Coagulation and hemolysis complications in neonatal ECLS: Role of devices

Published:November 16, 2022DOI:


      Neonatal extracorporeal life support (ECLS) has enjoyed a long history of successful patient support for both cardiac and respiratory failure. The small size of this patient population has provided many technical challenges from cannulation to pumps and oxygenators. This is further complicated by the relatively meager commercial options for equipment owing to the relatively low utilization of neonatal ECLS compared to adults, which has exploded following the H1N1 epidemic and the availability of the polymethylpentene oxygenator. This paper focuses on the impact of equipment choices on thrombosis and hemolysis in neonatal ECLS and the underlying mechanisms behind them. Based upon the available evidence, it is clear neonatal ECLS requires careful attention to the selection and operation of all parts of the ECLS system. Practitioners should also be aware of the factors that increase blood cell fragility, which can impact decisions around equipment and subsequent operation.


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        • Bartlett R.H.
        • Gazzaniga A.B.
        • Jefferies M.R.
        • Huxtable R.F.
        • Haiduc N.J.
        • Fong S.W.
        Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy.
        Trans Am Soc Artif Intern Organs. 1976; 22: 80-93
        • Lim M.W.
        The history of extracorporeal oxygenators.
        Anaesthesia. 2006; 61: 984-995
        • Boettcher W.
        • Merkle F.
        • Weitkemper H.H.
        History of extracorporeal circulation: the invention and modification of blood pumps.
        J Extra Corpor Technol. 2003; 35: 184-191
        • Olsen D.B.
        The history of continuous-flow blood pumps.
        Artif Organs. 2000; 24: 401-404
        • Extracorporeal Life Support Organization
        ELSO registry data definitions.
        Extracorporeal Life Support Organization, 2022 (2022)
        • Graziani L.J.
        • Gringlas M.
        • Baumgart S.
        Cerebrovascular complications and neurodevelopmental sequelae of neonatal ECMO.
        Clin Perinatol. 1997; 24: 655-675
        • Bulas D.
        • Glass P.
        Neonatal ECMO: neuroimaging and neurodevelopmental outcome.
        Semin Perinatol. 2005; 29: 58-65
        • Zhang M.
        • Pauls J.P.
        • Bartnikowski N.
        • et al.
        Anti-thrombogenic surface coatings for extracorporeal membrane oxygenation: a narrative review.
        ACS Biomater Sci Eng. 2021; 7: 4402-4419
        • Maul T.M.
        • Massicotte M.P.
        • Wearden P.D.
        ECMO biocompatibility: surface coatings, anticoagulation, and coagulation monitoring.
        in: Firstenberg M. Extracorporeal membrane oxygenation - Advances in therapy. Croatia. InTech, 2016
      1. ECLS registry report: US summary. Extracorporeal Life Support Organization, Ann Arbor, MI2021 (October, 2021)
        • Raffaeli G.
        • Pokorna P.
        • Allegaert K.
        • et al.
        Drug disposition and pharmacotherapy in neonatal ECMO: from fragmented data to integrated knowledge.
        Front Pediatr. 2019 Sep 3; 7 (PMID: 31552205; PMCID: PMC6733981): 360
        • Maul T.M.
        • Aspenleiter M.
        • Palmer D.
        • Sharma M.S.
        • Viegas M.L.
        • Wearden P.D.
        Impact of circuit size on coagulation and hemolysis complications in pediatric extracorporeal membrane oxygenation.
        Am Soc Artif Intern Organs J. 2020; 66: 1048-1053
        • Hastings S.M.
        • Ku D.N.
        • Wagoner S.
        • Maher K.O.
        • Deshpande S.
        Sources of circuit thrombosis in pediatric extracorporeal membrane oxygenation.
        Am Soc Artif Intern Organs J. 2017; 63: 86-92
        • Kaesler A.
        • Rudawski F.L.
        • Zander M.O.
        • et al.
        In-vitro visualization of thrombus growth in artificial lungs using real-time X-ray imaging: a feasibility study.
        Cardiovasc Eng Tech. 2022; 13: 318-330
        • Kaesler A.
