Description of the condition
Acute kidney injury (AKI) is a complex clinical entity characterised by an abrupt decline in kidney function (Mehta 2007). AKI incidence among adults admitted to intensive care units ranges from 5% to 20% (Hoste 2006; Joannidis 2005); incidence escalates to 10% in children (Schneider 2010). Despite its potential to be reversed, AKI is associated with high morbidity and mortality (Bagshaw 2007), and AKI-related mortality substantially increases among people with multi-organ failure, sepsis, or who are receiving renal replacement therapy (RRT) (Metnitz 2002; Sutherland 2010). More than 70% of people with AKI need renal support therapies. Despite advances in clinical care, people with AKI have high risks of mortality and morbidity, and require significant health care resources (Sutherland 2010; Uchino 2005).
Description of the intervention
Continuous RRT (CRRT) is an extracorporeal blood purification therapy, intended to support impaired kidney function. CRRT removes fluid slowly over prolonged periods (Foland 2004; Gibney 2008; Goldstein 2001; Mehta 1999); removes higher molecular weight solutes efficiently (Brunnet 1999; Clark 1999; Liao 2003; Ronco 2002; Sieberth 1995); and confers beneficial haemodynamic stability effects. CRRT modalities are defined by their main solute clearance mechanism. These are convection (continuous venovenous haemofiltration, CVVH), diffusion (continuous venovenous haemodialysis, CVVHD), or a combination of both convection and diffusion (continuous venovenous haemodiafiltration, CVVHDF) (Palevsky 2002). Several interventions have been used over the past three decades with the aim of improving the poor prognosis of people with AKI. A significant factor that may impact on CRRT outcomes is intensity of treatment (timing of CRRT for AKI will be investigated in a separate Cochrane review by the same author team; Fayad 2013).
Intensity in CRRT is generally related to the quantity of solute removal required to improve outcomes in people with AKI. CRRT intensity can be analysed based either on solute removal from the blood, or appearance of solutes in effluent fluid. Some published studies have used effluent flow rates, expressed as total effluent volume/weight and unit of time (mL/k/h) as a surrogate of dose (RENAL 2009; Ronco 2000), while accounting for effects of pre-dilution and modality differences (Claure-Del Granado 2011). Elsewhere, authors have considered that dialysis doses delivered as total effluent volume/clearance of solutes such as urea, creatinine is a better method to measure dose (Lyndon 2012). Equivalent renal urea clearance also provides a good estimate of delivered dialysis dose in CRRT (Claure-Del Granado 2012) which can be converted to effluent rate and expressed as mL/h/kg (Marshall 2006).
Few studies have assessed other dimensions of intensity such as electrolyte and acid-base homeostasis (Bellomo 2013; Bihorac 2005; Morimatsu 2003; Uchino 2001) and fluid balance/fluid overload (Bouchard 2009; Davenport 2010; Sutherland 2010) using effluent volume as the dose measure.
How the intervention might work
A hypothesis that high dialysis doses in RRT may improve survival has emerged from animal and human studies. These findings include indirect evidence from patients with ESKD (Lowrie 1981; Parker 1994).
Dose intensity based on a urea kinetics model was evaluated in animal studies by Grootendorst 1992, and in severe ill patients (sepsis, sepsis-shock) who received high dose (60 to 80 mL/k/h) reported improvement in haemodynamic state with possible benefits in clinical outcomes (Honore 2000). A retrospective study found that dose correlated with survival in patients with intermediate scores of illness (Paganini 1996). Although prospective dose studies demonstrated association of improved survival or renal recovery with high dose dialysis (Phu 2002; Ronco 2000; Saudan 2006), these advantages were not universally observed (RENAL 2009; VA/NIH 2008; Van Wert 2010; Vesconi 2009).
Few studies have researched other components of intensity that play important roles in clinical results. These include fluid balance and fluid overload associated with increased mortality risk (Bouchard 2009; Goldstein 2001); adequate homeostasis of electrolytes (sodium, potassium and hydrogen ions) related to cardiovascular stability; and the maintenance of renal blood flow (Uchino 2001).
Why it is important to do this review
Studies assessing CRRT intensity (high versus standard dose) either have not reported investigation of all variables inherent in therapy for people with AKI or report inconsistent results. We plan to investigate the relationship between CRRT dose intensity for people with AKI. Review evidence will have direct relevance to decisions about optimal CRRT timing to improve survival in critically ill patients with AKI.
This review aims to determine the effect of intensity of dialysis dose in continuous dialysis on mortality and recovery of kidney function in critically ill patients with AKI.
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at CRRT modalities for people with AKI in intensive care settings. For outcomes such us safety and costs, non-RCTs and cohort studies will be also included if sufficiently high quality, sampling is clearly described, patients characterised, proportions of patients who dropped out because of adverse events is adequately reported, the proportion of patients experiencing any adverse events, co-interventions described, and at least 80% of patients included were analysed after treatment.
Types of participants
We will include all patients with AKI in intensive care units being treated with CRRT regardless of age and gender. We will assign AKI definitions cited by included studies.
- Patients who received dialysis treatment before admission to intensive care units
- Patients admitted for a drug overdose (doses that exceed therapeutic requirements)
- Patients with acute poisoning (all toxins).
Types of interventions
We will compare high dialysis dose (≥ 35 mL/kg/h) versus standard dialysis dose (≥ 20 mL/kg/h) of CRRT as CVVH, CVVHD and CVVHDF modalities.
