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How to reduce the exposure to anticoagulants when performing haemodialysis in patients with a bleeding risk: a study of methods used in clinical practise
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Nursing.ORCID iD: 0000-0002-3052-6455
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. , 130 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1878
Keyword [en]
Acute kidney injury, dialysis, hemorrhage, anticoagulation
Keyword [sv]
Akut njursvikt, dialys, blödning, antikoagulation
National Category
Hematology Urology and Nephrology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-132204ISBN: 978-91-7601-655-8 (print)OAI: oai:DiVA.org:umu-132204DiVA: diva2:1078969
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: 2017-05-18Bibliographically approved
List of papers
1. Rinsing the extra corporeal circuit with a heparin and albumin solution reduces the need for systemic anticoagulant in hemodialysis
Open this publication in new window or tab >>Rinsing the extra corporeal circuit with a heparin and albumin solution reduces the need for systemic anticoagulant in hemodialysis
2013 (English)In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 36, no 10, 725-729 p.Article in journal (Refereed) Published
Abstract [en]

Background: Systemic anticoagulation during hemodialysis (HD) increases the risk for bleeding complications pre- or post-operatively. Based on the concept of blood-membrane interaction, we developed a heparin-albumin solution to rinse the dialysis circuit before start. The aim of this study was to investigate if this method was a valuable tool for our patients at risk for bleeding complications.

Material and methods: This retrospective, comparative, quality assessment study included 248 HD in 68 patients; Group 1: 178 treatments were performed at patients for risk of bleeding using heparin-albumin-priming and Group 2: 70 acute HD were performed on patients without increased risk of bleeding using a bolus of heparin at start and a continuous infusion of heparin. In Group 1 additional heparin was given upon suspicion of progressive clotting. One L saline contained albumin (1 g/I) and heparin (5000 U/I) used for priming. Excess priming solution was removed by filling the circuit with blood at start of treatment.

Results: In Group 1, a mean total dose of 2000 U of heparin was given during the HD (18% performed HD without any heparin) and Group 2 used a mean total dose of 5500 U (p<0.001). There was no increased incidence of clotting in Group 1 versus Group 2 compared to standard HD. No bleeding complications were reported during any of the HA-priming treatments.

Conclusions: Heparin-albumin priming resulted in a reduced total dose of heparin. There was no increased clotting and no incidence of bleeding was reported in either group.

Place, publisher, year, edition, pages
Milano: Wichtig Editore Srl, 2013
Keyword
Hemodialysis, Anticoagulation, Patency, Priming, Bleeding, Surgery
National Category
Hematology Surgery
Identifiers
urn:nbn:se:umu:diva-84795 (URN)10.5301/ijao.5000253 (DOI)000328712800007 ()24254840 (PubMedID)
Available from: 2014-01-28 Created: 2014-01-20 Last updated: 2017-03-07Bibliographically approved
2. Heparin albumin priming in a clinical setting for hemodialysis patients at risk for bleeding
Open this publication in new window or tab >>Heparin albumin priming in a clinical setting for hemodialysis patients at risk for bleeding
2017 (English)In: Hemodialysis International, ISSN 1492-7535, E-ISSN 1542-4758, Vol. 21, no 2, 180-189 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Intermittent hemodialysis (IHD) is sometimes necessary in patients with a bleeding risk, i.e., before/after surgery or brain hemorrhage. In such case IHD has to be modified to limit the conventional anticoagulation used to avoid clotting of the extracorporeal circuit (ECC). We evaluated if priming using a heparin and albumin (HA) mixture could minimize the exposure to heparin.

Methods: Retrospective data from 1995 to 2013 were collected from 1408 acute dialysis treatment protocols that included 321 patients. Comparisons were made between IHD patients that had increased risk for bleeding and were treated by standard anticoagulation (Group-S), and patients at increased risk of bleeding (Group-HA). The ECC in Group-HA was primed with a solution of unfractioned heparin (UFH) (5000 Units/L) and albumin (1 g/L) in saline that was discarded after priming. There were 16 different dialyzers in the material.

Findings: Comparing Group-S (n = 883) with Group-HA (n = 221), the mean age was 61.6 vs. 62.2 years (P = 0.8), dialysis time was 197 vs. 190 minutes (P = 0.002), and total dose of intravenous anticoagulant/IHD was at median 5000 Units vs. 1200 Units (P = 0.001). Twenty-four percent of patients were treated without any additional heparin. Clotting resulting in interrupted dialysis was similar in both groups (0.8% for Group-S vs. 1.0% for Group-HA, P = 0.8). No secondary bleeding was reported in either group.