        • Schlanstein P.C.
        • Hesselmann F.
        • et al.
        Experimental approach to visualize flow in a stacked hollow fiber bundle of an artificial lung with particle image velocimetry.
        Artif Organs. 2017; 41: 529-538
        • Conway R.G.
        • Zhang J.
        • Jeudy J.
        • et al.
        Computed tomography angiography as an adjunct to computational fluid dynamics for prediction of oxygenator thrombus formation.
        Perfusion. 2021; 36: 285-292
        • Meyer A.D.
        • Rishmawi A.R.
        • Kamucheka R.
        • et al.
        Effect of blood flow on platelets, leukocytes, and extracellular vesicles in thrombosis of simulated neonatal extracorporeal circulation.
        J Thromb Haemostasis. 2020; 18: 399-410
        • Méndez Rojano R.
        • Lai A.
        • Zhussupbekov M.
        • Burgreen G.W.
        • Cook K.
        • Antaki J.F.
        A fibrin enhanced thrombosis model for medical devices operating at low shear regimes or large surface areas.
        bioRxiv. 2006; (2022:2022.2006)494958
        • Diehl P.
        • Aleker M.
        • Helbing T.
        • et al.
        Increased platelet, leukocyte and endothelial microparticles predict enhanced coagulation and vascular inflammation in pulmonary hypertension.
        J Thromb Thrombolysis. 2011; 31: 173-179
        • Levi M.
        • van der Poll T.
        • Schultz M.
        Systemic versus localized coagulation activation contributing to organ failure in critically ill patients.
        Semin Immunopathol. 2011; 34: 1-13
        • Meyer D.M.
        • Jessen M.E.
        • Eberhart R.C.
        Neonatal extracorporeal membrane oxygenation complicated by sepsis. Extracorporeal Life Support Organization.
        Ann Thorac Surg. 1995; 59: 975-980
        • Rother R.P.
        • Bell L.
        • Hillmen P.
        • Gladwin M.T.
        The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin.
        JAMA, J Am Med Assoc. 2005; 293: 1653-1662
        • Lou S.
        • MacLaren G.
        • Best D.
        • Delzoppo C.
        • Butt W.
        Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: prevalence, risk factors, and outcomes.
        Crit Care Med. 2014; 42: 1213-1220
        • Leverett L.B.
        • Hellums J.D.
        • Alfrey C.P.
        • Lynch E.C.
        Red blood cell damage by shear stress.
        Biophys J. 1972; 12: 257-273
        • Maul T.M.
        • Kameneva M.V.
        • Wearden P.D.
        Mechanical blood trauma in circulatory-assist devices. vol. 13. ASME Press, New York2015
        Date accessed: April 10, 2015
        • Sutera S.P.
        Flow-induced trauma to blood cells.
        Circ Res. 1977; 41: 2-8
        • Jenks C.L.
        • Zia A.
        • Venkataraman R.
        • Raman L.
        High hemoglobin is an independent risk factor for the development of hemolysis during pediatric extracorporeal life support.
        J Intensive Care Med. 2019; 34: 259-264
        • Bohler T.
        • Leo A.
        • Stadler A.
        • Linderkamp O.
        Mechanical fragility of erythrocyte membrane in neonates and adults.
        Pediatr Res. 1992; 32: 92-96
        • Effenberger-Neidnicht K.
        • Hartmann M.
        Mechanisms of hemolysis during sepsis.
        2018 (Inflammation)
        • Hurd T.C.
        • Dasmahapatra K.S.
        • Rush Jr., B.F.
        • Machiedo G.W.
        Red blood cell deformability in human and experimental sepsis.
        Arch Surg. 1988; 123: 217-220
        • Kameneva M.V.
        • Undar A.
        • Antaki J.F.
        • Watach M.J.
        • Calhoon J.H.
        • Borovetz H.S.
        Decrease in red blood cell deformability caused by hypothermia, hemodilution, and mechanical stress: factors related to cardiopulmonary bypass.
        Am Soc Artif Intern Organs J. 1999; 45: 307-310
        • Horobin J.T.
