Timing of continuous renal replacement therapy initiation for acute kidney injury

  • Protocol
  • Intervention

Authors

  • Alicia I Fayad,

    Corresponding author
    1. Ricardo Gutierrez Children's Hospital, Pediatric Nephrology, Buenos Aires, Argentina
    • Alicia I Fayad, Pediatric Nephrology, Ricardo Gutierrez Children's Hospital, Institute for Clinical Effectiveness and Health Policy, Los Incas Av 4174, Buenos Aires, 1427, Argentina. aliciafayad@gmail.com. afayad@fibertel.com.ar.

    Search for more papers by this author
  • Daniel G Buamscha,

    1. Juan Garrahan Children's Hospital, Pediatric Critical Care Unit, Buenos Aires, Argentina
    Search for more papers by this author
  • Agustín Ciapponi

    1. Southern American Branch of the Iberoamerican Cochrane Centre, Argentine Cochrane Centre IECS, Institute for Clinical Effectiveness and Health Policy, Buenos Aires, Capital Federal, Argentina
    Search for more papers by this author

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

This review aims to determine the effect of timing in continuous dialysis on mortality and recovery of kidney function in critically ill patients with AKI.

Background

Description of the condition

Acute kidney injury (AKI) is a complex clinical entity characterised by an abrupt decline in kidney function (Mehta 2004; Mehta 2007). AKI incidence among adults admitted to intensive care units ranges from 5% to 20% (Joannidis 2005); incidence escalates to 10% in children (Schneider 2010). Despite its potential to be reversed, AKI is associated with high morbidity and mortality, 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 timing of treatment initiation (Intensity of CRRT for AKI will be investigated in a separate Cochrane review by the same author team; Fayad 2013).

Teschan 1960 reported improved survival rates relating to CRRT timing in patients commencing dialysis with low blood urea nitrogen. Observational studies and randomised controlled trials (RCTs) in CRRT have shown that early initiation of RRT may provide improved outcomes for critically ill patients with severe AKI (Bagshaw 2009; Liu 2006). However, an earlier study did not support these benefits (Bouman 2002). The effects of early versus late initiation of dialysis support for AKI on outcomes therefore remain unclear.

The optimal time (early versus late) for CRRT initiation to improve AKI outcomes remains unclear. The indication to start CRRT for people in intensive care is most often based on clinical and biochemical criteria. In our review, we will assign definitions given in included studies in relation to early and late initiation of CRRT.

How the intervention might work

A hypothesis that timing of RRT commencement may affect survival emerged from animal and human studies over the past decade. Animal studies investigating sepsis (Mink 1995) and pancreatitis (Yekebas 2002) suggested beneficial effects on physiologic and clinical endpoints when haemofiltration was started early, simultaneously, or two hours after injury. Several observational studies investigated the effect of timing in patients with AKI post trauma indicated improved survival in early haemofiltration (Gettings 1999), the same was found in patients with AKI post cardiac surgery (Demirkilic 2004; Elahi 2004). RCTs found in patients with pancreatitis that the survival was also significantly better in patients who received early haemofiltration (within 48 hours after onset of abdominal pain) than in the group with late haemofiltration (96 hours after onset abdominal pain) (Jiang 2005), while another RCT failed to demonstrate these advantages (Bouman 2002).

Why it is important to do this review

Observational studies that assessed CRRT timing (early versus late) have reported inconsistent results: earlier studies indicated significant improvements in survival and renal recovery; yet others, including a RCT, did not find these benefits. Given these inconsistent results, and the possibility of improving outcomes for ICU patients, we plan to investigate the relationship between CRRT timing and outcomes 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.

Objectives

This review aims to determine the effect of timing in continuous dialysis on mortality and recovery of kidney function in critically ill patients with AKI.

Methods

Criteria for considering studies for this review

Types of studies

All 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

Inclusion criteria

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. 

Exclusion criteria
  • 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 early versus late timing of initiation of CRRT as CVVH, CVVHD and CVVHDF modalities. We will assign definitions cited by included studies in relation to early and late CRRT initiation.

Types of outcome measures

Primary outcomes
Mortality
  • 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.

Secondary outcomes
Adverse events
  • Any adverse event

  • Drop-outs due to adverse events (technique or patient-dependent factors)

  • Inadequate electrolyte control, such as hyponatraemia/hypernatraemia and hypokalaemia/hyperkalaemia

  • Metabolic disturbances, such as acidosis or alkalosis

  • Inadequate fluid balance control: positive and negative balance

  • Inadequate serum phosphate and calcium control, such as hypocalcaemia/hypercalcaemia and hypophosphataemia/hyperphosphataemia

  • Hypotension

  • Bleeding

  • Malnutrition (serum albumin levels at admission and discharge)

  • Catheter-related complications (early and late). 

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.

Length of stay
  • Days in hospital

  • Days in intensive care.

Cost

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

  • number of days on CRRT.

All costs will be reported in international monetary units.

