The lower limit of intensity to control uremia during continuous renal replacement therapy

All patients older than 18 years admitted to one of the participating ICUs between January and December 2010 and treated with CRRT due to AKI according to the risk, injury, failure, loss, end-stage renal failure (RIFLE) criteria [21] were eligible. The following patients were excluded from this study: patients aged less than 18 years, patients with any renal replacement therapy (RRT) before ICU admission, and patients with end-stage renal failure on chronic dialysis. Patients with no information on their body weight at ICU admission were also excluded because their CRRT intensity could not be calculated. If a patient was admitted to the ICU and treated with CRRT more than once during the same hospital admission, only the first ICU admission was included.

The following data were obtained from case report forms: age, gender, body weight (measured or estimated at ICU admission based on the methods of each participating center), date of hospital admission, date of ICU admission, simplified acute physiology score (SAPS II) on the day of ICU admission [22] and primary diagnosis. Factors contributing to AKI were collected and categorized according to the following list: septic shock, major surgery, cardiogenic shock, hypovolemia, drug-induced, or other. Multiple choices were allowed if necessary. The following data were also collected at CRRT initiation: use of vasopressors and mechanical ventilation, mean arterial pressure (MAP), arterial partial pressure of oxygen/inspired oxygen fraction (PaO₂/FiO₂) ratio, lactate, Glasgow coma scale (GCS), platelet count, bilirubin, diuretic use, urine output, CRRT mode (continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemodiafiltration (CVVHDF)), and blood flow rate. Serum creatinine and urea levels were collected at CRRT initiation (day 1) and over the first 7 days of CRRT. Dates and times of CRRT start and stop, and dialysate and replacement flow rates were collected for each filter over the first 7 days of CRRT. The CRRT dose was defined as the sum of the dialysate and replacement flow rates (mL/h) because all CVVH and CVVHDF were performed with post-dilution. The CRRT intensity was defined as the CRRT dose divided by body weight (mL/kg/h). ICU and hospital mortality and RRT requirement at hospital discharge were also collected.

As this is a retrospective study, the CRRT dose was decided by treating physicians and could have changed every day according to patient conditions. We therefore evaluated the effect of CRRT intensity by two different definitions: daily intensity and average intensity. Daily intensity was defined as the mean intensity over each 24-h period (from 6:00 AM to 6:00 AM next day). For example, if CRRT was performed at 15 mL/kg/h for 4 h and also at 10 mL/kg/h for 10 h in one day (with a period of 10 h with no CRRT), the daily intensity was calculated as:

Average intensity was defined as the mean of daily intensity during the period while CRRT was performed in the ICU.

Relative and daily creatinine/urea changes were calculated as follows:

where C_{day N} is the concentration of creatinine or urea on day N and C_{day N+1} is the concentration of creatinine on the next day.

Data are presented as medians and interquartile ranges (25^th to 75^th percentiles) or percentages. To study the effect of different CRRT intensities on clearance of urea and creatinine, all patients/daily observations were arbitrarily allocated to one of four groups based on the average intensity (patients) and daily intensity (daily observations): <10, 10 to 15, 15 to 20, and >20 mL/kg/h. The Chi-square test was used for nominal variables and the Kruskal-Wallis test was used for numerical variables to compare differences among the four intensity groups. All tests were two-tailed, and P-values <0.05 were considered statistically significant. All statistical analyses were performed using a commercially available statistical package, JMP 10.0 (SAS Inc., Cary, NC, USA).

In this study, we have evaluated the impact of different delivered intensities of CRRT on the control of serum creatinine and urea in critically ill patients with severe AKI. We analyzed CRRT intensity by two different definitions: daily intensity and average intensity. Both analyses found that the lower limit of intensity necessary to control uremia during CRRT was approximately between 10 and 15 mL/kg/h in our cohort.

Many studies have been conducted in an attempt to improve the outcome of AKI patients in the ICU [7],[9],[10],[23]-[31]. Increasing the CRRT intensity is one of the methods used, and several studies have noted the effects of high intensity CRRT [7],[9],[10],[14],[15],[29]. However, two large randomized controlled trials demonstrated that there was no survival advantage to the use of high-intensity therapy (>35 mL/kg/h) compared with lower intensity (20 to 25 mL/kg/h) [7],[9]. Two recent meta-analyses have also shown similar results [28],[29]. According to these results, the recent KDIGO Clinical Practice Guideline recommended delivering an effluent volume of 20 to 25 mL/kg/h. They also recommended prescribing in the range of 25 to 30 mL/kg/h in order to achieve a delivered dose of 20 to 25 mL/kg/h. [11]. However, although current evidence seems adequate for recommending the upper limit of CRRT intensity, only limited information is available to support the lower intensity limit. Indeed, there has been no randomized controlled study comparing CRRT intensity lower than 20 to 25 mL/kg/h and only a few observational studies have looked at this issue [12],[13],[28]. For example, in our previous study [13], we compared high- and low-intensity therapy using our database (JSEPTIC) and the Beginning and Ending Supportive Therapy for the Kidney (BEST kidney) database [2]. Although CRRT intensity was lower in our database (14.3 mL/kg/h) compared with that of the BEST kidney database (20.4 mL/kg/h, P <0.001), patients in the JSEPTIC database tended to have lower hospital mortality (58.6% versus 64.2%, P =0.070) compared with the BEST study.

