, all patients treated with CRRT were severelyill, showing an average Simplified Acute Physiology IIscore of 48 with a predicted mortality of 42%. Almost80% of them required vasopressors/inotropes and mech-anical ventilation, and approximately 50% sufferedfrom sepsis or septic shock. This observation may ex-plain the relatively high incidence of hypotensive episodes

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observed (approaching 19%) during treatment, which of-ten demonstrates excellent haemodynamic stability as longas intravascular volume depletion is avoided and deferrednegative fluid balance is applied. Interestingly, by far themost frequent (ca. 70%) reason to start CRRT in this pa-tient group appeared to be oliguria/anuria followed by highserum creatinine/urea, metabolic acidosis and fluid over-load. This contrasts with the management of chronic renalfailure, where azotemia is the most prominent reason forinitiating renal replacement therapy. In addition, the ob-served daily practice seems to support the proposal of someauthors to start renal replacement therapy early, especiallyin cases of septic shock [5].

Secondly, CVVH appeared to be the preferred modal-ity, with pre- and post-dilution being almost equally per-formed, followed by CVVHDF. This implies that inten-sivists rely mainly on convective methods, with the as-sumed benefit of improved clearance of middle molecules,the clinical relevance of which, however, has never beenproven in critically ill patients by any large, randomisedclinical trial. According to this survey, only biocompatiblemembranes were used for CRRT, the choice of materialbeing based mainly upon local availability and price.

However, the most surprising aspect of the data pre-sented by Uchino and co-workers [2] is the significantvariation found in renal replacement dose applied inCRRT, which ranged from 1000 ml/h up to 3500 ml/h, cor-responding to a weight-adjusted dose of between 12.5 and31 ml/kg/h. This observation is remarkable, because thefirst large, randomised controlled trial showing improvedsurvival with an increased ultrafiltration rate of 35 ml/kg/hin CVVH [6] had already been published several monthsbefore collection of data was started and reflects the obser-vation that dissemination of medical evidence into clinicalpractice often occurs very slowly. Somewhat disturbingly,the results seem to imply that the CRRT dose did not haveany significant impact on patient survival. Even the lowestdose applied (i. e. < 20 ml/kg/h) was not associated withany increase in mortality when compared to the highestprescribed doses. This result appears discrepant with otherwork, such as that reported by Brause and co-workers [7],who demonstrated elegantly that azotemia cannot bereliably controlled in critically ill patients when filtrationvolumes of less than 1500 ml/h (i. e. < 21 ml/kg/h in a 70-kg adult) were applied. Moreover, several randomisedcontrolled studies have demonstrated a survival benefit ifhigher renal replacement doses were applied to criticallyill patients either continuously or intermittently [6, 8, 9].

Despite the large variations in CRRT dose appliedin the present study, both ICU and hospital mortal-ity were similar to those reported in other studies, with

observed mortalities approaching 55% and 64%, respec-tively [10, 11].

These results suggest that caution should be appliedwhen drawing conclusions from analysing databasesinstead of using prospective clinical trials with predefinedinclusion and exclusion criteria as well as clear predeter-mined primary and secondary endpoints. Retrospectivedata analysis cannot be controlled for uncertainties suchas bias resulting from selection of participating centresor patient case mix, which may result in data conflictingwith prospective clinical trials. Such investigations mayprovide an interesting overview of daily clinical practiceand provide some insight into whether existing clinicalevidence is disseminating into daily clinical practice,but are unsuitable for answering fundamental clinicalquestions such as the superiority of any one treatmentmodality over another.

This issue probably applies to the second majorfinding from this study concerning the anticoagulationregimens applied. The observed incidence of bleedingwas relatively low, reaching about 3%. Unfortunately,discrimination between major and minor bleeding was notperformed, rendering interpretation difficult. Nearly 20%of the patients were treated without anticoagulation, whichprovides further support for this procedure in patients withincreased bleeding risk and is in keeping with other workby the same authors [12, 13]. Furthermore, it appears thatunfractionated heparin (UFH) remains the preferred choicefor anticoagulation therapy in CRRT, followed by citrate,as confirmed by other publications [14]. Although only4% of all patients were treated with low-molecular-weightheparin (LMWH), the incidence of bleeding complicationsappeared to be increased in this group. Again, this findingcould have occurred by chance and contrasts with severalstudies comparing anticoagulation with UFH and LMWHduring CRRT. Applying either high [15, 16] or lowlevels [17] of anticoagulation did not result in an increasedincidence of bleeding when using LMWH.

Has clinical practice with regard to CRRT changedsignificantly since 2001? The results of a questionnaire putforward to participants of the 3rd International VicenzaCourse on Critical Care Nephrology in 2004, comprisingboth nephrologists and intensivists, provided a similar pic-ture with regard to choice of treatment modality and anti-coagulation, with two exceptions: citrate was used less fre-quently than LMWH and there appeared to be a tendencytowards the use of higher CRRT doses [18]. Althoughthese results are presumably also subject to selection bias,both studies [2, 18] demonstrate the lack of, and thereforethe need for, standardisation in the application of CRRT inthe critically ill.

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References

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