{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:20:40Z","timestamp":1787804440983,"version":"build-2784847793"},"reference-count":33,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["MOST 111-2314-B-182A-100-"],"award-info":[{"award-number":["MOST 111-2314-B-182A-100-"]}]},{"DOI":"10.13039\/501100005795","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["BMRPK60"],"award-info":[{"award-number":["BMRPK60"]}],"id":[{"id":"10.13039\/501100005795","id-type":"DOI","asserted-by":"publisher"}]},{"award":["BMRPK60"],"award-info":[{"award-number":["BMRPK60"]}],"id":[{"id":"https:\/\/ror.org\/02dnn6q67","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background: Cerebral blood flow (CBF) is essential for maintaining cerebral metabolism in extremely preterm infants; however, no universally accepted reference standard exists for CBF velocity (CBFV). This study aimed to establish physiological reference patterns of middle cerebral artery CBFV under strictly defined physiological stability using multimodal monitoring. Methods: This post-hoc analysis included extremely preterm infants (gestational age \u2264 28+6 weeks or birthweight 500\u20131000 g) from a prospective cohort study. Serial Doppler ultrasonography of the middle cerebral artery was performed along with near-infrared spectroscopy and electrical cardiometry. Normal CBFV datasets were defined based on systemic stability, adequate cardiac output (&gt;150 mL\/kg\/min), normal regional cerebral oxygen saturation (65\u201385%), and the absence of major comorbidities. Associations between Doppler parameters and postmenstrual age (PMA) and concurrent weight were analyzed using generalized estimating equations. Results: Forty infants contributed 194 normal CBFV datasets. Physiological reference ranges for peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV), resistance index (RI), and pulsatility index (PI) were established across PMA and concurrent weight strata. Both PSV and MV were associated with PMA and concurrent weight (p &lt; 0.01), whereas EDV, RI, and PI were not. Mean blood pressure was not significantly associated with CBFV parameters. Conclusions: PSV and MV were maturation-dependent cerebral perfusion markers. Multimodally defined physiological stability provides a robust framework for establishing clinically relevant reference values for middle cerebral artery CBFV in extremely preterm infants.<\/jats:p>","DOI":"10.3390\/children13091135","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T08:00:48Z","timestamp":1787644848000},"page":"1135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Longitudinal Physiological Reference Values of Middle Cerebral Artery Blood Flow Velocity in Extremely Preterm Infants: A Study Utilizing Multimodal Cerebral Hemodynamic Monitors"],"prefix":"10.3390","volume":"13","author":[{"given":"Wei-Hung","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Tang","family":"Juan","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8626-0933","authenticated-orcid":false,"given":"Shu-Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Chang Gung Memorial Hospital Taipei Branch, Taipei 10507, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1109-0665","authenticated-orcid":false,"given":"Ming-Chou","family":"Chiang","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Yin","family":"Lai","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Hsyuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Institute of Emergency and Critical Care Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Ming","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reyin","family":"Lien","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2852-6322","authenticated-orcid":false,"given":"Kai-Hsiang","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital Linkou Branch, Taoyuan 33305, Taiwan"},{"name":"School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1007\/s12975-017-0570-2","article-title":"Cerebral hypoperfusion and other shared brain pathologies in ischemic stroke and Alzheimer\u2019s disease","volume":"9","author":"Dong","year":"2018","journal-title":"Transl. Stroke Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.jpeds.2015.03.041","article-title":"Monitoring of cerebrovascular reactivity for determination of optimal blood pressure in preterm infants","volume":"167","author":"Czosnyka","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.jpeds.2012.09.038","article-title":"Cerebral oxygenation, extraction, and autoregulation in very preterm infants who develop peri-intraventricular hemorrhage","volume":"162","author":"Alderliesten","year":"2013","journal-title":"J. Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1055\/s-0042-111689","article-title":"Risk factors associated with intraventricular hemorrhage in preterm infants with \u226428 weeks gestational age","volume":"228","author":"Waitz","year":"2016","journal-title":"Klin. Padiatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1152\/japplphysiol.00667.2015","article-title":"Relationship between blood pressure and cerebral blood flow during supine cycling: Influence of aging","volume":"120","author":"Smirl","year":"2016","journal-title":"J. Appl. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1056\/NEJM198505233122104","article-title":"Reduction in intraventricular hemorrhage by elimination of fluctuating cerebral blood-flow velocity in preterm infants with respiratory distress syndrome","volume":"312","author":"Perlman","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.clp.2009.07.002","article-title":"Cerebral blood flow and metabolism in the developing fetus","volume":"36","year":"2009","journal-title":"Clin. Perinatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/uog.7722","article-title":"Normal reference ranges of fetal regional cerebral blood perfusion as measured by fractional moving blood volume","volume":"37","author":"Figueras","year":"2011","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1002\/uog.14881","article-title":"Association between fetal growth, cerebral blood flow and neurodevelopmental outcome in univentricular fetuses","volume":"47","author":"Hahn","year":"2016","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rouzer, S.K., Sreeram, A., and Miranda, R.C. (2024). Reduced fetal cerebral blood flow predicts perinatal mortality in a mouse model of prenatal alcohol and cannabinoid exposure. BMC Pregnancy Childbirth, 24.","DOI":"10.1186\/s12884-024-06436-9"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1111\/j.1469-8749.2002.tb00281.x","article-title":"Early postnatal Doppler assessment of cerebral blood flow velocity in healthy preterm and term infants","volume":"44","author":"Pezzati","year":"2002","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.ultrasmedbio.2005.12.007","article-title":"Neonatal color Doppler US study: Normal values of cerebral blood flow velocities in preterm infants in the first month of life","volume":"32","author":"Romagnoli","year":"2006","journal-title":"Ultrasound Med. Biol."