Optimizing the dose of renal replacement therapy 

Critically ill patients with acute kidney injury (AKI) often require renal replacement therapy. Compared to conventional, intermittent hemodialysis, continuous renal replacement therapy (CRRT) enables precise control of the volume status with gradual, and steady correction of acid-base and electrolyte abnormalities, in contrast to the fluctuating character of intermittent therapies.(1) The ideal approach to renal replacement therapy, however, remains unclear. Continuous therapies may be optimal in critically ill patients, especially in the presence of hemodynamic instability. Although CRRT may be preferred in most critically ill patients, optimization of the dose has been the subject of debate.  

Calculation of CRRT dose 

The total effluent rate represents the CRRT dose and correlates with the solute clearance during therapy. The effluent rate, or dose, depends on the modality of CRRT, and is expressed as ml/kg/hour. Calculation of the dose of CRRT with various modalities is as follows. Volumes are expressed in ml/kg/hour.

Continuous veno-venous hemofiltration (CVVH): Total replacement fluid (pre and post-dilution) + fluid removed 

Continous veno-venous hemodialysis (CVVHD): Dialysate fluid + fluid removed 

Continous veno-venous hemodiafiltration (CVVHDF): Total replacement fluid (pre and post-dilution) + dialysate + fluid removed 

There is no consensus on whether the actual or ideal body weight should be used to calculate the dose; however, it may be preferable to use the actual body weight as it more closely correlates with changes in volume distribution occurring from fluid overload.(2)

Evidence for dosing

In their seminal paper from more than two decades ago, Ronco et al. had suggested a dose of 35 ml/kg/hour with post-dilution CVVH.(3) They based this recommendation on lower mortality at 15-days after cessation of CVVH, compared with a dose of 25 ml/kg/hour. A still higher dose of 45 ml/kg/hour of this three-arm trial did not result in improved mortality compared to 35 ml/kg/hour. In a subsequent study, CVVH using a dose of 1–2.5l/hour of replacement fluid was compared to CVVDHF with an additional dialysate dose of 1–1.5 l/hour in a prospective randomized controlled trial (RCT). The high- and low-dose arms of this trial received 42 ml/kg/hour and 25 ml/kg/hour respectively. The 28-day and 3-month survival were significantly higher in the CVVHDF arm at a higher total dose.(4) In contrast to these early studies, most recent trials do not support high-dose CRRT. 

The VA/NIH Acute Renal Failure Trial Network study compared high with low-intensity renal replacement therapy in patients with AKI and at least one other organ failure or sepsis.(5) Hemodynamically stable patients with a cardiovascular SOFA score of 2 or less underwent intermittent hemodialysis while hemodynamically unstable patients with a score of 3 or 4 underwent CRRT. In the high-intensity arm, CVVHDF was carried out at 35 ml/kg/hour; intermittent therapy was performed six times a week in the sustained, low-efficiency dialysis mode. In the low-intensity arm, CVVHDF was carried out at 20 ml/kg/hour; sustained, low-efficiency dialysis was performed three times a week. A total of 1124 patients were randomized; 563 patients were included in the high-intensity arm and 561 patients in the low-intensity arm. All-cause mortality at 60 days, the primary endpoint, was 53.6% in the high-intensity and 51.5% in the low-intensity group; the difference was not statistically significant (OR:1.09; 95% confidence interval: 0.86 to 1.40; P = 0.47). Among the secondary outcomes, renal recovery at 28 days, RRT-free days until day 28, and hospital and ICU-free days until day 60 were also similar between the two groups. The progress of non-renal organ failure, according to organ-specific SOFA scores was also similar. A higher incidence of hypokalemia and hypophosphatemia were noted in the high-intensity group. 

