Autonomic Dysfunction in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia Impairs Physiological Responses to Routine Care Events

      Objective

      To evaluate whether infants with hypoxic-ischemic encephalopathy and evidence of autonomic dysfunction have aberrant physiological responses to care events that could contribute to evolving brain injury.

      Study design

      Continuous tracings of heart rate (HR), blood pressure (BP), cerebral near infrared spectroscopy, and video electroencephalogram data were recorded from newborn infants with hypoxic-ischemic encephalopathy who were treated with hypothermia. Videos between 16 and 24 hours of age identified 99 distinct care events, including stimulating events (diaper changes, painful procedures), and vagal stimuli (endotracheal tube manipulations, pupil examinations). Pre-event HR variability was used to stratify patients into groups with impaired versus intact autonomic nervous system (ANS) function. Postevent physiological responses were compared between groups with the nearest mean classification approach.

      Results

      Infants with intact ANS had increases in HR/BP after stimulating events, whereas those with impaired ANS showed no change or decreased HR/BP. With vagal stimuli, the HR decreased in infants with intact ANS but changed minimally in those with impaired ANS. A pupil examination in infants with an intact ANS led to a stable or increased BP, whereas the BP decreased in the group with an impaired ANS. Near infrared spectroscopy measures of cerebral blood flow/blood volume increased after diaper changes in infants with an impaired ANS, but were stable or decreased in those with an intact ANS.

      Conclusion

      HR variability metrics identified infants with impaired ANS function at risk for maladaptive responses to care events. These data support the potential use of HR variability as a real-time, continuous physiological biomarker to guide neuroprotective care in high-risk newborns.

      Keywords

      **Abbreviations:

      ANS ( Autonomic nervous system), BP ( Blood pressure), Hb ( Deoxyhemoglobin), HbD ( Hemoglobin difference), HbO2 ( Cerebral oxyhemoglobin), HbT ( Total hemoglobin), EEG ( Electroencephalogram*), ET ( Endotracheal tube), HF ( High-frequency), HIE ( Hypoxic ischemic encephalopathy), HR ( Heart rate), HRV ( Heart rate variability), ICU ( Intensive-care unit), LF ( Low-frequency), MRI ( Magnetic resonance imaging*), NICU ( Neonatal intensive care unit), NIRS ( Near infrared spectroscopy), RMS ( Root mean square), RMSL ( RMS long time scales), RMSs ( RMS short time scales)
      To read this article in full you will need to make a payment

