Cerebral Autoregulation in Preterm Infants. How to Measure It—And Why Care?
C
erebral autoregulation is associated with the risk of sesuperior vena cava flow as in indicator of low cardiac vere intracranial hemorrhage and death in preterm output, but surprisingly not with low blood pressure at infants, in the report by Riera et al in this issue of conventional thresholds. Finally, it could be expected The Journal,1 confirming evidence from many previous that low blood pressure and/or low superior vena cava studies. The report that opened the field was published in flow was associated with low levels of absolute cerebral The Journal in 1979.2 Cerebral blood flow, oxygenation, but it was not. See related article, p 897 as measured by 133Xe clearance, was Furthermore, cerebral oxygenation is not strongly associated with systolic blood pressure in 19 disthe same as cerebral blood flow. Cerebral oxygenation as tressed infants shortly after birth. The authors suggested measured by near-infrared spectroscopy is ‘venousthis to reflect absence of the normal cerebral autoregulation weighted,’ (ie, dominated by cerebrovenous oxygenation) and hypothesized that the lack of autoregulation could because the veins contain most of the blood. But even a small explain the risk of intracranial hemorrhage in this populashift in the relative volumes of the arterial and/or venous tion. Ever since, the term cerebral autoregulation has been compartments can induce a significant change in cerebral on the lips of neonatologists. Perhaps just this fact—the oxygenation and could possibly explain the mismatch beawareness of the potential vulnerability of the cerebral circutween dopamine-induced increase in cerebral blood flow lation and oxygenation in the preterm infant—has had a role and oxygenation in a newborn piglet.8 Unfortunately, there in the reduction of the incidence of germinal layer haemoris at present no simple and reliable method for the monirhage in the early 1980s,3 and the incidence of periventricular toring of cerebral blood flow in the preterm newborn infant and, therefore, the interest is focused on the use of cerebral leucomalacia in the 1990s.4 oxygenation as a surrogate. The report in this issue of The Journal makes the point that Does cerebral oxygenation from the relatively small volthe association between cerebral oxygenation and mean arteume of brain interrogated by the near-infrared sensor rial blood pressure in the time-domain appears to predict serepresent the entire brain? There is evidence that blood vere germinal layer hemorrhage better than the association flow in the hemispheric white matter decreases more durdetermined in the frequency-domain (coherence). What ing arterial hypotension than does blood flow to the brain does that mean? as a whole.9 In the special situation of extracorporeal memThe signal analytic methodology is complicated and likely to be beyond the interest of most readers of The Journal. In brane oxygenation, autoregulation of the right hemisphere simple terms, the benefit of the frequency-domain analysis (on the side of the arterial cannula) was reduced compared is that it is insensitive to the potential lag-time between with the left.10 changes in arterial blood pressure and the resultant changes Autoregulation is not likely to come on and off. The reacin cerebral blood flow and oxygenation. But, as demontivity of cerebral arteries and arterioles to changes in perfustrated here, this insensitivity makes it likely to pick up sion pressure is determined by vascular smooth muscle cell similar patterns of change that are far away in time and, constriction and relaxation in response to the transmural hence, pick up ‘false positive’ evidence of impaired autorepressure gradient11 and possibly also by feedback mecha5 gulation. In this, it confirms a previous study. But nothing nisms of oxygen sufficiency.12 Because these depend on mocomes for free, and the cost of the improved analysis, lecular mechanisms that are more or less expressed at a given combining time-domain analysis with pattern matching in point in time, the use of a specific threshold for classifying authe form of bivariate-autoregressive coherence, was that toregulation as ‘absent’ or ‘present’ is artificial and only determination of autoregulation failed in spite of several makes sense for calculation of predictive values. Furtherhours of recording time in as much as one-third of the more, because only the very low frequency band (0.003infants. 