Pannu and Gibney mortality rate and serum concentrations of various cytokines including TNF, IL1, IL6, and IL8. Most of these middle molecular weight molecules are water-soluble and are theoretically removable by hemofiltration-based plasma water purification. At the present time the immuno- modulatory effects of CRRT remain theoretical and have not been shown to affect outcome in human studies (Honore 2000; Cole 2002). Despite its apparent advantages over intermittent therapies, superiority of CRRT with respect to mortality or recovery of renal function has not been demonstrated. In the largest randomized controlled trial to date (n = 166), intermittent hemodialysis was associated with significantly lower in-hospital (48% vs 65%) and ICU mortality (42% vs 60%). However, patients with hypotension were excluded from participating in the study, and there was a significant difference in severity scores between the treatment arms despite randomization (Mehta et al 1996). Two recently published meta-analyses compared intermittent with continuous renal replacement therapies in unselected critically ill patients (Kellum, Angus, et al 2002; Tonelli et al 2002). Both concluded that there was no difference in terms of renal recovery. However, while Kellum concluded there was improved survival with CRRT, Tonelli found no survival benefit with either modality. Moreover, the sample size required to show a 20% mortality difference between IHD and CRRT would be in excess of 1200 patients (Tonelli et al 2002). There are also significant cost implications associated with modality choice for treatment of ARF in the ICU setting. A study comparing CRRT to alternate day IHD showed CRRT to be significantly more expensive, primarily because of the cost of CRRT fluid (Mann et al 2003). Cost differences also depend on whether these procedures are performed by critical care nurses or by renal unit nurses and whether inter-unit charges are applied. Further studies are needed to define the subset of patients with ARF who benefit from this therapy. Are there non-renal indications for CRRT? While the use of CRRT in critically ill patients with ARF is widely accepted, CRRT has also been used for some non- renal indications, most notably for the treatment of septic shock. Studies of high volume hemofiltration (HVHF) in canine (Silvester 1997) and porcine models (Grootendorst et al 1992) of sepsis showed significant improvement in CO, MAP, SV, and hepatic arterial flow. A small study found similar benefit in severe human septic shock (Honore 2000); however, a subsequent randomized clinical trial failed to confirm these findings (Bouman 2002). There are case reports and case series of CRRT use in a variety of other conditions including liver support, elevated ICP, intoxication, cardiac failure, ARDS, rhabdomyolysis, tumor lysis syndrome, post-cardiac surgery, but few if any prospective studies for many of these conditions (Schetz 1999). At present there are no established nonrenal indications for CRRT. Looking to the future As experience with these techniques grows, innovations in technology will likely keep pace. Over the last three years, most of the major manufacturers of dialysis equipment have developed new pumps dedicated for the use of these therapies. Most of these devices (Hospal/Gambro/Cobe- PRISMA, Fresenius-Acumen, Baxter-Accura, Edwards- Aquarius) offer automated fluid balancing, and sophisticated controls that are similar to those in regular dialysis machines. Membr ane technology is also evolving and anti- thrombogenic membranes are on the horizon (Yang 1991). Finally, the application of these therapies is likely to expand to other arenas including the treatment of sepsis, congestive heart failure, multiorgan failure, as a form of liver support, and in cardiopulmonary bypass for cytokine manipulation. It remains to be seen how these therapies will change our current management of these patient groups. References Abramson S, Niles JL. 1999. Anticoagulation in continuous renal replacement therapy. Curr Opin Nephrol Hypertens, 8:701–7. Bambauer R, Inniger R, Pirrung KJ, et al. 1994. Complications and side effects associated with large-bore catheters in the subclavian and internal jugular veins. Artif Organs, 18:318–21. Bellomo R, Teede H, Boyce N. 1993. Anticoagulant regimens in acute continuous hemodiafiltration: a comparative study. Intensive Care Med, 19:329–32. Bouman CS, Oudemans-Van Straaten HM, Tijssen J, et al. 2002. Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomized trial. Crit Care Med, 30:2205–11. Campbell IT. 1999. Limitations of nutrient intake: the effect of stressors: trauma, sepsis and multiple organ failure. Eur J Clin Nutr, 53(Suppl 1):S143–7. Chong BH, Magnani HN. 1992. Orgaran in heparin-induced thrombocytopenia. Hemostasis, 22:85–91. Cimochowski GE, Worley E, Rutherford WE, et al. 1990. Superiority of the internal jugular over the subclavian access for temporary dialysis. Nephron, 54:154–61. 148 Therapeutics and Clinical Risk Management 2005:1(2)