Abstract
Brain injury remains one of the major unsolved problems in neonatal care, with survivors at high risk of lifelong neurodisability. It is unlikely that a single intervention can ameliorate neonatal brain injury, given the complex interaction between pathological processes, developmental trajectory, genetic susceptibility, and environmental influences. However, a coordinated, interdisciplinary approach to understand the root cause enables early detection, and diagnosis with enhanced clinical care offering the best chance of improving outcomes and facilitate new lines of neuroprotective treatments. Adult neurointensive care has existed as a speciality in its own right for over 20 years; however, it is only recently that large prospective studies have demonstrated the benefit of this model of care. The ‘Neuro-intensive Care Nursery’ model originated at the University of California San Francisco in 2008, and since then a growing number of units worldwide have adopted this approach. As well as providing consistent coordinated care for infants from a multidisciplinary team, it provides opportunities for specialist education and training in neonatal neurology, neuromonitoring, neuroimaging and nursing. This review outlines the origins of brain-oriented care of the neonate and the development of the Neuro-NICU (neonatal intensive care unit) and discusses some of the challenges and opportunities in expanding this model of care.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Volpe, J. J. et al. Volpe’s Neurology of the Newborn 6th edn (Saunders, Elsevier, Philadelphia, 2018).
Mangham, L. J. et al. The cost of preterm birth through childhood in England and Wales. Pediatrics 123, e312–e327 (2009).
Honeycutt, A. et al. Centers for Disease Control and Prevention (CDC). Economic costs associated with mental retardation, cerebral palsy, hearing loss, and vision impairment—United States, 2003. Morb. Mortal. Wkly Rep. 53, 57–59 (2004).
Moore, T. et al. Neurological and developmental outcome in extremely preterm children born in England in 1995 and 2006: the EPICure studies. BMJ 345, e7961 (2012).
Younge, N. et al. Survival and neurodevelopmental outcomes among periviable infants. N. Engl. J. Med. 376, 617–628 (2017).
Liu, L. et al. Global, regional and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet 388, 3027–3035 (2016).
Jacobs, S. E. et al. Cooling for newborns with hypoxic–ischaemic encephalopathy. Cochrane Database Syst. Rev. 1, CD003311 (2013).
Smith, M. & Menon, D. In: Masterson, G. & Baudouin, S. eds. GPICS 2015 (ICS and FICM, London, 2015).
Patel, H. C. et al. Trauma Audit and Research Netwok. Trends in head injury outcome from 1989-2003 and the effect of neurosurgical care: an observational study. Lancet 366, 1538–1544 (2005).
Harrison, D. A. et al. Risk adjustment in neurocritical care (RAIN)—Prospective validation of risk prediction models for adult patients with acute traumatic brain injury to use to evaluate the optimum location and comparative costs of neurocritical care: a cohort study. Health Technol. Assess. 17, vii–viii (2013). 1–350.
Damian, M. S. et al. The effect of secular trends and specialist neurocritical care on mortality for patients with intracerebral haemorrhage, myasthenia gravis and Guillain‑Barr. Syndrome admitted to critical care: an analysis of the Intensive Care National Audit & Research Centre (ICNARC) national United Kingdom database. Intens. Care Med. 39, 1405–1412 (2013).
Samuels, O. et al. Impact of a dedicated neurocritical care team in treating patients with aneurysmal subarachnoid hemorrhage. Neurocrit. Care 14, 334–340 (2011).
Tweedie, I. Neuro-critical care versus general critical care for neurological injury: beneficial evidence. J. Neuroanaesthesiol. Crit. Care 3, 62–65 (2016).
Stroke Unit Trialists’ Collaboration. Organised inpatient (stroke unit) care for stroke. Cochrane Database Syst. Rev. 9, CD000197 (2013).
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587 (1995).
Fassbender, K. et al. Mobile stroke units for prehospital thrombolysis, triage and beyond: benefits and challenges. Lancet Neurol. 16, 227–237 (2017).
Kurinczuk, J. et al. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum. Dev. 86, 329–338 (2010).
Fluss, J., Dinomais, M. & Chabrier, S. Perinatal stroke syndromes: similarities and diversities in aetiology, outcome and management. Eur. J. Paediatr. Neurol. 23, 368–383 (2019).
Stoll, B. J. et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA 314, 1039–1051 (2015).
Back, S. A. White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol. 134, 331–349 (2017).
Twilhaar, E. S. et al. Cognitive outcomes of children born extremely or very preterm since the 1990s and associated risk factors a meta-analysis and meta-regression. JAMA Pediatr. 172, 361–367 (2018).
