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Am J Perinatol 2014; 31(10): 855-862
DOI: 10.1055/s-0033-1361937
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Depressed Heart Rate Variability is Associated with Abnormal EEG, MRI, and Death in Neonates with Hypoxic Ischemic Encephalopathy

Brooke D. Vergales
1   Division of Neonatology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia
,
Santina A. Zanelli
1   Division of Neonatology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia
,
Julie A. Matsumoto
2   Division of Neuroradiology, Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia
,
Howard P. Goodkin
3   Division of Pediatric Neurology, Department of Neurology, University of Virginia, Charlottesville, Virginia
,
Douglas E. Lake
4   Division of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia
5   Department of Statistics, University of Virginia, Charlottesville, Virginia
,
J. Randall Moorman
4   Division of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia
,
Karen D. Fairchild
1   Division of Neonatology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia
› Author Affiliations
Further Information

Publication History

07 March 2013

24 October 2013

Publication Date:
17 December 2013 (online)

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Abstract

Objective Asphyxia can lead to autonomic nervous system dysfunction, including depressed heart rate variability (HRV). We tested the hypothesis that low HRV is associated with adverse short-term outcomes of abnormalities on electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) and death in neonates with hypoxic ischemic encephalopathy (HIE).

Study Design Neonates undergoing hypothermia therapy for HIE underwent monitoring of HRV. HRV in the first day after birth and after hypothermia and rewarming (days 4–7) were analyzed in relation to death and severity of abnormal findings on EEG and MRI.

Results A total of 37 neonates had data available in the first 24 hour after birth and 67 had data days 2 to 7. Depressed HRV was significantly associated with adverse outcomes of death or moderate-to-severe abnormalities on EEG or MRI. In the first 24 hours, the odds ratio (OR) of one or more adverse outcomes for every 10-millisecond decrease in HRV was 3.19 (95% CI, 1.3–7.8; p = 0.01). HRV improved over time but low HRV remained significantly associated with adverse outcomes days 4 to 7 (OR, 2.72; CI, 1.32–5.61; p < 0.01).

Conclusions Monitoring HRV, which is reflected in the heart rate characteristic index, may provide useful adjunct information on the severity of brain injury in infants with HIE.

Keywords

hypoxic ischemic encephalopathy - heart rate variability - neonate - asphyxia - electroencephalogram
 