Patients with AKI deemed to require renal replacement therapy by the treating clinician and fulfilled pre-defined inclusion criteria were randomized to undergo high- or low-intensity CRRT in the RENAL trial.(6) CRRT was performed in the CVVHDF mode, with replacement fluid administered post-filter. In the high-intensity arm, an effluent flow of 40 ml/kg/hour was targeted, compared to 25 ml/kg/hour in the low-intensity arm. Among 1508 patients enrolled, 747 received high-intensity therapy, and 761, low-intensity therapy. Mortality at 60 days was nearly identical, at 44.7% in each group. RRT-dependence at 28 and 90 days was similar between the two groups. Among other key clinical outcomes, the duration of ICU and hospital stay, duration of mechanical ventilation, and the incidence of non-renal organ failure were also similar between the two groups of patients. The incidence of hypophosphatemia was significantly more in the high-intensity group. Compared to the VA/NIH Acute Renal Failure Trial Network study, the RENAL trial used CRRT as the sole modality of therapy, according to local practice guidelines. 

Meta-analysis comparing doses 

The evidence from RCTs is supported by meta-analysis that compared low vs. high-intensity RRT in critically ill patients. A 2016 Cochrane review included 5 RCTs. No significant difference was observed between high vs. low-intensity RRT in the mortality risk at 30 days or later. The number of patients who were RRT-free was also similar among patients who underwent different levels of intensity of RRT. As observed previously, hypophosphatemia was more common with higher intensity therapy.(7)

Wang et al. analyzed individual patient data in a meta-analysis of seven RCTs, including 3682 patients. The 28-day mortality was similar with standard compared to higher intensity RRT. However, RRT dependence at 28 days was greater with high-intensity therapy. Besides, cessation of RRT was significantly more delayed in the high-intensity compared to the standard intensity group. This meta-analysis also suggested no difference in mortality with high-intensity compared to standard-dose CRRT; besides, renal recovery appeared to be delayed with high-intensity therapy.(8) The meta-analysis by Jun et al. compared standard dose RRT at 20–25 ml/kg/hour or equivalent with high-intensity therapy of 35–48 ml/kg/hour or equivalent. Higher intensity therapy did not improve survival or renal recovery in patients with AKI.(9)

Prescribed vs. delivered dose 

Interruptions to therapy often occur during CRRT. Therapy may have to be temporarily halted for procedures that require transfer out of the ICU, filter clotting, or catheter malfunction, with delays in recommencement. Hence, the delivered dose may be considerably lower than the prescribed dose. The delivered dose should be evaluated at regular intervals to assess the efficacy of CRRT and may be calculated using the equation below.(10)

Delivered dose of CRRT Total effluent volume (V) × Urea nitrogen level in the effluent fluid (U) / Urea nitrogen level in the arterial limb of the circuit (P)

In a retrospective study by Venkataraman et al., the mean duration of CRRT was only around 16 hours per day. Although the mean prescribed dose was 24.46 ± 6.73 ml/kg/hour, the actual delivered dose was much lower at 16.55 ± 5.41 ml/kg/hour.(11) Similarly, among patients who were prescribed a CRRT dose of >35 ml/kg/hour, only 22% received the target dose.(12) In the VA/NIH Acute Renal Failure Trial Network study, 89% of the prescribed dose was delivered in the high-intensity arm compared to 95% in the low-intensity arm.(5) The RENAL study achieved 84% of the prescribed dose in the high-intensity compared to 88% in the low-intensity arm.(6) These studies suggest that a considerable gap may exist between the prescribed and delivered dose in patients who are on CRRT. Hence, appropriate adjustments in the prescribed dose need to be undertaken. The KDIGO recommends the prescription of a dose range between 25–30 ml/kg/hour aiming to deliver a dose of 20–25 ml/kg/hour, to compensate for possible interruptions to therapy. They also suggest frequent assessment and dose adjustment.(13)

High-volume hemofiltration (HVHF)

