Original Papers Biol Neonate 1991;59:329-335

© 1991 S. Karger AG, Basel 0006-3126/91/0596-0329S2.75/0

Cerebral Blood Flow Velocity Regulation in Preterm Infants Margot van de Bor1, Frans J. Wallher Division of Neonatology, Department of Pediatrics, University of Southern California School of Medicine, Los Angeles County and USC Medical Center, Los Angeles, Calif., USA

Key Words. Cerebral blood flow velocity • Pericallosal artery • Pulsed Doppler ultrasound • Arterial blood pressure • Preterm infants

Introduction Changes in cerebral blood flow during fluctuations in mean arterial blood pressure are prevented by cerebrovascular autoregu­ lation. This has been demonstrated over a wide range of arterial blood pressure values in human adults and term newborn animals [1-6]. Papile et al. [7] reported cerebrovas­ 1 Dr. van de Bor was the recipient of a Fulbright research scholarship.

cular autoregulation in preterm fetal lambs. Autoregulation of cerebral blood flow is pre­ sumed to be present in stable preterm and term newborn infants [8-14], Doppler ultrasound measurement of cere­ bral blood flow velocity in the pericallosal artery has been introduced and validated as an indirect technique to estimate cerebral blood flow [15]. If autoregulation of cerebral blood flow is present, cerebral blood flow velocity will be constant over a range of mean arterial blood pressures (MABPs). The

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Abstract. Cerebrovascular autoregulation is the mechanism by which changes in cerebral blood flow are prevented during fluctuations in mean arterial blood pressure. Doppler ultra­ sound measurement of cerebral blood flow velocity provides a reliable indirect technique to estimate cerebral blood flow. In 48 stable preterm infants < 32 weeks gestation, we studied the mean flow velocity in the pericallosal artery at 12, or at 12 and 72 h of age with twodimensional/pulsed Doppler ultrasound and correlated the mean flow velocity with the simultaneously obtained mean arterial blood pressure values. Mean flow velocity was stable at a mean arterial blood pressure ranging from 31 to 40 mm Hg, but changed proportionally with mean arterial blood pressure values outside this narrow range. Multiple regression analysis showed that mean flow velocity was primarily determined by mean arterial blood pressure. These data suggest that in preterm infants regulation of cerebral blood flow velocity occurs only over a narrow range of mean arterial blood pressure values.

van de Bor/Walther


Methods Patients. Forty-eight preterm infants born in Women's Hospital and admitted to the Neonatal In­ tensive Care Unit of Los Angeles County and Univer­ sity of Southern California Medical Center were en­ rolled into the study. The study protocol was ap­ proved by the research committee of the hospital and informed consent was obtained from the mother be­ fore enrollment into the study. Inclusion criteria for the study were: (1) gestational age < 32 completed weeks; (2) appropriate weight for gestational age [ 16]; (3) no fetal distress (normal fetal heart rate pattern, cord pH > 7.25, and 5-minute Apgar score 2:7); (4) no previous hypoxic events (pO; < 50 mm Hg); (5) no previous hypercarbic or hypocarbic events (pCCL < 30 or > 50 mm Hg); (6) no previous hypo­ tensive events [17]: (7) no metabolic acidosis (pH < 7 .2 5 and base deficit > -3 .0 ); (8) no medication influencing cerebral blood flow and/or MABP; (9) no periventricular-intraventricular hemorrhage; (10) no patent ductus arteriosus; (11) hematocrit between 4065%; (12) normoxia (pCL 50-80 mm Hg) and normocarbia (pCOi 30-50 mm Hg) at time of study, and (13) umbilical arterial line in the descending thoracic aorta. Of the 60 infants screened for inclusion into the study. 12 were excluded secondary to periventricularintraventricular hemorrhage during or after comple­ tion of the study. Gestational age was determined by the first day of the last menstrual period and/or Ballard scores [18]. When there was a difference of more than 2 weeks, the latter was used. MABP was obtained from the indwelling umbilical arterial line using a Corometrics’ pressure transducer and recorded on a Corometrics* monitor (Corometrics Medical Systems, model 512, Wallingford. Conn., USA). Periventricu­ lar-intraventricular hemorrhage was excluded by cra­ nial ultrasonography prior to. during, and after com­ pletion of the studies. Patent ductus arteriosus was ruled out by the absence of diastolic flow in the main pulmonary artery at echocardiography. Assisted ven­ tilation was not an exclusion criterion.

