Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy

Hiraku Tsujimoto; Yasushi Tsujimoto; Yukihiko Nakata; Tomoko Fujii; Sei Takahashi; Mai Akazawa; Yuki Kataoka

doi:10.1002/14651858.CD012467.pub2

. 2020 Mar 12;2020(3):CD012467. doi: 10.1002/14651858.CD012467.pub2

Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy

Hiraku Tsujimoto ^1,^✉, Yasushi Tsujimoto ², Yukihiko Nakata ³, Tomoko Fujii ⁴, Sei Takahashi ^2,⁵, Mai Akazawa ⁶, Yuki Kataoka ⁷

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC7067597 PMID: 32164041

Abstract

Background

Acute kidney injury (AKI) is a major comorbidity in hospitalised patients. Patients with severe AKI require continuous renal replacement therapy (CRRT) when they are haemodynamically unstable. CRRT is prescribed assuming it is delivered over 24 hours. However, it is interrupted when the extracorporeal circuits clot and the replacement is required. The interruption may impair the solute clearance as it causes under dosing of CRRT. To prevent the circuit clotting, anticoagulation drugs are frequently used.

Objectives

To assess the benefits and harms of pharmacological interventions for preventing clotting in the extracorporeal circuits during CRRT.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies up to 12 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

We selected randomised controlled trials (RCTs or cluster RCTs) and quasi‐RCTs of pharmacological interventions to prevent clotting of extracorporeal circuits during CRRT.

Data collection and analysis

Data were abstracted and assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) with 95% confidence intervals (CI). The primary review outcomes were major bleeding, successful prevention of clotting (no need of circuit change in the first 24 hours for any reason), and death. Evidence certainty was determined using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach.

Main results

A total of 34 completed studies (1960 participants) were included in this review. We identified seven ongoing studies which we plan to assess in a future update of this review. No included studies were free from risk of bias. We rated 30 studies for performance bias and detection bias as high risk of bias. We rated 18 studies for random sequence generation, six studies for the allocation concealment, three studies for performance bias, three studies for detection bias, nine studies for attrition bias, 14 studies for selective reporting and nine studies for the other potential source of bias, as having low risk of bias.

We identified eight studies (581 participants) that compared citrate with unfractionated heparin (UFH). Compared to UFH, citrate probably reduces major bleeding (RR 0.22, 95% CI 0.08 to 0.62; moderate certainty evidence). Citrate may have little or no effect on death at 28 days (RR 1.06, 95% CI 0.86 to 1.30, moderate certainty evidence), while citrate versus UFH may have little or no effect on successful prevention of clotting (RR 1.01, 95% CI 0.77 to 1.32; moderate certainty evidence). Citrate versus UFH may reduce the number of participants who drop out of treatment due to adverse events (RR 0.47, 95% CI 0.15 to 1.49; low certainty evidence). Compared to UFH, citrate may make little or no difference to the recovery of kidney function (RR 0.95, 95% CI 0.66 to 1.36; low certainty evidence). Compared to UFH, citrate may reduce thrombocytopenia (RR 0.39, 95% CI 0.14 to 1.03; low certainty evidence). It was uncertain whether citrate reduces a cost to health care services because of inadequate data.

For low molecular weight heparin (LMWH) versus UFH, six studies (250 participants) were identified. Compared to LMWH, UFH may reduce major bleeding (0.58, 95% CI 0.13 to 2.58; low certainty evidence). It is uncertain whether UFH versus LMWH reduces death at 28 days or leads to successful prevention of clotting. Compared to LMWH, UFH may reduce the number of patient dropouts from adverse events (RR 0.29, 95% CI 0.02 to 3.53; low certainty evidence). It was uncertain whether UFH versus LMWH leads to the recovery of kidney function because no included studies reported this outcome. It was uncertain whether UFH versus LMWH leads to thrombocytopenia. It was uncertain whether UFH reduces a cost to health care services because of inadequate data.

For the comparison of UFH to no anticoagulation, one study (10 participants) was identified. It is uncertain whether UFH compare to no anticoagulation leads to more major bleeding. It is uncertain whether UFH improves successful prevention of clotting in the first 24 hours, death at 28 days, the number of patient dropouts due to adverse events, recovery of kidney function, thrombocytopenia, or cost to health care services because no study reported these outcomes.

For the comparison of citrate to no anticoagulation, no completed study was identified.

Authors' conclusions

Currently, available evidence does not support the overall superiority of any anticoagulant to another. Compared to UFH, citrate probably reduces major bleeding and probably has little or no effect on preventing clotting or death at 28 days. For other pharmacological anticoagulation methods, there is no available data showing overall superiority to citrate or no pharmacological anticoagulation. Further studies are needed to identify patient populations in which CRRT should commence with no pharmacological anticoagulation or with citrate.

Plain language summary

Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy

What is the issue?   Acute kidney injury (AKI) is a major comorbidity in hospitalised patients. Patients with severe AKI require renal replacement therapy. Continuous renal replacement therapy (CRRT) is a type of blood dialysis therapy that is generally used for critically ill patients in the intensive care unit. Due to the slow clearance of waste products, CRRT typically runs continuously for 24 hours. Clotting in the dialysis circuits requires immediate circuit changes and leads to treatment interruption and inadequate treatment. The aim of this review was to evaluate the effectiveness and safety of different medications to prevent clotting of circuits in CRRT.

What did we do?  We searched the Cochrane Kidney and Transplant Specialised Register up to 12 September 2019. We summarized the results of 34 randomised controlled trials with 1960 participants in this review.

What did we find?

Citrate probably reduces major bleeding (e.g. the need for blood transfusion or surgery) compared to heparin without changing filter patency or death. For the other pharmacological comparisons, only inadequate data or low‐quality data were available.

Conclusions

The most effective anti‐clotting options for CRRT remain uncertain; however, citrate or no anticoagulation seems to be reasonable options to prevent the clotting of circuits in CRRT.

Summary of findings

Background

Description of the condition

Acute kidney injury (AKI) occurs in 11% to 18% of admitted patients (Fujii 2014; Zeng 2014) and contributes to about 1.7 million deaths every year (Mehta 2015). A large prospective multinational survey showed that around 40% to 50% of intensive care unit (ICU) patients had AKI and that death increased with AKI severity, as defined by the Kidney Disease Improving Global Outcomes (KDIGO) classification (Hoste 2015; Nisula 2013).

According to the US nationwide survey on World Kidney Day, AKI is the most common reason for nephrology consultation among hospitalised patients (Koyner 2014). The survey estimated that nephrologists in the USA handle about 4.5 million AKI consults each year (Koyner 2014). Notably, 958,000 of those consults required intermittent haemodialysis and 304,000 required some form of renal replacement therapy (RRT) (continuous RRT (CRRT) or slow low‐efficiency dialysis) annually (Koyner 2014). Furthermore, the Centers for Disease Control and Prevention in the USA reported that the number of patients with a diagnosis of AKI who faced an extension of hospital stay rose from 18/100,000 to 365/100,000 between 1980 and 2005 (CDC 2008; Parikh 2016). In addition, 5% to 6% of patients in the ICU required RRT or AKI (Parikh 2016). In Japan, a nationwide survey in 2011 revealed that 6478 (3.9%) out of 165,815 ICU patients who were hospitalised for at least three days received CRRT (Iwagami 2015). Of these patients, the average duration of CRRT was 4 and 6 days for 3201 survivors and 3277 non‐survivors, respectively (Iwagami 2015).

CRRT is a type of extracorporeal RRT provided continuously. In general, the indication of CRRT is a kidney failure with haemodynamic instability (Mehta 2015; Ronco 2011). The comparison between intermittent versus CRRT for AKI patients was inconclusively discussed in other reviews (Rabindranath 2007; Wang 2018). Due to the slow clearance of solute or water, CRRT typically runs over 24 hours with the requisite duration of at least 16 hours/day (Uchino 2003). Modalities of CRRT are continuous venovenous haemofiltration (CVVH), continuous venovenous haemodialysis (CVVHD), continuous venovenous haemodiafiltration (CVVHDF) and slow continuous ultrafiltration (SCUF) (Parikh 2014). Each of these modalities has its own unique features. CVVH is dependent on the convective removal of plasma solute across a semipermeable membrane while CVVHD relies on a diffusion‐based process (Parikh 2014). CVVHDF uses a combination of both convective removal and a diffusion‐based process. In contrast, SCUF uses only ultrafiltration employed on a continuous basis (Parikh 2014). Ultrafiltration uses hydrostatic pressure and is dependent on the convective removal of plasma water from blood across the semipermeable membrane (Parikh 2014). All modalities use extracorporeal circuits including the dialyser filter (with a built‐in semipermeable membrane) (Parikh 2014).

Although CRRT is prescribed assuming it is provided over 24 hours, "down‐time" can occur due to the clotting in the extracorporeal circuits (Uchino 2003). To achieve the optimal intensity of 20 to 25 mL/kg/hour in RRT for AKI (KDIGO 2012; RENAL Replacement Therapy Study Investigators 2009; VA/NIH Acute Renal Failure Trial Network 2008), it is crucial to reduce unexpected downtime. An observational study reported downtime of around one to three hours/day (Uchino 2003; Vesconi 2009). Clotting in the extracorporeal circuits requires immediate circuit changes and leads to an increase in the workload of medical staff and the cost of treatment (Gattas 2015a). Frequent circuit changes can cause futile downtime of the treatment.

Description of the intervention

Non‐pharmacological and pharmacological approaches provide two possible ways to prevent clotting in the circuits during CRRT. Non‐pharmacological interventions to prevent clotting include reducing blood viscosity inside the haemofilter (including the pre‐dilution method of fluid replacement and saline flush), reducing blood‐air contact to protect the site from excessive clotting, and the selection and the position of the catheter (Davies 2006; Joannidis 2007a; KDIGO 2012; Kirwan 2018). In this review, we did not address these non‐pharmacological interventions.

The pharmacological approach involves using an array of drugs including intravenous anticoagulants (e.g. unfractionated heparin (UFH), low‐molecular‐weight heparin (LMWH), nafamostat mesilate, argatroban, and citrate), oral anticoagulants (warfarin) and antiplatelet agents, as well as coagulation monitoring (activated coagulation time (ACT) or activated prothrombin time (APTT)). It should be noted here that up to 60% of patients treated with CRRT in large multinational studies did not receive any form of pharmacological anticoagulation (RENAL Replacement Therapy Study Investigators 2009: VA/NIH Acute Renal Failure Trial Network 2008). Clotting in the extracorporeal circuits sometimes results in blood loss in the circuits (Joannidis 2007a). Conversely, a multinational survey reported that bleeding complications occurred in 3.3% of patients (Uchino 2007). Thus, it is critical to address the issue of efficacy and safety of pharmacological interventions for preventing clotting in the circuits in CRRT.

How the intervention might work

The contact of blood with the foreign surface of the circuit may result in the activation of a coagulation pathway (KDIGO 2012). To prevent this, anticoagulation or antiplatelets are usually used. Systematic anticoagulation or antiplatelets can be a double‐edged sword as they raised the risk of bleeding. Therefore, techniques such as regional anticoagulation have been developed that can prevent clotting in the circuits but will not affect the patient's systemic coagulation system. Citrate forms a chelate with calcium and works as an anticoagulant regionally in the circuits. Citrate is expected to reduce the risk of bleeding compared with systemic administration, because it is metabolised into bicarbonate in the liver, skeletal muscles and renal cortex into bicarbonate (Schilder 2014). As accumulated citrate leads to hypocalcaemia, and calcium supplementation may be required. Using short half‐life anticoagulants may be an alternative to the regional anticoagulation, e.g. nafamostat mesilate. For instance, anticoagulation can be achieved with nafamostat mesilate without increasing bleeding complications (Maruyama 2011).