        • Sabapathy S.
        • Simmonds M.J.
        Repetitive supra-physiological shear stress impairs red blood cell deformability and induces hemolysis.
        Artif Organs, 2017
        • Lee S.S.
        • Antaki J.F.
        • Kameneva M.V.
        • et al.
        Strain hardening of red blood cells by accumulated cyclic supraphysiological stress.
        Artif Organs. 2007; 31: 80-86
        • Raval J.S.
        • Waters J.H.
        • Seltsam A.
        • et al.
        The use of the mechanical fragility test in evaluating sublethal RBC injury during storage.
        Vox Sang. 2010; 99: 325-331
        • Halbhuber K.J.
        • Feuerstein H.
        • Stibenz D.
        • Linss W.
        Membrane alteration during banking of red blood cells.
        Biomed Biochim Acta. 1983; 42: S337-S341
        • Dalton H.J.
        • Cashen K.
        • Reeder R.W.
        • et al.
        Hemolysis during pediatric extracorporeal membrane oxygenation: associations with circuitry, complications, and mortality.
        Pediatr Crit Care Med. 2018; 19: 1067-1076
        • Dalton H.J.
        • Hoskote A.
        There and back again: roller pumps versus centrifugal technology in infants on extracorporeal membrane oxygenation.
        Pediatr Crit Care Med. 2019; 20: 1195-1196
        • O'Brien C.
        • Monteagudo J.
        • Schad C.
        • Cheung E.
        • Middlesworth W.
        Centrifugal pumps and hemolysis in pediatric extracorporeal membrane oxygenation (ECMO) patients: an analysis of Extracorporeal Life Support Organization (ELSO) registry data.
        J Pediatr Surg. 2017; 52: 975-978
        • De Somer F.
        • Foubert L.
        • Vanackere M.
        • Dujardin D.
        • Delanghe J.
        • Van Nooten G.
        Impact of oxygenator design on hemolysis, shear stress, and white blood cell and platelet counts.
        J Cardiothorac Vasc Anesth. 1996; 10: 884-889
        • Kawahito S.
        • Maeda T.
        • Motomura T.
        • et al.
        Hemolytic characteristics of oxygenators during clinical extracorporeal membrane oxygenation.
        Am Soc Artif Intern Organs J. 2002; 48: 636-639
        • Kawahito S.
        • Maeda T.
        • Yoshikawa M.
        • et al.
        Blood trauma induced by clinically accepted oxygenators.
        Am Soc Artif Intern Organs J. 2001; 47: 492-495
        • Williams D.C.
        • Turi J.L.
        • Hornik C.P.
        • et al.
        Circuit oxygenator contributes to extracorporeal membrane oxygenation-induced hemolysis.
        Am Soc Artif Intern Organs J. 2015; 61: 190-195
        • Betrus C.
        • Remenapp R.
        • Charpie J.
        • et al.
        Enhanced hemolysis in pediatric patients requiring extracorporeal membrane oxygenation and continuous renal replacement therapy.
        Ann Thorac Cardiovasc Surg. 2007; 13: 378-383
        • Borasino S.
        • Kalra Y.
        • Elam A.R.
        • et al.
        Impact of hemolysis on acute kidney injury and mortality in children supported with cardiac extracorporeal membrane oxygenation.
        J Extra Corpor Technol. 2018; 50: 217-224
        • Pfaender L.M.
        Hemodynamics in the extracorporeal aortic cannula: review of factors affecting choice of the appropriate size.
        J Extra Corpor Technol. 1981; 4: 224-232
        • Matte G.S.
        Perfusion for congenital heart surgery: notes on cardiopulmonary bypass for a complex patient population.
        first ed. Wiley-Blackwell, 2015
        • Kojo M.
        • Yamada K.
        • Izumi T.
        Normal developmental changes in carotid artery diameter measured by echo-tracking.
        Pediatr Neurol. 1998; 18: 221-226
        • Nakayama S.
        • Yamashita M.
        • Osaka Y.
        • Isobe T.
        • Izumi H.
