Presence of microemboli during haemodialysis and methods umu.diva-...

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Presence of microemboli during haemodialysis and methods to reduce the exposure to microbubbles

Ulf Forsberg

Department of Public Health and Clinical Medicine

Ume 2013

Responsible publisher under Swedish law: the Dean of the Medical Faculty

This work is protected by the Swedish Copyright Legislation (Act 1960:729)

2013 Ulf Forsberg

ISBN: 978-91-7459-591-8

ISSN: 0346-6612; New Series number 1564

Elektronisk version tillgnglig p http://umu.diva-portal.org/

Tryck/Printed by: Print & Media

Ume, Sweden 2013

To my family

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CONTENTS

ABSTRACT vi SUMMARY IN SWEDISH/SAMMANFATTNING P SVENSKA viii ABBREVIATIONS x ORIGINAL PAPERS xi INTRODUCTION 1

The functions of kidney 1 Chronic versus acute renal failure 1 Kidney disease 3 Renal replacement therapy 3 Epidemiology 4 The history of haemodialysis 7 Physiological principles of dialysis 8 Diffusion 8 Ultrafiltration 8 Convective mass flow 9 Haemofiltration 9 Haemodiafiltration 10 Vascular access 10 The haemodialysis system 11 The blood system 11 The fluid system 12 Dialysis filters/dialyzer 13 Biocompatibility 14 Clearance 14 Embolism 16 Arterial embolism 17 Venous embolism 17 Paradoxical embolism 17 The physiological right-to-left shunt 18 Macro- and microembolism 19 Detection of emboli 19 Microembolism with arterial origin 20 Gas/air embolism 22 Formation of air embolism 22 Decompression sickness 22 Mechanical heart valves and air emboli 23 Heart-lung machine and air emboli 24 Haemodialysis and air emboli 25 Hazardous air volume? 26

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Haemodialysis and microembolic signals 26 Microbubbles 29 Microbubbles effects on tissues 30 Microbubbles in-vitro 31 Ultrasound device 34 Presence of microemboli during haemodialysis? 37

AIMS 38 MATERIALS AND METHODS 39

Paper I 39 Study population and design 39 Material 41 CMD-10: Cardiovascular Microbubble Detector 41 Paper II 43 Study population and design 43 Material 45 EMEX-25: Endovascular Microemboli Detector 46 Paper III 48 Study population and design 48 Material 51 Paper IV 51 Study population and design 51 Material 54 Paper V 54 Statistical analysis 55 Paper I 55 Paper II 55 Paper III 55 Paper IV 56 Ethical considerations 56

RESULTS 57 Paper I 57 Paper II 61 Paper III 63 Paper IV 64 Paper V 69

DISCUSSION 72 External validity 72 General discussion 74 Paper I 77 Paper II 78 Paper III 80 Paper IV 82 Paper V 83

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Clinical perspectives 86 CONCLUSIONS 87 ACKNOWLEDGEMENTS 88 REFERENCES 90 APPENDIX 106

PATIENTINFORMATION 106

ORIGINAL PAPERS

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ABSTRACT

Despite chronic dialysis treatment, patients with end stage renal disease undergoing maintenance haemodialysis (HD) remain at a substantially increased risk of morbidity. Previous reports using Doppler ultrasound (DU) during HD have revealed microembolic signals (ME) in the venous circulation. In vitro studies confirm the emergence of microbubbles of air that may pass the security system of the HD circuit without triggering the alarm. The aim of this thesis was to elucidate the presence of ME during HD and examine methods that might reduce exposure to ME in vivo.

The first study utilized DU to verify the presence of ME in 40 patients during standard HD. Investigation within 30 minutes after the start of HD and just before the end of session revealed the presence of ME in the venous blood line during both phases. The air trap did not alert for the presence of ME. This indicated that ME may pass into the patient during the entire HD run.

Study 2 analyzed the presence of ME prior to start and during HD when measured at the AV-access and also carotid artery. A total of 54 patients were examined using DU as the investigative technique. ME increased significantly after start of HD in the AV-access, but also at the carotid artery site. These data indicated that ME can enter the body and even pass the lung barrier. The question arose if microbubbles of air are resorbed or may cause ischemic lesions in organs such as the brain.

Study 3 examined whether the amount of ME detected in the AV-access would change by using either a high or a low blood level in the venous air trap/chamber. This was a prospective, randomized and double-blind study of 20 HD patients who were their own controls. After 30 min of standard HD, measurement of ME with DU was performed for two minutes. The chamber setting was changed and after another 30 minutes a new recording was carried out for two minutes. Data showed that setting a high blood level significantly reduced the extent of ME that entered the patient. The results also indicated that ME consisted mainly of microbubbles.

In study 4, twenty patients were randomized in a cross-over setting of HD. Three options were used: a wet-stored dialyzer with high blood

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level (WH) and a dry-stored dialyzer using either a high (DH) or a low (DL) blood level in the venous chamber. The exposure of ME, detected by DU, was least when using mode WF, more with mode DH, and most with mode DL. There was a correlation between higher blood flow and more extensive exposure to ME.