Why it is important to do this review

There are various methods to prevent clotting in the circuits, and the method of choice may differ across countries. Therefore, it is important to systematically summarize the benefits and harms of all the pharmacological methods.

Objectives

To assess the benefits and harms of pharmacological interventions for preventing clotting in the extracorporeal circuits during CRRT.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs or cluster 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 pharmacological interventions for preventing clotting of extracorporeal circuits during CRRT.

Types of participants

Inclusion criteria

We included all AKI patients receiving CRRT in the ICU regardless of age or sex.

Exclusion criteria

We excluded patients who received dialysis treatment before admission to the ICU.

Types of interventions

Citrate versus UFH
Citrate versus LMWH
Citrate versus nafamostat mesilate
Citrate versus argatroban
Citrate versus warfarin
Citrate versus no pharmacological anticoagulation
UFH versus LMWH
UFH versus nafamostat mesilate
UFH versus argatroban
UFH versus warfarin
UFH versus no pharmacological anticoagulation
LMWH versus nafamostat mesilate
LMWH versus argatroban
LMWH versus warfarin
LMWH versus no pharmacological anticoagulation
Nafamostat mesilate versus argatroban
Nafamostat mesilate versus warfarin
Nafamostat mesilate versus no pharmacological anticoagulation
Argatroban versus warfarin
Argatroban versus no pharmacological anticoagulation
Warfarin versus no pharmacological anticoagulation
Systematic anticoagulation versus regional anticoagulation
Antiplatelet agents versus no antiplatelet agents
Activated coagulation time (ACT) monitoring versus activated prothrombin time (APTT) monitoring

We considered all comparisons listed above. We also considered following other pharmacological interventions identified during our search.

Bivalirudin versus UFH
UFH versus UFH plus protamine
UFH plus protamine versus citrate
UFH plus protamine versus LMWH
Hirudin versus UFH
Citrate plus LMWH versus citrate
Citrate plus LMWH versus LMWH

We excluded studies comparing different doses of the same pharmacological intervention (e.g. high‐dose UFH versus low‐dose UFH).

Types of outcome measures

Primary outcomes

Major bleeding: incidence of major bleeding, defined as bleeding requiring blood transfusion, or as defined by the authors
Successful prevention of clotting: successful prevention of clotting is defined as no need for circuit change in the first 24 hours for any reason. If a study did not report the outcome with the timeframe of 24 hours, we adopted other time frames used in the study.

Death: death from any cause at day 28. If a study did not report an outcome with the timeframe of 28 days, we adopted hospital death, ICU death or death within the study period in this order of priority.

Secondary outcomes

Early termination with blood loss in the circuits: early termination was defined as the full prescribed dose that was not administered in the first 24 hours for any reason, and blood loss was defined as a failure to return blood for any reason
Catheter thrombotic event: incidence of catheter malfunction presumed due to thrombosis was defined as a failure to achieve a blood flow despite positional changes of the participants and additional saline flush or both, or as defined by the study authors
Recovery of kidney function: numbers of participants free of RRT after discontinuing CRRT at day 28
Thrombocytopenia: defined as emergent platelet count < 150,000/µL (150 x 10⁹/L) after starting CRRT, or as defined by the study authors
Adverse events
- Number of patients who dropped out of treatment because of adverse events (technique or patient‐dependent factors)
- Number of patients experiencing any adverse events
Hypocalcaemia: as defined by the study authors
Hypercalcaemia: as defined by the study authors
Hypernatraemia: as defined by the study authors
Metabolic disturbances: such as acidosis or alkalosis as defined by the study authors
Cost to health care services
- Types and number of dialyser filters and circuits
- Use/no use of anticoagulation
- Types of anticoagulation
- All costs were reported in dollar values using the Foreign Exchange Rates on 31 December 2018 which was reported by the Board of Governors of the Federal Reserve System.
Other adverse events: including allergic reactions, urticaria, and anaphylaxis (Wang 2016).

Search methods for identification of studies

Electronic searches

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Handsearching of kidney‐related journals and the proceedings of major kidney conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney and transplant journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

Reference lists of review articles, relevant studies and clinical practice guidelines.
Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The search strategy described was used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable; however, studies and reviews with potentially relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria. The two authors compared their lists and any differences in opinion between the two authors was resolved by discussion and, where this failed, through arbitration by a third author.

Data extraction and management

Data extraction was carried out independently by two authors using standard data extraction forms (Appendix 2). Differences in opinion on data collection was resolved by discussion and, where this failed, through arbitration by a third author. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was used in the analyses. Where relevant outcomes were only published in earlier versions, these data were used. Any discrepancy between published versions was highlighted.

Assessment of risk of bias in included studies

The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 3).

Was there adequate sequence generation (selection bias)?
Was allocation adequately concealed (selection bias)?
Was knowledge of the allocated interventions adequately prevented during the study?
- Participants and personnel (performance bias)
- Outcome assessors (detection bias)
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 dichotomous outcomes (e.g. death, major bleeding, hypocalcaemia, hypersensitivity reaction, other adverse events) results were expressed as risk ratio (RR) with 95% confidence intervals (CI).

We basically used the number of all participants who underwent randomised allocation as a denominator of their event risk calculation.

For outcomes being presumed as adverse events of interventions (e.g. major bleeding, metabolic disturbances, hypernatraemia, hypocalcaemia, hypercalcaemia, thrombocytopenia, catheter thrombotic event, or any adverse events), we used the number of all participants who underwent intervention after randomised allocation as a denominator of their event risk calculation.

Unit of analysis issues

We assessed unit of analysis issues in the included studies in three possible ways in which they might arise.

Multiple enrolments of the same participants from either individually randomised or cross‐over studies

If there were multiple enrolments of circuits used by the same individual following a need for repeated CRRT using new circuits (e.g. clotting of circuits), unit of analysis issues might arise. We considered to address them by first assessing each included study for any evidence of multiple enrolments (e.g. number of circuits exceeded the number of participants). We considered excluding those with multiple enrolments by entering the data of only the first circuit. However, such information was not available, and we performed our analysis based on whatever data the authors provided, using the total number of circuits as the denominator according to a priori defined protocol.

Clustering at the level of the enrolled units in cluster‐randomized trials

In dealing with cluster‐RCTs, for dichotomous data, we applied the design effect and calculated the effective sample size and number of events using the intra‐cluster correlation coefficient among each unit (ICC) and the average cluster size, as described in Chapter 16.3.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If the ICC had not been reported, we used the ICC of a similar study as a substitute. For continuous data only, the sample size was reduced; means and standard deviations remained unchanged (Higgins 2011).

Multiple comparisons

All intervention groups that were relevant to this review were included.

Dealing with missing data

Any further information required from the original author was requested by written correspondence (e.g. emailing corresponding author) and any relevant information obtained in this manner was 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 populations, was carefully performed. Attrition rates, for example drop‐outs, losses to follow‐up and withdrawals, were investigated. Issues of missing data and imputation methods (for example, last‐observation‐carried‐forward) was critically appraised (Higgins 2011).

Assessment of heterogeneity

We first assessed the heterogeneity by visual inspection of the forest plot. We quantified statistical heterogeneity using the I² statistic, which described the percentage of total variation across studies that was due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values was as follows.

0% to 40%: might not be important
30% to 60%: moderate heterogeneity
50% to 90%: substantial heterogeneity
75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi² test, or a confidence interval for I²) (Higgins 2011).

Assessment of reporting biases

If possible, funnel plots were used to assess for the potential existence of small study bias (Higgins 2011).

Data synthesis

Data were pooled using the random‐effects model, but the fixed‐effect model was also used to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was planned to explore possible sources of heterogeneity for the primary outcomes if sufficient studies were available. Heterogeneity among participants could be related to age (≥ 18 years or < 18 years) and prior condition (elderly patients, duration after a major operation, presence of liver disease, disseminated intravascular coagulopathy or other diseases of coagulation‐fibrinolysis system). Heterogeneity in treatments could be related to a prior or combined agent(s) used (e.g. protamine for UFH) and the agent, dose and duration of therapy (intensity of RRT, target APTT or ACT). Adverse effects were tabulated and assessed with descriptive techniques, as they were likely to be different for the various agents used. Where possible, the risk difference with 95% CI was calculated for adverse events, either compared to no treatment or to another agent.

Sensitivity analysis

We planned to conduct sensitivity analyses in order to explore the influence of the following factors on effect size; however, sufficient data were not available to determine the influence of these factors on the effect size.

Repeating the analysis excluding unpublished studies
Repeating the analysis taking account of risk of bias, as specified
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), and country.

Summary of findings and assessment of the certainty of the evidence

We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also includes an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defined the quality of a body of evidence as to the extent to which one could be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We presented the following outcomes in the 'Summary of findings' tables.

Major bleeding
Death at 28 days
Successful prevention of clotting in the first 24 hours
Dropped out of treatment because of adverse events
Recovery of kidney function
Thrombocytopenia
Cost to health care services

Results

Description of studies

Results of the search

Our searches identified 67 unique records from the electronic search and 12 unique records from other sources at the initial search on 16 January 2017. Update search identified four and two records, on 1 May 2018 and 12 September 2019, respectively. After the screening steps, a total of 43 reports of 34 completed studies were eligible to be included in this review (Figure 1). There were a total of 1960 randomised participants with 3218 observations (reported unit of outcome measurements including multiple measuring of the outcomes from the same participants due to the primary study design). We identified four ongoing studies (NCT01486485; NCT01839578; NCT02669589; NCT02860130) and one study awaiting classification (a completed study but its results have not published) (NCT02423642) which will be assessed in a future update of this review.

Included studies

Study characteristics including the dose of each intervention are individually shown in Characteristics of included studies.

Eight studies compared citrate versus UFH (Betjes 2007; CASH 2014; Hetzel 2011; Kutsogiannis 2005; Monchi 2004; Stucker 2015; Tiranathanagul 2011; Cui 2011).
Three studies compared citrate versus UFH plus protamine (Fealy 2007; FLIRRT 2014; Gattas 2015).
One study compared citrate versus LMWH (Oudemans‐van Straaten 2009).
Six studies compared UFH versus LMWH (Garces 2010; Joannidis 2007; Reeves 1999; Reeves 2003; van Doorn 2004; Victorino 2007).
Two studies compared nafamostat mesilate versus no anticoagulation (Choi 2015; Lee 2014b).
One study compared UFH vs UFH plus protamine versus no anticoagulation (Bellomo 1993).
One studies compared prostaglandin I₂ (PGI₂) versus UFH (Arcangeli 2010).
One study compared prostaglandin I₂ (PGI₂) versus UFH plus PGI₂ versus UFH (Langenecker 1994).
One study compared UFH plus PGI₂ versus UFH (Birnbaum 2007).
One study compared UFH plus protamine plus PGI₂ versus UFH (Fabbri 2010).
One study compared UFH plus prostaglandin E₁ (PGE₁) versus UFH plus PGI₂ versus UFH (Kozek‐Langenecker 2002).
One study compared UFH versus UFH plus tirofiban (Link 2008).
One study compared bivalirudin versus UFH (Kiser 2010).
Two study compared hirudin versus UFH (Vargas Hein 2001; Hein 2004).
One study compared low molecular weight dextran versus placebo (vehicle) (Palevsky 1995).
One study compared dalteparin (LMWH) versus nadroparin (LMWH) (de Pont 2000)
One study compared citrate vs LMWH versus citrate plus LMWH (Wu 2015b).
One study compared UFH plus protamine versus LMWH (van der Voort 2005).

Excluded studies

Twenty‐one studies were excluded.

