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.

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.

Read the full 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 strategy: 

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.

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