0.04 Hz) was analyzed, there was no representation of the Association does not mean causation. A statistically sigdynamic aspects of autoregulation (the speed of vascular nificant association between the arterial blood pressure reactivity) and, therefore, the result represents ‘static autosignal and cerebral oxygenation signal does not necessarily regulation.’ mean that it was the changes in blood pressure that actuWhat does all this mean? How do we progress from ally changed the oxygenation. There are multiple correlahere? Routine use of the present methodology to predict tions among variables in the systemic and cerebral circulation, among them heart rate, blood pressure, cerebral concentrations of oxy- and deoxy-hemoglobin, as The author declares no conflicts of interest. well as cerebral oxygenation index.6,7 In the present study, 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. lack of cerebral autoregulation was associated with low http://dx.doi.org/10.1016/j.jpeds.2014.07.031 885
THE JOURNAL OF PEDIATRICS
www.jpeds.com
brain injury or death is not indicated. Simpler signal analytic methods, as promised in the report by Riera et al, combined with large-scale monitoring of very preterm infants during intensive care could allow a prospective trial to examine if the predictive value is over and above the value of other simpler and clinically available information. Also, the time relation between cerebral autoregulation and the occurrence of germinal layer hemorrhage should be examined to determine if there is a window of opportunity for management. If so, the benefit and harm of the clinician knowing the incident autoregulatory ability of the individual infant could be tested in a randomized design. This could be an add-on to a trial of the benefit and harm of knowing the incident value of cerebral oxygenation.13 n Gorm Greisen, MD, Dr Med Sci Department of Neonatology Rigshospitalet Copenhagen University Copenhagen, Denmark Reprint requests: Gorm Greisen, MD, Dr Med Sci, Department of Neonatology, Rigshospitalet and Copenhagen University, Copenhagen, Denmark. E-mail: [email protected]
References 1. Riera J, Caba~ nas F, Serrano JJ, Bravo MC, L opez-Ortego P, Sanchez L, et al. New time-frequency method for cerebral autoregulation in newborns: predictive capacity for clinical outcomes. J Pediatr 2014;165: 897-902.
Vol. 165, No. 5 2. Lou HC, Lassen NA, Friis-Hansen B. Impaired autoregulation of cerebral blood flow in the distressed newborn infant. J Pediatr 1979;94: 118-21. 3. Szymonowicz W, Yu VY. Periventricular haemorrhage and leukomalacia in extremely low birthweight infants. Aust Paediatr J 1986;22:207-10. 4. Groenendaal F, Termote JU, van der Heide-Jalving M, van Haastert IC, de Vries LS. Complications affecting preterm neonates from 1991 to 2006: what have we gained? Acta Paediatr 2010;99:354-8. 5. Caicedo A, Naulaers G, Lemmers P, van Bel F, Wolf M, Van Huffel S. Detection of cerebral autoregulation by near-infrared spectroscopy in neonates: performance analysis of measurement methods. J Biomed Opt 2012;17:117003. 6. Zhang Y, Chan GS, Tracy MB, Lee QY, Hinder M, Savkin AV, et al. Spectral analysis of systemic and cerebral cardiovascular variabilities in preterm infants: relationship with clinical risk index for babies (CRIB). Physiol Meas 2011;32:1913-28. 7. Mitra S, Czosnyka M, Smielewski P, O’Reilly H, Brady K, Austin T. Heart rate passivity of cerebral tissue oxygenation is associated with predictors of poor outcome in preterm infants. Acta Paediatr 2014 May 21. http:// dx.doi.org/10.1111/apa.12696. [Epub ahead of print]. 8. Hahn GH, Hyttel-Sorensen S, Petersen SM, Pryds O, Greisen G. Cerebral effects of commonly used vasopressor-inotropes: a study in newborn piglets. PLoS One 2013;8:e63069. 9. Børch K, Lou HC, Greisen G. Cerebral white matter blood flow and arterial blood pressure in preterm infants. Acta Paediatr 2010;99: 1489-92. 10. Papademetriou MD, Tachtsidis I, Elliot MJ, Hoskote A, Elwell CE. Multichannel near infrared spectroscopy indicates regional variations in cerebral autoregulation in infants supported on extracorporeal membrane oxygenation. J Biomed Opt 2012;17:067008. 11. Hill MA, Zou H, Potocnik SJ, Meininger GA, Davis MJ. Invited review: arteriolar smooth muscle mechanotransduction: Ca2 signalling pathways underlying myogenic reactivity. J Appl Physiol (1985) 2001;91:973-83. 12. Wei EP, Kontos HA. Increased venous pressure causes myogenic constriction of cerebral arterioles during local hyperoxia. Circ Res 1984;55:249-52. 13. www.safeboosc.eu/. Assessed July 3, 2014.
