Determining the dose of dialysis

This chapter is related to the aims of Section H3(i) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the principles of dialysis and renal replacement fluid". Extending this definition some of the way towards the professional competencies of the Fellowship Exam candidates, one could probably justify positioning this chapter in the middle between Part I and Part II revision material. On one hand, prescribing dialysis is very much the prerogative of senior medical staff; on the other hand being able to explain how the prescription is determined seems like something we should all know from an early age. Ergo, the chapter will have heavy emphasis on definitions and basic foundational science, but with the option to digress into the evidence upon which current dialysis dosing is based. 

In brief:

Theoretically:

• Definition of "dose" in CRRT is volume of blood "purified."
• Measure of "dose" in CRRT: clearance rate of a representative marker solute.

Practically:

• Dialysis dose is equivalent to the effluent rate in ml/kg/hour.
• Effluent rate is the ultrafiltration rate for haemofiltration (CVVH), or the sum of ultrafiltration rate and dialysis rate for CVVHDF

Relevance to CRRT:

• Prescribed dose is the effluent rate
• No benefit in outcomes with doses in excess of 25ml/kg/hr
• Practically, higher doses may be necessary to compensate for circuit downtime

Dialysis dose

Traditionally, urea has been the marker solute since the clearance of all accumulated "renal toxins" correlates to some extent with urea clearance. However, it is not used to prescribe a dialysis dose.

Most studies prescribe weight-based effluent rates as their dose of dialysis. In practical terms, the "volume of blood purified" dose of dialysis is essentially the effluent flow rate (i.e. the combination of dialysate and ultrafiltrate flow rates). Thus, when one signs the patient up for "two litre exchanges" one is prescribing an effluent rate of 2000ml/hr, and a replacement rate of 2000ml/hr (that is the "exchange volume"). The "exchange" here being a term which recalls a time when CVVHF was the dominant modality, when in effect one would remove 2000ml of ultrafiltrate from the patient, "exchanging" it for 2000ml of clean replacement fluid. With CVVHDF, of the 2000 ml exchange volume, not all will be ultrafiltrate because some dialysate is also being discarded. 

This works out to be a dialysis dose of 2000ml/hr, or 28.6ml/kg/hr for a 70kg lump of human tissue. This prescribed "dose of effluent" is usually about 20% less than the actual dose of dialysis measured by marker solute, largely because the filter efficiency tends to diminish over the course of a CRRT session.

There is some disagreement as to what the ideal dialysis dose should be. Thus far, nobody has demonstrated any improvement in outcomes with doses higher than 25ml/kg/hr. Practically speaking, one may wish to prescribe a higher dose to compensate for anticipated filter downtime. 

Efficiency of CRRT

• Efficiency = clearance (K);
• Expressed in ml/min
• One may have high clearance for short periods (eg. with IHD) or low clearance for long period (eg. with CRRT).
• The latter may yield better mass transfer (i.e. more solute ends up being cleared, albeit inefficiently)

Intensity of CRRT

• • Expressed in ml/hr x (24hrs)

Efficacy of CRRT

• • This is the fractional clearance of a given solute.
  • Usually the "given solute" is urea.
  • Urea's volume of distribution is about equal to the total body water, which is about 60% of the total weight, or 0.6L/kg. Which, in a 70kg patient, this is 42 litres.
  • Thus, efficacy can be calculated as an example:
    • the Kt (60ml/min, which is 3.6litres per hr, over 24 hrs) = 86.4 litres. …divided by 42 litres, this gives an efficacy of 2.05.

Clearance indexed to body mass

• • (K, volume of blood cleared of solute) per kg per hour

How much should I prescribe? Surely more is better?

The RENAL group of investigators concluded that "increasing the intensity of continuous renal-replacement therapy from 25 to 40 ml of effluent flow per kilogram per hour does not reduce mortality or the rate of dependence on dialysis among critically ill patients".

How do I practically prescribe the dose of dialysis?

Yes, in theoretical terms the dose of dialysis is the volume of blood purified per unit time, and colloquially the "intensity" of dialysis is the scale of that dose (i.e. a higher dose is said to be more "intense"). In practical terms, the dose of dialysis is essentially the effluent flow rate (i.e. the combination of dialysate and ultrafiltrate flow rates).

Thus, when one signs the patient up for "two litre exchanges" one is prescribing an effluent rate of 2000ml/hr, and a replacement rate of 2000ml/hr (that is the "exchange"). This works out to be a dialysis dose of 28.6ml/kg/hr for a 70kg lump of human tissue.

This has been asked about in Question 12 from the first paper of 2010.

Specifically, " Briefly outline the relationship between dose of dialysis and outcome"

This question makes reference to the following "relevant studies":

• Ronco (2000)
• Bouman (2002)
• Saudan (2006)
• Tolwani (2008)
• VA/NIH (2008)
• RENAL study (2009)

Since then, there have been a few more:

• Vesconi (2009) - an observational study
• Van Wert (2010) - a meta-analysis
• Zhang et al (2012)
• IVOIRE study (2013) (sepsis)
• Clark (2014) ( sepsis)

In summary:

It seems beyond a certain dose, renal replacement therapy removes as many useful molecules as it does toxins, and the benefit from escalating the dose deteriorates.

