Summary of main results

Our systematic review and subsequent meta‐analysis examines the effect of different intensities of CRRT on mortality, kidney recovery function and adverse events among 3185 critically ill patients with AKI. Most of the included studies were assessed at low or unclear risk of bias for all domains. Within the intensity ranges assessed, more intensive CRRT did not demonstrate beneficial effects on mortality at different time points post randomisation (day 30 or after 30 days) and kidney recovery function (in all patients and among survivals at 30 and 90 days before randomisation) compared with less intensive therapy. The overall estimated effects on these outcomes are not statistically significant; the confidence intervals are sufficiently wide to include clinically benefits and harm (imprecision), with high level of heterogeneity (inconsistency). Treatment with more intensive CRRT increased the risk of hypophosphataemia, although it did not increase other adverse events when compared to less intensive CRRT. All results (except hypophosphataemia) were imprecise because the confidence intervals were wide which crossed the threshold for clinically meaningful effects.

An important limitation of this systematic review was the substantial heterogeneity found in the main results as mortality at day 30 or after 30 days (I² = 75% and I² = 65% respectively) and recovery of kidney function in all patients and among survivals at 30 (I² = 71% and I² = 69% respectively). However, there was no heterogeneity identified for recovery of kidney function at 90 days (I² = 0%). We explored this heterogeneity by two prespecified clinical subgroup analyses; severity of acute illness (patients with and without sepsis and high and low SOFA cardiovascular scores) and by aetiology of AKI. We found that in patients with surgery‐acquired AKI, intensive CRRT reduced mortality risk at day 30 compared to those patients with non‐surgically‐acquired AKI. Therefore, AKI aetiology was identified as a source of heterogeneity in the size of effect among included studies.

More intensive CRRT had uncertain effects on length of stay, number of days in ICU and number of days in hospital. These results should be interpreted with caution owing to the fact that only two small studies reported these data. Some studies have reported days in hospital and days in ICU but, in patients with a high short‐term mortality risk, the interpretation of such results may be misleading given the mortality is a competing end point for length of stay.

Overall completeness and applicability of evidence

See Description of studies; Characteristics of included studies

Six randomised studies (ATN Study 2005; Bouman 2002;RENAL Study 2006; Ronco 2000a; Saudan 2006; Tolwani 2008) evaluated the effect of different intensities of CRRT on survival and recovery of kidney function in critically ill patients with AKI. Two studies (Ronco 2000a; Saudan 2006) favoured more intensive therapy. In contrast, four other studies (ATN Study 2005; Bouman 2002;RENAL Study 2006; Tolwani 2008) have not demonstrated beneficial effects with an increased intensity of therapy on clinical outcomes. These results are consistent with those reported in our review.

Disparity and the heterogeneity found in these results among the studies probably may explained by several factors such as differences in methodological quality of studies, patients characteristics, delivered dialysis dose, and timing of CRRT initiation.

In a study of 425 patients, Ronco 2000a reported a decrease in mortality at day 15 from 59% to 43% with an increased in the intensity from 20 mL/kg/h to 35 or 45 mL/kg/h. We observed some limitations in this study: an absence of detailed description of randomisation and allocation concealment process (limiting the internal validity); a low incidence of patients with AKI‐related to sepsis (15%); and a non‐validated short‐term outcome (limiting the external validity). In Saudan 2006 (206 patients with AKI) there was a 26% reduction in all‐cause of mortality at day 90 (from 62% to 36%) with an increase in the intensity of CRRT from 25 mL/kg/h to 45 mL/kg/h. This study has an important imbalance in the severity of illness observed between CVVH treatment arms (limiting the internal validity). Additionally, both studies were unblinded, single‐centre studies (limiting the internal and external validity respectively). In contrast, three studies evaluating intensity in continuous therapy, and one study in combined modalities (Intermittent and continuous), did not demonstrate any effect of increased intensity of therapy on survival. Bouman 2002 conducted a small study evaluating both intensity and timing of initiation of CVVH in 106 critical patients with AKI. There were no differences on the survival for either intensities or initiation time. It is interesting to note that the actual delivered therapy in the high‐intensity arm was much less than the prescribed intensity. Furthermore, survival was greater than expected (survival at 28 days 69% to 75% in all groups) probably related to a low incidence of patients with AKI‐related to sepsis (limiting the external validity). The study was underpowered due to the small sample size. Similarly, Tolwani 2008 evaluated 200 patients with AKI. They found no difference on survival with intensive continuous therapy. This was an unblinded, single‐centre study (limiting the internal and external validity respectively). Finally, two large multicentre studies were conducted. In ATN Study 2005, 1124 critically ill patients with AKI were randomised to high‐intensity or low‐intensity. Within treatment groups, patients were allocated to CVVHDF or SLED and IHD according to cardiovascular SOFA score. In RENAL Study 2006, 1508 patients were randomly assigned to two intensities of CVVHDF (intensive or less intensive). All patients received CRRT as their first mode of RRT; only a small proportion of patients received IHD (7%). Both studies reported no beneficial effect on mortality and recovery of kidney function associated with a more intensive RRT.