Table 1. Perinatal data of the study population (n = 48)

Gestational age. weeks Birth weight, g Apgar score 5 min First arterial pH Mode of delivery, % Vaginal Cesarian section

Mean ± SD


29.0 ± 1.9 1.148 ±231 8.0 ±0.8 7.37 ±0.09

24-32 700-1.630 7-10 7.25-7.54

62 38

Table 2. Arterial blood gases, hematocrit, heart rate, and ventilator settings (mean ± SD) in the study population at the time of cerebral blood flow velocity and MABP measurements Mean ± SD pCF, mm Hg pCOi. mm Hg Hematocrit, % Heart rate, beats/min Fractional inspired oxygen Mean airway pressure. cm HiO

Cerebral Blood Flow


70.4 ±8.5 35.9±4.6 47.4 ±5.4 147± 13 0.43±0.29

51-80 30-49 40-59 121-172 0.21-1.00

5.2 ± 2.8


Velocity Measurements.

Two-dimensional/pulsed Doppler ultrasound was used to obtain blood flow velocity waveforms of the pericallosal artery. Using the anterior fontanel as an acoustic window, we insonated this vessel with a 5MHz Doppler crystal and 7.5-MHz imaging system (Ultramark 8, Advanced Technology Laboratories. Bothell. Wash., USA) at its curve around the corpus callosum 119]. The angle of insonation was deter­ mined before each examination and was always less than 5 degrees. The sample volume of the Doppler system was set at 1.5 mm and a 100-Ilz high-pass fil­ ter was used to reduce the noise from the pulsating arterial wall. The Doppler signals were subjected to real-time spectral analysis. Peak systolic flow veloci­ ty, end-diastolic flow velocity, and mean flow velocity

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aim of this study was to analyze the relation­ ship between MABP and cerebral blood flow velocity in the pericallosal artery in stable preterm infants.

Cerebral Blood Flow Velocity


Fig. 1. Relationship between MABP and MFV in the pericallosal artery in 28 preterm infants mea­ sured at 12 and 72 h.

Results Perinatal characteristics of the study pop­ ulation are shown in table 1. Mean p 0 2, pC 02, hematocrit, heart rate, and ventilator settings at the time of the cerebral blood flow velocity measurements are presented in ta­ ble 2. Mean ± SD MFV in the pericallosal artery was 10.6 ± 3.7 cm/s. The recorded MABPs ranged from 27 to 54 mm Hg and were within the blood pressure norms for infants of 12 and 72 h of age. Figure 1 displays the MFV and MABP values in the 28 preterm infants with multi­ ple cerebral blood flow velocity measure­ ments. Consideration of all 76 measure­ ments by polynomial regression analysis in­ dicates that MFV in the pericallosal artery platcaued and was stable at MABP values from 31 to 40 mm Hg (fig. 2). The square root of the coefficient of determination R2 of

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(MFV) were calculated from 3 sequential cardiac cy­ cles of optimal quality and expressed in cm/s. During the examination, the infants were in a stable condi­ tion and asleep in a supine position. Protocol. Cerebral blood (low velocity measure­ ments at 12 h of age were obtained in 48. and at both 12 and 72 h of age in 28 preterm infants. MABP. heart rate. pO:, pCOi. hematocrit and ventilator set­ tings were recorded simultaneously on each occasion. All infants had MABP values within the blood pres­ sure norms of Cabal et al. [ 17] at 12 h of age and the norms of Fanaroff and Wright [20] at 72 h of age. Fifty-six of the 76 studies were done in intubated infants. All measurements were performed with the infants in undisturbed quiet sleep for a minimum of 20 min. Statistical Analysis. The data are presented as mean ± standard deviation. Multiple regression anal­ ysis w'as used to analyze the relationship between MFV in the pericallosal artery and MABP. pOi, pCTK hematocrit, heart rate, gestational age, birth weight and mean airway pressures. A curve of MFV versus MABP was constructed using 4th-order poly­ nomial regression analysis with least squares fit (Sigmaplot 4.01. Jandel Scientific, Corte Madera. Calif.).