Effect of prostacyclin (PGI₂) on platelets function (Kozek‐Langenecker 2003)
Twenty‐nine consecutive patients with septic shock and treated by CVVH (Lafargue 2008)
Two circuit configurations with different administration dilutions of UFH (Leslie 1996)
Different dose of PGE₁ (Kozek‐Langenecker 1998)
Anticoagulation for patients with multiple organ disorder (Lin 2007)
Heparin rinse of the circuit before the CRRT procedure (Opatrny 2002b)
Filtration flow speed (Oudemans‐van Straaten 2009a)
Albumin (human blood preparations) priming of the circuit (Reeves 1997)
CVVHF on blood heparin levels (as measured by anti‐Factor Xa activity) (Singer 1994)
Catheter locking fluid (VERROU‐REA 2014)
Anticoagulation method of sustained low‐efficiency dialysis (one of the intermittent dialysis methods) (NCT01228292; Tingli 2014; Wang 2014b)
Different doses of citrate (Anstey 2016; NCT02194569)
Anticoagulation of high‐dose dialysis (not continuous) (Wang 2009e)
Different doses of LMWH (Robinson 2014)
Concentration of unfractionated heparin (NCT01318811)
Clearance of thromboxane A2 (Ambros Checa 1995)
Different doses of UFH (ISRCTN01121161)
Argatroban versus lepirudin on critically ill heparin‐induced thrombocytopenia (HIT) patients (ALicia 2014).

Risk of bias in included studies

None of the included studies were free from risk of bias. Risk of bias assessment for included studies are shown in Figure 2; Figure 3. The details of the assessment for each study are shown in Characteristics of included studies. The summary of judgment across each domain is shown below.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Random sequence generation

We judged 18 studies (53%) as having low risk of bias (Bellomo 1993; Betjes 2007; CASH 2014; Choi 2015; Fabbri 2010; FLIRRT 2014; Garces 2010; Gattas 2015; Kozek‐Langenecker 2002; Kutsogiannis 2005; Lee 2014b; Link 2008; Monchi 2004; Oudemans‐van Straaten 2009; Palevsky 1995; Reeves 1999; Stucker 2015; van der Voort 2005); 15 studies (44%) (Arcangeli 2010; Birnbaum 2007; Cui 2011; de Pont 2000; Fealy 2007; Hetzel 2011; Joannidis 2007; Kiser 2010; Langenecker 1994; Reeves 2003; Tiranathanagul 2011; van Doorn 2004; Vargas Hein 2001; Victorino 2007; Wu 2015b) as unclear risk of bias. One study (3%) (Hein 2004) was judged to be at high risk of bias because inappropriate block randomisation.

Allocation concealment

We judged six studies (17%) (CASH 2014: FLIRRT 2014: Gattas 2015; Monchi 2004; Stucker 2015; van der Voort 2005) as having low risk of bias; 17 studies (50%) (Arcangeli 2010; Bellomo 1993; Birnbaum 2007; Choi 2015; Garces 2010; Hetzel 2011; Joannidis 2007; Kozek‐Langenecker 2002; Kutsogiannis 2005; Langenecker 1994; Link 2008; Palevsky 1995; Reeves 1999; Reeves 2003; Tiranathanagul 2011; van Doorn 2004; Victorino 2007) as unclear risk of bias, and 11 studies (32%) (Betjes 2007; Cui 2011; de Pont 2000; Fabbri 2010; Fealy 2007; Hein 2004; Kiser 2010; Lee 2014b; Oudemans‐van Straaten 2009; Vargas Hein 2001; Wu 2015b) as high risk of bias.

Blinding

Performance bias

We judged three studies (9%) (de Pont 2000; Fabbri 2010; Kiser 2010) as having low risk of bias; one study (3%) (Kozek‐Langenecker 2002) as unclear risk of bias, and 30 studies (81%) (Arcangeli 2010; Bellomo 1993; Betjes 2007; Birnbaum 2007; CASH 2014; Choi 2015; Cui 2011; Fealy 2007; FLIRRT 2014; Garces 2010; Gattas 2015; Hein 2004; Hetzel 2011; Joannidis 2007; Kutsogiannis 2005 Langenecker 1994; Lee 2014b; Link 2008; Monchi 2004; Oudemans‐van Straaten 2009; Palevsky 1995; Reeves 1999; Reeves 2003; Stucker 2015; Tiranathanagul 2011; van der Voort 2005; van Doorn 2004; Vargas Hein 2001; Victorino 2007; Wu 2015b) as high risk of bias due to open‐label design.

Detection bias

We judged three studies (9%) (de Pont 2000; Fabbri 2010; Kiser 2010) as having low risk of bias; one study (3%) (Kozek‐Langenecker 2002) as unclear risk of bias, and 30 studies (88%) (Arcangeli 2010; Bellomo 1993; Betjes 2007; Birnbaum 2007; CASH 2014; Choi 2015; Cui 2011; Fealy 2007; FLIRRT 2014; Garces 2010; Gattas 2015; Hein 2004; Hetzel 2011; Joannidis 2007; Kutsogiannis 2005; Langenecker 1994; Lee 2014b; Link 2008; Monchi 2004; Oudemans‐van Straaten 2009; Palevsky 1995; Reeves 1999; Reeves 2003; Stucker 2015; Tiranathanagul 2011; van der Voort 2005; van Doorn 2004; Vargas Hein 2001; Victorino 2007; Wu 2015b) as high risk of bias regarding the outcomes detection, assessment or follow‐up due to unblinded design.

Incomplete outcome data

We judged nine studies (26%) as having low risk of bias (Arcangeli 2010; CASH 2014; Gattas 2015; Hetzel 2011; Joannidis 2007; Kiser 2010; Link 2008; Oudemans‐van Straaten 2009; Stucker 2015); six studies (18%) (Bellomo 1993; Cui 2011; Kozek‐Langenecker 2002; van Doorn 2004; Victorino 2007; Wu 2015b) as unclear risk of bias. Nineteen studies (56%) (Betjes 2007; Birnbaum 2007; Choi 2015; de Pont 2000; Fabbri 2010; Fealy 2007; FLIRRT 2014; Garces 2010; Hein 2004; Kutsogiannis 2005; Langenecker 1994; Lee 2014b; Monchi 2004; Palevsky 1995; Reeves 1999; Reeves 2003; Tiranathanagul 2011; van der Voort 2005; Vargas Hein 2001) were judged to be at high risk of bias because of considerable lost to follow‐up (≥ 10%) or outcome reporting from the same participants with biased number of multiple enrolments possibly due to treatment cessation during cross‐over or multiple enrolment.

Selective reporting

We judged 14 studies (41%) as having low risk of bias (CASH 2014; Choi 2015; Gattas 2015; Hein 2004; Hetzel 2011; Kiser 2010; Kutsogiannis 2005; Lee 2014b; Monchi 2004; Oudemans‐van Straaten 2009; Stucker 2015; Tiranathanagul 2011; Vargas Hein 2001; Wu 2015b); three studies (11%) (Birnbaum 2007; de Pont 2000; Fabbri 2010) as unclear risk of bias, and 17 studies (50%) (Arcangeli 2010; Bellomo 1993; Betjes 2007: Cui 2011; Fealy 2007; FLIRRT 2014; Garces 2010; Joannidis 2007; Kozek‐Langenecker 2002; Langenecker 1994; Link 2008; Palevsky 1995; Reeves 1999; Reeves 2003; van der Voort 2005; van Doorn 2004; Victorino 2007) as carrying high risk of bias because death or their protocol‐defined safety‐related outcomes were not reported.

Other potential sources of bias

We assessed the reporting of financial conflict of interest (COI) by author‐reported information and the possibility of academic COI judged by the relative number of included studies from the same research group for particular interventions. We judged nine studies (26%) (Arcangeli 2010; Choi 2015; FLIRRT 2014; Garces 2010; Gattas 2015; Kiser 2010: Monchi 2004; Tiranathanagul 2011; Wu 2015b) as having low risk of bias; 12 studies (35%) (Bellomo 1993; Betjes 2007; Birnbaum 2007; Cui 2011; de Pont 2000; Fabbri 2010; Fealy 2007; Oudemans‐van Straaten 2009; Palevsky 1995; van der Voort 2005; van Doorn 2004; Victorino 2007) as unclear risk of bias and 13 studies (38%) (CASH 2014; Hein 2004; Hetzel 2011; Joannidis 2007; Kutsogiannis 2005; Langenecker 1994; Kozek‐Langenecker 2002; Lee 2014b; Link 2008; Reeves 1999; Reeves 2003; Stucker 2015; Vargas Hein 2001) as high risk of bias.

Effects of interventions

See: Table 1; Table 2; Table 3

Summary of findings for the main comparison. Citrate versus unfractionated heparin for continuous renal replacement therapy.

Citrate versus UFH for CRRT
Patient or population: CRRT  Setting: ICU  Intervention: citrate  Comparison: UFH
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with UFH	Risk with citrate	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Major bleeding	102 per 1,000	22 per 1,000  (8 to 63)	RR 0.22  (0.08 to 0.62)	535 (7)	⊕⊕⊕⊝  MODERATE ^{1 2}
Death at 28 days	384 per 1,000	407 per 1,000  (330 to 500)	RR 1.06  (0.86 to 1.30)	462 (5)	⊕⊕⊕⊝  MODERATE ³
Successful prevention of clotting	321 per 1,000	324 per 1,000  (247 to 424)	RR 1.01  (0.77 to 1.32)	88 (3)	⊕⊕⊕⊝  MODERATE ²
Treatment cessation due to adverse events	141 per 1,000	66 per 1,000  (21 to 211)	RR 0.47  (0.15 to 1.49)	412 (3)	⊕⊕⊝⊝  LOW ^{2 4}
Recovery of kidney function	311 per 1,000	296 per 1,000  (206 to 424)	RR 0.95  (0.66 to 1.36)	242 (2)	⊕⊕⊝⊝  LOW ^{2 4}
Thrombocytopenia	78 per 1,000	30 per 1,000  (11 to 80)	RR 0.39  (0.14 to 1.03)	412 (3)	⊕⊕⊝⊝  LOW ^{2 4}
Cost to health care services	not reported	not reported	‐‐	‐‐	‐‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    UFH: unfractionated heparin; CRRT: continuous renal replacement therapy; ICU: intensive care unit; CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

UFH versus LMWH for CRRT
Patient or population: CRRT  Setting: ICU  Intervention: UFH  Comparison: LMWH
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with LMWH	Risk with UFH	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Major bleeding	103 per 1,000	60 per 1,000  (13 to 267)	RR 0.58  (0.13 to 2.58)	153 (5)	⊕⊕⊝⊝  LOW ^{1 2 3}
Death: unknown time frame	857 per 1,000	669 per 1,000  (437 to 1,000)	RR 0.78  (0.51 to 1.18)	29 (1)	⊕⊝⊝⊝  VERY LOW ^{1 3 4}
Successful prevention of clotting	655 per 1,000	839 per 1,000  (616 to 1,000)	RR 1.28  (0.94 to 1.76)	54 (1)	⊕⊝⊝⊝  VERY LOW ^{1 3 4}
Treatment cessation due to adverse events	105 per 1,000	31 per 1,000  (2 to 372)	RR 0.29  (0.02 to 3.53)	77 (2)	⊕⊕⊝⊝  LOW ^{1 3}
Recovery of kidney function	not reported	not reported	‐‐	‐‐	‐‐
Thrombocytopenia	66 per 1,000	115 per 1,000  (40 to 331)	RR 1.76  (0.61 to 5.05)	124 (2)	⊕⊝⊝⊝  VERY LOW ^{1 3 4}
Cost to health care services	not reported	not reported	‐‐	‐‐	‐‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    UFH: unfractionated heparin; LMWH: low molecular weight heparin; CRRT: continuous renal replacement therapy; ICU: intensive care unit; CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

