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  • Original Article
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Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia

Abstract

Objective:

To evaluate whether heart rate variability (HRV) measures are predictive of neurological outcome in babies with hypoxic ischemic encephalopathy (HIE).

Study Design:

This case–control investigation included 20 term encephalopathic newborns treated with systemic hypothermia in a regional neonatal intensive care unit. Electrocardiographic data were collected continuously during hypothermia. Spectral analysis of beat-to-beat heart rate interval was used to quantify HRV. HRV measures were compared between infants with adverse outcome (death or neurodevelopmental impairment at 15 months, n=10) and those with favorable outcome (survivors without impairment, n=10).

Result:

HRV differentiated infants by outcome during hypothermia through post-rewarming, with the best distinction between groups at 24 h and after 80 h of life.

Conclusion:

HRV during hypothermia treatment distinguished HIE babies who subsequently died or had neurodevelopmental impairment from intact survivors. This physiological biomarker may identify infants in need of adjuvant neuroprotective interventions. These findings warrant further investigation in a larger population of infants with HIE.

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References

  1. Shankaran S, Woldt E, Koepke T, Bedard MP, Nandyal R . Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev 1991; 25: 135–148.

    Article  CAS  Google Scholar 

  2. Dilenge ME, Majnemer A, Shevell MI . Long-term developmental outcome of asphyxiated term neonates. J Child Neurol 2001; 16: 781–792.

    Article  CAS  Google Scholar 

  3. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353: 1574–1584.

    Article  CAS  Google Scholar 

  4. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009; 361: 1349–1358.

    Article  CAS  Google Scholar 

  5. Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ et al. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011; 165: 692–700.

    Article  Google Scholar 

  6. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663–670.

    Article  Google Scholar 

  7. Gunn AJ, Wyatt JS, Whitelaw A, Barks J, Azzopardi D, Ballard R et al. Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy. J Pediatr 2008; 152: 55–58, 8 e1.

    Article  Google Scholar 

  8. Shankaran S, Laptook AR, Tyson JE, Ehrenkranz RA, Bann CM, Das A et al. Evolution of encephalopathy during whole body hypothermia for neonatal hypoxic-ischemic encephalopathy. J Pediatr 2012; 160: 567–572, e3.

    Article  Google Scholar 

  9. McKinstry RC, Miller JH, Snyder AZ, Mathur A, Schefft GL, Almli CR et al. A prospective, longitudinal diffusion tensor imaging study of brain injury in newborns. Neurology 2002; 59: 824–833.

    Article  CAS  Google Scholar 

  10. Barkovich AJ, Miller SP, Bartha A, Newton N, Hamrick SE, Mukherjee P et al. MR imaging, MR spectroscopy, and diffusion tensor imaging of sequential studies in neonates with encephalopathy. AJNR Am J Neuroradiol 2006; 27: 533–547.

    CAS  PubMed  Google Scholar 

  11. 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: 93–95.

    Article  Google Scholar 

  12. 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.

    Article  Google Scholar 

  13. Matic V, Cherian PJ, 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.

    Article  CAS  Google Scholar 

  14. Sarnat HB, Sarnat MS . Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33: 696–705.

    Article  CAS  Google Scholar 

  15. Bayley N . Manual for the Bayley scales of infant development. Psychological Corporation: New York, 1969.

    Google Scholar 

  16. Bayley N . Bayley Scales of Infant Development. 3rd edn, Harcourt Assessment: San Antonio, TX, 2006.

    Google Scholar 

  17. Govindan RB, Vairavan S, Ulusar UD, Wilson JD, McKelvey SS, Preissl H et al. A novel approach to track fetal movement using multi-sensor magnetocardiographic recordings. Ann Biomed Eng 2011; 39: 964–972.

    Article  CAS  Google Scholar 

  18. Ulusar UD, Govindan RB, Wilson JD, Lowery CL, Preissl H, Eswaran H . Adaptive rule based fetal QRS complex detection using hilbert transform. Conf Proc IEEE Eng Med Biol Soc 2009; 1: 4666–4669.

    Google Scholar 

  19. Halliday DM, Rosenberg JR, Amjad AM, Breeze P, Conway BA, Farmer SF . 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.

    Article  CAS  Google Scholar 

  20. Govindan RB, Massaro AN, Niforatos N, duPlessis A . Mitigating the effect of non-stationarity in spectral analysis- an application to neonate heart rate analysis. Comput Biol Med 2013; 43: 2001–2006.