The evidence

In detail:

• Ronco (2000):
  • 425 patients, single centre RCT
  • Compared 20ml/kg/hr, 35ml/kg/hr, 45ml/kg/hr
  • Observed survival at 15 days after cessation of dialysis
  • Survival in the three groups was 41%, 57%, and 58%
  • Conclusion: "We recommend that ultrafiltration...should reach at least 35 mL/kg/hr"

• Bouman (2002)
  • 106 patients, two-centre RCT
  • Compared 19ml/kg/hr performed later with 20ml/kg/hr performed earlier, and 48ml/kg/hr performed earlier.
  • Observed survival at 28 days
  • For the three grous, 28 day survival was 75%, 68.8% and 74.3%
  • Conclusion: "survival ... and recovery of renal function were not improved using high ultrafiltrate volumes"

• Saudan (2006)
  • 206 patients, single centre RCT
  • CVVH (25ml/kg/hr) compared with CVVHDF (42ml/kg/hr)
  • Observed survival at 28 and 90 days
  • Survival at 90 days was 34% for CVVH and 59% for CVVHDF
  • Conclusion: "increasing the dialysis dose especially for low molecular weight solutes confers a better survival"

• Tolwani (2008)
  • 200 patients, single-centre RCT
  • 20ml/kg/hr compared with 35ml/kg/hr
  • Observed in-ICU survival or 30 day survival, whichever happened first
  • Survival for low-dose CRRT patients was 56%, vs. 49% for the high-dose group
  • Conclusion: "a difference in patient survival or renal recovery was not detected"

• VA/NIH (2008)
  • 1124 patients, massive multicentre RCT
  • Compared 35ml/kg/hr and 20ml/kg/hr
  • Observed 60 day survival, as well as many other parameters
  • Survival for low-dose CRRT was 51.5% and 53.6% for high-dose group
  • Conclusion:"Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure"

• RENAL study (2009)
  • 1508 patients, massive multicentre RCT
  • Compared 25ml/kg/hr to 40ml/kg/hr
  • Observed 90 day survival
  • Survival in both groups was the same: 44.7%
  • Conclusion: " treatment with higher-intensity continuous renal-replacement therapy did not reduce mortality at 90 days"

So, though small trials occasionally found a mortality benefit, large well-designed studies were unable to detect one. At this stage, the issue could be said to have been put to rest. Subsequent investigators have made attempts to find subtle non-survival benefits, or to investigate higher dialysis doses in patients with sepsis. More negative trials ensued.

• Vesconi (2009)
  • 15,200 patients - prospective multicentre observational study.
  • Groups were separated by CRRT dose, according to whether they received less or more than 35ml/kg/hr.
  • Outcome measures included ICU mortality, ICU length of stay and duration of mechanical ventilation.
  • Higher CRRT dose patient mortality was 60.8% vs. 52.5% for the low-dose group
  • However, the higher CRRT dose was associated with shorter ICU stay and more rapid extubation among the survivors.
  • Conclusion: "no evidence for a survival benefit afforded by higher dose RRT"

• Van Wert (2010) - a meta-analysis.
  • 12 trials met inclusion criteria (3999 patients).
  • Mortality was only one among numerous parameters assessed.
  • Meta-analyses found no effect of high-dose renal replacement therapy on mortality.
  • Conclusion: "High-dose renal replacement therapy in acute kidney injury does not improve patient survival or recovery of renal function overall or in important patient subgroups, including those with sepsis."

• Zhang et al (2012)
  • 141 patients with sepsis and AKI; single centre RCT.
  • Compared super-high CRRT doses: 50ml/kg/hr vs 85ml/kg/hr.
  • Observed survival at 28, 60 and 90 days.
  • No difference between the groups was found at any timeframe.
  • Conclusion: "increasing the intensity of renal replacement therapy... had no effect on survival"

• IVOIRE study (2013)
  • 140 patients with septic shock and AKI, multicentre RCT.
  • Compared 35ml/kg/hr vs 70ml/kg/hr (HVHF, High Volume HaemoFiltration).
  • Primary endpoint was 28 day mortality.
  • Mortality was 40.8% vs 37.9%.
  • Conclusion: "HVHF... cannot be recommended for treatment of septic shock complicated
    by AKI"

• Clark (2014) - a meta-analysis specific for CRRT intensity in sepsis
  • 4 trials (470 patients) met inclusion criteria.
  • Comparion of standard intensity to high intensity (over 50ml/kg/hr)
  • 28 day mortality was the main outcome measure.
  • Pooled analysis did not show any meaningful difference.
  • Conclusion: "Insufficient evidence exists of a therapeutic benefit".
  • Furthermore, "further trials should focus on alternative extracorporeal therapies as an adjuvant therapy for septic AKI rather than HVHF". Essentially, the authors are saying that this is a dead end, and we should think about something else.