UFH versus no pharmacological anticoagulation for CRRT
Patient or population: CRRT  Setting: ICU  Intervention: UFH  Comparison: no anticoagulation
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with no anticoagulation	Risk with UFH	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Major bleeding	200 per 1,000	100 per 1,000  (10 to 934)	RR 0.50  (0.05 to 4.67)	10 (1)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
Death at 28 days	not reported	not reported	‐‐	‐‐	‐‐
Successful prevention of clotting	not reported	not reported	‐‐	‐‐	‐‐
Treatment cessation due of adverse events	not reported	not reported	‐‐	‐‐	‐‐
Recovery of kidney function	not reported	not reported	‐‐	‐‐	‐‐
Thrombocytopenia	not reported	not reported	‐‐	‐‐	‐‐
Cost to health care services	not reported	not reported	‐‐	‐‐	‐‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    UFH: unfractionated heparin; CRRT: continuous renal replacement therapy; ICU: intensive care unit; CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Study ID	Thrombocytopenia (n/N)	Platelet count
CASH 2014	Citrate: 0/66 UFH: 6/73	Not reported
Hetzel 2011	Citrate: 4/87 UFH: 8/83	Not reported
Stucker 2015	Citrate: 1/54 UFH: 2/49	Not reported
Oudemans‐van Straaten 2009	Citrate: 3/97 LMWH: 4/103	Not reported
Reeves 1999	UFH: 4/22 (1 confirmed as HIT) LMWH: 8/25 (3 confirmed as HIT)	The mean (± SE) reduction in platelet count during HF was: UFH: 63 ± 25.8 x 10⁹ LMWH: 41.8 ± 26.6 x 10⁹
Birnbaum 2007	UFH + PGI₂: 1/10 UFH: 0/10	UFH + PGI₂: drop to 16/nL in one patient due to sepsis
Hein 2004	Hirudin: 0/12 UFH: 2/14	UFH: 2 patients had bleeding complications and platelet counts were 69/nL and 17/nL

Study ID	Adverse events	Intervention: events/participants
Betjes 2007	All bleeding events	Citrate: 0/27 UFH: 9/21
	Alkalosis	Citrate: 0/27 UFH: 2/21
	Hypocalcaemia	Citrate: 2/27 UFH: 0/21
CASH 2014	Bleeding within 28 days	Citrate: 3/66 UFH: 10/73
	HIT	Citrate: 0/66 UFH: 6/73
	Citrate accumulation	Citrate: 4/66 UFH: 0/73
	Miscellaneous	Citrate: 1/66 UFH: 3/73
	Alkalaemia	Citrate: 1/66 UFH: 0/73
	Hypernatraemia	Citrate: 4/66 UFH: 3/73
	Hypermagnesaemia	Citrate: 8/66 UFH: 6/73
Hetzel 2011	HIT	Citrate: 4/87 UFH: 8/83
	All bleeding events	Citrate: 5/87 UFH: 12/83
	Citrate accumulation	Citrate: 1/87 UFH: 0/83
Kutsogiannis 2005	All bleeding events	Citrate: 1/16 UFH: 8/14
	Metabolic alkalosis	Citrate: 1/16 UFH: 0/14
	Hypocalcaemia	Citrate: 1/16 UFH: 0/14
Monchi 2004	All bleeding events	Citrate: 0/26 UFH: 1/23
	Hypocalcaemia	Citrate: 1/26 UFH: 0/23
	Alkalosis	Citrate: 1/26 UFH: 0/23
Stucker 2015	All bleeding events	Citrate: 0/54 UFH: 4/49
	HIT	Citrate: 1/54 UFH: 2/49
	Metabolic disorders	Citrate: 14/54 UFH: 3/49
Tiranathanagul 2011	All bleeding events	Citrate: 0/10 UFH: 0/10

Database	Search terms
CENTRAL	MeSH descriptor: [Renal Replacement Therapy] this term only MeSH descriptor: [Renal Dialysis] this term only MeSH descriptor: [Hemofiltration] explode all trees MeSH descriptor: [Ultrafiltration] this term only #5continuous venovenous hemofiltration or CVVH:ti,ab,kw (Word variations have been searched) continuous venovenous hemodialysis or CVVHD:ti,ab,kw (Word variations have been searched) continuous venovenous hemodiafiltration or CVVHDF:ti,ab,kw (Word variations have been searched) slow continuous ultrafiltration or SCUF:ti,ab,kw (Word variations have been searched) MeSH descriptor: [Acute Kidney Injury] explode all trees "acute kidney failure" or "acute renal failure":ti,ab,kw (Word variations have been searched) "acute kidney injury" or "acute renal injury":ti,ab,kw (Word variations have been searched) "acute kidney insufficiency" or "acute renal insufficiency":ti,ab,kw (Word variations have been searched) "acute tubular necrosis":ti,ab,kw (Word variations have been searched) ARI or AKI or ARF or AKF or ATN:ti,ab,kw (Word variations have been searched) {or #1‐#14} MeSH descriptor: [Anticoagulants] explode all trees MeSH descriptor: [Citrates] explode all trees MeSH descriptor: [Platelet Aggregation Inhibitors] explode all trees UFH or heparin or lmwh or antixarin or ardeparin or bemiparin or certoparin or clexane:ti,ab,kw (Word variations have been searched) "cy 222" or "cy 216" or dalteparin or danaparoid or embolex or "EMT‐996" or "EMT‐967" or enoxaparin or fondaparinux or fraxiparin or fragmin or innohep or "Ihn 1" or klexane:ti,ab,kw (Word variations have been searched) "kabi 2165" or K2165 or logiparin or lovenox or nadroparin or monoembolex or parnaparin or reviparin or "rd 11885" or "pk‐10169" or tedelparin:ti,ab,kw (Word variations have been searched) seleparin or tinzaparin or tedegliparin or warfarin or dabigatran or bivalirudin or argatroban or desirudin or rivaroxaban or apixaban or endoxaban or nafamostat:ti,ab,kw (Word variations have been searched) alprostadil or aspirin or acetylsalicylic acid or dipyridamole or disintegrins or epoprostenol or iloprost or ketanserin or milrinone or pentoxifylline or S‐nitrosoglutathione or S‐nitrosothioles:ti,ab,kw (Word variations have been searched) trapidil or ticlopidine or clopidogrel or sulfinpyrazone or sulphinpyrazone or cilostazol or prasugrel or ticagrelor or cangrelor or elinogrel or abciximab:ti,ab,kw (Word variations have been searched) eptifibatide or tirofiban or defibrotide or picotamide or beraprost or ticlid or aggrenox:ti,ab,kw (Word variations have been searched) {or #16‐#25} {and #15, #26}
MEDLINE	Renal Replacement Therapy/ Renal Dialysis/ exp Hemofiltration/ Ultrafiltration/ (continuous venovenous h$emofiltration or CVVH).tw. (continuous venovenous h$emodialysis or CVVHD).tw. (continuous venovenous h$emodiafiltration or CVVHDF).tw. (slow continuous ultrafiltration or SCUF).tw. exp Acute Kidney Injury/ (acute kidney failure or acute renal failure).tw. (acute kidney injur$ or acute renal injur$).tw. (acute kidney insufficie$ or acute renal insufficie$).tw. acute tubular necrosis.tw. (ARI or AKI or ARF or AKF or ATN).tw. or/1‐14 exp Anticoagulants/ exp Citrates/ exp Platelet Aggregation Inhibitors/ UFH.tw. heparin$.tw. lmwh.tw. antixarin.tw. ardeparin.tw. bemiparin.tw. certoparin.tw. clexane.tw. ("cy 222" or "cy 216").tw. dalteparin$.tw. danaparoid.tw. embolex.tw. ("EMT‐996" or "EMT‐967").tw. enoxaparin$.tw. fondaparinux.tw. fraxiparin$.tw. fragmin$.tw. innohep.tw. "Ihn 1".tw. klexane.tw. (kabi 2165 or K2165).tw. logiparin$.tw. lovenox.tw. nadroparin$.tw. monoembolex.tw. parnaparin.tw. reviparin.tw. "rd 11885".tw. "pk‐10169".tw. tedelparin$.tw. seleparin.tw. tinzaparin$.tw. tedegliparin.tw. warfarin.tw. dabigatran.tw. bivalirudin.tw. argatroban.tw. desirudin.tw. rivaroxaban.tw. apixaban.tw. endoxaban.tw. nafamostat.tw. Sulfinpyrazone/ alprostadil.tw. aspirin.tw. acetylsalicylic acid.tw. dipyridamole.tw. disintegrins.tw. epoprostenol.tw. iloprost.tw. ketanserin.tw. milrinone.tw. pentoxifylline.tw. S‐nitrosoglutathione.tw. S‐nitrosothioles.tw. trapidil.tw. ticlopidine.tw. clopidogrel.tw. (sulfinpyrazone or sulphinpyrazone).tw. cilostazol.tw. (P2Y12 adj2 antagonis$).tw. prasugrel.tw. ticagrelor.tw. cangrelor.tw. elinogrel.tw. abciximab.tw. eptifibatide.tw. tirofiban.tw. defibrotide.tw. picotamide.tw. beraprost.tw. ticlid.tw. aggrenox.tw. or/16‐91 and/15,92
EMBASE	exp continuous renal replacement therapy/ (continuous venovenous h$emofiltration or CVVH).tw. (continuous venovenous h$emodialysis or CVVHD).tw. (continuous venovenous h$emodiafiltration or CVVHDF).tw. (slow continuous ultrafiltration or SCUF).tw. acute kidney failure/ acute kidney tubule necrosis/ (acute kidney failure or acute renal failure).tw. (acute kidney injur$ or acute renal injur$).tw. (acute kidney insufficie$ or acute renal insufficie$).tw. acute tubular necrosis.tw. (ARI or AKI or ARF or AKF or ATN).tw. or/6‐12 exp anticoagulant agent/ exp heparin/ exp low molecular weight heparin/ exp thrombin inhibitor/ exp coumarin derivative/ exp blood clotting factor 10a inhibitor/ heparin$.tw. dextran sulphate$.tw. bivalirudin.tw. argatroban.tw. lepirudin.tw. coumarin$.tw. warfarin.tw. fondaparinux.tw. factor Xa inhibitor$.tw. direct thrombin inhibitor$.tw. UFH.tw. lmwh.tw. antixarin.tw. ardeparin.tw. bemiparin.tw. certoparin.tw. clexane.tw. (Cy 222 or cy 216).tw. dalteparin$.tw. danaparoid.tw. embolex.tw. (emt‐996 or emt‐967).tw. enoxaparin$.tw. fondaparinux.tw. fraxiparin$.tw. fragmin$.tw. innohep.tw. ihn1.tw. (kabi 2165 or k2165).tw. klexane.tw. logiparin$.tw. lovenox.tw. monoembolex.tw. nadroparin$.tw. parnaparin.tw. pk‐10169.tw. rd 11885.tw. reviparin.tw. seleparin$.tw. tedelparin$.tw. tinzaparin$.tw. warfarin.tw. dabigatran.tw. desirudin.tw. rivaroxaban.tw. apixaban.tw. endoxaban.tw. Citric acid/ citrate$.tw. exp antithrombocytic agent/ or/14‐69 and/13,70