Guthrie, R. & Bickel, H. The introduction of newborn screening for phenylketonuria: a personal history. Eur. J. Pediatr. 155, S4–S5 (1996).
Pisano, T. et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 56, 685–691 (2015).
Tseng, C.-E. et al. Verbal fluency is affected by altered brain lateralisation in adults who were born very preterm. eNeuro 6, e0274–18.2018 (2019).
Pape, K. E. et al. Ultrasound detection of brain damage in preterm infants. Lancet 8129, 1261–1264 (1979).
Cady, E. B. et al. Non-invasive investigation of cerebral metabolism in newborn infants by phosphorus nuclear magnetic resonance spectroscopy. Lancet 8333, 1059–1062 (1983).
Thoresen, M. et al. Mild hypothermia after severe transient hypoxia–ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr. Res. 37, 667–670 (1995).
Gunn, A. J. et al. Therapeutic hypothermia translates from ancient history in to practice. Pediatr. Res. 81, 202–209 (2017).
Watson, H. I., Shepherd, A. A., Rhodes, J. K. J. & Andrews, P. Revisited: a systematic review of therapeutic hypothermia for adult patients following traumatic brain injury. Crit. Care Med. 46, 972–979 (2018).
Wyllie, J. et al. Part 11: neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Resuscitation 81(Suppl. 1), e260–e287 (2010).
Azzopardi, D. V. et al. Moderate hypothermia to treat perinatal asphyxia encephalopathy. N. Engl. J. Med. 361, 1349–1358 (2009).
Azzopardi, D. et al. Implementation and conduct of hypothermia for perinatal asphyxia encephalopathy in the UK—analysis of national data. PLoS ONE 7, e38504 (2012).
Chaudhary, R., Farrer, K., Broster, S., McRitchie, L. & Austin, T. Active versus passive cooling during neonatal transport. Pediatrics 132, 841–846 (2013).
Glass, H. C. et al. Neurocritical care for neonates. Neurocrit. Care 12, 421–429 (2010).
Bashir, R. A. et al. Implemenation of a neurocritical care program: improved seizure detection and decreased antiseizure medication at discharge in neonates with hypoxic–ischemic encephalopathy. Pediatr. Neurol. 64, 38–43 (2016).
Harbert, M. J. et al. Impact of a neuro-intensive care service for newborns. J. Neonatal Perinat. Med. 11, 173–178 (2018).
Glass, H. C., Ferreiro, D. M., Rowitch, D. H. & Shimotake, T. K. The neurointensive nursery: concept, development and insights gained. Curr. Opin. Pediatr. 31, 202–209 (2019).
Leotsakosi, A. et al. Standardization in patient safety: the WHO high 5s project. J. Qual. Health Care 26, 109–116 (2014).
Woolf, S. H. Practice guidelines: a new reality in medicine. I. Recent developments. Arch. Intern. Med. 150, 1811–1818 (1990).
Maynard, D., Prior, P. F. & Scott, D. F. Device for continuous monitoring of cerebral activity in resuscitated patients. BMJ 4, 545–546 (1969).
Viniker, D. A., Maynard, D. E. & Scott, D. F. Cerebral function monitor studies in neonates. Clin. Electroencephalogr. 15, 185–192 (1984).
Hellstrom-Westas, L., Rosen, I. & Swenningsen, N. W. Silent seizures in sick infants in early life. Diagnosis by continuous cerebral function monitoring. Acta Paediatr. Scand. 74, 741–748 (1985).
Gluckman, P. D. et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365, 663–670 (2005).
Gunn, J. K. et al. Perioperative amplitude-integrated EEG and neurodevelopment in infants with congenital heart disease. Intens. Care Med. 38, 1539–1547 (2012).
Olischar, M. et al. Amplitude-integrated electroencephalography in newborns with inborn errors of metabolism. Neonatology 102, 203–211 (2012).
Burdjalov, V. F., Baumgart, S. & Spitzer, A. R. Cerebral function monitoring: a new scoring system for the evaluation of brain maturation in neonates. Pediatrics 112, 855–861 (2003).
Lloyd, R. O., OʼToole, J. M., Pavlidis, E., Filan, P. M. & Boylan, G. B. Electrographic seizures during the early postnatal period in preterm infants. J. Pediatr. 187, 18–25 (2017).
Shellbaas, R. A. et al. The American Clinical Neurophysiology Society’s guideline on continuous electroencephalography monitoring in neonates. J. Clin. Neurophysiol. 28, 611–617 (2011).
da Costa, C. S., Greisen, G. & Austin, T. Is near-infrared spectroscopy clinically useful in the preterm infant? Arch. Dis. Child Fetal Neonatal Ed. 100, F558–F561 (2015).
