Original Article| Volume 110, P42-48, September 2020

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Neuroprotection Care Bundle Implementation to Decrease Acute Brain Injury in Preterm Infants



      We assessed the impact of an evidence-based neuroprotection care bundle on the risk of brain injury in extremely preterm infants.


      We implemented a neuroprotection care bundle consisting of a combination of neuroprotection interventions such as minimal handling, midline head position, deferred cord clamping, and protocolization of hemodynamic and respiratory managements. These interventions targeted risk factors for acute brain injury in extremely preterm infants (born at gestational age less than 29 weeks) during the first three days of birth. Implementation occurred in a stepwise manner, including care bundle development by a multidisciplinary care team based on previous evidence and experience, standardization of outcome assessment tools, and education. We compared the incidence of the composite outcome of acute preterm brain injury or death preimplementation and postimplementation.


      Neuroprotection care bundle implementation associated with a significant reduction in acute brain injury risk factors such as the use of inotropes (24% before, 7% after, P value < 0.001) and fluid boluses (37% before, 19% after, P value < 0.001), pneumothorax (5% before, 2% after, P value = 0.002), and opioid use (19% before, 7% after, P value < 0.001). Adjusting for confounding factors, the neuroprotection care bundle significantly reduced death or severe brain injury (adjusted odds ratio, 0.34; 95% confidence interval, 0.20 to 0.59; P value < 0.001) and severe brain injury (adjusted odds ratio, 0.31; 95% confidence interval, 0.17 to 0.58; P < 0.001).


      Implementation of neuroprotection care bundle targeting predefined risk factors is feasible and effective in reducing acute brain injury in extremely preterm infants.