Sustained Inflations as the Initiating Positive Pressure Support for Preterm Infants—Not Yet Ready for Prime Time
T
breaths with those delivered by an endotracheal tube and he use of prolonged inflations for the support of found the face mask delivered only one-third of the newborn infants was first reported over 30 years ago measured expired volume compared with an endotracheal with the observations of Vyas et al.1 They reported breath, and was rarely associated with adequate alveolar that when giving positive pressure breaths to intubated inventilation.2 This same group has also shown that preterm fants in need of resuscitation, air continued to inflate the lung at 1 second. Prolonging the inspirainfants required more endotracheal breaths See related article, p 903 tion to 5 seconds also resulted in improved to establish adequate ventilation than similung inflation and improved the establishment of a funclarly treated term infants, and had less spontaneous respirational residual capacity. Using an inflation pressure that tion in response to such breaths.3 increased over 3 to 5 seconds also avoided an opening pressure. Subsequently, these authors compared face mask CPAP SI
Continuous positive airway pressure Sustained inflation
N.F. is a paid consultant for Fisher and Paykel, Discovery Laboratories, and Sharp Mary Birch Hospital for Women and Newborns. A.K. declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.07.029
886
C
erebral autoregulation is associated with the risk of sesuperior vena cava flow as in indicator of low cardiac vere intracranial hemorrhage and death in preterm output, but surprisingly not with low blood pressure at infants, in the report by Riera et al in this issue of conventional thresholds. Finally, it could be expected The Journal,1 confirming evidence from many previous that low blood pressure and/or low superior vena cava studies. The report that opened the field was published in flow was associated with low levels of absolute cerebral The Journal in 1979.2 Cerebral blood flow, oxygenation, but it was not. See related article, p 897 as measured by 133Xe clearance, was Furthermore, cerebral oxygenation is not strongly associated with systolic blood pressure in 19 disthe same as cerebral blood flow. Cerebral oxygenation as tressed infants shortly after birth. The authors suggested measured by near-infrared spectroscopy is ‘venousthis to reflect absence of the normal cerebral autoregulation weighted,’ (ie, dominated by cerebrovenous oxygenation) and hypothesized that the lack of autoregulation could because the veins contain most of the blood. But even a small explain the risk of intracranial hemorrhage in this populashift in the relative volumes of the arterial and/or venous tion. Ever since, the term cerebral autoregulation has been compartments can induce a significant change in cerebral on the lips of neonatologists. Perhaps just this fact—the oxygenation and could possibly explain the mismatch beawareness of the potential vulnerability of the cerebral circutween dopamine-induced increase in cerebral blood flow lation and oxygenation in the preterm infant—has had a role and oxygenation in a newborn piglet.8 Unfortunately, there in the reduction of the incidence of germinal layer haemoris at present no simple and reliable method for the monirhage in the early 1980s,3 and the incidence of periventricular toring of cerebral blood flow in the preterm newborn infant and, therefore, the interest is focused on the use of cerebral leucomalacia in the 1990s.4 oxygenation as a surrogate. The report in this issue of The Journal makes the point that Does cerebral oxygenation from the relatively small volthe association between cerebral oxygenation and mean arteume of brain interrogated by the near-infrared sensor rial blood pressure in the time-domain appears to predict serepresent the entire brain? There is evidence that blood vere germinal layer hemorrhage better than the association flow in the hemispheric white matter decreases more durdetermined in the frequency-domain (coherence). What ing arterial hypotension than does