Basic information
Study ID
Trial registration number
language of publication
Country
Types of study
NOTE:
Study characteristics
Single or multicentre?
Participants
Number of participants
Diagnostic criteria of AKI
Age(mean, median, range)
Sex (male numbers/%)
Underlying cause of AKI
Pre‐existence of ESKD
Bleeding risk Elderly patients (> 60 years) Duration after major operation Presence of disseminated intravascular clotting (DIC) Liver disease Other risk Very high/High/Moderate/Low risk:
NOTE:
Baseline laboratory data
Baseline haemoglobin Baseline platelet count Baseline APTT Baseline PT‐INR Baseline ACT Baseline Ca Baseline Na Baseline arterial Blood pH
Dialysis
Number of circuits Types of CRRT Types of circuits Types of filters Catheter position Blood flow Dialysate flow Co‐intervention Filtration dose
Types of intervention
Types of intervention Types of comparison Target APTT Target ACT Target PT‐INR Antiplatelet use
NOTE:
Results (number of people)
Primary outcomes Major bleeding Incidence of major bleeding, defined as bleeding requiring blood transfusion, or as defined by the authors Successful prevention of clotting Successful prevention of clotting is defined as no need of circuit change in the first 24 hours for any reason Death Death from any cause at days 28
Secondary outcomes Early termination with blood loss in the circuits Early termination is defined as the full prescribed dose is not administered in the first 24 hours for any reason Blood loss is defined as impossible return of participants' own blood to them from circuits for any reason Thrombotic event Incidence of catheter malfunction presumed due to thrombosis defined as a failure to achieve a blood flow despite positional changes of the patient and additional saline flush or both, or as defined by the study authors Recovery of kidney function Numbers of participants free of RRT after discontinuing CRRT at days 28 Thrombocytopenia Thrombocytopenia defined as an emergent platelet count < 150,000/µL (150 x 10⁹/L) after starting CRRT, or as defined by the study authors Adverse events Numbers of participants who dropped out because of adverse events (technique or participants dependent factors) Numbers of patients experiencing any adverse events Hypocalcaemia Hypocalcaemia, defined as defined by the study authors Hypercalcaemia Hypercalcaemia as defined by the study authors Hypernatraemia Hypernatraemia as defined by the study authors Metabolic disturbances Metabolic disturbances, such as acidosis or alkalosis as defined by the study authors Other adverse events Other adverse events including allergic reactions, urticaria and anaphylaxis Cost to health care services types and number of dialyser filters and circuits use/no use of anticoagulation types of anticoagulation
Other information
Dropouts Numbers of participants who dropped out for any reason
NOTE:
Additional information
Conflict of interest Financial support Other possible conflict of interest
NOTE:

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 standardized 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. sub‐scales) 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.

Comparisons and outcomes	No. of studies	Effect size (RR)	95% CI	CoE ^a
Citrate versus UFH
Major bleeding	7	0.22	0.08 to 0.62	moderate
Death at 28 days	5	1.06	0.86 to 1.30	moderate
Successful preventing of clotting	3	1.01	0.77 to 1.32	moderate
Metabolic disturbances	5	2.88	1.12 to 7.39	low
Hypernatraemia	3	1.47	0.34 to 6.35	very low
Hypocalcaemia	5	4.51	1.31 to 15.55	moderate
Hypercalcaemia	2	no events reported	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	2	0.95	0.66 to 1.36	low
Thrombocytopenia	3	0.39	0.14 to 1.03	low
Catheter thrombotic event	4	1.03	0.42 to 2.48	low
Dropouts due to adverse events ^c	3	0.47	0.15 to 1.49	low
Adverse events ^d	6	0.59	0.36 to 0.99	low
Cost to health care services	1	see main text	‐‐	‐‐
Citrate versus UFH plus protamine
Major bleeding	3	0.34	0.01 to 8.24	low
Death at 28 days	2	1.11	0.76 to 1.64	low
Successful prevention of clotting	2	0.97	0.72 to 1.31	low
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	1	4.20	0.24 to 74.48	low
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	1	1.16	0.53 to 2.51	low
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	3	0.92	0.28 to 3.01	very low
Adverse events ^d	3	0.71	0.13 to 3.80	very low
Cost to health care services	1	see main text	‐‐	‐‐
Citrate versus LMWH
Major bleeding	2	0.45	0.21 to 0.97	moderate
Death at 28 days	2	0.79	0.61 to 1.02	very low
Successful prevention of clotting	1	0.91	0.73 to 1.15	very low
Metabolic disturbances	2	1.57	0.12 to 20.97	very low
Hypernatraemia	2	3.18	0.13 to 77.23	very low
Hypocalcaemia	2	3.29	0.81 to 13.46	low
Hypercalcaemia	1	0.19	0.04 to 0.85	low
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	2	1.01	0.38 to 2.67	very low
Thrombocytopenia	2	0.80	0.18 to 3.47	very low
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	2	0.11	0.03 to 0.44	low
Adverse events ^d	2	See Table 25	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
UFH versus LMWH
Major bleeding	5	0.58	0.13 to 2.58	low
Death at 28 days	1	0.78	0.51 to 1.18	very low
Successful prevention of clotting	1	1.28	0.94 to 1.76	very low
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	2	1.76	0.61 to 5.05	very low
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	2	0.29	0.02 to 3.53	low
Adverse events ^d	1	0.97	0.14 to 6.57	very low
Cost to health care services	0	‐‐	‐‐	‐‐
UFH versus no pharmacological anticoagulation
Major bleeding	1	0.50	0.05 to 4.67	very low
Death at 28 days	0	‐‐	‐‐	‐‐
Successful prevention of clotting	0	‐‐	‐‐	‐‐
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
UFH plus protamine versus UFH
Major bleeding	1	no events	‐‐	‐‐
Death at 28 days	0	‐‐	‐‐	‐‐
Successful prevention of clotting	0	‐‐	‐‐	‐‐
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
Nafamostat mesilate versus no anticoagulation
Major bleeding	2	1.06	0.37 to 3.04	low
Death at 28 days	2	1.00	0.72 to 1.41	low
Successful prevention of clotting	0	‐‐	‐‐	‐‐
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	1	2.32	0.70 to 7.66	very low
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	1	1.55	0.31 to 7.76	very low
Dropouts due to adverse events ^c	1	5.14	0.26 to 103.39	very low
Adverse events ^d	2	1.09	0.58 to 2.02	low
Cost to health care services	0	‐‐	‐‐	‐‐
PGI₂ versus UFH
Major bleeding	1	no events	‐‐	‐‐
Death at 28 days	0	‐‐	‐‐	‐‐
Successful prevention of clotting	1	1.09	0.64 to 1.87	low
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
UFH plus PGI₂ versus PGI₂
Major bleeding	1	no events	‐‐	‐‐
Death at 28 days	0	‐‐	‐‐	‐‐
Successful prevention of clotting	0	‐‐	‐‐	‐‐
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
UFH plus PGI₂ versus UFH
Major bleeding	3	0.16	0.01 to 2.88	very low
Death at 28 days	0	‐‐	‐‐	‐‐
Successful prevention of clotting	2	1.83	1.27 to 2.63	low
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	1	3.00	0.14 to 65.90	very low
Catheter thrombotic event	1	3.00	0.14 to 65.90	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	2	0.19	0.03 to 1.40	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
UFH plus protamine and PGI₂ versus UFH
Major bleeding	1	0.30	0.07 to 1.39	very low
Death at 28 days	1	0.81	0.19 to 3.44	very low
Successful prevention of clotting	1	4.48	2.70 to 7.44	very low
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse event ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
UFH plus PGI₂ versus UFH plus PGE₁
Major bleeding	1	0.40	0.02 to 9.06	very low
Death at 28 days	0	‐‐	‐‐	‐‐
Successful prevention of clotting	1	1.09	0.85 to 1.41	very low
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
UFH plus PGE₁ versus UFH
Major bleeding	1	0.31	0.04 to 2.74	very low
Death at 28 days	0	‐‐	‐‐	‐‐
Successful prevention of clotting	1	1.71	1.16 to 2.52	low
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
UFH plus tirofiban versus UFH
Major bleeding	1	no events	‐‐	‐‐
Death at 28 days	1	1.14	0.51 to 2.55	very low
Successful prevention of clotting	0	‐‐	‐‐	‐‐
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
Bivalirudin versus UFH
Major bleeding	1	0.33	0.02 to 6.65	very low
Death at 28 days	1	0.50	0.06 to 3.91	very low
Successful prevention of clotting	0	‐‐	‐‐	‐‐
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	1	0.50	0.16 to 1.59	very low
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
Hirudin versus UFH
Major bleeding	2	1.37	0.04 to 43.22	very low
Death at 28 days	2	1.24	0.63 to 2.43	very low
Successful prevention of clotting	0	‐‐	‐‐	‐‐
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	1	0.23	0.01 to 4.38	very low
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
Low molecular weight dextran versus placebo (vehicle)
Major bleeding	0	‐‐	‐‐	‐‐
Death at 28 days	0	‐‐	‐‐	‐‐
Successful prevention of clotting	1	1.08	0.68 to 1.71	very low
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
Dalteparin (LMWH) versus nadroparin (LMWH)
Major bleeding	0	‐‐	‐‐	‐‐
Death at 28 days	0	‐‐	‐‐	‐‐
Successful prevention of clotting	1	1.67	0.69 to 4.04	very low
Metabolic disturbances	0	‐‐	‐‐	‐‐
Hypernatraemia	0	‐‐	‐‐	‐‐
Hypocalcaemia	0	‐‐	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	0	‐‐	‐‐	‐‐
Thrombocytopenia	0	‐‐	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	0	‐‐	‐‐	‐‐
Adverse events ^d	0	‐‐	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
Citrate plus LMWH versus citrate
Major bleeding	1	0.39	0.04 to 3.95	very low
Death at 28 days	1	0.92	0.39 to 2.17	very low
Successful prevention of clotting	1	1.16	0.93 to 1.44	very low
Metabolic disturbances	1	1.05	0.28 to 4.00	very low
Hypernatraemia	1	no events	‐‐	‐‐
Hypocalcaemia	1	0.27	0.01 to 6.11	very low
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	1	1.58	0.47 to 5.29	very low
Thrombocytopenia	1	no events	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	1	no events	‐‐	‐‐
Adverse events ^d	1	See Table 35	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐
Citrate plus LMWH versus LMWH
Major bleeding	1	0.25	0.03 to 2.04	very low
Death at 28 days	1	1.40	0.54 to 3.64	very low
Successful prevention of clotting	1	1.05	0.91 to 1.22	very low
Metabolic disturbances	1	9.00	0.52 to 156.41	very low
Hypernatraemia	1	no events	‐‐	‐‐
Hypocalcaemia	1	no events	‐‐	‐‐
Hypercalcaemia	0	‐‐	‐‐	‐‐
Early termination with blood loss in the circuits	0	‐‐	‐‐	‐‐
Recovery of kidney function	1	2.00	0.58 to 6.85	very low
Thrombocytopenia	1	no events	‐‐	‐‐
Catheter thrombotic event	0	‐‐	‐‐	‐‐
Dropouts due to adverse events ^c	1	no events	‐‐	‐‐
Adverse events ^d	1	see Table 36	‐‐	‐‐
Cost to health care services	0	‐‐	‐‐	‐‐