There were also differences in the prescribed and delivered doses of CRRT. In ATN Study 2005, the dose delivered was 89% of that prescribed for higher‐intensity treatment, Tolwani 2008 reported a value of 83%, and in RENAL Study 2006 the delivered dose was 84%. For the lower‐intensity treatment, the doses delivered were 95% in ATN Study 2005, 85% in Tolwani 2008, and 88% in RENAL Study 2006. In all other studies (Bouman 2002; Ronco 2000a; Saudan 2006) delivered doses were less than 85% of the prescribed doses. The difference between the prescribed and the delivered dose highlights the risk of overestimating the effective delivery of therapy and the need to improve operational measures in CRRT.

Although the analysis included data obtained from a comprehensive and rigorous search, we identified gaps in several areas. The majority of participants of the included studies were adults, limiting the applicability of our finding to children. In general, the incidence of AKI secondary to sepsis is very high in ICU (50% to 60%); however, in two studies it was observed that the majority of patients had post‐surgical AKI, and relatively few had sepsis or pre‐existing chronic kidney disease, limiting the applicability of our results to general ICU population. Three included studies were single‐centre studies, limiting the external validity of the results.

While the urea kinetics remains widely used to measure intensity of RRT in AKI‐patients, this approach provides an incomplete assessment of dose of RRT, especially in the critically ill patients with AKI.

An important challenge when examining the evidence of dialysis intensity in patients with AKI is to determine the exact number of patients who received IHD or CRRT in those studies using a combination of both strategies (ATN Study 2005), as well as distinguishing which patients remained dialysis‐depend after ICU discharge or received transitory IHD without regard to the original assigned treatment. In view of this, we contacted the authors for more information. The long‐term kidney outcomes after hospital discharge among survivors of AKI remain poorly characterised. The studies did not report data on mortality and kidney function recovery in patients with pre‐existing chronic kidney disease and with low or intermediate scores of severity of illness. The results on length of stay (days in hospital and in the ICU) and recovery of kidney function should be interpreted with caution, especially when the mortality risk is taken into account.

We are aware that an important aspect to consider in term of efficacy is the timing in which CRRT are indicated. Currently, we are trying to answer this question with a systematic review specified (Fayad 2013a).

We included only RCTs with the purpose of reducing bias.

Quality of the evidence

We conducted this review according to the process described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Our review was based on evidence from six RCTs (3185 participants) that compared different intensities of CRRT in critically ill patients with AKI. The quality of evidence for our main outcomes was drawn from studies assessed at low risk of bias for random sequence generation and allocation concealment processes, incomplete outcome data, intention to treat analysis, selective outcomes reporting, performance bias and other sources of bias; and unclear risk for detection bias.