Sepsis is characterized by a dysregulated host response to infection, leading to high circulating levels of cytokines as part of the inflammatory response. The use of HVHF may enable convective clearance of middle molecules including endotoxin, cytokines, and oxygen free radicals that may potentially improve clinical outcomes in sepsis. Techniques aimed at cytokine removal may offer putative benefits by halting the inflammatory cascade and preventing cytokine accumulation, thereby, mitigating organ dysfunction.(14) HVHF is conventionally defined as a dose of >35 ml/kg/hour, although most studies have used a dose of >50 ml/kg/hour.(15)  

The HEROICS study evaluated the effect of HVHF at 80 ml/kg/hour compared to standard care in patients with severe shock 3–24 hours post-cardiac surgery.(16) The authors hypothesized that convective removal of toxins and pro-inflammatory mediators, and correction of metabolic acidosis may improve clinical outcomes. However, no reduction was observed in the 30-d mortality compared to standard care involving delayed CVVHDF only for conventional indications in AKI. 

In a study on septic patients, Zhang et al. compared HVHF at a dose of 50 ml/kg/hour with “extra” HVHF at a dose of 85 ml/kg/hour. The mortality at 28, 60, and 90 days was comparable between the two groups; besides, the renal outcomes among survivors at 90 days did not differ.(17)

The multicenter IVOIRE study compared high vs. conventional volume hemofiltration therapy among patients with septic shock and AKI. In this RCT, HVHF was performed at 70 ml/kg/hour compared to standard therapy with 35 ml/kg/hour for 96 hours.(18) Although the study was ceased prematurely, no reduction was noted in the 28-day mortality in patients who underwent CVVHDF. Besides, there was no apparent improvement in the hemodynamic status or organ dysfunction. Excessive removal of antibiotics was noted during therapy, which could have offset possible beneficial effects. Meta-analyses of RCTs do not support the use of HVHF in patients with sepsis, with no difference observed in mortality or organ dysfunction.(19–21)

Key points

  • CRRT is preferred over intermittent therapies in critically ill patients with AKI; it enables precise control of the volume status with gradual, and steady correction of acid-base and electrolyte abnormalities
  • The optimal dose of CRRT has been the focus of intense research; early studies had suggested improved clinical outcomes with a dose of  ≥35 ml/kg/hour 
  • More recent RCTs suggest that high-dose therapy does not lead to improved clinical outcomes; besides, it may lead to adverse outcomes including hypophosphatemia, hyperkalemia, and excessive removal of antibiotics
  • The efficacy of CRRT depends on uninterrupted therapy; however, interruptions in therapy are common in critically ill patients who frequently undergo procedures that require transfer out of the ICU. Filter clotting may occur with the delayed recommencement of therapy. Hence, the delivered dose may be considerably lower than the prescribed dose. Consequently, periodic evaluation of the delivered dose is a crucial component of care
  • Based on the available evidence, a prescribed dose of 25–30 ml/kg/hour may be appropriate, targeting a delivered dose of 20–25 ml/kg/hour
  • High-volume hemofiltration (>50 ml/kg/hour) has been investigated for possible benefits from convective removal of endotoxin, cytokines, and oxygen free radicals; however, there is no evidence to support improvement in clinical outcomes 

References

1.         Ronco C, Ricci Z. Renal replacement therapies: physiological review. Intensive Care Med. 2008 Dec;34(12):2139–46. 

2.         Vásquez Jiménez E, Anumudu SJ, Neyra JA. Dose of Continuous Renal Replacement Therapy in Critically Ill Patients: A Bona Fide Quality Indicator. Nephron. 2021;145(2):91–8. 

3.         Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet. 2000 Jul 1;356(9223):26–30. 

4.         Saudan P, Niederberger M, De Seigneux S, Romand J, Pugin J, Perneger T, et al. Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int. 2006 Oct;70(7):1312–7. 

5.         VA/NIH Acute Renal Failure Trial Network, Palevsky PM, Zhang JH, O’Connor TZ, Chertow GM, Crowley ST, et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008 Jul 3;359(1):7–20. 