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding	10		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 Citrate versus UFH	7	702	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.08, 0.62]
1.2 Citrate versus UFH plus protamine	3	262	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.01, 8.24]
2 Death at 28 days	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 Citrate versus UFH	5	462	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.86, 1.30]
2.2 Citrate versus UFH plus protamine	2	242	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.76, 1.64]
3 Successful prevention of clotting	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Citrate versus UFH	3	211	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.77, 1.32]
3.2 Citrate versus UFH plus protamine	2	229	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.72, 1.31]
4 Metabolic disturbances	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 Citrate versus UFH	5	369	Risk Ratio (M‐H, Random, 95% CI)	2.88 [1.12, 7.39]
5 Hypernatraemia	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1 Citrate versus UFH	3	236	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.34, 6.35]
6 Hypocalcaemia	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.1 Citrate versus UFH	5	400	Risk Ratio (M‐H, Random, 95% CI)	4.51 [1.31, 15.55]
6.2 Citrate versus UFH plus protamine	1	30	Risk Ratio (M‐H, Random, 95% CI)	4.2 [0.24, 74.48]
7 Hypercalcaemia	2	158	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.1 Citrate versus UFH	2	158	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 Recovery of kidney function	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1 Citrate versus UFH	2	242	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.66, 1.36]
8.2 Citrate versus UFH plus protamine	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.53, 2.51]
9 Thrombocytopenia	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
9.1 Citrate versus UFH	3	412	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.14, 1.03]
10 Catheter thrombotic events	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
10.1 Citrate versus UFH	4	301	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.42, 2.48]
11 Treatment cessation due to any adverse event	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
11.1 Citrate versus UFH	3	412	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.15, 1.49]
11.2 Citrate versus UFH plus protamine	3	1129	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.28, 3.01]
12 Treatment attempts with any adverse events	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
12.1 Citrate versus UHF	6	539	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.36, 0.99]
12.2 Citrate versus UFH plus protamine	3	1129	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.13, 3.80]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding	2	234	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.21, 0.97]
2 Death	2	253	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.61, 1.02]
3 Successful prevention of clotting	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Metabolic disturbances	2	234	Risk Ratio (M‐H, Random, 95% CI)	1.57 [0.12, 20.97]
5 Hypernatraemia	2	234	Risk Ratio (M‐H, Random, 95% CI)	3.18 [0.13, 77.23]
6 Hypocalcaemia	2	234	Risk Ratio (M‐H, Random, 95% CI)	3.29 [0.81, 13.46]
7 Hypercalcaemia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8 Recovery of kidney function	2	253	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.38, 2.67]
9 Thrombocytopenia	2	234	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.18, 3.47]
10 Treatment cessation due to any adverse event	2	234	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.03, 0.44]

Study ID	Adverse events	Intervention: events/participants
Choi 2015	GI bleeding	Nafamostat mesilate: 2/31 No anticoagulation: 0/24
Lee 2014b	All adverse events	Nafamostat mesilate: 33/36 No anticoagulation: 33/37
	Grade 1 pulmonary haemorrhage	Nafamostat mesilate: 1/36 No anticoagulation: 0/37
	Grade 1 GI bleeding	Nafamostat mesilate: 0/36 No anticoagulation: 1/37
	Grade 2 GI bleeding	Nafamostat mesilate: 0/36 No anticoagulation: 2/37
	Grade 4 GI bleeding	Nafamostat mesilate: 1/36 No anticoagulation: 0/37
	Grade 1 vaginal bleeding	Nafamostat mesilate: 1/36 No anticoagulation: 0/37
	Variceal bleeding	Nafamostat mesilate: 0/36 No anticoagulation: 1/37
	Catheter insertion site oozing	Nafamostat mesilate: 0/36 No anticoagulation: 1/37

Study ID	Adverse events	Intervention: events/participants
Kiser 2010	Alveolar haemorrhage	Bivalirudin: 0/5 UFH: 1/5
Kiser 2010	Deep vein thrombosis	Bivalirudin: 0/5 UFH: 1/5

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding	5	233	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.13, 2.58]
2 Death (unknown time frame)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Successful prevention of clotting	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Metabolic disturbances	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Hypernatraemia	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Hypocalcaemia	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Thrombocytopenia	2	124	Risk Ratio (M‐H, Random, 95% CI)	1.76 [0.61, 5.05]
8 Treatment cessation due to any adverse event	2	117	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.02, 3.53]
9 Any adverse event	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding	2	115	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.37, 3.04]
2 Death at 28 days	2	133	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.72, 1.41]
3 Recovery of kidney function	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Catheter thrombotic events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5 Treatment cessation due to any adverse event	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6 Treatment attempts with any adverse events	2	128	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.58, 2.02]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding	3	81	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.01, 2.88]
2 Successful prevention of clotting	2	158	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.27, 2.63]
3 Thrombocytopenia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Catheter thrombotic events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5 Any adverse event	2	52	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.03, 1.40]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding	1	35	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.04, 2.74]
2 Successful prevention of clotting	1	135	Risk Ratio (M‐H, Random, 95% CI)	1.71 [1.16, 2.52]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding	2	43	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.04, 43.22]
2 Death at 28 days	2	45	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.63, 2.43]
3 Thrombocytopenia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Methods	Study design: parallel RCT Study duration: not reported Study follow‐up period: 24 hours
Participants	Country: Italy Setting: ICU; single centre Inclusion criteria: patients with AKI requiring CVVHDF and were sedated and mechanically ventilated, and additional therapy was administered according to the Intensive Care standard protocols; AKI was classified according to the RIFLE criteria Number analysed/randomised: treatment group (10/11); UFH group (11/12) Mean age ± SD (years): treatment group (65.6 ± 11.9), control group (67.8 ± 16.7) Sex (M/F ratio): treatment group (7:10), control group (7:11) Other relevant information Respiratory failure: treatment group (4); control group (6) Sepsis /septic shock: treatment group (3); control group (2) Aortic aneurysm repair: treatment group (1); control group (1) Liver transplant/haemorrhagic shock: treatment group (1); control group (1) Pancreatitis: treatment group (1); control group (2) Guillain‐Barré syndrome: treatment group (0); control group (1) Exclusion criteria: therapy with aspirin or other NSAID in the previous 7 days; concomitant treatment with other extracorporeal organ‐assist devices and any other drug affecting coagulation or platelets
Interventions	Treatment group PGI: prepared as indicated by the manufacturer [0.5 mg/50 mL), from a sterile lyophilised preparation reconstituted immediately before use in sterile glycine buffer, obtaining a solution of 10 μg/mL and was infused into the arterial‐line of the circuit at 4 ng/kg/min Duration: 24 hours Control group UFH: prepared using our standard protocol: 2 mL of an already‐stored solution containing 5000 IU/mL of UFH were diluted in 20 mL of saline obtaining a final concentration of 500 IU/mL, and infused pre‐filter at 6 IU/kg/hour, according to the post‐filter activated clotting time (ACT: Hemochron, Fresenius, normal values 80 to 150 sec) measured hourly, and adjusted to obtain a value between 180 and 200 sec Duration: 24 hours
Outcomes	Successful prevention of clotting (ITT analysis) In the UFH group, 3/12 patients had a filter lifespan below 24 hours (16, 18 and 22 hours) In the PGI group, 2/11 patients had below 24‐hour filter duration (12 hours each)
Notes	Supported in part by the European Commission FP6 funding (LSHMCT‐2004‐005033) 23 patients were enrolled; 2 patients were excluded from the analysis because of severe thrombocytopenia at baseline (1) or need for low‐molecular weight heparin during the CVVHDF (1), thus 21 patients were randomised
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised; method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Two patients (from total 23 patient) were excluded from the analysis because of severe thrombocytopenia at baseline (1) or need for low‐molecular weight heparin during the CVVHDF (1), thus 21 patients were analysed
Selective reporting (reporting bias)	High risk	Death‐related outcomes were not reported
Other bias	Low risk	The authors had no conflicts of interest to disclose. Supported in part by the European Commission FP6 funding (LSHMCT‐2004‐005033)

Methods	Study design: cross‐over RCT Study duration: not reported Study follow‐up period: not reported
Participants	Country: Australia Setting: ICU, single centre Inclusion criteria: critically ill patients receiving ACHD Number: treatment group 1 (15); treatment group 2 (16); treatment group 3 (33) Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group 1 Low dose (500 IU/hour) pre‐filter heparin (unclear number of patients) versus regional anticoagulation* (unclear number of patients) in patients on CAVHD via A‐V shunt Treatment group 2 Low dose pre‐filter heparin (10) versus no anticoagulation (10) in patients receiving CAVHD via femoral cannula Treatment group 3 Low dose pre‐filter heparin (unclear number of patients) versus regional anticoagulation* (unclear number of patients) in patients on continuous CVVHD (total 54) *The regional anticoagulant regimen called for administration of pre‐filter heparin and post‐filter protamine, starting at a 100:1 heparin:protamine ratio
Outcomes	Major bleeding One patient on low dose heparin CVVHD experienced prolonged oozing of blood from the site of insertion of the double lumen catheter (subclavian vein). This eventually stopped after prolonged and repeated pressure but required transfusion of 2 units of blood. Two patients from the group that received no anticoagulation had clinically significant oozing from tracheostomy sites. They both required surgical revision and blood transfusion with additional platelets and fresh frozen plasma. Both had a platelet count < 50 x 10⁹/L and disseminated intravascular coagulation
Notes	Funding: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were assigned randomly by a random numbers table to start ACHD either with low dose heparin or with regional anticoagulation"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Missing patients were not reported
Selective reporting (reporting bias)	High risk	Most important outcomes were not reported
Other bias	Unclear risk	No information of conflicts of interest or funding