MABP, mm Hg

van de Bor/Walthcr


the polynomial regression curve was 0.92319 (p < 0.001). Multiple regression analysis, using all 76 observations, with MFV in the pericallosal artery as dependent variable and MABP, pC>2 , pC 02, hematocrit, heart rate, gesta­ tional age, birth weight and mean airway pressures as independent variables revealed that MFV was primarily determined by MABP (F ratio 200.35, p < 0.001).

Discussion Pulsed Doppler ultrasound measure­ ments of cerebral blood How velocity have been validated as reliable indicators of cere­ bral bloow flow, providing that no major changes in heart rate occur, and the angle of vessel insonation during the measurements is known or constant [21-25]. In our study, the infants were at rest and in a stable condi­ tion, no noticeable changes in heart rate oc­ curred during the measurements. The angle

of insonation was always less than 5 degrees. The mean MFV values which we measured in the pericallosal artery were similar to val­ ues reported by others [19] and MABP val­ ues were within the normal range for birth weight [17]. We chose to study flow velocity in the pericallosal artery because of its posi­ tion distal to the circle of Willis, and because an increase in MABPs especially leads to constriction of the large intracranial vessels [26]. All infants were studied at 12 h of age to exclude the effects of early postnatal adapta­ tion on cerebral blood flow velocity [12, 27, 28] and MABP [29]. Abnormal p 0 2, pC 02, and hematocrit values and high-pressure ventilation are known to affect cerebral blood flow velocity in newborn infants [14, 23, 30-37], Therefore, we included only in­ fants who had been normoxic and normocarbic, and had had a normal hematocrit. High peak inspiratory pressures may cause large fluctuations in cerebral blood flow velocity [13, 37], but multiple regression analysis

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Fig. 2. Relationship between MABP and MFV in the pericallosal artery (n = 76).

Cerebral Blood Flow Velocity

between MABP and cerebral blood flow ve­ locity at 12 and 72 h of age. Although it is difficult in clinical research to control for all variables that may influence cerebral blood flow velocity, our inclusion criteria defined a study population that can be considered as a reference group for cere­ bral blood flow velocity and MABP. Our data indicate the presence of cerebral auto­ regulation over a narrow range of MABP val­ ues in the preterm infant.

References 1 Harper AM:Autoregulation of the cerebral blood flow: Influence of the arterial pressure on blood flow through the cerebral cortex. J Neurol Neurosurg Psychiatry 1966;29:398-403. 2 Hernandez MJ, Brennan RW, Bowman GS: Au­ toregulation of cerebral blood flow in the newborn dog. Brain Res 1980;184:199-202. 3 Vanucci RC, Hernandez MJ: Perinatal cerebral blood flow: in Sinclair JC. Warshaw JB. Blom RD (eds): Perinatal Brain Insult. Mead Johnson Symp Perinat Dev Med, Evansville, Ind.. 1981. pp 1819.

4 Tweed WA. Cote J, Pash M. et al: Arterial oxygen­ ation determines autoregulation of cerebral blood flow in the fetal lamb. Pediatr Res 1983; 17:246— 249. 5 Pasternak JF. Groothuis DR: Autoregulation of cerebral blood flow in the newborn beagle puppy. Biol Neonate 1985:48:100-109. 6 Brubakk A-M: Brain Blood Flow in the Neonate. Thesis State University Leiden, 1985. 7 Papile L-A, Rudolph AM. Heymann MA: Auto­ regulation of cerebral blood flow in the preterm fetal lamb. Pediatr Res 1985;19:159-161. 8 Lou HC, Lassen NA, Friis-Hansen B: Impaired autoregulation of cerebral blood flow in the dis­ tressed newborn infant. J Pediatr 1979:94:118— 121.