},{"key":"ref_13","unstructured":"Volpe, J.J. (2018). Volpe\u2019s Neurology of the Newborn, Elsevier. [6th ed.]."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/jpc.13663","article-title":"Cerebral blood flow velocities and cerebrovascular resistance in normal-term neonates in the first 72 hours","volume":"54","author":"Forster","year":"2018","journal-title":"J. Paediatr. Child Health"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/pr.2015.231","article-title":"New developments in cerebral blood flow autoregulation analysis in preterm infants: A mechanistic approach","volume":"79","author":"Riera","year":"2016","journal-title":"Pediatr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.siny.2015.03.008","article-title":"Near-infrared spectroscopy: Applications in neonates","volume":"20","author":"Sood","year":"2015","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"O\u2019Neill, R., Dempsey, E.M., Garvey, A.A., and Schwarz, C.E. (2020). Non-invasive cardiac output monitoring in neonates. Front. Pediatr., 8.","DOI":"10.3389\/fped.2020.614585"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/jp.2016.2","article-title":"Hemodynamic reference for neonates of different age and weight: A pilot study with electrical cardiometry","volume":"36","author":"Hsu","year":"2016","journal-title":"J. Perinatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1159\/000475774","article-title":"Electrical cardiometry to monitor cardiac output in preterm infants with patent ductus arteriosus: A comparison with echocardiography","volume":"112","author":"Hsu","year":"2017","journal-title":"Neonatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"304","DOI":"10.3345\/cep.2025.02117","article-title":"Prolonged cerebral oxygenation surveillance with algorithm-based management: A neurocritical care bundle for extremely preterm infants","volume":"69(4)","author":"Hsu","year":"2026","journal-title":"Clin. Exp. Pediatr."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dix, L.M.L., van Bel, F., and Lemmers, P.M.A. (2017). Corrigendum: Monitoring cerebral oxygenation in neonates: An update. Front. Pediatr., 5.","DOI":"10.3389\/fped.2017.00160"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jpeds.2019.08.057","article-title":"Effects of patent ductus arteriosus on organ blood flow in infants born very preterm: A prospective study with serial echocardiography","volume":"216","author":"Hsu","year":"2020","journal-title":"J. Pediatr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1007\/s00330-001-1150-z","article-title":"Advanced cranial ultrasound: Transfontanellar Doppler imaging in neonates","volume":"11","author":"Couture","year":"2001","journal-title":"Eur. Radiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Costerus, S.A., Kortenbout, A.J., Vos, H.J., Govaert, P., Tibboel, D., Wijnen, R.M.H., de Jong, N., Bosch, J.G., and de Graaff, J.C. (2021). Feasibility of Doppler ultrasound for cortical cerebral blood flow velocity monitoring during major non-cardiac surgery of newborns. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.656806"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"R773","DOI":"10.1152\/ajpregu.00487.2013","article-title":"Cerebral vascular regulation and brain injury in preterm infants","volume":"306","author":"Brew","year":"2014","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_26","first-page":"328","article-title":"Cerebral vascular resistance in premature infants","volume":"137","author":"Daven","year":"1983","journal-title":"Am. J. Dis. Child."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Leon, R.L., Ortigoza, E.B., Ali, N., Angelis, D., Wolovits, J.S., and Chalak, L.F. (2021). Cerebral blood flow monitoring in high-risk fetal and neonatal populations. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.748345"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"H1678","DOI":"10.1152\/ajpheart.00281.2011","article-title":"Cerebral and myocardial blood flow responses to hypercapnia and hypoxia in humans","volume":"301","author":"Beaudin","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1097\/SHK.0000000000000388","article-title":"The effect of milrinone on splanchnic and cerebral perfusion in infants with congenital heart disease prior to surgery: An observational study","volume":"44","author":"Bianchi","year":"2015","journal-title":"Shock"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.jtcvs.2025.11.016","article-title":"Postnatal and postinterventional cerebral Doppler ultrasound in neonates with critical congenital heart disease","volume":"171","author":"Bosch","year":"2026","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_31","first-page":"205","article-title":"Association between middle cerebral artery Doppler flow parameters and intraventricular hemorrhage in preterm infants","volume":"46","author":"Mert","year":"2025","journal-title":"Neuro Endocrinol. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.siny.2015.02.004","article-title":"Hemodynamic antecedents of peri\/intraventricular hemorrhage in very preterm neonates","volume":"20","author":"Noori","year":"2015","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/s41390-021-01786-y","article-title":"Normal regional tissue oxygen saturation in neonates: A systematic qualitative review","volume":"96","author":"Bruckner","year":"2024","journal-title":"Pediatr. Res."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/13\/9\/1135\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:16:52Z","timestamp":1787804212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/13\/9\/1135"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["children13091135"],"URL":"https:\/\/doi.org\/10.3390\/children13091135","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}