Dose of dialysis in the intensive care unit: is the venom in the dose or in the clinical experience?
Critical Care volume 13, Article number: 155 (2009)
Many studies on the most 'adequate' dose of renal replacement therapy (RRT) in critically ill patients with acute kidney injury have obtained contradictory results. The previous issue of Critical Care reports a multi-centre study showing that a higher than conventional dose of RRT, whether continuous RRT or intermittent RRT, is not associated with better survival of these patients. This commentary highlights some of the problems associated with the interpretation of this and previously published studies. These problems include the use of targets of Kt/V urea or the ultrafiltration rate in millilitres per kilogram body weight, the latter quite difficult to estimate in these patients, the divergent co-morbidities of the patients, and the local experience of intensivists or nephrologists with either continuous RRT or intermittent RRT. The last factor could explain why some single centre studies did find an impact of dialysis dose on the survival of these patients whereas multi-centre studies did not.
In the previous issue of Critical Care, an article by Vesconi and colleagues  describes the impact of the dose of renal replacement therapy (RRT) on clinical outcomes in critically ill patients with acute kidney injury. This study was performed in a number of European intensive care units (ICUs). Dialysis dose was defined as more intensive (continuous RRT (CRRT), >35 ml/kg/h; intermittent RRT (IRRT), >6 sessions/week) or less intensive (CRRT, <35 ml/kg/h; IRRT, <6 sessions/week). The study did not provide evidence for a survival benefit of a higher dose of RRT. However, more intensive RRT was associated with a favourable effect on ICU stay and duration of mechanical ventilation among the surviving patients. Studies of this nature are not easy to perform and the authors are to be commended for their initiative.
This paper highlights many of the controversial aspects of RRT management in these patients, including when to start, which modality is preferable, and what dose to apply. These controversies are partly fuelled by a lack of consistent data, which are difficult to obtain in this heterogeneous patient group, with wide ranges of applied practices and underlying diseases and the absence of universally accepted definitions.
For example, analysis of Table 1 in the paper by Vesconi and colleagues  reveals the wide diversity of the patient study population involved; the distribution of the RIFLE classification at the start of RRT is intriguing as a substantial portion of the patients was started on dialysis without even having class 'I' of RIFLE. Besides the fact that the RIFLE criteria are not intended to be a guide as to when to start RRT, this means that some of these patients had near 'normal' serum creatinine levels at the beginning of RRT. The question can be raised as to whether the inclusion of such patients influenced the outcome, although it is unclear how and to what extent this might be the case.
Another question to be considered is how the results of this study should be interpreted in the context of other dose of dialysis/outcome randomized trials using CRRT (continuous haemofiltration or haemodiafiltration), IRRT – including the conventional 3 to 4 hour sessions or the prolonged slow extended dialysis (SLED) method – or both. Obviously, such studies produced mixed results. Some showed a benefit of the 'higher than usual doses' [2–4], but others did not [5–8]. All these studies were accompanied by a number of critical reviews and editorial comments [9–12]. Although none of the studies showing no benefit of higher dose of RRT were perfect, all have one advantage: they reflect daily practice. This is also the conclusion of the paper by Vesconi and colleagues. Does this mean that dialysis dose is not important? Probably not. The problem is that we have no correct understanding of what 'dose' means and higher doses implicitly mean more complications and/or comorbidities.
In the study by Vesconi and colleagues, differences in dose for CRRT were not pursued intentionally but seem to have been the consequence of external conditions, of which body weight of the patients was the main one. The patients with the lowest dose of CRRT were approximately 33% heavier than those with the highest dose. This is, of course, an important and remarkable confounder. In interventional studies where dialysis dose is normalized to body weight, other difficulties may arise as well. What should be considered as 'body weight': dry weight, weight before admission, real ad hoc weight, distribution volume of urea, or something else? And how do we estimate this sometimes quite fluctuating 'body weight' in a critically ill patient? In the IRRT group, the dose was expressed as the number of dialysis days per week, targeting a Kt/V urea threshold. However, as long as we know neither the nature nor the kinetics of many of the 'toxins' involved in the acute 'uraemic syndrome' we will always have to rely on surrogate markers, of which the volume status of the patient – which should be frequently clinically evaluated – and electrolyte and acid-base disturbances – which should be managed – are probably the most important. As such, the fact that absolute ultrafiltered volumes were comparable in both the less and more intensive patient groups makes it questionable whether there really was a difference of dose in the study by Vesconi and colleagues. Interestingly, there was also no difference in obtained net ultrafiltration between low and intensive dose groups in the VA/NIH trial  and a study by Tolwani and colleagues . So, maybe our 'concept' of what dose actually means in ICU patients needs to be redefined.