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showed that peak inspiratory, positive end expiratory, and mean airway pressure did not have a significant impact on cerebral blood How velocity in our study popula­ tion. However, most infants were ventilated at low settings (peak inspiratory pressures < 20.0 cm H20 and mean airway pressures < 5.0 cm H20 ) at the time of cerebral blood flow velocity measurements. Using the l33Xe clearance technique in ventilated preterm infants, Greisen and Trojaborg [13] did not find a relationship between MABP and cerebral blood flow. With the same technique, Younkin et al. [14] found no correlation between systolic arterial blood pressure and cerebral blood flow in 15 asphyxiated preterm infants. Their patients were maturer (mean gesta­ tional age 31 weeks) and older at examina­ tion (mean postnatal age 3.7 weeks) than ours. With the two-dimensional/pulsed Doppler technique, Jorch and Jorch [38] failed to demonstrate cerebral autoregula­ tion in a heterogeneous group of sick pre­ term and term infants. These three studies [13, 14, 38] investigated sick and instable infants. Therefore we limited our study to a highly selected group of preterm infants without adverse factors influencing cerebral blood flow in the neonatal period. Our re­ sults are similar to those of Papile et al. [7], who demonstrated cerebrovascular autoreg­ ulation in preterm fetal lambs. These lambs had higher resting MABP values (45-80 mm Hg) and were relatively maturer than our infants. Clinical events associated with MABP fluctuations and loss of cerebral blood flow autoregulation (e.g. periventricular-intraven­ tricular hemorrhage) usually occur during the first days of life in preterm infants [10, 39]. Therefore, we studied the relationship



23 Rosenberg AA. Narayanan V. Jones MD: Com­













parison of anterior cerebral artery blood flow ve­ locity and cerebral blood flow during hypoxia. Pediatr Res 1985:19:67-70. Greisen G, Johansen K, Ellison PH. et al: Cerebral blood flow in the newborn infant: Comparison of Doppler ultrasound and m xenon clearance. J Pe­ diatr 1984:104:411-418. Perlman J, Herscovitch P. Corriveau S. et al: The relationship of cerebral blood flow velocity, deter­ mined by Doppler, to regional cerebral blood flow, determined by positron emission tomogra­ phy. Pediatr Res 1985;19:357A. Kontos HA. Wei EP. Navari RM, et al: Responses of cerebral arteries and arterioles to acute hypo­ tension and hypertension. Am J Physiol 1987:234: H371-H383. Calvert SA, Ohlsson A, Hosking MC, et al: Serial measurements of cerebral blood flow velocity in preterm infants during the first 72 hours of life. Acta Paediatr Scand 1988:77:625-631. Sonesson S-E. Winbcrg P. Lundell BPW: Early postnatal changes in intracranial arterial blood flow velocities in term infants. Pediatr Res 1987; 22:461-464. Iwamoto HS. Teitel D. Rudolph AM: Effects of birth-related events on blood flow distribution. Pediatr Res 1987:22:634-640. Niijima S. Shortland DB, Levene ML et al: Tran­ sient hyperoxia and cerebral blood flow velocity in infants born prematurely and at full term. Arch Dis Child 1988:63:1126-1130. Archer LNJ. Evans DH. Paton JY. et al: Con­ trolled hypercapnia and neonatal cerebral artery Doppler ultrasound waveforms. Pediatr Res 1986; 20:218-221. Hansen NB. Brubakk A-M. Bratlid D, et al: The effects of variations in PaCO; on brain blood flow and cardiac output in the newborn piglet. Pediatr Res 1986:18:1132-1136. Brubakk A-M. Oh W. Stonestreet BS: Prolonged hypercarbia in the awake newborn piglet: Effect on brain blood flow and cardiac output. Pediatr Res 1987;21:29-33. Greisen G, Munck H, Lou H: Severe hypocarbia in preterm infants and neurodcvclopmental defi­ cit. Acta Paediatr Scand 1987;76:401-404. Rosenkrantz TS. Oh W: Cerebral blood flow ve­ locity in infants with polycythemia and hypervis-

