The key finding of this study is that RCA plus infusion of unfractionated heparin might be superior to RCA alone for prolonging circuit life and reducing filter losses during CRRT in COV + AKI patients, with similar rates of adverse events (bleeding or the need of blood transfusion).
In addition to the increased demand for dialysis, COVID-19 patients are especially predisposed to thrombotic events, theoretically increasing the propensity for filter clotting (9, 14–16). However, despite the initial impression that the life spans of dialysis filters are shorter in COV + AKI patients, a diagnosis of COVID-19 was not found to be a major risk factor for filter clotting in the present study. Nevertheless, CRRT filter clotting is still a major concern in critically ill patients because CRRT filter clotting not only can result in shortages of medical equipment and consumables but also may be associated with blood loss and shorter dialysis times. Therefore, it is crucial to maintain appropriate, effective anticoagulation during dialysis (17, 18).
Various anticoagulation strategies have been studied (19). Randomized controlled trials have shown RCA to be clearly superior to the use of heparin, with a better adverse-event profile (19–22). Unless contraindicated, citrate is also recommended as the first-line option in CRRT (12). However, none of those studies involved COV + AKI patients or other known prothrombotic factors. In addition, there have been no studies comparing the use of the combination of citrate and heparin with the use of either of those anticoagulation strategies, even in patients without COVID-19.
Our findings suggest that the use of systemic heparin plus RCA blunts the excessive prothrombotic effect that RRT has on filter patency in COVID-19 patients (9, 15, 16). Although some groups are already using this strategy informally in the management of CRRT in COVID-19 patients (9, 10, 14, 16), there have been few studies comparing different anticoagulation strategies in that context.
Our data are in agreement with the findings of Shankaranarayanan et al. (10), who showed that, in COVID-19 patients, the concomitant use of systemic heparin and citrate could lead to fewer thrombotic events in CRRT circuits when compared with other strategies, including citrate alone and heparin alone. Those authors reported a median filter life of just 21 hours for no anticoagulation, compared with 40 hours for citrate alone and > 72 hours for citrate plus heparin. Similarly, in the present study, in which no procedures were performed without anticoagulation, the median filter survival was 45 hours for citrate alone and > 72 hours for heparin associated with citrate. Wen et al. (16) also showed longer circuit life when heparin-based regimens were used in sustained low-efficiency dialysis.
In the present study, the adverse-event profile was similar between the ACD-A-only and ACD-A + UH groups. Heparin use was not found to be associated with lower platelet counts. We found a low incidence of bleeding episodes, so it is possible that they may not be sufficient to determine if adverse events rates are certainly different between groups. However, despite the relatively small number of patients studied, this is currently the greatest casuistic regarding anticoagulation in CRRT in patients with COVID-19 in the literature. To our knowledge, this is the first report of the safety profile of the heparin-citrate combination in CRRT. We also found that in-hospital mortality was similar to that previously reported for COV + AKI and COV − AKI (23, 24), the former being more lethal than the latter.
Another important aspect of the thrombotic potential of COVID-19 is related to D-dimer levels (1). In COVID-19 patients, an elevated D-dimer level has been shown to be predictive of thrombotic complications (25). In the present study, elevated D-dimer levels were found to predispose to higher rates of filter clotting in CRRT. That differs from the findings of a previous study comparing diverse anticoagulation strategies in COVID-19 (16), in which D-dimer levels had no apparent effect on circuit clotting. However, that study evaluated only sustained low-efficiency dialysis, with a median of < 36 hours per session in all groups, and the reported D-dimer levels were much lower. Therefore, it was not possible to draw comparisons with the present study.
To our knowledge, ours is the largest study comparing ACD-A alone and ACD-A plus unfractionated heparin in CRRT performed in COVID-19 patients. We believe that it is also the first study to address safety concerns regarding the use of the latter combination.
Our study has some limitations. To meet the challenge of the potential for clotting in CRRT performed in COVID-19 patients, we not only added systemic heparin to the regimen but also increased the ACD-A concentration and lowered the target post-filter iCa concentration. Therefore, in the ACD-A + UH group, the proportion of patients in whom the target citrate concentration was 4 mmol/L (rather than 3 mmol/L) was higher, and the outcome may in part be a consequence of the success of the anticoagulation with ACD-A, which may interfere in generalizability to other centers. That could have influenced our results, although a target citrate concentration of 4 mmol/L was not found to be a protective factor in the multivariate Cox analysis. However, the addition of heparin was found to be a consistent protective factor, and we believe that this combined strategy should be adopted in settings in which there is a high risk of clotting. In addition, because of the retrospective study design, data regarding D-dimer levels were not available for the COV − AKI patients. It would have been interesting to determine whether higher D-dimer levels are associated with higher mortality. That would also have allowed us to investigate whether the supposed higher risk of filter clotting in COV + AKI patients is attributable solely to D-dimer levels. Furthermore, also because of the retrospective study design, our results might be attributable to other, unmeasured co-interventions. Moreover, our study reflects the experience of a single center in Brazil and therefore may not reflect the reality for all COV + AKI patients.