  • References

  • 1 Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 2010; 86 (6) 329-338
    CrossrefPubMedGoogle Scholar
  • 2 Pin TW, Eldridge B, Galea MP. A review of developmental outcomes of term infants with post-asphyxia neonatal encephalopathy. Eur J Paediatr Neurol 2009; 13 (3) 224-234
    CrossrefPubMedGoogle Scholar
  • 3 Edwards AD, Brocklehurst P, Gunn AJ , et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010; 340: c363
    CrossrefPubMedGoogle Scholar
  • 4 Gonzalez FF, Ferriero DM. Neuroprotection in the newborn infant. Clin Perinatol 2009; 36 (4) 859-880 , vii
    CrossrefPubMedGoogle Scholar
  • 5 Massaro AN, Chang T, Kadom N , et al. Biomarkers of brain injury in neonatal encephalopathy treated with hypothermia. J Pediatr 2012; 161 (3) 434-440
    CrossrefPubMedGoogle Scholar
  • 6 Biswas AK, Scott WA, Sommerauer JF, Luckett PM. Heart rate variability after acute traumatic brain injury in children. Crit Care Med 2000; 28 (12) 3907-3912
    CrossrefPubMedGoogle Scholar
  • 7 Goldstein B, Kempski MH, DeKing D , et al. Autonomic control of heart rate after brain injury in children. Crit Care Med 1996; 24 (2) 234-240
    CrossrefPubMedGoogle Scholar
  • 8 Keren O, Yupatov S, Radai MM , et al. Heart rate variability (HRV) of patients with traumatic brain injury (TBI) during the post-insult sub-acute period. Brain Inj 2005; 19 (8) 605-611
    CrossrefPubMedGoogle Scholar
  • 9 Kox M, Vrouwenvelder MQ, Pompe JC, van der Hoeven JG, Pickkers P, Hoedemaekers CW. The effects of brain injury on heart rate variability and the innate immune response in critically ill patients. J Neurotrauma 2012; 29 (5) 747-755
    CrossrefPubMedGoogle Scholar
  • 10 Aliefendioğlu D, Doğru T, Albayrak M, Dibekmısırlıoğlu E, Sanlı C. Heart rate variability in neonates with hypoxic ischemic encephalopathy. Indian J Pediatr 2012; 79 (11) 1468-1472
    CrossrefPubMedGoogle Scholar
  • 11 Rapenne T, Moreau D, Lenfant F , et al. Could heart rate variability predict outcome in patients with severe head injury? A pilot study. J Neurosurg Anesthesiol 2001; 13 (3) 260-268
    CrossrefPubMedGoogle Scholar
  • 12 Fairchild KD, O'Shea TM. Heart rate characteristics: physiomarkers for detection of late-onset neonatal sepsis. Clin Perinatol 2010; 37 (3) 581-598
    CrossrefPubMedGoogle Scholar
  • 13 Moorman JR, Carlo WA, Kattwinkel J , et al. Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: a randomized trial. J Pediatr 2011; 159 (6) 900-906 , e1
    CrossrefPubMedGoogle Scholar
  • 14 Griffin MP, O'Shea TM, Bissonette EA, Harrell Jr FE, Lake DE, Moorman JR. Abnormal heart rate characteristics preceding neonatal sepsis and sepsis-like illness. Pediatr Res 2003; 53 (6) 920-926
    CrossrefPubMedGoogle Scholar
  • 15 Lowensohn RI, Weiss M, Hon EH. Heart-rate variability in brain-damaged adults. Lancet 1977; 1 (8012) 626-628
    PubMedGoogle Scholar
  • 16 Westgate JA, Bennet L, Gunn AJ. Fetal heart rate variability changes during brief repeated umbilical cord occlusion in near term fetal sheep. Br J Obstet Gynaecol 1999; 106 (7) 664-671
    CrossrefPubMedGoogle Scholar
  • 17 Buchman TG, Stein PK, Goldstein B. Heart rate variability in critical illness and critical care. Curr Opin Crit Care 2002; 8 (4) 311-315
    CrossrefPubMedGoogle Scholar
  • 18 George S, Gunn AJ, Westgate JA, Brabyn C, Guan J, Bennet L. Fetal heart rate variability and brain stem injury after asphyxia in preterm fetal sheep. Am J Physiol Regul Integr Comp Physiol 2004; 287 (4) R925-R933
    CrossrefPubMedGoogle Scholar
