Pre-Vent: the prematurity-related ventilatory control study



The increasing incidence of bronchopulmonary dysplasia in premature babies may be due in part to immature ventilatory control, contributing to hypoxemia. The latter responds to ventilation and/or oxygen therapy, treatments associated with adverse sequelae. This is an overview of the Prematurity-Related Ventilatory Control Study which aims to analyze the under-utilized cardiorespiratory continuous waveform monitoring data to delineate mechanisms of immature ventilatory control in preterm infants and identify predictive markers.


Continuous ECG, heart rate, respiratory, and oxygen saturation data will be collected throughout the NICU stay in 500 infants < 29 wks gestation across 5 centers. Mild permissive hypercapnia, and hyperoxia and/or hypoxia assessments will be conducted in a subcohort of infants along with inpatient questionnaires, urine, serum, and DNA samples.


Primary outcomes will be respiratory status at 40 wks and quantitative measures of immature breathing plotted on a standard curve for infants matched at 36–37 wks. Physiologic and/or biologic determinants will be collected to enhance the predictive model linking ventilatory control to outcomes.


By incorporating bedside monitoring variables along with biomarkers that predict respiratory outcomes we aim to elucidate individualized cardiopulmonary phenotypes and mechanisms of ventilatory control contributing to adverse respiratory outcomes in premature infants.

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  1. 1.

    Stoll, B. J. et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA 314, 1039–1051 (2015).

  2. 2.

    Bancalari, E. & Jain, D. Bronchopulmonary dysplasia: can we agree on a definition? Am. J. Perinatol. 35, 537–540 (2018).

  3. 3.

    Ren, C.L. et al. Tidal breathing measurements at discharge and clinical outcomes in extremely low gestational age neonates. Ann. Am. Thora. Soc. 15, 1311–1319 (2018).

  4. 4.

    Bancalari, E. & Claure, N. Respiratory instability and hypoxemia episodes in preterm infants. Am. J. Perinatol. 35, 534–536 (2018).

  5. 5.

    Darnall, R. A. The role of CO(2) and central chemoreception in the control of breathing in the fetus and the neonate. Respir. Physiol. Neurobiol. 173, 201–212 (2010).

  6. 6.

    Eichenwald, E. C. Apnea of Prematurity. Pediatrics 137, e1–e7 (2016).

  7. 7.

    Schmidt, B. et al. Long-term effects of caffeine therapy for apnea of prematurity. New Engl. J. Med. 357, 1893–1902 (2007).

  8. 8.

    Rhein, L. M. et al. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr. 168, 250–257 (2014).

  9. 9.

    Coste, F. et al. Ventilatory control and supplemental oxygen in premature infants with apparent chronic lung disease. Archives of disease in childhood. Fetal Neonatal Ed. 100, F233–F237 (2015).

  10. 10.

    Poets, C. F. et al. Association between intermittent hypoxemia or bradycardia and late death or disability in extremely preterm infants. JAMA 314, 595–603 (2015).

  11. 11.

    Fairchild, K. D. & Lake, D. E. Cross-correlation of heart rate and oxygen saturation in very low birthweight infants: association with apnea and adverse events. Am. J. Perinatol. 35, 463–469 (2018).

  12. 12.

    Clark, M. T. et al. Stochastic modeling of central apnea events in preterm infants. Physiol. Meas. 37, 463–484 (2016).

  13. 13.

    Fairchild, K. et al. Clinical associations of immature breathing in preterm infants: part 1-central apnea. Pediatr. Res. 80, 21–27 (2016).

  14. 14.

    Mohr, M. A. et al. Quantification of periodic breathing in premature infants. Physiol. Meas. 36, 1415–1427 (2015).

  15. 15.

    Patel, M. et al. Clinical associations with immature breathing in preterm infants: part 2-periodic breathing. Pediatr. Res. 80, 28–34 (2016).

  16. 16.

    Gee, A. H., Barbieri, R., Paydarfar, D. & Indic, P. Predicting bradycardia in preterm infants using point process analysis of heart rate. IEEE Trans. bio-Med. Eng. 64, 2300–2308 (2017).

  17. 17.

    Amperayani VNSA, P. I., Travers, C. P., Barbieri, R., Paydarfar, D. & Ambalavanan, N. An algorithm for risk stratification of preterm infants. Comput. Cardiol. 44, 1–4 (2017).

  18. 18.

    Di Fiore, J. M. et al. The relationship between patterns of intermittent hypoxia and retinopathy of prematurity in preterm infants. Pediatr. Res. 72, 606–612 (2012).

  19. 19.

    Nanduri, J. & Prabhakar, N. R. Developmental programming of O(2) sensing by neonatal intermittent hypoxia via epigenetic mechanisms. Respir. Physiol. Neurobiol. 185, 105–109 (2013).

  20. 20.

    Gerhardt, T. & Bancalari, E. Apnea of prematurity: I. Lung function and regulation of breathing. Pediatrics 74, 58–62 (1984).

  21. 21.

