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938 PART 8: Renal and Metabolic Disorders

(sTNFR-1, snTFR-2, IL-1ra) were removed. While there was a cor- remains institution dependent rather than standardized and depends on
responding initial fall in plasma levels after initiation of CVVH, levels equipment available. Convective therapies, due to their use of “solvent
subsequently increased. Further, it appears that the majority of cytokine drag” for clearance rather than diffusion have theoretically and conven-
removal occurred via filter adsorption rather than ultrafiltration. tionally been thought to be more effective at removal of “middle-sized”
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These study results suggest that while conventional dose hemofiltra- molecules (10 -40 kDa), leading some nephrologists to argue the poten-
tion removes some cytokines in the setting of sepsis-associated AKI, it tial benefit of convective over diffusive therapies. The validity of this
does not effectively lower circulating cytokine levels and the removal is assumption with modern dialytic therapies is questionable. A prospec-
adsorptive rather than dependent on convective clearance. tive, crossover study of convective versus diffusive therapies in critically
One potential limitation of these studies is the dose of convective ill patients with AKI examined the relative clearance of small (urea,
therapy, because cytokine removal is dependent on the volume of creatinine) solutes and middle-sized (β -microglobulin) solutes. Fifteen
2
hemofiltration. Perhaps in order to observe significant, sustained lower- consecutive patients underwent a total of 30 treatments (15 CVVH and
ing of blood cytokine levels, higher volume hemofiltration is required. 15 CVVHD). Median clearance for urea (31.6 mL/min for CVVH vs
Accordingly, high-volume hemofiltration has demonstrated promise in 35.7 mL/min for CVVHD; p = NS) and creatinine (38.1 mL/min for
improving hemodynamics and mortality in animal models of AKI with CVVH vs 35.6 mL/min for CVVHD; p = NS) was not significantly
critical illness; however, data in humans remain limited. 33-35 Twenty different. Clearance of β -microglobulin was greater in the convective
2
patients with refractory shock and severe sepsis (MAP <55 mm Hg and therapy group, but this difference did not reach statistical significance
cardiac index <2.5 L/min/m despite maximum norepinephrine, dopa- (16.3 mL/min for CVVH vs 6.27 mL/min for CVVHD; p = 0.055).
2
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mine, and epinephrine dose of 0.5 µg/kg/min for >2 hours) were treated An in vitro study comparing clearance of solutes ranging from 10 to
with short-term high-volume hemofiltration. Hemofiltration was set at 100 kDa with convective versus diffusive therapy also demonstrated
8.75 L/h for 4 hours, followed by 1 L/h for the remainder of the treatment no significant difference between the two modalities. The results of
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time. Investigators assessed if four clinical parameters improved after existing studies suggest that the assumption that convective therapy is
therapy—after 2 hours, increase in cardiac index by ≥50%, increase in superior to diffusive therapy with regard to middle molecule clearance
mixed venous saturation by ≥25% and after 4 hours, increase in arte- may not apply to modern dialytic techniques using more porous (higher
rial pH to 7.3 and a ≥50% reduction in epinephrine dose. Eleven out of “flux”) membranes. Outcomes other than solute clearance have not been
20 patients demonstrated a clinical response—meeting all of the established thoroughly examined. The crossover study of convective versus diffusive
criteria. Responders were more likely to survive (9/11 responders sur- clearance outlined above did compare circuit filter time as part of its
vived at day 28 vs all 9 nonresponders died by hour 24 after initiation). analysis and found that filter life was longer in diffusive therapy (37 vs
APACHE II and SAPS II scores did differ between the two groups. 19 hours; p = 0.03) Nevertheless, the existing literature suggests no
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36
This uncontrolled study suggests a potential role for acute high-volume definitive advantage between diffusive and convective therapies.
hemofiltration to support patients with severe critical illness and AKI.