6.         Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, et al. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med. 2009 Oct 22;361(17):1627–38. 

7.         Fayad AI, Buamscha DG, Ciapponi A. Intensity of continuous renal replacement therapy for acute kidney injury. Cochrane Database Syst Rev. 2016 Oct 4;10:CD010613. 

8.         Wang Y, Gallagher M, Li Q, Lo S, Cass A, Finfer S, et al. Renal replacement therapy intensity for acute kidney injury and recovery to dialysis independence: a systematic review and individual patient data meta-analysis. Nephrol Dial Transplant. 2018 Jun 1;33(6):1017–24. 

9.         Jun M, Heerspink HJL, Ninomiya T, Gallagher M, Bellomo R, Myburgh J, et al. Intensities of renal replacement therapy in acute kidney injury: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2010 Jun;5(6):956–63. 

10.       Macedo E, Claure-Del Granado R, Mehta RL. Effluent volume and dialysis dose in CRRT: time for reappraisal. Nat Rev Nephrol. 2011 Nov 1;8(1):57–60. 

11.       Venkataraman R, Kellum JA, Palevsky P. Dosing patterns for continuous renal replacement therapy at a large academic medical center in the United States. J Crit Care. 2002 Dec;17(4):246–50. 

12.       Vesconi S, Cruz DN, Fumagalli R, Kindgen-Milles D, Monti G, Marinho A, et al. Delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury. Crit Care. 2009;13(2):R57. 

13.       Kellum JA, Lameire N, Aspelin P, Barsoum RS, Burdmann EA, Goldstein SL, et al. Kidney disease: Improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney International Supplements. 2012 Mar;2(1):1–138. 

14.       Ronco C, Ricci Z, Bellomo R. Importance of increased ultrafiltration volume and impact on mortality: sepsis and cytokine story and the role of continuous veno-venous haemofiltration. Curr Opin Nephrol Hypertens. 2001 Nov;10(6):755–61. 

15.       Joannes-Boyau O, Dewitte A, Honoré PM. High-Volume Hemofiltration in the Intensive Care Unit. In: Critical Care Nephrology [Internet]. Elsevier; 2019 [cited 2022 Jul 19]. p. 1034-1037.e2. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780323449427001710

16.       Combes A, Bréchot N, Amour J, Cozic N, Lebreton G, Guidon C, et al. Early High-Volume Hemofiltration versus Standard Care for Post-Cardiac Surgery Shock. The HEROICS Study. Am J Respir Crit Care Med. 2015 Nov 15;192(10):1179–90. 

17.       Zhang P, Yang Y, Lv R, Zhang Y, Xie W, Chen J. Effect of the intensity of continuous renal replacement therapy in patients with sepsis and acute kidney injury: a single-center randomized clinical trial. Nephrol Dial Transplant. 2012 Mar;27(3):967–73. 

18.       Joannes-Boyau O, Honoré PM, Perez P, Bagshaw SM, Grand H, Canivet JL, et al. High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial. Intensive Care Med. 2013 Sep;39(9):1535–46. 

19.       Lehner GF, Wiedermann CJ, Joannidis M. High-volume hemofiltration in critically ill patients: a systematic review and meta-analysis. Minerva Anestesiol. 2014 May;80(5):595–609. 

20.       Clark E, Molnar AO, Joannes-Boyau O, Honoré PM, Sikora L, Bagshaw SM. High-volume hemofiltration for septic acute kidney injury: a systematic review and meta-analysis. Crit Care. 2014 Jan 8;18(1):R7. 

21.       Borthwick EM, Hill CJ, Rabindranath KS, Maxwell AP, McAuley DF, Blackwood B. High-volume haemofiltration for sepsis in adults. Cochrane Database Syst Rev. 2017 Jan 31;1:CD008075. 

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