How to reduce the exposure to anticoagulants when performing haemodialysis in patients with a bleeding risk : a study of methods used in clinical practise

Sammanfattning: When a patient suffers from kidney failure and also has an enhanced risk of bleeding, the standard haemodialysis (HD) treatment becomes a problem. When human blood comes in contact with artificial material, as in the tubing system and in the dialyser (the extra corporeal circuit, ECC), the coagulation system is activated. If there is no increased risk of bleeding a bolus dose of anticoagulation is given intravenous to the patient before HD to avoid clotting. The most common anticoagulants used during HD are unfractionated heparin (UFH) and low molecule weight heparins (LMWH). Without anticoagulants there will be a total coagulation (clotting) of the blood in the ECC, an interrupted treatment and a blood loss of up to 300 ml for the patient. With an ongoing bleeding or an increased risk of bleeding in a patient that also needs HD, there are various alternatives that can be used to avoid or lower the need of anticoagulation. However, there is no golden standard, neither in Sweden or worldwide.The overall aim of this Thesis was to evaluate the safety and the efficacy of various models of anticoagulation that may be used in patients with a bleeding risk.The first study examined a low-dose anticoagulation model that was locally developed in Umeå, Sweden in the 1980s. The primary aim was to clarify to what extent this priming model was safe and efficient during intermittent HD for patients with a bleeding risk. Consecutive acute HD treatment protocols (248 procedures in 68 patients) were included. There were 178 patients with an increased bleeding risk who had their ECC (tubes, chambers and dialyser) flushed through (priming) with Heparin-Albumin-priming (HA-priming). There were 70 patients with no increased bleeding risk who received standard intermittent HD (priming with saline); these patients also received a bolus dose of anticoagulation intravenous before dialysis.The low-dose method entailed priming of the ECC with HA-priming with the intention to coat the surfaces with the solution and protect from blood to attach to it. Comparisons were made to dialysis in patients with no increased bleeding risk, who had received standard anticoagulation (SHD) with UFH or LMWH. The priming solutions were always discarded before HD was initiated. None or limited doses of UFH were added during the HD. There was no difference in extent of prematurely interrupted HA-primed dialysis compared to SHD (2.2 vs. 4.3%, p = 0.62). No secondary bleeding due to anticoagulation was reported in the protocols.Study 2 was performed to further clarify data in an extended group of acute intermittent HD using either HA-priming (885 treatments in 221 patients at risk of bleeding) or SHD (523 treatments in 100 patients with no bleeding risk who had received standard anticoagulation). In this extended study there was no difference in the extent of prematurely interrupted HA-dialysis (0.8%) compared to SHD (1%, p = 0.8). The results also showed less clotting for dialysers with a membrane area ≤ 1.7 m2. No secondary bleeding due to anticoagulation was reported in the protocols.Study 3 was an experimental in vitro study. The aim was to compare the anticoagulation effect of priming the ECC with different concentrations of albumin and/or heparin in saline. Priming with saline only was also evaluated. The priming fluids were always discarded after priming. Fresh whole blood from healthy human donors was used to perform in vitro dialyses in a recirculation system. The donated blood was equally divided into two bags, whereas one bag represented the control group and the other the intervention group. Priming with saline only and priming with albumin in saline resulted in rapid clotting of the blood in the ECC. These experiments indicated that HA-priming or priming with heparin in saline enabled fulfilment of all the in vitro dialyses.Study 4 was a clinical randomized cross-over study. The aim was to minimize the use of anticoagulant during HD in patients with a bleeding risk. Four different low-dose anticoagulation models were compared to SHD. Stable chronic HD patients participated in the study. The patients were their own controls. Aside from SHD, the four models of low-dose anticoagulation used were Heparin priming (H), HA-priming (HA), HA-priming in combination with a citrate containing dialysate (HAC), and a dialyser manufactured with a heparin-grafted membrane (Evodial®). The H-model was least suitable with 33 % interrupted treatments and the most extra doses of UFH needed. The HAC and Evodial® models were most preferable, both with an activated partial thromboplastin time (APTT) within references and with the least amounts of UFH needed. Evodial® had a lower urea reduction rate compared to the other models. HAC was the only model with no interrupted treatment. One patient suffered from a severe hypersensitivity reaction using Evodial®. No other side-effects were reported during the study.In conclusion an acute kidney injury is a life-threating situation that also includes patients with an increased bleeding risk and in need of HD for survival. If intermittent HD is the selected option, a priming of the ECC with a HA-solution in combination with a citrate containing dialysis fluid (HAC) is a safe and sufficient option for anticoagulation. Another option could be the heparin-grafted dialyser (Evodial®), although with a lower clearance coefficient and with a caution for a risk for hypersensitivity reaction or anaphylaxis.