    Sovik, S., Eriksen, M., Lossius, K., Grogaard, J. & Walloe, L. A method of assessing ventilatory responses to chemoreceptor stimulation in infants. Acta paediatrica (Oslo, Norway: 1992) 88, (563–570 (1999).

  22. 22.

    Pryhuber, G. S. et al. Prematurity and respiratory outcomes program (PROP): study protocol of a prospective multicenter study of respiratory outcomes of preterm infants in the United States. BMC Pediatr. 15, 37 (2015).

  23. 23.

    Giffen, C. A. et al. Providing contemporary access to historical biospecimen collections: development of the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biopreservation biobanking 13, 271–279 (2015).

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We thank D.E. McKaig and J.B. Delos, College of William and Mary, for Fig. 4. The National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) provided grant support. NHLBI staff had input into the study design, conduct, analysis, and manuscript drafting. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Participating sites collected and stored the data. The site PIs had full access to individual site data and take responsibility for the integrity of the waveforms. The lead data coordinating center analyzed the data. Drs. Moorman and Lake take responsibility for the integrity of the data and accuracy of the data analysis. We are indebted to our medical and nursing colleagues and infants and parents who agreed to take part in this study. The following investigators participated in this study: Providence, RI: P.A. Dennery, Brown University, Rhode Island Hospital, Hasbro Children’s Hospital Bethesda, MD: A.D. Laposky, A. Natarajan, B.Schmetter., J. Troendle; National Institutes of Health, National Heart, Lung and Blood Institute. Charlottesville, VA: J.R. Moorman, D. Lake, K. Nash Krahn, A.M. Zimmet, A.K. Camblos, S.A. Fowler, K.D. Fairchild, A.A. Flower, P. Pramoonjago, C.A. Rumpel; University of Virginia. Cleveland, OH: A.M. Hibbs, R.J. Martin, J.M. Di Fiore, T. Raffay, P.M. MacFarlane; Case Western Reserve University, University Hospitals Cleveland Medical Center, Rainbow Babies and Children’s Hospital A. Zadell, University Hospitals Cleveland Medical Center, Rainbow Babies & Children’s Hospital C. Tatsuoka, Case Western Reserve University. Valencia, Spain: M.Vento, University and Polytechnic Hospital La Fe, Health Research Institute La Fe. Chicago, IL: A. Hamvas, D. Weese-Mayer, R.A. DeRegnier; Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago and Stanley Manne Children’s Research Institute A. Bradley, M. Carroll, E. Dunne, S. Fair, B. Hopkins, C. Rand, M. Schau; Ann & Robert H. Lurie Children’s Hospital of Chicago and Stanley Manne Children’s Research Institute C.R. Estabrook, Northwestern University. Birmingham, AL: N. Ambalavanan, A. Nakhmani, W.A. Carlo, D. Laney, B. Troxler, C.P. Travers; University of Alabama. P. Indic, University of Texas Tyler, Tyler, TX; University of Alabama. Austin, TX: D. Paydarfar, University of Texas Austin. Worcester, MA: E. Salisbury, University of Massachusetts. Miami, FL: E. Bancalari, N. Claure, A.C. Aguilar, C. D’Ugard, D. Jain, D. Ludwig, A. Schott, S. Vanbuskirk; University of Miami, Holtz Children’s Hospital - Jackson Memorial Medical Center. St. Louis, MO: J. Kemp, R. Colvin, B. Bellm, M. McLeland, J. Hoffmann, K. Schechtman, J. Shimony, C. Smyser, L. Linneman, J. Hoover, B. Warner; Washington University. J. Egan, H. Pyles; St. Louis Children’s Hospital. Little Rock, AR: J.L. Carroll, University of Arkansas. Melbourne, Australia: B. Edwards, Monash University. Supported by NIH grants U01 HL133708, U01 HL133643, U01 HL133704, U01 HL133536, U01 HL133689, U01 HL133700.

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P.A.D., J.M.D.F., N.A., E.B., J.L.C., N.C., A.H., A.M.H., P.I., J.K., K.N.K., D.L., A.L., R.J.M., A.N., C.R., M.S., D.E.W.-M., A.M.Z., and J.R.M. provided substantial contributions to conception and design, and proposed acquisition of data, or analysis and interpretation of data; P.A.D., J.M.D.F., N.A., E.B., J.L.C., N.C., A.H., A.M.H., P.I., J.K., K.N.K., D.L., A.L., R.J.M., A.N., D.E.W.-M., A.M.Z., and J.R.M. participated in drafting the article or revising it critically for important intellectual content; and P.A.D. provided final approval of the version to be published

Correspondence to Phyllis A. Dennery.

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Competing interests

DL has a small equity share (<1%) in Medical Predictive Science Corporation, which markets the HeRO heart rate monitoring system. JRM is Chief Medical Officer and shareholder, Advanced Medical Predictive Devices, Diagnostics and Displays, and shareholder, Medical Predictive Science Corporation, both in Charlottesville, VA. All other authors declare no competing interests.

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