Data comparing the effect of higher intensity versus lower intensity CRRT on mortality at day 30 or after were obtained from six well‐conducted RCTs respectively, but we downgraded the quality of evidence to low, mainly due to inconsistencies (I² values of 65% and 75%) and imprecision (CIs included a range of plausible values with clinically important benefits but also included harms). Similarly, we downgraded the quality of evidence to low for recovery of kidney function in all patients and among survivors at day 30 due to inconsistencies (I² values of 71% and 69%) and rated as moderate data obtained for recovery of kidney function among survivors at day 90 by indirectness (the recovery of kidney function in this high risk group is affected when the risk of death is taken into account).

Data used to assess the impact of intensive versus less intensive CRRT on adverse events were obtained from three well‐conducted RCTs, providing treatment effects with clinically important harms; however, we downgraded the quality of evidence to moderate due to imprecision (CIs included both clinically important benefits and harm). One study provided data on hypophosphataemia. We rated this as high quality evidence.

Potential biases in the review process

While this review was conducted according to rigorous methods developed by the Cochrane Collaboration, some bias may be present in the review process. We searched for all relevant studies using sensitive and validated strategies in major medical databases and grey literature sources. However, it is possible that some studies (such as unpublished data and studies with negative or no effects) were not identified. An analysis for evidence to assess the risk of publication bias was not possible for all outcomes due to the small number of studies available in each meta‐analysis (Figure 4).

It was difficult to identify the number of patients who received IHD in the included study using a combination of both therapies (intermittent and continuous), as well also in studies evaluating CRRT intensity, in which patients remained dialysis‐dependent after ICU or hospital discharge, many were likely to have transitioned to IHD regardless of the original study‐assigned dose of CRRT.

Several subgroup analyses were planned to explore potential sources of heterogeneity in our review, however a lack of data prevented us from doing these analyses.

Agreements and disagreements with other studies or reviews

Our systematic review in keeping with previous meta‐analysis on intensity in CRRT (Negash 2011) or in mixed modality, combining intermittent, sustained and continuous dialysis (Jun 2010; Van Wert 2010), has not found beneficial effects of more intensive RRT with respect to mortality and kidney recovery function in critically ill patients with AKI compared to less intensive therapy.

There has been increased interest in recovery of kidney function. Indeed, lack of recovery of kidney function implies the need for long‐term dialysis associated with low quality of life. Our review has not demonstrated benefits on recovery of kidney function with intensive therapy. These findings are consistent with four individual RCTs (ATN Study 2005; Bouman 2002; RENAL Study 2006; Tolwani 2008) and do not agree with those reported of two previous RCTs (Ronco 2000a; Saudan 2006). It is important to note that relevant differences on recovery of kidney function between ATN Study 2005 and RENAL Study 2006 were observed (45.2% versus 13.3% of survivors depend on RRT at day 28 respectively). These differences may be due to several factors including different populations, prevalence of intermittent dialysis, pre‐existing chronic kidney disease and timing of RRT initiation. A review by Palevsky 2005 on factors affecting kidney recovery following AKI did not recommend either intensities with regard to recovery of kidney function when the mortality risk is taken into account (given that mortality is a competing end point for recovery of kidney function).

The hypothesis that in critically ill patients, especially those with sepsis or systemic inflammatory responses, could benefit from an intensive CRRT was proposed by several researchers. It is interesting to note that we did not find benefit from higher intensity CRRT in this subgroup of patients in our review. These results were consistent with previous meta‐analysis (Jun 2010; Van Wert 2010). Additionally, previous reviews explored the effect of high volume haemofiltration (HVHF) specifically in critically ill patients with severe sepsis or septic shock in an ICU setting (Borthwick 2013; Clark 2014; Lehner 2014). These reviews applied different thresholds for HVHF: Borthwick 2013 defined HVHF as > 35 mL/kg/h, while more recent reviews define HVHF as >50 mL/kg/h (Clark 2014) and HVHF and pulse high volume haemofiltration (PHVHF) as 85 mL/Kg/h (Lehner 2014). These reviews included studies we excluded from our review due to the very‐high intensity applied (Boussekey 2008; IVOIRE Study 2013; Sanchez 2010b; Zhang 2012) or no requirement of AKI for enrolment (Jiang 2005) These reviews found insufficient evidence of a therapeutic benefit for routine use of HVHF for septic AKI.