blood flow to the brain does that mean? as a whole.9 In the special situation of extracorporeal memThe signal analytic methodology is complicated and likely to be beyond the interest of most readers of The Journal. In brane oxygenation, autoregulation of the right hemisphere simple terms, the benefit of the frequency-domain analysis (on the side of the arterial cannula) was reduced compared is that it is insensitive to the potential lag-time between with the left.10 changes in arterial blood pressure and the resultant changes Autoregulation is not likely to come on and off. The reacin cerebral blood flow and oxygenation. But, as demontivity of cerebral arteries and arterioles to changes in perfustrated here, this insensitivity makes it likely to pick up sion pressure is determined by vascular smooth muscle cell similar patterns of change that are far away in time and, constriction and relaxation in response to the transmural hence, pick up ‘false positive’ evidence of impaired autorepressure gradient11 and possibly also by feedback mecha5 gulation. In this, it confirms a previous study. But nothing nisms of oxygen sufficiency.12 Because these depend on mocomes for free, and the cost of the improved analysis, lecular mechanisms that are more or less expressed at a given combining time-domain analysis with pattern matching in point in time, the use of a specific threshold for classifying authe form of bivariate-autoregressive coherence, was that toregulation as ‘absent’ or ‘present’ is artificial and only determination of autoregulation failed in spite of several makes sense for calculation of predictive values. Furtherhours of recording time in as much as one-third of the more, because only the very low frequency band (0.003infants. 0.04 Hz) was analyzed, there was no representation of the Association does not mean causation. A statistically sigdynamic aspects of autoregulation (the speed of vascular nificant association between the arterial blood pressure reactivity) and, therefore, the result represents ‘static autosignal and cerebral oxygenation signal does not necessarily regulation.’ mean that it was the changes in blood pressure that actuWhat does all this mean? How do we progress from ally changed the oxygenation. There are multiple correlahere? Routine use of the present methodology to predict tions among variables in the systemic and cerebral circulation, among them heart rate, blood pressure, cerebral concentrations of oxy- and deoxy-hemoglobin, as The author declares no conflicts of interest. well as cerebral oxygenation index.6,7 In the present study, 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. lack of cerebral autoregulation was associated with low http://dx.doi.org/10.1016/j.jpeds.2014.07.031 885
THE JOURNAL OF PEDIATRICS
www.jpeds.com
brain injury or death is not indicated. Simpler signal analytic methods, as promised in the report by Riera et al, combined with large-scale monitoring of very preterm infants during intensive care could allow a prospective trial to examine if the predictive value is over and above the value of other simpler and clinically available information. Also, the time relation between cerebral autoregulation and the occurrence of germinal layer hemorrhage should be examined to determine if there is a window of opportunity for management. If so, the benefit and harm of the clinician knowing the incident autoregulatory ability of the individual infant could be tested in a randomized design. This could be an add-on to a trial of the benefit and harm of knowing the incident value of cerebral oxygenation.13 n Gorm Greisen, MD, Dr Med Sci Department of Neonatology Rigshospitalet Copenhagen University Copenhagen, Denmark Reprint requests: Gorm Greisen, MD, Dr Med Sci, Department of Neonatology, Rigshospitalet and Copenhagen University, Copenhagen, Denmark. E-mail: [email protected]
References 1. Riera J, Caba~ nas F, Serrano JJ, Bravo MC, L opez-Ortego P, Sanchez L, et al. New time-frequency method for cerebral autoregulation in newborns: predictive capacity for clinical outcomes. J Pediatr 2014;165: 897-902.