However, given the lack of a control group, the exact effect of the CRRT DOSE OF THERAPY
on improving hemodynamics in the responders is unclear. Using pulsed,
high-volume hemofiltration (CVVH with effluent rate of 85 mL/kg/h Integral to the discussion regarding optimal RRT in the critically ill
for 6 hours, followed by 35 mL/kg/h for the remaining 18 hours a day), is the consideration of the intensity (dose) of therapy. Clinicians have
other investigators examining the effect of high-volume hemofiltration adopted the results of studies assessing dose adequacy in maintenance
on hemodynamic variables and mortality found similar results. Fifteen hemodialysis patients to the management of patients with AKI requiring
subjects with severe sepsis or septic shock that required RRT were RRT. For maintenance hemodialysis treatments, the available literature
studied. Investigators observed a significant, sustained fall in noradrena- supports the current Kidney Disease Outcome Quality Initiative
line dose required for vasoactive support and, accordingly, a significant (KDOQI) guidelines of a urea reduction ratio (the difference between
and sustained increase in systolic blood pressure while receiving pulsed, the predialysis urea nitrogen and postdialysis urea reduction divided by
high-volume hemofiltration. The observed mortality was also lower the predialysis urea nitrogen expressed as a percentage) of at least 65%
than predicted by APACHE II or SAPS II scores (46.7% vs 72% and 68%, with a target dose of 70%. This correlates to a single-pool Kt/V (dialyzer
respectively). The available studies suggest potential promise in using clearance of urea in mL/min multiplied by duration of dialysis in minutes
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hemofiltration, especially high-volume hemofiltration, in modifying the divided by volume of distribution of urea) of at least 1.2 with a target of
cytokine milieu and improving hemodynamics in the setting of severe 1.4 per dialysis treatment. A survey of clinicians (of the ATN trial net-
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sepsis and AKI. However, the above studies represent the results of work) demonstrated significant variability in dose prescribing pattern
uncontrolled interventional trials. The limited controlled data available for both intermittent and continuous therapies for RRT-requiring AKI.
have only demonstrated more effective removal of cytokines with high- Specifically, 52% of patients were treated with intermittent hemodialysis
volume hemofiltration as compared to conventional CVVH without a three times weekly or every other day, 32% of patients received IHD
comparison to intermittent therapy or demonstrating effects on hospital four times weekly, and 7% of patients received IHD six or more times
course, renal recovery, or mortality. 38,39 Overall, the lack of controlled per week. With regard to CRRT, 17.9% of practitioners prescribed
data with clinically significant outcomes precludes any recommendation weight-based dosing, with 80% of those prescribing an effluent rate of
to favor the use of CRRT in the setting of severe sepsis and AKI based 35 mL/kg/h. The remainder varied in their prescription between effluent
on potential immunomodulatory effects, which have never been dem- rates of 1 and 2.5 L/h. 43
onstrated at the doses used for renal replacement therapy. The argument for higher dose therapy was supported by the results of
a retrospective study assessing the effect of dose on outcome in critically
MODALITY OF CRRT: DIFFUSIvE vERSUS ill patients with AKI. Higher dose therapy was further supported by two
CONvECTIvE THERAPIES prospective randomized studies of higher dose intermittent and con-
tinuous renal replacement therapy. In the study examining optimal dose
The literature reviewed above has included studies performed with a of intermittent hemodialysis, investigators assigned 160 patients to one
variety of continuous therapies, hemofiltration (CVVH or CAVH), of two IHD strategies: daily versus conventional (three times weekly)
hemodialysis (CVVHD or CAVHD), or combination therapy (CVVHDF dialysis with a prescribed Kt/V of 1.2. Individuals assigned to daily
or CAVHDF), and has assumed that diffusive and convective modalities hemodialysis were more likely to recover renal function and survive.
of CRRT are equivalent with regard to their effect on amelioration of Specifically, the daily hemodialysis group recovered their renal function
uremic syndrome and maintaining fluid, electrolyte, and acid-base after a mean of 9 days versus 16 days in the alternate-day hemodialysis
balance. Whether diffusive, convective, or combination therapy is used group (p = 0.001) and the mortality rate in the daily hemodialysis group

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