    Article  Google Scholar 

  21. Piccirillo G, Magri D, Ogawa M, Song J, Chong VJ, Han S et al. Autonomic nervous system activity measured directly and QT interval variability in normal and pacing-induced tachycardia heart failure dogs. J Am Coll Cardiol 2009; 54: 840–850.

    Article  Google Scholar 

  22. Piccirillo G, Ogawa M, Song J, Chong VJ, Joung B, Han S et al. Power spectral analysis of heart rate variability and autonomic nervous system activity measured directly in healthy dogs and dogs with tachycardia-induced heart failure. Heart Rhythm 2009; 6: 546–552.

    Article  Google Scholar 

  23. Shah AJ, Lampert R, Goldberg J, Veledar E, Bremner JD, Vaccarino V . Posttraumatic stress disorder and impaired autonomic modulation in male twins. Biol Psychiatry 2013; 73: 1103–1110.

    Article  Google Scholar 

  24. Andriessen P, Oetomo SB, Peters C, Vermeulen B, Wijn PF, Blanco CE . Baroreceptor reflex sensitivity in human neonates: the effect of postmenstrual age. J Physiol 2005; 568: 333–341.

    Article  CAS  Google Scholar 

  25. Johnston MV, Fatemi A, Wilson MA, Northington F . Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011; 10: 372–382.

    Article  Google Scholar 

  26. Hon EH . The electronic evaluation of the fetal heart rate; preliminary report. Am J Obstet Gynecol 1958; 75: 1215–1230.

    Article  CAS  Google Scholar 

  27. Haji-Michael PG, Vincent JL, Degaute JP, van de Borne P . Power spectral analysis of cardiovascular variability in critically ill neurosurgical patients. Crit Care Med 2000; 28: 2578–2583.

    Article  CAS  Google Scholar 

  28. Biswas AK, Scott WA, Sommerauer JF, Luckett PM . Heart rate variability after acute traumatic brain injury in children. Crit Care Med 2000; 28: 3907–3912.

    Article  CAS  Google Scholar 

  29. Yiallourou SR, Witcombe NB, Sands SA, Walker AM, Horne RS . The development of autonomic cardiovascular control is altered by preterm birth. Early Hum Dev 2013; 89: 145–152.

    Article  Google Scholar 

  30. Golder V, Hepponstall M, Yiallourou SR, Odoi A, Horne RS . Autonomic cardiovascular control in hypotensive critically ill preterm infants is impaired during the first days of life. Early Hum Dev 2013; 89: 419–423.

    Article  Google Scholar 

  31. Fairchild KD, O'Shea TM . Heart rate characteristics: physiomarkers for detection of late-onset neonatal sepsis. Clin Perinatol 2010; 37: 581–598.

    Article  Google Scholar 

  32. Stone ML, Tatum PM, Weitkamp JH, Mukherjee AB, Attridge J, McGahren ED et al. Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis. J Perinatol 2013; 33: 847–850.

    Article  CAS  Google Scholar 

  33. Gang Y, Malik M . Heart rate variability in critical care medicine. Curr Opin Crit Care 2002; 8: 371–375.

    Article  Google Scholar 

  34. 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. Circulation 1996; 93: 1043–1065.

    Article  Google Scholar 

  35. Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC, Cohen RJ . Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 1981; 213: 220–222.

    Article  CAS  Google Scholar 

  36. Assaf N, Weller B, Deutsh-Castel T, Cohen A, Tirosh E . The relationship between heart rate variability and epileptiform activity among children–a controlled study. J Clin Neurophysiol 2008; 25: 317–320.

    Article  Google Scholar 

  37. Malarvili MB, Mesbah M . Combining newborn EEG and HRV information for automatic seizure detection. Conf Proc IEEE Eng Med Biol Soc 2008; 2008: 4756–4759.

    CAS  PubMed  Google Scholar 

  38. Malarvili MB, Mesbah M . Newborn seizure detection based on heart rate variability. IEEE Trans Biomed Eng 2009; 56: 2594–2603.

    Article  CAS  Google Scholar 

  39. Billman GE . The LF/HF ratio does not accurately measure cardiac sympatho-vagal balance. Front Physiol 2013; 4: 26.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This project was supported by Award Numbers UL1RR031988 and KL2 RR031987 from the NIH National Center for Research Resources. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health

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Correspondence to A N Massaro.

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Massaro, A., Govindan, R., Al-Shargabi, T. et al. Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia. J Perinatol 34, 836–841 (2014). https://doi.org/10.1038/jp.2014.108

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