Hyttel-Sorensen, S. et al. Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial. BMJ 350, g7635 (2015).
Siegel, M. et al. Hypoxic–ischemic encephalopathy in term infants: diagnosis and prognosis evaluated by ultrasound. Radiology 152, 395–399 (1984).
Archer, L., Levene, M. & Evans, D. Cerebral artery Doppler ultrasonography for prediction of outcome after perinatal asphyxia. Lancet 328, 1116–1118 (1986).
Boo, N. et al. Early cranial ultrasound changes as predictors of outcome during first year of life in term infants with perinatal asphyxia. J. Paediatr. Child Health 36, 363–369 (2000).
Shankaran, S. et al. Neonatal magnetic resonance imaging pattern of brain injury as a biomarker of childhood outcomes following a trial of hypothermia for neonatal hypoxic–ischemic encephalopathy. J. Pediatr. 167, 987–993 (2015).
Lally, P. J. et al. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. Lancet Neurol. 18, 35–45 (2019).
Hintz, S. R. et al. Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics 135, e32–e42 (2015).
Laptook, A. R. et al. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics 115, 673–680 (2005).
Broitman, E. et al. Clinical data predict neurodevelopmental outcome better than head ultrasound in extremely low birth weight infants. J. Pediatr. 151, 500–505 (2007).
Woodward, L. J., Anderson, P. J., Austin, N. C., Howard, K. & Inder, T. A. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N. Engl. J. Med. 355, 685–694 (2006).
Edwards, A. D. et al. Effect of MRI on preterm infants and their families: a randomised trial with nested diagnostic and economic evaluation. Arch. Dis. Child Fetal Neonatal Ed. 103, F15–F21 (2018).
Peloquin, S., Carley, A., Bonifacio, S. L. & Glass, H. C. The neurointensive care nursery and evolving roles for nursing. Neonatal Netw. 35, 87–94 (2016).
Smyser, C. D. et al. Fellowship training in the emerging fields if fetal–neonatal neurology and neonatal neurocritical care. Pediatr. Neurol. 63, 39–44 (2016).
Mulkey, S. B. & Swearingen, C. J. Advancing neurologic care in the neonatal intensive care unit with a neonatal neurologist. J. Child Neurol. 29, 31–35 (2014).
Wietstock, S. O. et al. Continuous video electroencephalographic (EEG) monitoring for electrographic seizure diagnosis in neonates: a single-center study. J. Child Neurol. 31, 328–332 (2016).
Wietstock, S. O. et al. Neonatal neurocritical care service is associated with decreased administration of seizure medication. J. Child Neurol. 30, 1135–1141 (2015).
Rhodes, A. et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intens. Care Med. 43, 304–377 (2017).
Adams-Chapman, I. Necrotizing enterocolitis and neurodevelopmental outcome. Clin. Perinatol. 45, 453–466 (2018).
Chiriboga, N. et al. Successful implementation of an intracranial (ICH) bundle in reducing severe ICH: a quality improvement project. J. Perinatol. 39, 143–151 (2019).
Chollat, C., Sentihes, L. & Marret, S. Protection of brain development by antenatal magnesium sulphate for infants born preterm. Dev. Med. Child Neurol. 61, 25–30 (2019).
Azzopardi, D. et al. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial. Lancet Neurol. 15, 145–153 (2016).
Juul, S. E. et al. High-dose erythropoietin for asphyxia and encephalopathy (HEAL): a randomized controlled trial: background, aims, and study protocol. Neonatology 113, 331–338 (2018).
Maiwald, C. A. et al. Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic–ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicentre trial for superiority (phase III). BMC Pediatr. 19, 210 (2019).
Chalak, L., Latremouille, S., Mir, I., Sanchez, P. J. & Sant’Anna, G. A review of the conundrum of mild hypoxic–ischemic encephalopathy: current challenges and moving forward. Early Hum. Dev. 120, 88–94 (2018).
Farnaes, L. et al. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalisation. NPJ Genom. Med. 3, 10 (2018).
Elliott, A. M. et al. RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit-successes and challenges. Eur. J. Pediatr. 178, 1207–1218 (2019).
French, C. E. et al. Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children. Intens. Care Med. 45, 627–636 (2019).
Wilkinson, D. J. C., Barnett, C., Savulescu, J. & Newson, A. J. Genomic intensive care: should we perform genome testing in critically ill newborns? Arch. Dis. Child Fetal Neonatal Ed. 101, F94–F98 (2016).