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        • Diwakar K.
        • Hader W.J.
        • Soraisham A.
        • et al.
        Long-term neurodevelopmental and growth outcomes of premature infants born at <29 week gestational age with post-hemorrhagic hydrocephalus treated with ventriculo-peritoneal shunt.
        Indian J Pediatr. 2017; 84: 662-669
        • van Zanten S.A.
        • de Haan T.R.
        • Ursum J.
        • van Sonderen L.
        Neurodevelopmental outcome of posthemorrhagic ventricular dilatation at 12 and 24 months corrected age with high-threshold therapy.
        Eur J Paediatr Neurol. 2011; 15: 487-492
        • Bolisetty S.
        • Dhawan A.
        • Abdel-Latif M.
        • et al.
        Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants.
        Pediatrics. 2014; 133: 55-62
        • Calisici E.
        • Eras Z.
        • Oncel M.Y.
        • Oguz S.S.
        • Gokce I.K.
        • Dilmen U.
        Neurodevelopmental outcomes of premature infants with severe intraventricular hemorrhage.
        J Matern Fetal Neonatal Med. 2015; 28: 2115-2120
        • Synnes A.
        • Luu T.M.
        • Moddemann D.
        • et al.
        Determinants of developmental outcomes in a very preterm Canadian cohort.
        Arch Dis Child Fetal Neonatal Ed. 2017; 102 (F235-F234)
        • Leijser L.M.
        • de Vries L.S.
        Preterm brain injury: germinal matrix-intraventricular hemorrhage and post-hemorrhagic ventricular dilatation.
        Handb Clin Neurol. 2019; 162: 173-199
        • Ment L.R.
        • Duncan C.C.
        • Ehrenkranz R.A.
        • et al.
        Intraventricular hemorrhage in the preterm neonate: timing and cerebral blood flow changes.
        J Pediatr. 1984; 104: 419-425
        • Perlman J.M.
        • Volpe J.J.
        Intraventricular hemorrhage in extremely small premature infants.
        Am J Dis Child. 1986; 140: 1122-1124
        • Marba S.T.
        • Caldas J.P.
        • Vinagre L.E.
        • Pessoto M.A.
        Incidence of periventricular/intraventricular hemorrhage in very low birth weight infants: a 15-year cohort study.
        J Pediatr (Rio J). 2011; 87: 505-511
        • Horbar J.D.
        • Edwards E.M.
        • Greenberg L.T.
        • et al.
        Variation in performance of neonatal intensive care units in the United States.
        JAMA Pediatr. 2017; 171: e164396
        • Handley S.C.
        • Passarella M.
        • Lee H.C.
        • Lorch S.A.
        Incidence trends and risk factor variation in severe intraventricular hemorrhage across a population based cohort.
        J Pediatr. 2018; 200: 24-29.e3
        • Lee J.Y.
        • Kim H.S.
        • Jung E.
        • et al.
        Risk factors for periventricular intraventricular hemorrhage in premature infants.
        J Korean Med Sci. 2010; 25: 418-424
        • McCrea H.J.
        • Ment L.R.
        The diagnosis, management, and postnatal prevention of intraventricular hemorrhage in the preterm neonate.
        Clin Perinatol. 2008; 35 (vii): 777-792
        • Fowlie P.W.
        • Davis P.G.
        • McGuire W.
        Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants.
        Cochrane Database Syst Rev. 2010; 2010: CD000174
        • Schmid M.B.
        • Reister F.
        • Mayer B.
        • Hopfner R.J.
        • Fuchs H.
        • Hummler H.D.
        Prospective risk factor monitoring reduces intracranial hemorrhage rates in preterm infants.
        Dtsch Arztebl Int. 2013; 110: 489-496
        • Papile L.A.
        • Burstein J.
        • Burstein R.
        • Koffler H.
        Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.
        J Pediatr. 1978; 92: 529-534
        • Antes S.
        • Welsch M.
        • Kiefer M.
        • Glaser M.
        • Korner H.
        • Eymann R.
        The frontal and temporal horn ratio to assess dimension of paediatric hydrocephalus: a comparative volumetric study.
        Acta Neurochir Suppl. 2013; 118: 211-214
        • Brouwer M.J.
        • de Vries L.S.
        • Pistorius L.
        • Rademaker K.J.
        • Groenendaal F.
        • Benders M.J.
        Ultrasound measurements of the lateral ventricles in neonates: why, how and when? A systematic review.
        Acta Paediatr. 2010; 99: 1298-1306
        • Levene M.I.
        Measurement of the growth of the lateral ventricles in preterm infants with real-time ultrasound.
        Arch Dis Child. 1981; 56: 900-904
        • Kaiser J.R.
        Both extremes of arterial carbon dioxide pressure and the magnitude of fluctuations in arterial carbon dioxide pressure are associated with severe intraventricular hemorrhage in preterm infants.
        Pediatrics. 2007; 119 (author reply -40): 1039
        • Ryan M.
        • Lacaze-Masmonteil T.
        • Mohammad K.
        Neuroprotection from acute brain injury in preterm infants.
        Paediatr Child Health. 2019; 24: 276-290
        • Fenton T.R.
        • Nasser R.
        • Eliasziw M.
        • Kim J.H.
        • Bilan D.
        • Sauve R.
        Validating the weight gain of preterm infants between the reference growth curve of the fetus and the term infant.
        BMC Pediatr. 2013; 13: 92
        • Richardson D.K.
        • Gray J.E.
        • McCormick M.C.
        • Workman K.
        • Goldmann D.A.
        Score for neonatal acute physiology: a physiologic severity index for neonatal intensive care.
        Pediatrics. 1993; 91: 617-623
        • Singh R.
        • Gorstein S.V.
        • Bednarek F.
        • Chou J.H.
        • McGowan E.C.
        • Visintainer P.F.
        A predictive model for SIVH risk in preterm infants and targeted indomethacin therapy for prevention.
        Sci Rep. 2013; 3: 2539
        • Altimier L.
        • Phillips R.
        The neonatal integrative developmental care model: advanced clinical applications of the seven core measures for neuroprotective family-centered developmental care.
        Newborn Infant Nurs Rev. 2016; 16: 230-244
        • Malusky S.
        • Donze A.
        Neutral head positioning in premature infants for intraventricular hemorrhage prevention: an evidence-based review.
        Neonatal Netw. 2011; 30: 381-396
        • Brown G.
        NICU noise and the preterm infant.
        Neonatal Netw. 2009; 28: 165-173
        • Ranger M.
        • Grunau R.E.
        Early repetitive pain in preterm infants in relation to the developing brain.
        Pain Manag. 2014; 4: 57-67
        • Fanaroff J.M.
        • Wilson-Costello D.E.
        • Newman N.S.
        • Montpetite M.M.
        • Fanaroff A.A.
        Treated hypotension is associated with neonatal morbidity and hearing loss in extremely low birth weight infants.
        Pediatrics. 2006; 117: 1131-1135
        • Greenough A.
        • Cheeseman P.
        • Kavvadia V.
        • Dimitriou G.
        • Morton M.
        Colloid infusion in the perinatal period and abnormal neurodevelopmental outcome in very low birth weight infants.
        Eur J Pediatr. 2002; 161: 319-323
        • Martens S.E.
        • Rijken M.
        • Stoelhorst G.M.
        • et al.
        Is hypotension a major risk factor for neurological morbidity at term age in very preterm infants?.
        Early Hum Dev. 2003; 75: 79-89
        • Lightburn M.H.
        • Gauss C.H.
        • Williams D.K.
        • Kaiser J.R.
        Observational study of cerebral hemodynamics during dopamine treatment in hypotensive ELBW infants on the first day of life.
        J Perinatol. 2013; 33: 698-702
        • Kuint J.
        • Barak M.
        • Morag I.
        • Maayan-Metzger A.
        Early treated hypotension and outcome in very low birth weight infants.
        Neonatology. 2009; 95: 311-316
        • Abdul Aziz A.N.
        • Thomas S.
        • Murthy P.
        • et al.
        Early inotropes use is associated with higher risk of death and/or severe brain injury in extremely premature infants.
        J Matern Fetal Neonatal Med. 2019; : 1-8
        • Chau V.
        • Poskitt K.J.
        • McFadden D.E.
        • et al.
        Effect of chorioamnionitis on brain development and injury in premature newborns.
        Ann Neurol. 2009; 66: 155-164
        • Noori S.
        • Anderson M.
        • Soleymani S.
        • Seri I.
        Effect of carbon dioxide on cerebral blood flow velocity in preterm infants during postnatal transition.
        Acta Paediatr. 2014; 103: e334-e339
        • Fabres J.
        • Carlo W.A.
        • Phillips V.
        • Howard G.
        • Ambalavanan N.
        Both extremes of arterial carbon dioxide pressure and the magnitude of fluctuations in arterial carbon dioxide pressure are associated with severe intraventricular hemorrhage in preterm infants.
        Pediatrics. 2007; 119: 299-305
        • Erickson S.J.
        • Grauaug A.
        • Gurrin L.
        • Swaminathan M.
        Hypocarbia in the ventilated preterm infant and its effect on intraventricular haemorrhage and bronchopulmonary dysplasia.
        J Paediatr Child Health. 2002; 38: 560-562
        • Hatch L.D.
        • Grubb P.H.
        • Lea A.S.
        • et al.
        Endotracheal intubation in neonates: a prospective study of adverse safety events in 162 infants.
        J Pediatr. 2016; 168: 62-66.e6
        • Shangle C.E.
        • Haas R.H.
        • Vaida F.
        • Rich W.D.
        • Finer N.N.
        Effects of endotracheal intubation and surfactant on a 3-channel neonatal electroencephalogram.
        J Pediatr. 2012; 161: 252-257