Vol. 165, No. 5 2. Lou HC, Lassen NA, Friis-Hansen B. Impaired autoregulation of cerebral blood flow in the distressed newborn infant. J Pediatr 1979;94: 118-21. 3. Szymonowicz W, Yu VY. Periventricular haemorrhage and leukomalacia in extremely low birthweight infants. Aust Paediatr J 1986;22:207-10. 4. Groenendaal F, Termote JU, van der Heide-Jalving M, van Haastert IC, de Vries LS. Complications affecting preterm neonates from 1991 to 2006: what have we gained? Acta Paediatr 2010;99:354-8. 5. Caicedo A, Naulaers G, Lemmers P, van Bel F, Wolf M, Van Huffel S. Detection of cerebral autoregulation by near-infrared spectroscopy in neonates: performance analysis of measurement methods. J Biomed Opt 2012;17:117003. 6. Zhang Y, Chan GS, Tracy MB, Lee QY, Hinder M, Savkin AV, et al. Spectral analysis of systemic and cerebral cardiovascular variabilities in preterm infants: relationship with clinical risk index for babies (CRIB). Physiol Meas 2011;32:1913-28. 7. Mitra S, Czosnyka M, Smielewski P, O’Reilly H, Brady K, Austin T. Heart rate passivity of cerebral tissue oxygenation is associated with predictors of poor outcome in preterm infants. Acta Paediatr 2014 May 21. http:// dx.doi.org/10.1111/apa.12696. [Epub ahead of print]. 8. Hahn GH, Hyttel-Sorensen S, Petersen SM, Pryds O, Greisen G. Cerebral effects of commonly used vasopressor-inotropes: a study in newborn piglets. PLoS One 2013;8:e63069. 9. Børch K, Lou HC, Greisen G. Cerebral white matter blood flow and arterial blood pressure in preterm infants. Acta Paediatr 2010;99: 1489-92. 10. Papademetriou MD, Tachtsidis I, Elliot MJ, Hoskote A, Elwell CE. Multichannel near infrared spectroscopy indicates regional variations in cerebral autoregulation in infants supported on extracorporeal membrane oxygenation. J Biomed Opt 2012;17:067008. 11. Hill MA, Zou H, Potocnik SJ, Meininger GA, Davis MJ. Invited review: arteriolar smooth muscle mechanotransduction: Ca2 signalling pathways underlying myogenic reactivity. J Appl Physiol (1985) 2001;91:973-83. 12. Wei EP, Kontos HA. Increased venous pressure causes myogenic constriction of cerebral arterioles during local hyperoxia. Circ Res 1984;55:249-52. 13. www.safeboosc.eu/. Assessed July 3, 2014.
Sustained Inflations as the Initiating Positive Pressure Support for Preterm Infants—Not Yet Ready for Prime Time
T
breaths with those delivered by an endotracheal tube and he use of prolonged inflations for the support of found the face mask delivered only one-third of the newborn infants was first reported over 30 years ago measured expired volume compared with an endotracheal with the observations of Vyas et al.1 They reported breath, and was rarely associated with adequate alveolar that when giving positive pressure breaths to intubated inventilation.2 This same group has also shown that preterm fants in need of resuscitation, air continued to inflate the lung at 1 second. Prolonging the inspirainfants required more endotracheal breaths See related article, p 903 tion to 5 seconds also resulted in improved to establish adequate ventilation than similung inflation and improved the establishment of a funclarly treated term infants, and had less spontaneous respirational residual capacity. Using an inflation pressure that tion in response to such breaths.3 increased over 3 to 5 seconds also avoided an opening pressure. Subsequently, these authors compared face mask CPAP SI
Continuous positive airway pressure Sustained inflation
N.F. is a paid consultant for Fisher and Paykel, Discovery Laboratories, and Sharp Mary Birch Hospital for Women and Newborns. A.K. declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.07.029
886