      References

        • Dilenge M.E.
        • Majnemer A.
        • Shevell M.I.
        Long-term developmental outcome of asphyxiated term neonates.
        J Child Neurol. 2001; 16: 781-792
        • Jacobs S.E.
        • Berg M.
        • Hunt R.
        • Tarnow-Mordi W.O.
        • Inder T.E.
        • Davis P.G.
        Cooling for newborns with hypoxic ischaemic encephalopathy.
        Cochrane Database Syst Rev. 2013; (CD003311)
        • Shankaran S.
        • Laptook A.R.
        • Ehrenkranz R.A.
        • Tyson J.E.
        • McDonald S.A.
        • Donovan E.F.
        • et al.
        Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.
        N Engl J Med. 2005; 353: 1574-1584
        • Shankaran S.
        • Pappas A.
        • McDonald S.A.
        • Vohr B.R.
        • Hintz S.R.
        • Yolton K.
        • et al.
        Childhood outcomes after hypothermia for neonatal encephalopathy.
        N Engl J Med. 2012; 366: 2085-2092
        • Azzopardi D.
        • Strohm B.
        • Marlow N.
        • Brocklehurst P.
        • Deierl A.
        • Eddama O.
        • et al.
        Effects of hypothermia for perinatal asphyxia on childhood outcomes.
        N Engl J Med. 2014; 371: 140-149
        • Shah P.S.
        Hypothermia: a systematic review and meta-analysis of clinical trials.
        Semin Fetal Neonatal Med. 2010; 15: 238-246
        • Tagin M.A.
        • Woolcott C.G.
        • Vincer M.J.
        • Whyte R.K.
        • Stinson D.A.
        Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis.
        Arch Pediatr Adolesc Med. 2012; 166: 558-566
        • Bohanon F.J.
        • Mrazek A.A.
        • Shabana M.T.
        • Mims S.
        • Radhakrishnan G.L.
        • Kramer G.C.
        • et al.
        Heart rate variability analysis is more sensitive at identifying neonatal sepsis than conventional vital signs.
        Am J Surg. 2015; 210: 661-667
        • Fairchild K.D.
        Predictive monitoring for early detection of sepsis in neonatal ICU patients.
        Curr Opin Pediatr. 2013; 25: 172-179
        • Fairchild K.D.
        • Sinkin R.A.
        • Davalian F.
        • Blackman A.E.
        • Swanson J.R.
        • Matsumoto J.A.
        • et al.
        Abnormal heart rate characteristics are associated with abnormal neuroimaging and outcomes in extremely low birth weight infants.
        J Perinatol. 2014; 34: 375-379
        • Gang Y.
        • Malik M.
        Heart rate variability in critical care medicine.
        Curr Opin Crit Care. 2002; 8: 371-375
        • Golder V.
        • Hepponstall M.
        • Yiallourou S.R.
        • Odoi A.
        • Horne R.S.
        Autonomic cardiovascular control in hypotensive critically ill preterm infants is impaired during the first days of life.
        Early Hum Dev. 2013; 89: 419-423
        • Griffin M.P.
        • Lake D.E.
        • Bissonette E.A.
        • Harrell Jr, F.E.
        • O'Shea T.M.
        • Moorman J.R.
        Heart rate characteristics: novel physiomarkers to predict neonatal infection and death.
        Pediatrics. 2005; 116: 1070-1074
        • Griffin M.P.
        • O'Shea T.M.
        • Bissonette E.A.
        • Harrell Jr, F.E.
        • Lake D.E.
        • Moorman J.R.
        Abnormal heart rate characteristics preceding neonatal sepsis and sepsis-like illness.
        Pediatr Res. 2003; 53: 920-926
        • Griffin M.P.
        • Scollan D.F.
        • Moorman J.R.
        The dynamic range of neonatal heart rate variability.
        J Cardiovasc Electrophysiol. 1994; 5: 112-124
        • Kaltman J.R.
        • Hanna B.D.
        • Gallagher P.R.
        • Gaynor J.W.
        • Godinez R.I.
        • Tanel R.E.
        • et al.
        Heart rate variability following neonatal heart surgery for complex congenital heart disease.
        Pacing Clin Electrophysiol. 2006; 29: 471-478
        • Malarvili M.B.
        • Mesbah M.
        Newborn seizure detection based on heart rate variability.
        IEEE Trans Biomed Eng. 2009; 56: 2594-2603
        • Rosenstock E.G.
        • Cassuto Y.
        • Zmora E.
        Heart rate variability in the neonate and infant: analytical methods, physiological and clinical observations.
        Acta Paediatr. 1999; 88: 477-482
        • Stone M.L.
        • Tatum P.M.
        • Weitkamp J.H.
        • Mukherjee A.B.
        • Attridge J.
        • McGahren E.D.
        • et al.
        Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis.
        J Perinatol. 2013; 33: 847-850
        • Sullivan B.A.
        • Fairchild K.D.
        Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock.
        Semin Fetal Neonatal Med. 2015; 20: 255-261
        • Sullivan B.A.
        • Grice S.M.
        • Lake D.E.
        • Moorman J.R.
        • Fairchild K.D.
        Infection and other clinical correlates of abnormal heart rate characteristics in preterm infants.
        J Pediatr. 2014; 164: 775-780
        • Rahman F.
        • Pechnik S.
        • Gross D.
        • Sewell L.
        • Goldstein D.S.
        Low frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation.
        Clin Auton Res. 2011; 21: 133-141
        • Aliefendioglu D.
        • Dogru T.
        • Albayrak M.
        • Dibekmisirlioglu E.
        • Sanli C.
        Heart rate variability in neonates with hypoxic ischemic encephalopathy.
        Indian J Pediatr. 2012; 79: 1468-1472
        • Goulding R.M.
        • Stevenson N.J.
        • Murray D.M.
        • Livingstone V.
        • Filan P.M.
        • Boylan G.B.
        Heart rate variability in hypoxic ischemic encephalopathy: correlation with EEG grade and 2-y neurodevelopmental outcome.
        Pediatr Res. 2015; 77: 681-687
        • Massaro A.N.
        • Govindan R.B.
        • Al-Shargabi T.
        • Andescavage N.N.
        • Metzler M.
        • Chang T.
        • et al.
        Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia.
        J Perinatol. 2014; 34: 836-841
        • Matic V.
        • Cherian P.J.
        • Widjaja D.
        • Jansen K.
        • Naulaers G.
        • Van Huffel S.
        • et al.
        Heart rate variability in newborns with hypoxic brain injury.
        Adv Exp Med Biol. 2013; 789: 43-48
        • Vergales B.D.
        • Zanelli S.A.
        • Matsumoto J.A.
        • Goodkin H.P.
        • Lake D.E.
        • Moorman J.R.
        • et al.
        Depressed heart rate variability is associated with abnormal EEG, MRI, and death in neonates with hypoxic ischemic encephalopathy.
        Am J Perinatol. 2014; 31: 855-862
        • Sarnat H.B.
        • Sarnat M.S.
        Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study.
        Arch Neurol. 1976; 33: 696-705
        • Soul J.S.
        • Taylor G.A.
        • Wypij D.
        • Duplessis A.J.
        • Volpe J.J.
        Noninvasive detection of changes in cerebral blood flow by near-infrared spectroscopy in a piglet model of hydrocephalus.
        Pediatr Res. 2000; 48: 445-449
        • Tsuji M.
        • duPlessis A.
        • Taylor G.
        • Crocker R.
        • Volpe J.J.
        Near infrared spectroscopy detects cerebral ischemia during hypotension in piglets.
        Pediatr Res. 1998; 44: 591-595
        • Anderson N.G.
        • Warfield S.K.
        • Wells S.
        • Spencer C.
        • Balasingham A.
        • Volpe J.J.
        • et al.
        A limited range of measures of 2-D ultrasound correlate with 3-D MRI cerebral volumes in the premature infant at term.
        Ultrasound Med Biol. 2004; 30: 11-18
        • Wyatt J.S.
        • Cope M.
        • Delpy D.T.
        • Richardson C.E.
        • Edwards A.D.
        • Wray S.
        • et al.
        Quantitation of cerebral blood volume in human infants by near-infrared spectroscopy.
        J Appl Physiol. 1990; 68: 1086-1091
        • Govindan R.
        • Al-Shargabi T.
        • Metzler M.
        • Andescavage N.N.
        • Joshi R.
        • du Plessis A.
        A spike correction approach for variability analysis of heart rate sick infants.
        Physica A. 2016; 444: 35-42
        • Govindan R.B.
        • Massaro A.N.
        • Niforatos N.
        • du Plessis A.
        Mitigating the effect of non-stationarity in spectral analysis-an application to neonate heart rate analysis.
        Comput Biol Med. 2013; 43: 2001-2006
        • Ulusar U.D.
        • Govindan R.B.
        • Wilson J.D.
        • Lowery C.L.
        • Preissl H.
        • Eswaran H.
        Adaptive rule based fetal QRS complex detection using Hilbert transform.
        Conf Proc IEEE Eng Med Biol Soc. 2009; 2009: 4666-4669
        • Halliday D.M.
        • Rosenberg J.R.
        • Amjad A.M.
        • Breeze P.
        • Conway B.A.
        • Farmer S.F.
