We completed a multi-center, concealed-allocation, randomized trial comparing hemofiltration and hemodialysis in critically ill patients with AKI. This pilot trial achieved its primary objective of confirming the feasibility of performing a large-scale trial evaluating RRT clearance mode in AKI. There was also a non-significant trend towards reduced organ dysfunction, driven by decreased vasopressor requirements, early after the initiation of RRT in patients who received hemofiltration. These feasibility data and the importance of the clinical question justify the conduct of a large trial with adequate power to evaluate the primary outcome of 60-day mortality. With a power of 0.80, type I error of 0.05, and a mortality reduction of 10% in patients treated with CVVH (estimated 60-day mortality in the CVVHD arm 55%), we estimate that such a trial would require the enrolment of nearly 400 patients per arm. A more conservative mortality reduction of 7.5% would require the enrolment of 700 patients per arm.
Little is known about the optimal mode of clearance in renal replacement for AKI. Although both convection and diffusion remove small molecules with equal efficiency, convection may remove larger molecules that are not cleared by diffusive mechanisms [13
]; previous studies have examined effects on inflammatory markers and have been too small to reliably determine effects on clinical outcomes. In addition, the profile of larger molecules removed by convection is relatively non-specific and may also include molecules that dampen inflammation or crucial medications such as antibiotics [14
]. A randomized crossover study of 13 patients with AKI and the systemic inflammatory response syndrome found that CVVH for 24 hrs reduced plasma concentrations of TNFα and cleared more IL-6, compared to CVVHD. However, there was no effect on plasma concentrations of IL-6, IL-10, SL-selectin, or endotoxin [15
]. Morgera and coworkers randomized 24 patients with sepsis-associated AKI to treatment with CVVH or CVVHD using a high cutoff membrane permeable to molecules up to 60 kilodaltons in size. Plasma concentration and clearance for IL-6 did not differ, but clearance of IL-1 receptor antagonist, an anti-inflammatory mediator, was enhanced by CVVH [16
]. Of note, protein losses were higher in patients who received CVVH. In a prospective crossover study involving 15 patients with AKI who sequentially received CVVH and CVVHD, β2
-microglobulin clearance was non-significantly higher among CVVH recipients (P
= 0.055) [17
]. Among trials focusing on clinical outcomes, a single-centre RCT (n = 20) did not demonstrate a difference in survival, renal recovery or ICU stay in patients treated with CVVH vs. CVVHD administered at fixed doses of 1.7 to 2.0 L/hr [18
]. Similarly, a recent unpublished 65-patient RCT of CVVH vs continuous venovenous hemodiafiltration (both at 40 mL/kg/hr) did not demonstrate a survival difference at 28 days [19
While interventional trials involving devices and processes of care that are susceptible to large variations in practice are challenging, we achieved our feasibility objectives. Specifically, we were able to recruit the majority of eligible subjects, implement the protocolized therapy for > 85% of the prescribed time and ascertain vital status at 60 days for all participants. When accounting for actual time on therapy, the delivered dose exceeded 80% of that prescribed in both treatment arms, thereby surpassing our feasibility threshold of 75%. Accordingly, we believe our study strongly supports the feasibility of a large definitive randomized trial comparing hemofiltration and hemodialysis in critically ill patients with severe AKI.
This is the largest published trial to date to study the mode of solute clearance in AKI. Given the challenges of recruiting participants and implementing interventions in a population with a high burden of illness, the success of our pilot was a necessary precursor to a principal trial that examines patient-relevant clinical outcomes. Our eligibility criteria were pragmatic and assured the inclusion of individuals in North America who typically receive CRRT. A minority of individuals for whom no SDM could be found were enroled with deferred consent, thereby limiting exclusion of potentially eligible patients and mitigating selection bias. Of interest, no subject enroled by deferred consent had an SDM who subsequently withdrew consent or withdrew consent personally after regaining capacity. Finally, other than the clearance mode, all other aspects of RRT including stepdown to intermittent hemodialysis and withdrawal of RRT were performed in a manner consistent with usual practice.
Our study has several limitations. As this was an unblinded trial, we cannot exclude the effect of co-interventions in either treatment arm. However, the nature of our intervention made blinding impractical, and we ensured that the two groups received equivalent RRT doses. There is also no definite intervention related to RRT prescription that has been shown to modify outcomes in critically ill patients with AKI. In addition, we cannot exclude the possibility that patients who were eligible but not randomized were systematically different than trial participants. Our protocol specified a target clearance of 35 mL/kg/hr, which was generally achieved in both arms. The decision to use this dose was guided by the fact that our trial was designed when higher dose CRRT was felt to be potentially beneficial based on data from two trials [20
]. This pre-dated more recent trials and meta-analyses demonstrating no advantage of higher dose CRRT over doses of 20 to 25 mL/kg/hr, which would likely be the standard in a future trial comparing convection and diffusion [4
]. However, since high dose therapy appears safe and may positively modify the effect of convective clearance [20
], our higher dose target was reasonable. It should be noted that while 35 ml/kg/hr was prescribed to all participants, actual solute clearance may have been significantly lower due to changes in filter permeability [24
]. On the other hand, when calculating the prescribed dose, we did not consider clearance associated with net ultrafiltration or removal of volume associated with the administration of anticoagulants. This approach would tend to underestimate the actual solute clearance that was delivered. Importantly, any deviation in dose from our 35 mL/kg/hr target would affect participants in both intervention arms to a similar extent. The Prismaflex CRRT system requires that all patients (even those predominantly getting hemodialysis) receive a small amount of post-filter hemofiltration (up to 200 ml/hr) to prevent clotting in the machine's deaeration chamber. In addition, CVVHD recipients would have had other unavoidable sources of convective clearance, specifically for the achievement of net fluid removal, and for the isovolemic removal of volume associated with the administration of the anticoagulant (citrate or heparin). Thus, CVVHD recipients did not receive purely diffusive solute clearance. We nonetheless estimate that the typical patient enrolled in the CVVHD arm still received > 80% of therapy in the form of diffusive clearance, which reassures us that this trial truly compared two different modes of solute clearance. Our trial was conducted using the AN69 polyacryonitrile filter, which has unique adsorptive characteristics [14
]. While this is a widely used membrane in the administration of CRRT, the adsorptive characteristics of filters may differ and we cannot generalize our findings to settings in which other filters are utilized. Moreover, we did not collect data to evaluate the relative effect of CVVH or CVVHD on the removal of molecules of varying size. This trial was conducted using continuous RRT. Although the question of hemodialysis vs. hemofiltration is applicable to patients stable enough to receive intermittent RRT, machines to deliver intermittent hemofiltration were not widely available in North America when the trial was conducted. Among trial participants who became more hemodynamically stable, intermittent hemodialysis was utilized even when the initial CRRT mode was hemofiltration, thereby potentially diluting the benefits associated with CVVH. Finally, while we observed a trend towards improved organ failure scores, this finding must be interpreted with caution given the small sample size of our trial. Moreover, disease severity scores such as the SOFA score are surrogate markers that cannot supplant hard clinical endpoints.