Thewissen, L. et al. Measuring near-infrared spectroscopy derived cerebral autoregulation in neonates: from research tool toward bedside multimodal monitoring. Front. Pediatr. 6, 117 (2018).
Temko, A. et al. Toward a personalized real-time diagnosis in neonatal seizure detection. IEEE J. Transl. Eng. Health Med. 5, 2800414 (2017).
Joshi, R. et al. Pattern discovery in critical alarms originating from neonates under intensive care. Physiol. Meas. 37, 564–579 (2016).
Vellido, A., Ribas, V., Morales, C., Ruiz Sanmartín, A. & Ruiz Rodríguez, J. C. Machine learning in critical care: state-of-the-art and a sepsis case study. Biomed. Eng. Online 17, 135 (2018).
Sortica da Costa, C. et al. Complexity of brain signals is associated with outcome in preterm infants. J. Cereb. Blood Flow Metab. 37, 3368–3379 (2017).
Blencowe, H. et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 379, 2162–2172 (2012).
Pauliah, S. S., Shankaran, S., Wade, A., Cady, E. B. & Thayyil, S. Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis. PLoS ONE 8, e58834 (2013).
Variane, G. F. et al. Therapeutic hypothermia in Brazil: a multiprofessional national survey. Am. J. Perinatol. https://doi.org/10.1055/s-0038-1676052 (2018).
Althabe, F. et al. A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster randomised trial. Lancet 385, 629–639 (2015).
Als, H. et al. Individualised behavioural and environmental care for the very low birth weight preterm infant at high risk for bronchopulmonary dysplasia: meonatal intensive care unit and developmental outcome. Pediatrics 78, 1123–1132 (1986).
Ohlsson, A. & Jacobs, S. E. NIDCAP: a systematic review and meta-analyses of randomized controlled trials. Pediatrics 131, e881–e893 (2013).
Franck, L. S. & O’Brien K. The evolution of family-centred care: from supporting parent-delivered interventions to a model of family integrated care. Birth Defects Res. https://doi.org/10.1002/bdr2.1521 (2019).
Brummelte, S. et al. Procedural pain and brain development in premature newborns. Ann. Neurol. 71, 385–396 (2012).
Santos, J., Pearcea, S. E. & Stroustrupa, A. Impact of hospital-based environmental exposures on neurodevelopmental outcomes of preterm infants. Curr. Opin. Pediatr. 27, 254–260 (2015).
Almadhoob, A. & Ohlsson, A. Sound reduction management in the neonatal intensive care unit for preterm or very low birth weight infants. Cochrane Database Syst. Rev. 1, CD010333 (2015).
Morag, I. & Ohlsson, A. Cycled light in the intensive care unit for preterm and low birth weight infants. Cochrane Database Syst. Rev. 8, CD006982 (2016).
Bennet, L., Walker, D. W. & Horne, R. S. C. Waking up too early—the consequences of preterm birth on sleep development. J. Physiol. 596, 5687–5708 (2018).
Van Veenendaal, N. R. et al. Hospitalising preterm infants in single family rooms versus open bay units: a systematic review and meta-analysis. Lancet Child Adolesc. Health 3, 147–157 (2019).
Acknowledgements
The author receives funding from NIHR Cambridge Biomedical Research Centre (www.cambridgebrc.nihr.ac.uk) and NIHR Brain Injury MedTech Co-Operative (www.brainmic.nihr.ac.uk).
Author information
Authors and Affiliations
Contributions
I can confirm that I, T.A., am the sole author of this paper, having conceived of the idea for the manuscript, undertaken the relevant literature search into the subject and written the manuscript.
Corresponding author
Ethics declarations
Competing interests
The author declares no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Austin, T. The development of neonatal neurointensive care. Pediatr Res 96, 868–874 (2024). https://doi.org/10.1038/s41390-019-0729-5
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41390-019-0729-5
This article is cited by
-
Neural Responses to Hypoxic Injury in a Vascularized Cerebral Organoid Model
Neuroscience Bulletin (2025)
-
Nursing practice of routine gastric aspiration in preterm infants and its link to necrotizing enterocolitis: is the practice still clinically relevant?
BMC Nursing (2024)
-
The newborn delivery room of tomorrow: emerging and future technologies
Pediatric Research (2024)
-
General Movements trajectories and outcome at 12 months in very preterm infants: An analysis of tendencies and pathological persistence
Scientific Reports (2023)
-
Neuromonitoring in neonatal critical care part I: neonatal encephalopathy and neonates with possible seizures
Pediatric Research (2023)