        A framework for the analysis of mixed time series/point process data–theory and application to the study of physiological tremor, single motor unit discharges and electromyograms.
        Prog Biophys Mol Biol. 1995; 64: 237-278
        • Malliani A.
        • Pagani M.
        • Lombardi F.
        • Cerutti S.
        Cardiovascular neural regulation explored in the frequency domain.
        Circulation. 1991; 84: 482-492
        • Pomeranz B.
        • Macaulay R.J.
        • Caudill M.A.
        • Kutz I.
        • Adam D.
        • Gordon D.
        • et al.
        Assessment of autonomic function in humans by heart rate spectral analysis.
        Am J Physiol. 1985; 248: H151-H153
        • Lasky R.E.
        • Parikh N.A.
        • Williams A.L.
        • Padhye N.S.
        • Shankaran S.
        Changes in the PQRST intervals and heart rate variability associated with rewarming in two newborns undergoing hypothermia therapy.
        Neonatology. 2009; 96: 93-95
        • Govindan R.B.
        • Massaro A.N.
        • Al-Shargabi T.
        • Andescavage N.N.
        • Chang T.
        • Glass P.
        • et al.
        Detrended fluctuation analysis of non-stationary cardiac beat-to-beat interval of sick infants.
        Europhys Lett. 2014; 108: 40005
        • Johnston M.V.
        • Fatemi A.
        • Wilson M.A.
        • Northington F.
        Treatment advances in neonatal neuroprotection and neurointensive care.
        Lancet Neurol. 2011; 10: 372-382
        • Barkovich A.J.
        • Hajnal B.L.
        • Vigneron D.
        • Sola A.
        • Partridge J.C.
        • Allen F.
        • et al.
        Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems.
        AJNR Am J Neuroradiol. 1998; 19: 143-149
        • Kota S.
        • Yarlagadda P.
        • Gupta L.
        • Molfese D.L.
        Central-tendency estimation and nearest-estimate classification of multi-channel evoked potentials.
        Conf Proc IEEE Eng Med Biol Soc. 2009; 2009: 2575-2578
        • Limperopoulos C.
        • Gauvreau K.K.
        • O'Leary H.
        • Moore M.
        • Bassan H.
        • Eichenwald E.C.
        • et al.
        Cerebral hemodynamic changes during intensive care of preterm infants.
        Pediatrics. 2008; 122: e1006-e1013
        • Massaro A.N.
        • Govindan R.B.
        • Vezina G.
        • Chang T.
        • Andescavage N.N.
        • Wang Y.
        • et al.
        Impaired cerebral autoregulation and brain injury in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.
        J Neurophysiol. 2015; 114: 818-824
        • Segar J.L.
        • Merrill D.C.
        • Chapleau M.W.
        • Robillard J.E.
        Hemodynamic changes during endotracheal suctioning are mediated by increased autonomic activity.
        Pediatr Res. 1993; 33: 649-652
        • Fyfe K.L.
        • Yiallourou S.R.
        • Wong F.Y.
        • Horne R.S.
        The development of cardiovascular and cerebral vascular control in preterm infants.
        Sleep Med Rev. 2014; 18: 299-310
        • Gilmore M.M.
        • Stone B.S.
        • Shepard J.A.
        • Czosnyka M.
        • Easley R.B.
        • Brady K.M.
        Relationship between cerebrovascular dysautoregulation and arterial blood pressure in the premature infant.
        J Perinatol. 2011; 31: 722-729
        • Verma P.K.
        • Panerai R.B.
        • Rennie J.M.
        • Evans D.H.
        Grading of cerebral autoregulation in preterm and term neonates.
        Pediatr Neurol. 2000; 23: 236-242
        • Wong F.Y.
        • Leung T.S.
        • Austin T.
        • Wilkinson M.
        • Meek J.H.
        • Wyatt J.S.
        • et al.
        Impaired autoregulation in preterm infants identified by using spatially resolved spectroscopy.
        Pediatrics. 2008; 121: e604-e611
        • Yanowitz T.D.
        • Potter D.M.
        • Bowen A.
        • Baker R.W.
        • Roberts J.M.
        Variability in cerebral oxygen delivery is reduced in premature neonates exposed to chorioamnionitis.
        Pediatr Res. 2006; 59: 299-304
      1. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.
        Eur Heart J. 1996; 17: 354-381
        • Govindan R.B.
        • Al-Shargabi T.
        • Massaro A.N.
        • Metzler M.
        • Andescavage N.N.
        • Joshi R.
        • et al.
        Baroreflex dysfunction in sick newborns makes heart rate an unreliable surrogate for blood pressure changes.
        Pediatr Res. 2016; 79: 929-933