  • 19 Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33 (10) 696-705
    CrossrefPubMedGoogle Scholar
  • 20 Griffin MP, Lake DE, Bissonette EA, Harrell Jr FE, O'Shea TM, Moorman JR. Heart rate characteristics: novel physiomarkers to predict neonatal infection and death. Pediatrics 2005; 116 (5) 1070-1074
    CrossrefPubMedGoogle Scholar
  • 21 Moorman JR, Lake DE, Griffin MP. Heart rate characteristics monitoring for neonatal sepsis. IEEE Trans Biomed Eng 2006; 53 (1) 126-132
    CrossrefPubMedGoogle Scholar
  • 22 Griffin MP, Lake DE, O'Shea TM, Moorman JR. Heart rate characteristics and clinical signs in neonatal sepsis. Pediatr Res 2007; 61 (2) 222-227
    CrossrefPubMedGoogle Scholar
  • 23 Griffin MP, Lake DE, Moorman JR. Heart rate characteristics and laboratory tests in neonatal sepsis. Pediatrics 2005; 115 (4) 937-941
    CrossrefPubMedGoogle Scholar
  • 24 Zanelli SA, Naylor M, Dobbins N , et al. Implementation of a 'Hypothermia for HIE' program: 2-year experience in a single NICU. J Perinatol 2008; 28 (3) 171-175
    CrossrefPubMedGoogle Scholar
  • 25 Shankaran S, Laptook AR, Ehrenkranz RA , et al; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353 (15) 1574-1584
    CrossrefPubMedGoogle Scholar
  • 26 Fairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. J Perinatol 2010; 30 (5) 324-329
    CrossrefPubMedGoogle Scholar
  • 27 American Clinical Neurophysiology Society. Guideline two: minimum technical standards for pediatric electroencephalography. J Clin Neurophysiol 2006; 23 (2) 92-96
    CrossrefPubMedGoogle Scholar
  • 28 Burnsed J, Quigg M, Zanelli S, Goodkin HP. Clinical severity, rather than body temperature, during the rewarming phase of therapeutic hypothermia affect quantitative EEG in neonates with hypoxic ischemic encephalopathy. J Clin Neurophysiol 2011; 28 (1) 10-14
    CrossrefPubMedGoogle Scholar
  • 29 Shellhaas RA, Gallagher PR, Clancy RR. Assessment of neonatal electroencephalography (EEG) background by conventional and two amplitude-integrated EEG classification systems. J Pediatr 2008; 153 (3) 369-374
    CrossrefPubMedGoogle Scholar
  • 30 Barkovich AJ, Miller SP, Bartha A , et al. MR imaging, MR spectroscopy, and diffusion tensor imaging of sequential studies in neonates with encephalopathy. AJNR Am J Neuroradiol 2006; 27 (3) 533-547
    PubMedGoogle Scholar
  • 31 Mercuri E, Ricci D, Cowan FM , et al. Head growth in infants with hypoxic-ischemic encephalopathy: correlation with neonatal magnetic resonance imaging. Pediatrics 2000; 106 (2 Pt 1) 235-243
    CrossrefPubMedGoogle Scholar
  • 32 Griffin MP, Moorman JR. Toward the early diagnosis of neonatal sepsis and sepsis-like illness using novel heart rate analysis. Pediatrics 2001; 107 (1) 97-104
    CrossrefPubMedGoogle Scholar
  • 33 Beuchée A, Carrault G, Bansard JY, Boutaric E, Bétrémieux P, Pladys P. Uncorrelated randomness of the heart rate is associated with sepsis in sick premature infants. Neonatology 2009; 96 (2) 109-114
    CrossrefPubMedGoogle Scholar
  • 34 Fairchild KD. Predictive monitoring for early detection of sepsis in neonatal ICU patients. Curr Opin Pediatr 2013; 25 (2) 172-179
    CrossrefPubMedGoogle Scholar
  • 35 Griffin MP, O'Shea TM, Bissonette EA, Harrell Jr FE, Lake DE, Moorman JR. Abnormal heart rate characteristics are associated with neonatal mortality. Pediatr Res 2004; 55 (5) 782-788
    CrossrefPubMedGoogle Scholar
  • 36 Richman JS, Lake DE, Moorman JR. Sample entropy. Methods Enzymol 2004; 384: 172-184
    PubMedGoogle Scholar