Types of outcome measures
- Death from any cause at days 7, 15, 30, 60 and 90
- Death or non-recovery at 90 days.
Recovery of kidney function
- Numbers of patients free of RRT after discontinuing CRRT
- Numbers of patients free of RRT after discontinuing CRRT at days 30, 60 and 90.
- Numbers of patients who normalised serum electrolytes (potassium, sodium) concentration during CRRT
- Numbers of patients who normalised serum bicarbonate and base-excess concentration during CRRT
- Numbers of patients who normalised serum urea and creatinine concentration during CRRT.
- Numbers of patients who achieved adequate fluid balance during CRRT.
- Numbers of patients who dropped out because of adverse events (technique or patients dependent factors)
- Numbers of patients experiencing any adverse events
- Numbers of patients with intervention-related complications (e.g. disequilibrium, hypokalaemia, hypophosphataemia, hypocalcaemia, bleeding, hypotension)
- Numbers of patients with catheter-related complications (early and late).
We will look for differences in overall dropout rates and any adverse effects by type (mild or severe). We will define the severity of any adverse event when it implies any medical therapeutic intervention. Withdrawal due to protocol violation or loss to follow-up are not counted as adverse events.
Length of stay
- Days in hospital
- Days in intensive care.
We will look for differences in overall drop-out rates and any adverse effects by type (mild or severe). We will define adverse event severity where medical therapeutic interventions are implied in reporting. Withdrawal due to protocol violation or loss to follow-up will not be included in counts of adverse events, but will be reported elsewhere as required.
We will assess costs of CRRT modalities including:
- type and number of dialyser filters
- use/no use of anticoagulation
- types of anticoagulation and anticoagulants
- use of replacement fluid
- numbers of days on CRRT.
All costs will be reported in international monetary units.
- Cost per day of CRRT (expressed in international monetary units)
- Length of hospital stay with CRRT
- Length of ICU stay with CRRT
Search methods for identification of studies
We will search the Cochrane Renal Group's Specialised Register through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
The Cochrane Renal Group’s Specialised Register contains studies identified from:
- Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
- Weekly searches of MEDLINE OVID SP
- Handsearching of renal-related journals and the proceedings of major renal conferences
- Searching of the current year of EMBASE OVID SP
- Weekly current awareness alerts for selected renal journals
- Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the specialised register section of information about the Cochrane Renal Group.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
- LILACS (Latin American and Caribbean Health Sciences)
- Reference lists of review articles and relevant studies.
- Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous studies.
Data collection and analysis
Selection of studies
The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.
Data extraction and management
Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted.
Assessment of risk of bias in included studies
- Was there adequate sequence generation (selection bias)?
- Was allocation adequately concealed (selection bias)?
- Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
- Participants and personnel
- Outcome assessors
- Were incomplete outcome data adequately addressed (attrition bias)?
- Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
- Was the study apparently free of other problems that could put it at a risk of bias?
Measures of treatment effect
For normally distributed outcomes, we will calculate summary estimates of treatment effects using the inverse variance method. For dichotomous outcomes (mortality, renal recovery and adverse events) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (length of stay, cost) the mean difference (MD) will be used or the standardised mean difference (SMD) if different scales have been used.
Dealing with missing data
Any further information required from the original author will be requested by written correspondence (e.g. emailing and/or writing to corresponding author/s) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population will be carefully performed. Attrition rates, for example drop-outs, losses to follow-up and withdrawals will be investigated. Issues of missing data and imputation methods (for example, last-observation-carried-forward) will be critically appraised (Higgins 2011).
Assessment of heterogeneity
Heterogeneity will be analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.
Assessment of reporting biases
If possible, funnel plots will be used to assess the potential existence of small study bias (Higgins 2011).
Data will be pooled using the random-effects model but the fixed-effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. age, gender, fluid overload (< 10% and > 10% in body weight relative to baseline), RRT dose for AKI in homogenous subpopulation such as cardiac surgery or sepsis patients, effects of dialysis dose on severity of illness - high, intermediate and low. We will use appropriate scores of illness severity, such as Pediatric Risk of Mortality (PRISM), Pediatric Index of Mortality (PIM), Acute Physiology and Chronic Health Evaluation (Apache), Sequential Organ Failure Assessment (SOFA), and Cleveland Clinic ICU Acute Renal Failure (CCF)).
Heterogeneity among participants could be related to age and renal pathology. Heterogeneity in treatments could be related to CTRRT modality, dose and duration of therapy. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.
We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:
- repeating the analysis excluding unpublished studies
- repeating the analysis taking account of risk of bias
- repeating the analysis excluding any very long or large studies to establish how much they dominate the results
- repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.
We are very grateful to the the referees and the Cochrane Renal Group for their input and assistance with this protocol.
Appendix 1. Electronic search strategies
Appendix 2. Risk of bias assessment tool
Contributions of authors
- Draft the protocol: AF, DB, AC
- Study selection: AF, DB
- Extract data from studies: AF, DB
- Enter data into RevMan: AF
- Carry out the analysis: AF, AC
- Interpret the analysis: AF, DB, AC
- Draft the final review: AF, DB, AC
- Disagreement resolution: AC
- Update the review: AF
Declarations of interest
None to declare.
Sources of support
- No sources of support supplied, Not specified.
- No sources of support supplied