Discussion: HA priming minimized the risk of clotting and enabled acute IHD in vulnerable patients without increased bleeding, thus allowing completion of IHD to the same extent as for standard HD.

Keyword
Acute hemodialysis, anticoagulation, bleeding, priming, heparin, albumin
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-128521 (URN)10.1111/hdi.12472 (DOI)000398574500010 ()27576541 (PubMedID)
Available from: 2016-12-06 Created: 2016-12-06 Last updated: 2017-06-12Bibliographically approved
3. Heparin and albumin as part of the priming solution limits exposure to anticoagulation during hemodialysis: in vitro studies
Open this publication in new window or tab >>Heparin and albumin as part of the priming solution limits exposure to anticoagulation during hemodialysis: in vitro studies
2014 (English)In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 37, no 10, 734-740 p.Article in journal (Refereed) Published
Abstract [en]

Background: Hemodialysis patients who are subject to increased risk of hemorrhage may need specific dialysis regimes to avoid bleeding. The aim of this study was to determine in vitro which of various anticoagulation options were most beneficial.

Materials and method: 60 in vitro hemodialyses (HD) were performed in parallel using blood from healthy donors. The dialysis circuits were rinsed with either 1 L of 0.9% NaCl alone (n = 6), or with 1 L saline and the addition of either 5 mL 20% albumin (Alb, n = 6), 5,000 U of heparin (Hep, n = 6), Hep and Alb in combination (HA, n = 30), 20,000 U of Hep and Alb (4H-A, n = 6), and finally Hep and 20 mL 20% albumin (H-4A, n = 6). The blood was recirculated for a maximum of 192 min. Clotting was graded.

Results: A 192 min dialysis was completed with all series of HA, 4H-A, and H-4A, all with a slight grade of clotting. In contrast to the above settings (p = 0.002, Fisher's test), a total clotting of the dialysis circuit occurred for all series using the NaCl rinsing alone (median time to stop: 21, range: 18-27 min, p = 0.026 compared to the HA setting) and for the Alb rinsing (median 26, range: 19-35 min, p = 0.028).

Conclusions: Priming using HA, Hep, 4H-A, and H-4A reduced clotting and allowed 192 min of HD. Clinical studies need to confirm these data in vivo.

Keyword
Hemodialysis, Anticoagulation, Patency, Priming, Bleeding, Surgery
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-96822 (URN)10.5301/ijao.5000358 (DOI)000343851300002 ()25361181 (PubMedID)
Available from: 2014-12-09 Created: 2014-12-03 Last updated: 2017-03-07Bibliographically approved
4. An evaluation of four modes of low-dose anticoagulation during haemodialysis
Open this publication in new window or tab >>An evaluation of four modes of low-dose anticoagulation during haemodialysis
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: Unfractionated heparin (UFH) or e.g., a bolus of tinzaparin is used to prevent clotting during standard haemodialysis (HD). For patients at risk of bleeding, exposure to UFH must be minimized. Our aim was to clarify the safety and efficacy during HD for four low-dose anticoagulation alternatives.

Design, Settings and Patients: Twenty-three chronic HD-patients participated in this randomised cross-over study where the patients served as their own controls.

Intervention: HD with a single bolus of tinzaparin at start was compared to HD only priming the extracorporeal circuit at the start (no bolus UFH): 1) with UFH in saline (H) 2) UFH and albumin in saline (HA), 3) HA in combination with a citratecontaining dialysate (HAC), 4) saline and a heparin-coated filter (Evodial®). Priming fluid was discarded before HD. Smaller bolus doses of UFH (500 Units/dose) were allowed during the modes to avoid interruption by clotting.

Measurements: Blood samples were collected at 0, 30 and 180 min during HD to measure bleeding time, biocompability and changes in triglycerides. Visual evaluation of the extra corporeal circuit was made by experienced dialysis nurses.

Main results: The mean activated partial thromboplastin (APTT) time was highest with SHD and least with HAC and Evodial®. Mode H vs. SHD had the highest rate of prematurely interrupted dialyses (33%, p=0.008). The urea-reduction rate was less with Evodial® vs. SHD (p<0.01). For one patient a hypersensitivity reaction occurred with Evodial®. UFH in the lock solution of central dialysis catheters may interfere with bleeding risk. Changes in blood cell concentrations and triglycerides differed between the modes. Of the four modes, HAC and Evodial® appeared most preferable with the lowest APTT increase and lowest risk for prematurely clotted dialyzers in contrast to the least plausible H-mode.

Keyword
Hemodialysis, hemorrhage, priming, anticoagulation, acute kidney injury, biocompatibility
National Category
Hematology
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-132227 (URN)
Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2017-03-07

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