Another problem of 'dose' is that it comes at a price. The high dose group in the VA/NIH study  suffered a substantially higher number of complications, such as haemodynamic instability and electrolyte disturbances. The potential benefit of achieving more clearance can thus be eliminated by a higher complication rate. Complication rates might, in turn, be corrected by centre experience; this could explain why the first, but single centre, study of Ronco and colleagues  found that dialysis dose did have an impact whereas the multicentre VA/NIH study  did not. As the latter study enrolled approximately 500 patients in 30 centres, it can be presumed that a substantial number of the study centres recruited less than 10 patients per year. The 'dose of experience' with RRT in the ICU might be a greater determining factor of outcome in critically ill acute kidney injury patients than the dose of dialysis.
Finally, despite the previous seminal study  by the senior author of the paper by Vesconi and colleagues demonstrating that a 'high' dose of 35 ml/kg/h CRRT is advantageous, the latter study shows that, in daily clinical practice, this dose is quite difficult to achieve. It should be appreciated by readers that the same advocates of a high dose of RRT are now amending their previous recommendations.
intensive care unit
renal replacement therapy.
Vesconi S, Cruz DN, Fumagalli R, Kindgen-Milles D, Monti G, Marinho A, Mariano F, Formica M, Marchesi M, René R, Livigni S, Ronco C, for the DOse REsponse Multicentre International collaborative Initiative (DO-RE-MI Study Group): Delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury. Crit Care 2009, 13: R57. 10.1186/cc7784
Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000, 356: 26-30. 10.1016/S0140-6736(00)02430-2
Saudan P, Niederberger M, De Seigneux S, Romand J, Pugin J, Perneger T, Martin PY: Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int 2006, 70: 1312-1317. 10.1038/sj.ki.5001705
Schiffl H, Lang SM, Fischer R: Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002, 346: 305-310. 10.1056/NEJMoa010877
Bouman CS, Oudemans-van Straaten HM, Tijssen JG, Zandstra DF, Kesecioglu J: Effects of early high-volume continuous ven-ovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomized trial. Crit Care Med 2002, 30: 2205-2211. 10.1097/00003246-200210000-00005
Faulhaber-Walter R, Hafer C, Jahr N, Vahlbruch J, Hoy L, Haller H, Fliser D, Kielstein JT: The Hannover Dialysis Outcome Study: comparison of standard versus intensified extended dialysis for patients with acute kidney injury in the intensive care unit. Nephrol Dial Transplant 2009, in press.
VA/NIH Acute Renal Failure Trial Network, Palevsky PM, Zhang JH, O'Connor TZ, Chertow GM, Crowley ST, Choudhury D, Finkel K, Kellum JA, Paganini E, Schein RM, Smith MW, Swanson KM, Thompson BT, Vijayan A, Watnick S, Star RA, Peduzzi P: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008, 359: 7-20. 10.1056/NEJMoa0802639
Tolwani AJ, Campbell RC, Stofan BS, Lai KR, Oster RA, Wille KM: Standard versus high-dose CVVHDF for ICU-related acute renal failure. J Am Soc Nephrol 2008, 19: 1233-1238. 10.1681/ASN.2007111173
Bonventre JV: Dialysis in acute kidney injury – more is not better. N Engl J Med 2008, 359: 82-84. 10.1056/NEJMe0803765
Humes HD, Ding F, Song JH: Dialysis dosing in critically ill patients with acute kidney injury. Am J Kidney Dis 2008, 52: 649-652. 10.1053/j.ajkd.2008.07.033
Lameire N, Van Biesen W, Vanholder R: Acute kidney injury. Lancet 2008, 372: 1863-1865. 10.1016/S0140-6736(08)61794-8
Ronco C, Cruz D, van Straaten HO, Honore P, House A, Bin D, Gibney N: Dialysis dose in acute kidney injury: no time for therapeutic nihilism – a critical appraisal of the Acute Renal Failure Trial Network study. Crit Care 2008, 12: 308. 10.1186/cc7016
The authors declare that they have no competing interests.
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Lameire, N., Van Biesen, W. & Vanholder, R. Dose of dialysis in the intensive care unit: is the venom in the dose or in the clinical experience?. Crit Care 13, 155 (2009). https://doi.org/10.1186/cc7873
- Renal Replacement Therapy
- Acute Kidney Injury
- Continuous Renal Replacement Therapy
- Acute Kidney Injury Patient
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