As the one of aims of performing CRRT is to control uremia, low-intensity therapy may be thought inadequate and unacceptable when low molecular-weight solutes increase during CRRT. Urea and creatinine, clinically measured low molecular-weight solutes, are commonly used as surrogate markers for the toxic metabolites of renal failure. However, no previous studies have evaluated the impact of different CRRT intensity on controlling uremia. In Japan, replacement/dialysis fluid use of only 10 to 16 mL/kg/h (15 to 24 L/day) is allowed because of the Japanese medical insurance system. Therefore, using our database collected in 14 Japanese ICUs, we studied for relationship between different CRRT intensity and serum creatinine/urea control. As this is a retrospective study and the CRRT dose could have changed every day according to patient conditions, we evaluated the effect of CRRT intensity by two different definitions: daily intensity and average intensity. Both analyses found that creatinine and urea increased only in the <10 group and decreased with the increasing intensity in the other groups. From our findings, delivered CRRT intensity of around 10 to 15 mL/kg/h seems to be the lower limit to control uremia.

Conducting CRRT is not without complications. Unnecessarily high-intensity CRRT could lead to electrolyte abnormalities such as hypophosphatemia and hypomagnesemia, frequent machine troubles, and inadequate drug administration, especially antibiotics. Therefore, seeking the lower limit of CRRT intensity seems clinically important.

Furthermore, the advantage of lower intensity CRRT is also related to the economic problem of CRRT. It is reported that the cost of CRRT is higher than that of intermittent hemodialysis (IHD) [32], and the cost of higher-intensity CRRT is more than that of lower-intensity CRRT because of the greater volume of replacement/dialysis fluid required [33],[34]. This high cost can have a major impact, particularly on low- or middle-income countries.

There are several strengths in this study. As far as we know, this is the first study to evaluate the effect of different CRRT intensity on solute control. We were able to conduct such an evaluation because it is common to perform low-dose CRRT in Japan and we rarely see difficulty in small solute control in our patients with severe AKI requiring CRRT. Another strength of this study is that we collected information for each filter and evaluated the delivered dose of CRRT, not the prescribed dose. In clinical practice, delivery usually falls substantially short of the prescribed dose. Although it has been reported that on average the delivered dose is approximately 80% of the prescribed dose [10],[21], such a shortfall can be quite varied day to day and among patients. Using the delivered dose in our study should provide more accurate evaluation of the effect on daily solute control.

There are also several limitations to our study. First, this is a retrospective observational study with a relatively small sample size, which inevitably contains various biases, including differences in patient background and decision-making about prescribed CRRT intensity by a treating physician. For example, it is likely that the CRRT dose was often prescribed regardless of patient body weight. Also, in many cases, the CRRT intensity was between 10 and 15 mL/kg/h because of the Japanese medical insurance system. This resulted in a smaller number (approximately one third) of patients in the higher-intensity group (>20 mL/kg/h) compared with that in the lower-intensity groups (10 to 15 mL/kg/h). Second, the CRRT intensity was calculated using body weight measured or estimated at ICU admission based on methods that differed between the participating centers. The accuracy of body weight measurements may also have been affected by patient’s condition before ICU admission, such as differences in fluid balance and protein catabolism. Third, serum creatinine and urea levels depend on the balance between the body’s production, amount of fluid balance/hemodilution and clearance by CRRT and the kidneys. We did not collect information on small solute clearance from residual kidney function and daily body fluid balance, and therefore, we might have overestimated (or underestimated) creatinine/urea changes at some time points or in some patients. Finally, and most importantly, we did not evaluate the relationship between CRRT intensity and mortality/morbidity, such as renal recovery, weaning of vasopressors and mechanical ventilation, ICU and hospital length of stay. With all the limitations and drawbacks of this study, we cannot recommend to the ICU medical community to routinely use 10 to 15 mg/kg/h.