Study 5 was an autopsy study of a chronic HD patient with the aim of searching for microbubbles deposited in organs. Microbubbles of gas were verified in the vessels of the lungs, brain and heart. By using a fluorescent stain of anti-fibrinogen it was verified that the microbubbles were covered by clots that had to be preformed before death occurred. This indicated that air microbubbles are not completely absorbed and could result in embolic deposition in the organs of HD patients.

In conclusion, these in vivo studies showed that ME pass the air trap without inducing an alarm and enter the venous blood line of the patient. The data confirmed the presence of ME in the AV-access and also in the carotid artery. Autopsy data of a deceased HD patient demonstrated the presence of microbubbles in the capillaries of the lungs, but also in the systemic circulation such as in the brain and the heart. A high blood level in the venous chamber and wet-stored dialyzer can reduce, but not eliminate the exposure to microbubbles for patients undergoing HD.

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SUMMARY IN SWEDISH/ SAMMANFATTNING P SVENSKA

En av njurarnas viktigaste uppgift r att rena blodet frn avfallsprodukter, som uppkommer vid kroppens mnesomsttning (metabolism). mnesomsttning r ett sammanfatttande namn p de processer dr nringsmnen tas upp, omvandlas och bryts ner i kroppen fr att till slut omsttas till energi. Vid lngt gngen njursvikt ansamlas avfallsprodukterna i kroppen. Fr eliminering av dessa mnen krvs en speciell blodreningsprocedur som t.ex. hemodialys (bloddialys). Hemodialysapparaten fr ut blod frn patienten, renar blodet och terfr det till patienten. Fr att frhindra att luft (frn t.ex. slangkopplingar) av misstag kommer in i patienten finns speciella luftvakter i dialysapparaten. Enbart i Sverige sker rligen mer n 400.000 hemodialysbehandlingar.

Det r sedan lnge knt att mikroskopiskt sm embolier (partiklar som fljer med blodstrmmen), upptckta med hjlp av Doppler-ultraljudsteknik, frekommer i dialyspapparatens blodfyllda slangar under pgende hemodialys. I vra tidigare experimentiella studier har resultaten talat fr att dessa mikroembolier till strsta del bestr av gasbubblor, som passerar luftvakten utan att den larmar. Syftet med avhandlingen var att underska frekomst av mikroembolier vid hemodialys och hitta metoder att minska patienternas exponering fr mikrobubblor. I frsta studien undersktes 40 patienter, med Doppler-ultraljudsapparat (DU), med avseende p mikroembolier under pgende hemodialys (HD). Patienterna undersktes inom 30 minuter efter dialysstart och precis innan avslut. Vid bda mttillfllena fann vi mikroembolier i blodslangarna efter luftvakten. Vid inget tillflle larmade luftvakten. Detta indikerar att mikroembolier kan passera in i patienten under hela HD behandlingen. I den andra studien mttes frekomst av mikroembolier i patienternas AV-access (blodkrlet dr blodet frs in i och sedan ut frn HD apparatens slangar) och halspulsdern (a.carotis). Mtningarna gjordes fre och under pgende HD. Totalt undersktes 54 patienter med DU. Antalet mikroembolier kades signifikant efter start av HD bde i AV-accessen och i halspulsdern. Dessa data talar fr att mikroembolier passerar in i patienten och

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ven passerar lungbarriren. Frgan uppkom om mikrobubblor frn HD absorberas i blodet eller om de kan orsaka skador i organ som t.ex. hjrnan. I den tredje studien undersktes om antalet mikroembolier, mtningarna skedde i AV-accessen, skulle pverkas av att blodnivn i luftvakten ndrades. Lg niv jmfrdes med hg niv i luftvakten. 20 kroniska HD patienter lottades till att genomg en standardbehandling med endera blodniv i luftvakten. Efter 30 minuters behandling genomfrdes en mtning under tv minuter med hjlp av DU. Drefter ndrades blodnivn till den motsatta och efter 30 minuter gjordes en till mtning under tv minuter. Data visade att antalet mikroembolier som passerade in i patienten minskades signifikant om blodnivn i luftvakten var hg. Resultatet indikerade ocks att den strsta andelen av mikroembolierna bestr av mikrobubblor. I den fjrde studien lottades 20 patienter till olika sorters HD behandling. Tre olika varianter av HD behandling anvndes. Behandling med 1) Vtlagrat dialysfilter med hg blodniv i luftvakten (VH), 2) torrlagrat filter med antingen hg (TH) eller 3) lg blodniv i luftvakten (TL). Exponeringen av mikroembolier, som registrerades med hjlp av DU, var minst vid behandlingsvariant VH, mer vid TH och mest om behandling med TL anvndes. I den femte studien obducerades en kronisk HD-patient med syftet att leta efter mikrobu