  • Cost/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

Electronic searches

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:

  1. Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal-related journals and the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal journals

  6. 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

  1. LILACS (Latin American and Caribbean Health Sciences)

  2. Reference lists of review articles and relevant studies.

  3. 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 or non-Spanish 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

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • 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 synthesis

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 CRRT 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.

Sensitivity analysis

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.

Acknowledgements

We are very grateful to the referees and the Cochrane Renal Group for their input and assistance with this protocol.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. MeSH descriptor Acute Kidney Injury explode all trees

  2. "acute kidney failure" :ti,ab,kw or "acute renal failure":ti,ab,kw in Clinical Trials

  3. "acute kidney injury" :ti,ab,kw or "acute renal injury":ti,ab,kw in Clinical Trials

  4. "acute kidney insufficiency":ti,ab,kw or "acute renal insufficiency":ti,ab,kw in Clinical Trials

  5. "acute tubular necrosis":ti in Clinical Trials

  6. (ARI or AKI or ARF or AKF or ATN):ti,ab,kw in Clinical Trials

  7. (#1 OR #2 OR #3 OR #4 OR #5 OR #6)

  8. MeSH descriptor Renal Replacement Therapy, this term only

  9. MeSH descriptor Renal Dialysis explode all trees

  10. continuous NEAR/2 hemofiltration:ti,ab,kw in Clinical Trials

  11. continuous NEAR/2 hemodiafiltration:ti,ab,kw in Clinical Trials

  12. continuous NEAR/2 haemodialysis:ti,ab,kw in Clinical Trials

  13. continuous NEAR/2 hemodialysis:ti,ab,kw in Clinical Trials

  14. (continuous NEXT ultrafiltration):ti,ab,kw in Clinical Trials

  15. (continuous NEAR/2 hemofiltration):ti,ab,kw in Clinical Trials

  16. (CVVH or CVVHDF or CVVHD or SCUF or CRRT):ti,ab,kw in Clinical Trials

  17. (renal replacement therap*):ti,ab,kw in Clinical Trials

  18. (#8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17)

  19. (#7 AND #18)

MEDLINE
  1. exp Acute Kidney Injury/

  2. (acute kidney failure or acute renal failure).tw.

  3. (acute kidney injur$ or acute renal injur$).tw.

  4. (acute kidney insufficie$ or acute renal insufficie$).tw.

  5. acute tubular necrosis.tw.

  6. (ARI or AKI or ARF or AKF or ATN).tw.

  7. or/1-6

  8. Renal Replacement Therapy/

  9. exp Renal Dialysis/

  10. (continuous adj3 hemofiltration).tw.

  11. (continuous adj3 hemodiafiltration).tw.

  12. (continuous adj3 h?emodialysis).tw.

  13. continuous ultrafiltration.tw.

  14. (CVVH or CVVHDF or CVVHD or SCUF or CRRT).tw.

  15. renal replacement therap$.tw.

  16. or/8-15

  17. and/7,16

EMBASE
  1. acute kidney failure/

  2. (acute kidney failure or acute renal failure).tw.

  3. (acute kidney injur$ or acute renal injur$).tw.

  4. (acute kidney insufficie$ or acute renal insufficie$).tw.

  5. acute tubular necrosis.tw.

  6. (ARI or AKI or ARF or AKF or ATN).tw.

  7. or/1-6

  8. continuous renal replacement therapy/ or exp renal replacement therapy/

  9. (continuous adj3 hemofiltration).tw.

  10. (continuous adj3 hemodiafiltration).tw.

  11. (continuous adj3 h?emodialysis).tw.

  12. continuous ultrafiltration.tw.

  13. (CVVH or CVVHDF or CVVHD or SCUF or CRRT).tw.

  14. renal replacement therap$.tw.

  15. or/8-14

LILACS
  1. insuficiência renal aguda/

  2. (injuria renal aguda or insuficiencia renal aguda) tw.

  3. necrosis tubular aguda.tw.

  4. or/1-3

  5. terapias de reemplazo renal continuo/

  6. (hemofiltración veno-venosa contínua or Hemofiltracao venovenosa continua).tw.

  7. (hemodiafiltración veno-venosa contínua or Hemodiafiltracao venovenosa continua).tw.

  8. (hemodialisis veno-venosa contínua or Hemodiálise venovenosa continua).tw.

  9. or/5-8

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be implemented without a random element, and this is considered to be equivalent to being random)
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention
Unclear: Insufficient information about the sequence generation process to permit judgement

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes)
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure
Unclear: Randomisation stated but no information on method used is available

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon)
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias

Contributions of authors

  1. Draft the protocol: AF, DB, AC

  2. Study selection: AF, DB

  3. Extract data from studies: AF, DB

  4. Enter data into RevMan: AF

  5. Carry out the analysis: AF, AC

  6. Interpret the analysis: AF, DB, AC

  7. Draft the final review: AF, DB, AC

  8. Disagreement resolution: AC

  9. Update the review: AF

Declarations of interest

None to declare.

Ancillary