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An evaluation of four modes of low-dose anticoagulation during intermittent haemodialysis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Nephrology, Centre of Medicine, University Hospital of Umeå, Umeå, Sweden.ORCID iD: 0000-0002-3052-6455
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2018 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 3, p. 267-274Article in journal (Refereed) Published
Abstract [en]

Intensive care participants that need dialysis frequently suffer from increased risk of bleeding. Standard intermittent haemodialysis (SHD) includes anticoagulation to avoid clotting of the dialysis system. The aim of this study was to clarify which of four different low-dose anticoagulant modes was preferable in reducing the exposure to i.v. unfractionated heparin (heparin) and maintaining patency of the dialysis circuit. Twenty-three patients on SHD were included to perform haemodialysis with four modes of low-dose anticoagulation. For comparative analyses, patients served as their own control. Haemodialysis with a single bolus of tinzaparin at the start was compared to haemodialysis initiated without i.v. heparin but priming with (1) heparin in saline (H), (2) heparin and albumin in saline (HA), (3) heparin and albumin in combination with a citrate-containing dialysate (HAC), (4) saline and usinga heparin-coated filters (EvodialA (R)). The priming fluid was discarded before dialysis started. Blood samples were collected at 0, 30 and 180 min during haemodialysis. Smaller bolus doses of heparin (500 Units/dose) were allowed during the modes to avoid interruption by clotting. The mean activated partial thromboplastin (APTT) time as well as the doses of anticoagulation administered was highest with SHD and least with HAC and EvodialA (R). Mode H versus SHD had the highest rate of prematurely interrupted dialyses (33%, p = 0.008). The urea reduction rate was less with EvodialA (R) vs. SHD (p < 0.01). One hypersensitivity reaction occurred with EvodialA (R). Changes in blood cell concentrations and triglycerides differed between the modes. If intermittent haemodialysis is necessary in patients at risk of bleeding, anticoagulation using HAC and EvodialA (R) appeared most preferable with least administration of heparin, lowest APTT increase and lowest risk for prematurely clotted dialyzers in contrast to the least plausible H mode.

Place, publisher, year, edition, pages
Springer, 2018. Vol. 74, no 3, p. 267-274
Keyword [en]
Haemodialysis, Haemorrhage, Priming, Anticoagulation
National Category
Hematology Pharmacology and Toxicology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-132227DOI: 10.1007/s00228-017-2389-xISI: 000424708300002PubMedID: 29198062OAI: oai:DiVA.org:umu-132227DiVA, id: diva2:1078998
Note

First published in thesis in manuscript form with the title "An evaluation of four modes of low-dose anticoagulation during haemodialysis".

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2018-03-13Bibliographically approved
In thesis
1. How to reduce the exposure to anticoagulants when performing haemodialysis in patients with a bleeding risk: a study of methods used in clinical practise
Open this publication in new window or tab >>How to reduce the exposure to anticoagulants when performing haemodialysis in patients with a bleeding risk: a study of methods used in clinical practise
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Abstract [sv]

När njurarnas funktion sviktar kan dialysbehandling behövas. Vid dialysbehandling utan någon förestående blödningsrisk administreras en dos blodförtunnande läkemedel intravenöst innan behandlingen startas. Detta minskar risken för att blodet ska koagulera i systemet.

Om det däremot finns en ökad risk för blödning uppstår ett dilemma: patienten behöver dialys utan att en blödning uppstår eller att en pågående blödning förvärras. När blod kommer i kontakt med främmande material aktiveras koagulationen. Det material som finns i de slangar, kamrar och det dialysfilter som blodet ska passera många varv genom under dialysen är just ett, för blodet, främmande material. Om blodet koagulerar i systemet kan det leda till att behandlingen måste avbrytas i förtid, effekten av dialysen blir sämre än planerat och patienten kan dessutom förlora 300 ml blod som inte går att återföra från slangarna.

Det finns olika metoder för att genomföra dialys utan, eller med en reducerad dos, blodförtunnande läkemedel. Det finns däremot ingen uttalad 'golden standard'.

Syftet med den här avhandlingen var att klargöra säkerheten och effekten, både vad gäller blödningsrisk och dialyseffekt, vid användande av Heparin-Albumin-priming (HA) - en metod som är utformad vid Norrlands universitetssjukhus i Umeå på 1980-talet. Syftet var också att undersöka olika priming-lösningar in vitro varvid de med bästa resultat prövades i en klinisk studie där de jämfördes mot andra metoder.

Studie 1 utvärderade data från 248 behandlingsprotokoll från akuta dialysbehandlingar av 68 patienter. Jämförelse gjordes mellan dialyser av:

- Patienter med en ökad blödningsrisk som därför fått dialyssystemet igenomspolat (primat) med HA-priming (HA, 178 st)

- Patienter utan blödningsrisk som fick dialyssystemet primat med koksalt och fick en dos blodförtunnande läkemedel intravenöst (SHD, 70 st).