Methods	Study design: parallel RCT, multiple enrolment (no individual data available for each enrolment) Study duration: December 2004 to January 2006 Study follow‐up period: 72 hours
Participants	Country: The Netherlands Setting: a combined medical and surgical ICU of a university hospital Inclusion criteria: > 18 years and had been admitted to a combined medical and surgical ICU of the university hospital; the need for KRT was based on clinical grounds by the consulting nephrologist. Number: treatment group 1 (27); treatment group 2 (21) *Mean age ± SD (years): treatment group 1 (55.2 ± 2.8); treatment group 2 (57.8 ± 4.2) Sex (M/F): treatment group 1 (19/8); treatment group 2 (15/6) Other relevant information Operation within 48 hours before starting CVVH: treatment group 1 (4, 15%); treatment group 2 (3, 14%) Septic shock: treatment group 1 (16, 59%); treatment group 2 (16, 76%) Exclusion criteria For UFH: heparin‐induced thrombocytopenia, a platelet count < 20,000/mL, severe coagulopathy, a recent history (< month) of GI bleeding or intracranial haemorrhage or any other condition which constituted a high risk of bleeding as judged on clinical grounds by the treating physician For citrate: severe circulatory shock, acute liver failure and an ionised plasma calcium concentration < 0.8 mmol/L
Interventions	Treatment group 1 UFH: bolus of 3,000 to 5,000 IU, depending on weight and pre‐existing APPT. This was followed by a continuous infusion of UFH of 1,500 IU/hour, and the infusion rate was adjusted if needed to achieve an APPT between 50 and 70 seconds. The level of anticoagulation was monitored every 4 to 6 hours The lifetime of the dialysis circuit was limited to 72 hours, because thereafter the manufacturer did not guarantee the patency of the connecting lines. Treatment group 2 Trisodium citrate: 13% solution of trisodium citrate was made up at the hospital pharmacy. This solution was started at 55 mL/min and given on the arterial bloodline before the haemofilter. Within 1 hour, and every 6 hours thereafter, the serum ionised calcium concentration was determined at the venous outlet of the haemofilter and in the patient. The post filter ionised calcium concentration was kept at 0.25 to 0.30 by adjusting the infusion of trisodium citrate. If the systemic serum ionised calcium concentration dropped below 0.9 mmol/L, an infusion of calcium chloride (1 g/10 mL) was started at a rate of 10 mL/hour, which was increased if necessary. The lifetime of the dialysis circuit was limited to 72 hours, because thereafter the manufacturer did not guarantee the patency of the connecting lines
Outcomes	Major bleeding: defined as bleeding requiring transfusion, bleeding at a critical site (retroperitoneal, intracranial, intraocular or intra‐articular), bleeding associated with haemodynamic instability because of hypovolaemia or bleeding resulting in > 2 g/dL (> 1.6 mmol/L) drop in Hb. The number of units of packed RBC administered per patient was recorded, and the mean number of packed RBC/day of CVVH treatment was calculated. The decrease in Hb concentration per CVVH treatment was calculated in every patient, as the Hb concentration at the start of the dialysis minus the Hb concentration within 4 hours after disconnection of the extracorporeal system. For this calculation, the data obtained within a period of CVVH treatment in which the patient received no blood transfusion were analysed Successful prevention of clotting (circuit survival < 72 hours): defined as the time of commencement to the time of elective discontinuation or spontaneous failure due to clotting within the circuit Metabolic alkalosis exceeding a pH of 7.55 Hypocalcaemia Hypernatraemia Catheter thrombotic event
Notes	Funding: not reported Conflict of interest statement: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was done using a random number generator (Excel 2000)
Allocation concealment (selection bias)	High risk	Allocation was not concealed
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias)   All outcomes	High risk	Multiple enrolment and no detailed information
Selective reporting (reporting bias)	High risk	Death‐related outcomes were not reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: parallel RCT with multiple enrolment Study duration: April 2012 to December 2012 Study follow‐up period: not reported
Participants	Country: New Zealand Setting: single centre ICU Inclusion criteria: > 18 years; diagnosis of AKI with an indication for KRT as assessed by one or more of the following criteria: Oliguria (urine output < 100 mL in a 6‐hour period); unresponsive to fluid resuscitation; volume overload, not correctable by diuretics despite adequate blood pressure and creatinine > 100umol.L; increase of SCr > 300 µmol/L or BUN > 25 mmol/L; increase of serum potassium > 6.5 mmol/L due to AKI Number: treatment group 1 (19); treatment group 2 (11) Mean age ± SD (years): treatment group 1 (64 ± 13); treatment group 2 (51 ± 17) Sex (M/F): treatment group 1 (13/6); treatment group 2 (7/11) Other relevant information Non‐operative: treatment group 1 (12, 63%); treatment group 2 (7, 64%) Cardiovascular system: treatment group 1 (3, 16%); treatment group 2 (4, 36%) Respiratory system: treatment group 1 (5, 26%); treatment group 2 (1, 9%) Genitourinary system: treatment group 1 (2, 11%); treatment group 2 (2, 18%) Septic shock: treatment group 1 (4, 21%); treatment group 2 (1, 9%) Trauma: treatment group 1 (1, 5%); treatment group 2 (2, 18%) Other system: treatment group 1 (4, 21%); treatment group 2 (1, 9%) Mechanical ventilation: treatment group 1 (17, 89%); treatment group 2 (10, 91%) Mechanical ventilation hours (median, IQR); treatment group 1 (179, 81 to 398.5); treatment group 2 (144, 86 to 151) Exclusion criteria: weight < 30 kg; inability to enter randomisation due to a contraindication to one of the treatment arms; indication for systemic anticoagulation with heparin (therapeutic range APTT) or an equivalent therapeutic dose of LMWH (does not include routine thromboprophylaxis with these agents); prior development of HIT; history of anaphylaxis to heparin, protamine or citrate; pregnancy, or lactation; patients on chronic KRT prior to ICU presentation; indication for therapeutic hypothermia; previous participation in the same study; indication for a filter set other than the AN69 ST100 1 m² set or a specific dialysis prescription differing from the study protocol (as deemed by the treating physician)
Interventions	Treatment group 1 Citrate: initial citrate dose and monitoring and adjustment of citrate (every 60 min) determined by arterial ionised calcium concentration Treatment group 2 UFH: currently implemented Alfred ICU regional heparin (± protamine) circuit anticoagulation protocol Heparin is given via a standard infusion pump at a protocol defined rate with APTT monitoring to avoid systemic anticoagulation
Outcomes	Major bleeding Death at 28 days Recovery of kidney function Adverse events: number of treatment attempts leading to treatment dropout
Notes	Supported by Alfred Hospital Small Project Grant ($10,000) Conflict of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was by a computer web‐based system
Allocation concealment (selection bias)	Low risk	Allocation was concealed
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not blinded Quote: "Due to the significant differences in fluids and monitoring, blinding of researchers to treatment protocols was not practical"
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not blinded Quote: "Due to the significant differences in fluids and monitoring, blinding of researchers to treatment protocols was not practical"
Incomplete outcome data (attrition bias)   All outcomes	High risk	Multiple enrolment and no detailed information
Selective reporting (reporting bias)	High risk	Some of safety primary outcomes in the protocol were not reported
Other bias	Low risk	Supported by Alfred Hospital Small Project Grant

Methods	Study design: parallel RCT Study duration: not reported *Study follow‐up period: the treatment phase was equal to the time on CVVH until death, recovery of kidney function or switch to another KRT. The follow‐up phase was the time from discontinuation of CVVH until discharge from the ICU up to a maximum of 30 days
Participants	Country: Germany Setting: multicentre (9 ICUs) Inclusion criteria: written informed consent; > 18 years ; diagnosis of AKI and indication for KRT as assessed by one of the following criteria: (i) volume over‐ load, not correctable by diuretics despite adequate blood pressure and SCr > 1.2 mg/dL; (ii) increase of SCr > 2.5 mg/ dL or BUN > 50 mg/dL; and (iii) increase of serum potassium > 5.5 mmol/L due to oligoanuria; patients who at the time of inclusion had not yet started with KRT; arterial line as vascular access; mechanical ventilation Number: treatment group 1 (87); treatment group 2 (83) Mean age ± SD (years): treatment group 1 (61.72 ± 15.29); treatment group 2 (65.11 ± 12.46) Sex (M/F): treatment group 1 (57); treatment group 2 (59) Other relevant information Sepsis: treatment group 1 (67); treatment group 2 (61) Post‐operative: treatment group 1 (41); treatment group 2 (41) Exclusion criteria: HIT; need to continue effective systemic heparin anticoagulation with an APTT > 20% above the upper limit of the normal range; metabolic alkalosis as defined by a pH > 7.50 and base excess of >+4 mmol/L; pregnancy, lactation period ; on chronic KRT; participation in another study during the preceding 3 months; previous participation in the same study Patient withdrawal and dropout: severe metabolic alkalosis as defined by an increase of pH > 7.55 and base excess of > +8 mmol/L without possibility of respiratory/ventilational compensation; severe citrate accumulation as defined by pH < 7.20 and BE < −10 mmol/L and no obvious cause other than citrate overload, especially no intoxication, ketoacidosis, or lactacidosis ; HIT developing during study ; wish of the patient or legal representative (withdrawal of the declaration of consent) ; general deviation from the study protocol; decision of the investigator
Interventions	Treatment group 1 Citrate: citrate‐based CVVH solution as regional citrate anticoagulation. Flow rates of blood and substitution fluid were adopted to the equivalent of ˜4 mmol citrate/1000 mL of treated whole blood and then adapted to the patient’s weight range. Calcium losses caused by the extracorporeal clearance of citrate–calcium complexes were substituted by IV infusion of a 5.5% calcium chloride solution Treatment group 2 Heparin: systemic heparin anticoagulation and a bicarbonate‐based CVVH solution
Outcomes	Major bleeding (documented in 4 patients in the citrate group and 5 patients in the heparin group) Mild: no clinical symptoms, no drop in Hb > 2 g/dL/day Moderate and severe bleeding episodes: drop in Hb > 2 g/dL/day or the need for red cell transfusions, were documented in four patients in the HF‐Citrate group and five patients in the HF‐Bicarbonate group. 28‐day death: death at 30 days from starting observation Thrombocytopenia Adverse events: number of treatment attempts leading to treatment dropout (1 patient with known liver cirrhosis in the citrate group had to be withdrawn from the study according to the protocol due to assumed citrate accumulation) Number of treatment attempts with adverse events
Notes	Funding: Sponsored by Fresenius Medical Care, Germany (Dialysis related medical supply company)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised; method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Patients who did not receive study medication were excluded for the analysis: citrate (0/87); heparin (4/87)
Selective reporting (reporting bias)	Low risk	Important outcomes were reported
Other bias	High risk	Sponsored by Fresenius Medical Care, Germany (Dialysis medical supply company)

PERMALINK

Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy

Hiraku Tsujimoto

Yasushi Tsujimoto

Yukihiko Nakata

Tomoko Fujii

Sei Takahashi

Mai Akazawa

Yuki Kataoka

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Multiple enrolments of the same participants from either individually randomised or cross‐over studies

Clustering at the level of the enrolled units in cluster‐randomized trials

Multiple comparisons

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation

Allocation concealment

Blinding

Performance bias

Detection bias

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Citrate versus unfractionated heparin for continuous renal replacement therapy.

Summary of findings 2. Unfractionated heparin versus low molecular weight heparin for continuous renal replacement therapy.

Summary of findings 3. Unfractionated heparin versus no pharmacological anticoagulation for continuous renal replacement therapy.

Citrate versus unfractionated heparin

Major bleeding

1.1. Analysis.

4.

Methods	Study design: multi‐enrolment parallel RCT Study duration: not reported Study follow‐up period: not reported
Participants	Country: Austria Setting: single centre ICU Inclusion criteria: adults requiring haemofiltration for treatment of AKI secondary to sepsis or major surgery; all patients were sedated, mechanically ventilated and additional therapy was administered according to the ICU's standard protocol; all patients received UFH as anticoagulant infused into the extracorporeal circuit before the haemofilter Number: treatment group 1 (17); treatment group 2 (15); treatment group 3 (18) Mean age ± SD (years): treatment group 1 (64 ± 18); treatment group 2 (60 ± 15); treatment group 3 (62 ± 10) Sex (M/F): not reported Other relevant information Abdominal surgery: treatment group 1 (10); treatment group 2 (9); treatment group 3 (8) Liver transplantation: treatment group 1 (2); treatment group 2 (3); treatment group 3 (2) Thoracic surgery: treatment group 1 (5); treatment group 2 (4); treatment group 3 (5) Peritonitis: treatment group 1 (1); treatment group 2 (2); treatment group 3 (3) Exclusion criteria: pre‐existing CKD; therapy with aspirin or other cyclooxygenase inhibitors; concomitant treatment with other extracorporeal organ assist devices
Interventions	The initial drug dose of heparin was 5 IU/kg/hour and the dose was adjusted to achieve an activated clotting time in the extracorporeal system of > 120 sec. The ACT monitoring was done at least every 12 hours. All haemofilters were primed with 5000 IU heparin Treatment group 1 Heparin group: infusion of normal saline Treatment group 2 Heparin plus prostaglandin I2: infusion of prostaglandin I2 (5 ng/kg/min) Treatment group 3 Heparin plus prostaglandin E1: infusion of prostaglandin E1 (5 ng/kg/min)
Outcomes	Major bleeding Successful prevention of clotting Proposition of adequate haemofilter life span (> 24 hour) The life span was documented for the first 10 days of haemofiltration treatment <Criteria of end of filter life> Arterial pressure of > 250 mmHg Decrease of ultrafiltration rate 16 mL/min Grossly visible clotting within extracorporeal circuit The incidence and severity of bleeding were recorded and classified into three categories: none, trivial, or significant. Trivial bleeding was defined as the occurrence of blood‐stained secretions or ecchymoses Significant bleeding was defined as the occurrence of bleeding requiring transfusion of blood products Direct variable costs/patients/day were derived by adding up the acquisition costs of anticoagulants (including sterile syringes, infusion pump giving sets, and three‐way tapes), as well as disposable haemofiltration equipment (haemofilter, catheters, blood warmer tubing, gloves) Cost to health care services: costs were those actually paid by the hospitals pharmacy at the time of treatment (one haemofilter set including the line system: 143.9 Euro; 0.5mg PGE1: 8.1 Euro; 0.5mg prostacyclin: 142.5 Euro; 100.000 IU heparin: 3.2 Euro). The costs for substitution fluids have not been included because of high variability of volume management in our patients. All electively discontinued haemofilter were excluded from cost analysis
Notes	Funding: Department of Anaesthesiology and General Intensive Care, University of Vienna
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated sequence were used
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Test solution was administered in double blind manner. No detailed information was available
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Test solution was administered in double blind manner. No detailed information was available
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Multiple enrolment and no information of missing data
Selective reporting (reporting bias)	High risk	Death‐related outcomes not reported
Other bias	High risk	Funding: Department of Anaesthesiology and General Intensive Care, University of Vienna The same research group reported several RCTs comparing similar intervention. Academic COI were suspected. Financial conflict of interest was not reported