        Right internal jugular vein venography in infants and children.
        Anesth Analg. 2001; 93 (332nd contents page): 331-334
        • Gbadegesin R.
        • Zhao S.
        • Charpie J.
        • Brophy P.
        • Smoyer W.
        • Lin J.-J.
        Significance of hemolysis on extracorporeal life support after cardiac surgery in children.
        Pediatr Nephrol. 2009; 24: 589-595
      2. ASTM. Standard practice for assessment of hemolysis in continuous flow blood pumps. In. Medical device Standards and implant Standards2005.

      3. Center for Devices and Radiologic Health. US department of human and health services. Guidance for cardiopulmonary bypass oxygenators 510(k) submissions; final guidance for industry and FDA staff. [Updated].

        • Vieira Jr., F.U.
        • Costa E.T.
        • Vieira R.W.
        • Antunes N.
        • Petrucci Jr., O.
        • de Oliveira P.P.
        The effect on hemolysis of the raceway profile of roller pumps used in cardiopulmonary bypass.
        Am Soc Artif Intern Organs J. 2011; : 40-45
        • Zhang J.
        • Gellman B.
        • Koert A.
        • et al.
        Computational and experimental evaluation of the fluid dynamics and hemocompatibility of the CentriMag blood pump.
        Artif Organs. 2006; 30: 168-177
        • Lawson D.S.
        • Ing R.
        • Cheifetz I.M.
        • et al.
        Hemolytic characteristics of three commercially available centrifugal blood pumps.
        Pediatr Crit Care Med. 2005; 6: 573-577
        • Hodge A.B.
        • Deitemyer M.A.
        • Duffy V.L.
        • et al.
        Plasma free hemoglobin generation using the EOS PMP oxygenator and the CentriMag blood pump.
        J Extra Corpor Technol. 2018; 50: 94-98
        • Meyer A.D.
        • Wiles A.A.
        • Rivera O.
        • et al.
        Hemolytic and thrombocytopathic characteristics of extracorporeal membrane oxygenation systems at simulated flow rate for neonates.
        Pediatr Crit Care Med : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2012; 13: e255-e261
        • Gross-Hardt S.
        • Hesselmann F.
        • Arens J.
        • et al.
        Low-flow assessment of current ECMO/ECCO2R rotary blood pumps and the potential effect on hemocompatibility.
        Crit Care. 2019; 23: 348
        • Schöps M.
        • Gross-Hardt S.H.
        • Schmitz-Rode T.
        • et al.
        Hemolysis at low blood flow rates: in-vitro and in-silico evaluation of a centrifugal blood pump.
        J Transl Med. 2021; 19: 2
        • Dasse K.A.
        • Gellman B.
        • Kameneva M.V.
        • et al.
        Assessment of hydraulic performance and biocompatibility of a MagLev centrifugal pump system designed for pediatric cardiac or cardiopulmonary support.
        Am Soc Artif Intern Organs J. 2007; 53: 771-777
        • Chan C.H.H.
        • Ki K.K.
        • Zhang M.
        • et al.
        Extracorporeal membrane oxygenation-induced hemolysis: an in vitro study to appraise causative factors.
        Membranes. 2021; 11
        • Makhro A.
        • Huisjes R.
        • Verhagen L.P.
        • et al.
        Red cell properties after different modes of blood transportation.
        Front Physiol. 2016; 7: 288
        • Giani M.
        • Scaravilli V.
        • Stefanini F.
        • et al.
        Continuous renal replacement therapy in venovenous extracorporeal membrane oxygenation: a retrospective study on regional citrate anticoagulation.
        Am Soc Artif Intern Organs J. 2020; 66: 332-338
        • Harris E.
        • Schulzke S.M.
        • Patole S.K.
        Pentoxifylline in preterm neonates: a systematic review.
        Paediatr Drugs. 2010; 12: 301-311
        • Golbasi I.
        • Akbas H.
        • Ozdem S.
        • et al.
        The effect of pentoxifylline on haemolysis during cardiopulmonary bypass in open-heart surgery.
        Acta Cardiol. 2006; 61: 7-11