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10 Perlman JM. Volpe JJ: Cerebral blood flow veloc­ ity in relation to intraventricular hemorrhage in the premature infant. J Pediatr 1982:100:956— 959. 11 Perlman JM. Volpe JJ: Suctioning in the preterm infant: Effects on cerebral blood flow velocity, intracranial pressure, and arterial blood pressure. Pediatrics 1983:72:329-334. 12 Van Bel F. Van de Bor M, Stijncn T. et al: Aetiological role of cerebral blood flow alterations in development and extension of peri-intraventricu­ lar haemorrhage. Dev Med Child Neurol 1987:29: 601-614. 13 Greisen G, Trojaborg W: Cerebral blood flow, PaCOi changes, and visual evoked potentials in mechanically ventilated infants. Acta Paediatr Scand 1987;76:394-400. 14 Younkin DP. Reivich M, Jaggi JL. ct al: The effect of hematocrit and systolic blood pressure on cere­ bral blood flow in newborn infants. J Cereb Blood Flow Metab 1987;7:295-299. 15 Volpe JJ: Neurology of the Newborn. Philadel­ phia. Saunders, 1987, pp 114-117. 16 Lubchenco LO. Hansman C, Boyd E: Intrauterine growth in length and head circumference as esti­ mated from live births at gestational ages from 26 to 42 weeks. Pediatrics 1966:37:403-408. 17 Cabal LA. Siassi B. Hodgman JE: Neonatal clini­ cal cardiopulmonary monitoring: in Fanaroff AA, Martin RJ (cds): Neonatal-Perinatal Medicine. St. Louis. Mosby, 1987, pp 343-359. 18 Ballard JL. Kazmaier-Novak K. Driver M: A sim­ plified score for assessment of fetal maturation of newly born infants. J Pediatr 1979:95:769-774. 19 Grant EG. White EM. Schellinger D. et al: Cranial duplex sonography of the infant. Radiology 1987; 163:177-185. 20 Fanaroff A. Weight E: Profiles of mean arterial blood pressure (MAP) for infants weighing 501 — 1.500 grams. Pediatr Res 1990:27:205A. 21 Hansen NB. Stonestreet BS, Rosenkrantz TS. et al: Validity of Doppler measurements of anterior cerebral artery blood flow velocity: Correlation with brain blood flow in piglets. Pediatrics 1983: 72:526-531. 22 Batton DG. Hellmann J, Hernandez MJ. et al: Regional cerebral blood flow, cerebral blood ve­ locity, and pulsatility index in newborn dogs. Pe­ diatr Res 1983:17:908-912.

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39 Van de Bor M, Van Bel F. Lineman R, et al: Peri­ natal factors and periventricular-intraventricular hemorrhage in preterm infants. Am J Dis Child 1986:140: l'l 25-1130.

Frans J. Walthcr. MD. PhD Division of Neonatology Department of Pediatrics King/Drew Medical Center 12021 S. Wilmington Ave Los Angeles, CA 90059 (USA)

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cosity: Effects of partial exchange transfusion with plasmanate. J Pcdiatr 1982;101:94-98. 36 Hudak ML. Koehler RC, Rosenberg AA. et al: Effect of hematocrit on cerebral blood flow. Am J Physiol 1986;251: H63—Ii 70. 37 Cowan F, Thoresen M: The effects of intermittent positive pressure ventilation on cerebral arterial and venous blood velocities in the newborn in­ fant. Acta Paediatr Scand 1987;76:239-247. 38 Jorch G. Jorch N: Failure of autoregulation of cerebral blood flow in neonates studied by the pulsed Doppler ultrasound of the internal carotid artery. Eur J Pcdiatr 1987;146:468-472.


Cerebral blood flow velocity regulation in preterm infants.

Cerebrovascular autoregulation is the mechanism by which changes in cerebral blood flow are prevented during fluctuations in mean arterial blood press...
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