Study	Reason for exclusion
ALicia 2014	Wrong population: HIT patients in ICU
Ambros Checa 1995	Wrong intervention: Evaluates the use of CVVHF vs no CVVHF to improve the clearance of thromboxane A2
Anstey 2016	Wrong intervention: dose comparison of citrate was assessed
ISRCTN01121161	Wrong intervention: dose comparison of heparin was assessed
Kozek‐Langenecker 1998	Wrong intervention: effect of different dose of PGE₁ was investigated
Kozek‐Langenecker 2003	Wrong intervention: effect of prostacyclin (PGI₂) on platelets function was investigated
Lafargue 2008	Wrong population: 29 consecutive patients with septic shock and treated by CVVH were included
Leslie 1996	Wrong intervention: 2 circuit configurations with different heparin administration dilutions were compared. In combination A, standard CVVHD blood lines and heparin concentration (100 U/ml) were used. In combination B, heparin was delivered in a more dilute volume (10 U/mL) via a modified circuit design with an administration port immediately adjacent to the venous access
Lin 2007	Wrong population: CVVHDF anticoagulation for multiple organ disorder patients were investigated
NCT01228292	Wrong intervention: Anticoagulation of sustained low efficiency dialysis (one of intermittent dialysis methods) was assessed
NCT01318811	Wrong intervention: effect of concentration of unfractionated heparin was assessed
NCT02194569	Wrong intervention: effect of different dose of citrate will be assessed
Opatrny 2002b	Wrong intervention: effect of heparin rinse of the circuit on circuit biocompatibility before the CRRT procedure was assessed
Oudemans‐van Straaten 2009a	Wrong intervention: effect of filtration flow speed was assessed
Reeves 1997	Wrong intervention: effect of albumin (human blood preparations) priming of circuit were assessed
Robinson 2014	Wrong intervention: dose comparison of enoxaparin was assessed
Singer 1994	Wrong intervention: effect of continuous venovenous haemofiltration on blood heparin levels (as measured by anti‐Factor Xa activity)
Tingli 2014	Wrong intervention: anticoagulation of sustained low efficiency dialysis (one of intermittent dialysis methods) was assessed
VERROU‐REA 2014	Wrong intervention: effects of catheter locking fluid were assessed
Wang 2009e	Wrong intervention: anticoagulation of high dose dialysis (not continuous) was assessed
Wang 2014b	Wrong intervention: anticoagulation of sustained low efficiency dialysis (one of intermittent dialysis methods) was assessed

Methods	Study design: parallel RCT Blinding: double (participant, outcomes assessor)
Participants	Inclusion criteria SIRS ≥ 2 meets definition; AKI in ICU; requiring CVVHF Exclusion criteria Pregnancy; cirrhosis; ESKD; HIV infection; SCr in males > 2 mg/dL and females > 1.5 mg/dL; bleeding
Interventions	Treatment group 1 Regional citrate anticoagulation Filter: AQUAMAX™ (Edwards Lifesciences) Control group No anticoagulation or heparin Filter: AQUAMAX™ (Edwards Lifesciences)
Outcomes	Primary outcome measures Functions of inflammatory cells: 24 hours CD11b expression on PMN and HLA‐DR expression on monocyte  Regulation of inflammatory reactions and opsonization in microorganisms: 24 hours C3a and C5a  Activity of acute phase protein during acute inflammation: 24 hours PAI‐1  Secondary outcome measures Survival rate: 28 days Length of ICU stay: 28 days
Notes	No contact information

Trial name or title	Circuit survival and efficacy for middle molecular‐weight solute elimination between nafamostat infusion and heparinized saline priming
Methods	Study design: parallel RCT Blinding: none (open label)
Participants	Inclusion criteria Injury stage of RIFLE criteria or more (> 2‐fold increase in the SCr or urine output < 0.5 mL/kg/hour for 12 hours); any dialysis treatment before admission to the ICU or patients with ESKD and receiving dialysis; informed consent Exclusion criteria < 20 years or > 85 years; life expectancy < 3 months (ex. terminal stage of malignancy); Child‐Pugh class C liver cirrhosis; pregnancy or lactation; history of anticoagulation prior to the randomisation; bleeding tendency (platelet count < 50,000/µL, INR > 2.5, PTT > 65, or fibrinogen < 1.00 g/L); history of haemorrhagic disease (excluding GI bleeding, cerebral haemorrhage, pulmonary haemorrhage)
Interventions	Treatment group 1 Heparinised saline priming Treatment group 2 Nafamostat infusion after heparinised saline priming
Outcomes	Primary outcome The time of 1st membrane exchange Secondary outcomes Clearance of small molecule (urea) Clearance of middle molecule (beta‐2 microglobulin) ACT measurements after 1 hour of CRRT Haemorrhagic complication
Starting date	March 2012
Contact information	Responsible party: Seoul National University Hospital
Notes

Trial name or title	Regional citrate versus systemic heparin anticoagulation for super high‐flux continuous hemodialysis in septic shock: effect on middle molecular weight molecules clearances
Methods	Study design: parallel RCT Blinding: none (open label)
Participants	Inclusion criteria Male or female critically ill patients > 18 years; AKI requiring CRRT defined using RIFLE classification with criterion I or worse; septic shock as defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference; written informed consent Exclusion criteria Pregnancy; participation in another research study protocol; known HIT or contraindication to heparin; pre‐existing CKD on chronic dialysis; therapeutic anticoagulation with heparin for another reason (e.g. chronic arrhythmia); Severe liver failure (15% PT)
Interventions	Treatment group 4% trisodium citrate: infusion titrated to maintain postfilter ionised calcium between 0.25 and 0.35 mmol/L Calcium chloride solution (100 mmol/L): infusion titrated to maintain systemic ionised calcium between 1.12 and 1.2 mmol/L Dialysate flow rate: 35 mL/kg/hour Blood flow rate: adjusted to maintain a ratio blood flow rate/dialysate flow rate of 3; adapted to the acid‐base status Control group Continuous infusion of unfractionated heparin: starting infusion rate at 600 IU/hour then adjusted to maintain partial thromboplastin time at 1 to 1.4 times the normal value Dialysate flow rate: 35 mL/kg/hour Blood flow rate: adjusted to maintain a ratio blood flow rate/dialysate flow rate
Outcomes	Primary outcome Middle molecular weight molecules clearances: 1 hour, 4 hours, 12 hours; 24 hours, 48 hours, 72 hours At each time point of the study, blood and post‐filter samplings will be taken in order to calculate kappa and lambda light chains of immunoglobulin clearances Secondary outcomes Clearances of cytokines and molecules of interest: 1 hour, 4 hours, 12 hours; 24 hours, 48 hours, 72 hours At each time point of the study sampling will be simultaneously collected from blood and post‐filter in order to determine cytokines (IL‐1 ra, IL‐10, IL‐6, IL‐8, beta‐2 microglobulin), urea, creatinine and albumin clearances Haemodynamic parameters: 1 hour, 4 hours, 12 hours; 24 hours, 48 hours, 72 hours At each time point of the study, clinical data and blood sampling will be collected in order to assess mean arterial pressure, heart rate, vasopressor requirement and lactate level. Respiratory parameters: 1 hour, 4 hours, 12 hours; 24 hours, 48 hours, 72 hours At each time point of the study PaO₂/FIO₂ ratio will be measured by blood sampling and clinical data collection. Death: 28th day
Starting date	May 2013
Contact information	Responsible party: Hospices Civils de Lyon
Notes

Trial name or title	Clinical evaluation of use of prismocitrate 18 in patients undergoing acute continuous renal replacement therapy (CRRT)
Methods	Study design: parallel RCT Blinding: none (open label)
Participants	Inclusion criteria Receiving medical care in an ICU; adult patients with AKI or other serious conditions who require treatment with CRRT; expected to remain in the ICU and on CRRT for at least 72 hours after randomisation; already receiving standard‐of‐care CRRT must be randomised within 24 hours of initiation of their standard‐of‐care CRRT Exclusion criteria Requiring systemic anticoagulation with antithrombotic agents for reasons other than CRRT (exception is patients receiving SC heparin for deep vein thrombosis prophylaxis according to institutional practice or patients on aspirin may be enrolled); citrate anticoagulation is contraindicated (known allergy to citrate or who have experienced adverse events associated with citrate products including patients with a prior history of citrate toxicity or patients with uncorrected severe hypocalcaemia, whether in the context of current citrate administration or due to the underlying disease state); not candidates for CRRT; receiving extracorporeal membrane oxygenation therapy; severe coagulopathy (platelets < 30,000/mm³, INR > 2, PTT > 50 sec, HIT, idiopathic thrombocytopenia purpura), and thrombotic thrombocytopenia purpura); fulminant acute liver failure or acute on chronic liver failure as documented by a Child‐Pugh Liver Failure Score > 10; refractory shock associated persistent, worsening with lactic acidosis (lactate > 4 mmol/L), patients with improving subsequent serum lactate levels may be enrolled; unlikely to survive at least 72 hours; pregnant, lactating, or planning to become pregnant during the study period; currently participating in another interventional clinical study; medical condition that may interfere with the study objectives
Interventions	Treatment group Regional citrate anticoagulation (Prismocitrate 18) Control group No anticoagulation
Outcomes	Primary outcome measure Time to occurrence of selected Prismaflex® System alarms/conditions: up to 120 hours post CRRT treatment initiation Secondary outcome measures Systemic blood iCa concentrations: baseline and up to 120 hours post CRRT treatment initiation Post‐filter blood iCa concentrations: up to 120 hours post CRRT treatment initiation; post‐filter blood iCa concentrations will only be measured in the citrate arm Delivery of prescribed CRRT dose: up to 120 hours post CRRT treatment initiation Prismocitrate 18 training assessment: prior to study use of Prismocitrate 18; training to be completed on administration of Prismocitrate 18. Users, as delegated by the Principal Investigator, will be required to pass an assessment to demonstrate the understanding of how to use the solution Serum bicarbonate: baseline and up to 120 hours post CRRT treatment initiation pH: baseline and up to 120 hours post CRRT treatment initiation Base excess: baseline and up to 120 hours post CRRT treatment initiation Blood total calcium concentration: baseline and up to 120 hours post CRRT treatment initiation Serum sodium: baseline and up to 120 hours post CRRT treatment initiation Serum anion gap: baseline and up to 120 hours post CRRT treatment initiation Serum magnesium: baseline and up to 120 hours post CRRT treatment initiation Serum phosphate: baseline and up to 120 hours post CRRT treatment initiation Serum potassium: baseline and up to 120 hours post CRRT treatment initiation Serum chloride: baseline and up to 120 hours post CRRT treatment initiation Number, location, and duration of bleeding events: up to 120 hours post CRRT treatment initiation Blood transfusions: up to 120 hours post CRRT treatment initiation Adverse events: up to 30 days post study CRRT treatment completion Blood pressure: baseline and up to 120 hours post CRRT treatment initiation Respiratory rate: baseline and up to 120 hours post CRRT treatment initiation Temperature: baseline and up to 120 hours post CRRT treatment initiation Pulse: baseline and up to 120 hours post CRRT treatment initiation
Starting date	September 27, 2016
Contact information	Responsible Party: Baxter Healthcare Corporation
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