  • 37 Kovatchev BP, Farhy LS, Cao H, Griffin MP, Lake DE, Moorman JR. Sample asymmetry analysis of heart rate characteristics with application to neonatal sepsis and systemic inflammatory response syndrome. Pediatr Res 2003; 54 (6) 892-898
    CrossrefPubMedGoogle Scholar
  • 38 Cao H, Lake DE, Griffin MP, Moorman JR. Increased nonstationarity of neonatal heart rate before the clinical diagnosis of sepsis. Ann Biomed Eng 2004; 32 (2) 233-244
    CrossrefPubMedGoogle Scholar
  • 39 Griffin MP, Scollan DF, Moorman JR. The dynamic range of neonatal heart rate variability. J Cardiovasc Electrophysiol 1994; 5 (2) 112-124
    CrossrefPubMedGoogle Scholar
  • 40 Flower AA, Moorman JR, Lake DE, Delos JB. Periodic heart rate decelerations in premature infants. Exp Biol Med (Maywood) 2010; 235 (4) 531-538
    CrossrefPubMedGoogle Scholar
  • 41 Fleisher LA, Frank SM, Sessler DI, Cheng C, Matsukawa T, Vannier CA. Thermoregulation and heart rate variability. Clin Sci (Lond) 1996; 90 (2) 97-103
    PubMedGoogle Scholar
  • 42 Hallioglu O, Okuyaz C, Mert E, Makharoblidze K. Effects of antiepileptic drug therapy on heart rate variability in children with epilepsy. Epilepsy Res 2008; 79 (1) 49-54
    CrossrefPubMedGoogle Scholar
  • 43 Frasch MG, Müller T, Weiss C, Schwab K, Schubert H, Schwab M. Heart rate variability analysis allows early asphyxia detection in ovine fetus. Reprod Sci 2009; 16 (5) 509-517
    CrossrefPubMedGoogle Scholar
  • 44 Goldstein B, Toweill D, Lai S, Sonnenthal K, Kimberly B. Uncoupling of the autonomic and cardiovascular systems in acute brain injury. Am J Physiol 1998; 275 (4 Pt 2) R1287-R1292
    PubMedGoogle Scholar
  • 45 Norman GJ, Karelina K, Berntson GG, Morris JS, Zhang N, Devries AC. Heart rate variability predicts cell death and inflammatory responses to global cerebral ischemia. Front Physiol 2012; 3: 131
    PubMedGoogle Scholar
  • 46 Adrie C, Adib-Conquy M, Laurent I , et al. Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation 2002; 106 (5) 562-568
    CrossrefPubMedGoogle Scholar
  • 47 Fairchild KD, Saucerman JJ, Raynor LL , et al. Endotoxin depresses heart rate variability in mice: cytokine and steroid effects. Am J Physiol Regul Integr Comp Physiol 2009; 297 (4) R1019-R1027
    CrossrefPubMedGoogle Scholar
  • 48 Haensel A, Mills PJ, Nelesen RA, Ziegler MG, Dimsdale JE. The relationship between heart rate variability and inflammatory markers in cardiovascular diseases. Psychoneuroendocrinology 2008; 33 (10) 1305-1312
    CrossrefPubMedGoogle Scholar
  • 49 Fowler MB, Laser JA, Hopkins GL, Minobe W, Bristow MR. Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response. Circulation 1986; 74 (6) 1290-1302
    CrossrefPubMedGoogle Scholar
  • 50 Tiainen M, Parikka HJ, Mäkijärvi MA, Takkunen OS, Sarna SJ, Roine RO. Arrhythmias and heart rate variability during and after therapeutic hypothermia for cardiac arrest. Crit Care Med 2009; 37 (2) 403-409
    CrossrefPubMedGoogle Scholar
  • 51 Lasky RE, Parikh NA, Williams AL, Padhye NS, Shankaran S. Changes in the PQRST intervals and heart rate variability associated with rewarming in two newborns undergoing hypothermia therapy. Neonatology 2009; 96 (2) 93-95
    CrossrefPubMedGoogle Scholar
  • 52 Westgate JA, Bennet L, Gunn AJ. Fetal heart rate variability changes during brief repeated umbilical cord occlusion in near term fetal sheep. Br J Obstet Gynaecol 1999; 106 (7) 664-671
    CrossrefPubMedGoogle Scholar
  • 53 Addison K, Griffin MP, Moorman JR, Lake DE, O'Shea TM. Heart rate characteristics and neurodevelopmental outcome in very low birth weight infants. J Perinatol 2009; 29 (11) 750-756
    CrossrefPubMedGoogle Scholar