Resultatet visade signifikant lägre heparindoser vid behandling efter HA-priming jämfört med SHD (medianvärden: HA 2000 enheter (E) mot SHD 5500E, p < 0.001).

Det var inte någon skillnad i antal avbrutna behandlingar på grund av clotting: HA 2.2 % och SHD 4.3 % (p = 0.62). 

Ingen nytillkommen eller tilltagande blödning hade noterats på protokollen.

Studie 2 var en utvidgad studie av data från behandlingsprotokoll från 1408 akuta dialysbehandlingar av 321 patienter mellan åren 1997-2013. Syftet var att utvärdera resultatet från studie ett och att även utöka mängden data. Genom att inkludera flera olika dialysatorer kunde en eventuell variation över tid upptäckas. Jämförelser gjordes mellan:

- HA-priming - 883 behandlingar med totalt 221 patienter som fick ingen eller minimal dos antikoagulation efter att systemet spolats igenom med heparin och albumin-priming.

- SHD - 523 behandlingar med totalt 100 patienter som fick systemisk antikoagulation.

Jämförelser gjordes också mellan olika material i dialysatorernas membran, membranens storlek (m2) och porstorlek, samt den bakomliggande orsaken till akuta dialysbehandling.

Resultatet visade att dialys efter HA-priming genomfördes med signifikant lägre doser heparin i genomsnitt (1200E) jämfört med SHD (5000E, medianvärden, p < 0.001). Trots signifikant lägre heparindoser med HA sågs ingen skillnad i antalet avbrutna behandlingar på grund av clotting (HA 1 % och SHD 0.8 %, p = 0.8).

Studien visade att det är större risk för clotting med en dialysator vars area är ≥1.7m2. Det var ingen skillnad i clotting mellan olika membranmaterial eller mellan high-flux dialysatorer och low-flux-dialysatorer.

Studie tre var en experimentell in vitro-studie med syfte att utvärdera effekten av priming med:  

- Olika koncentrationer av Heparin och Albumin tillsammans i koksalt.

- Heparin i koksalt

- Albumin i koksalt

- Priming med endast koksalt

Syftet var att undersöka om någon kombination var mer fördelaktig än någon annan. Blod donerat från friska försökspersoner användes för dialys i ett slutet kretslopp efter priming. Varje donators blod delades upp i två lika delar som dialyserades parallellt. Den ena delen fungerade som kontroll och den andra användes till intervention och donator blev på så vis sin egen kontroll.

Studien visade att priming med enbart heparin i koksalt samt HA-priming var goda alternativ. Priming med albumin i koksalt eller endast koksalt resulterade i total clotting av filer och dialysslang efter i genomsnitt 20 minuters dialys.

Studie fyra var en klinisk randomiserad cross-over studie. Syftet var att jämföra fyra olika metoder för att minimera tillförsel av blodförtunnande läkemedel.

Slangar, kamrar och dialysfilter primades med:

1) Heparin i koksalt (H-priming)

2) Heparin och Albumin i koksalt (HA-priming)

3) Heparin och Albumin i koksalt kombinerat med dialysvätska innehållande Citrat (HAC)

4) Koksalt i kombination med en dialysator som har heparin fixerat på membranytan (Evodial®).

Studiedeltagare var 23 personer med kronisk njursvikt som behandlades med regelbunden hemodialys. Deltagarna var sina egna kontroller genom hela studien.

För att få utgångsvärden genomfördes också en behandling med deltagarnas vanliga dos av heparin eller tinzaparin inom ramarnaa för studien.

Resultaten visade att H-priming var minst fördelaktigt eftersom den krävde höga doser av heparin för att förhindra clotting. Med H-priming fick 33 % av dialyserna avslutas i förtid på grund av clotting. Vid analys av APTT resulterade H-priming i medelvärden över referensvärde (22 - 36 sekunder).

Minst mängd heparin krävdes med HA-priming, HAC och Evodial®. De tre metoderna hade även ett medelvärde av APTT som låg inom normala referensvärden. HAC var den enda metod som inte hade någon avbruten behandling. Evodial® klarade flest behandlingar helt utan heparin men gav en sämre rening än de andra metoderna.

Vid behandling med Evodial® fick en patient en kraftig överkänslighetsreaktion som medförde att behandlingen avbröts. Inga andra komplikationer tillstötte under studien.

 

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. p. 130
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1878
Keyword
Acute kidney injury, dialysis, hemorrhage, anticoagulation, Akut njursvikt, dialys, blödning, antikoagulation
National Category
Hematology Urology and Nephrology
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-132204 (URN)978-91-7601-655-8 (ISBN)
Public defence
2017-06-08, Sal D, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2017-05-18 Created: 2017-03-07 Last updated: 2018-04-03Bibliographically approved

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