Acta PBdiatr 81: 504-10. 1992
Cerebral and aortic blood flow velocity patterns in preterm infants receiving prophylactic surfactant treatment Frank van Bel, Peter J de Winter, Hannie BG Wijnands, Margot van de Bor and Johannes Egberts Departments of Pediatrics and Obstetrics and Gynecology, University Hospital, Leiden. The Netherlad
van Be1 F, de Winter PJ, Wijnands HBG, van de Bor M, Egberts J. Cerebral and aortic blood flow velocity patterns in preterm infants receiving prophylactic surfactant treatment. Acta Paediatr 1992; 81:50410. Stockholm. ISSN 0803-5253 Blood velocity in the internal carotid artery (ICA) and in the descending thoracic aorta (DAo) was investigated used Duplex-Dopplqr ultrasound in 14 infants of < 30 weeks gestation, treated prophylactically with surfactant, and in 1 1 comparable infants with relatively mature lungs who served as controls. After surfactant administration, blood gases, pH or FiOz were not different between the groups. Temporal mean blood velocity in the ICA was used as a relative measure of cerebral flow (TMFV-cer), and its coefficient of variation (CV-cer) was used to assess fluctuations in cerebral blood velocity. The pulsatility index (PI) in the ICA (PI-cer) and DAo (PI-DAo) was used to estimate if a left-to-right shunt was present. During surfactant instillation TMFV-cer was abnormally low and CV-cer indicated a fluctuating cerebral blood velocity. At 10 min after surfactant administration, TMFV-cer of the treated infants was higher compared to the controls, while CV-cer was stable in both groups. PI-cer and PI-DAo were abnormally high during the first hour of life after surfactant treatment, suggesting a left-to-right shunt without, however, clinical signs of a hemodynamically important ductus arteriosus. We suggest that cerebral perfusion is affected during and at 10 min after surfactant instillation. Left-to-right shunting appears to be a common event following surfactant treatment. 0 Aortic, blood velocity, cerebral, neonate, surfactant F van Bel. Department o$ Pediatrics, University Hospital Leiden, Building 35, P.O.Box 9600,2300 RC Leiden. The Netherlands
Most studies of surfactant replacement therapy for the treatment of respiratory distress syndrome in the preterm infant report positive effects on pulmonary function and on mortality and morbidity (1, 2). Despite the positive effects of surfactant therapy, however, no beneficial effects on the incidence of periventricularintraventricular hemorrhage (PIVH) have been found: a recent study of Horbar et al. (3) even reported an increase in the incidence of PIVH. Moreover, an increased incidence of hemodynamically important patent ductus arteriosus (PDA) after surfactant replacement has been reported by several investigators (4, 5). These findings give rise to the question of whether or not the benefit of surfactant replacement therapy may be reduced by introducing risk factors that cannot be controlled properly. Indeed, recent studies suggest that cerebral and systemic hemodynamics are affected after surfactant treatment, which may contribute to the occurrence of these complications (5-9). To investigate the acute and sustained effects of surfactant treatment on neonatal cerebral and systemic circulation we determined the patterns of cerebral blood flow velocity and of blood flow velocity in the descending thoracic aorta (DAo) before, during, and up to the fifth postnatal day after surfactant instillation in 14
preterm babies receiving treatment with surfactant prophylactically at birth. Eleven comparable untreated neonates, but with relatively mature lungs, served as controls.
Materials Fourteen preterm infants received a single dose of 200 mg/kg (2.5 ml/kg) porcine surfactant (Curosurf) within 10 min after birth (surf group). As controls (control group) we selected infants who did not receive prophylactic surfactant and did not need rescue treatment (if FiOz>0.6 at 6 h of age). These infants had relatively mature lungs and the changes in cerebral and aortic blood flow velocities can be considered normal variations occurring in infants of this selected gestational age group during the first five days of life. All infants were included in the present study after informed parental consent was obtained. All infants were born at the University Hospital of Leiden and participated in a multicenter prophylactic surfactant treatment trial with the following entry criteria: gestational age less than 30 weeks; endotracheally intubated immediately after birth; and no major congenital abnormalities. The study
Surfactant treatment and cerebral blood flow velocity
ACTA PRDIATR 81 (1992)
was approved by the scientific board of the Department of Pediatrics and by the Ethics Committee of the Hospital. The surfactant was administered through a nasogastric tube inserted into the endotracheal tube with the baby's head first turned to the left and then to the right side to instill surfactant to the right and left lung, respectively. Between each instillation we ventilated the infant for 1 min. Ventilator settings were adjusted according to the routines of our department. These imply that, when Pa02 increases, inspired oxygen concentration should be lowered first, then the peak inspiratory pressure, the frequency and the inspiration : expiration ratio. Control infants did not receive a placebo. Cerebral and aortic blood @ow velocity studies Cerebral and aortic blood flow velocity were investigated with a real-time duplex-Doppler ultrasound scanner (Ultramark-4, Advanced Technology Laboratories, Bothell, Wash). All scans were obtained with a 7.5-MHz real-time mechanical sector transducer and a 5-MHz Doppler crystal. The sample volume of the Doppler system ranged from 1.5 to 2.5 mm. A 100 Hz high-pass filter was used to reduce noise from the pulsating arterial wall. For serial investigation of cerebral blood flow, the internal carotid artery (ICA) was insonated, using the anterior fontanel as an acoustic window, just beneath the lateral edge of the sella turcica where it runs straight towards the fontanel. The velocity wave form was then determined at an angle of insonation (angle between Doppler beam and flow direction of the blood) of approximately zero degrees.
505
For serial assessment of changes in aortic blood velocity the DAo was insonated as proximal as possible, but well distal to the origin of the ductus arteriosus to avoid any turbulence of flow, using a longitudinal abdominal approach with the transducer directed in'the anterio-posterior position (Fig. 1). The angle of insonation was always larger than 15" and mostly between 45 and 60". Optimalization of the sample volume position in both instances was obtained by acoustic and visual control. Ten sequential cardiac cycles of the velocity waveforms of ICA and DAo were subjected to real-time spectral analysis. Peak systolic flow velocity (PSFV), temporal mean flow velocity (TMFV: the time mean of the maximum flow velocity envelope curve) and enddiastolic flow velocity (EDFV) were determined and the pulsatility index (PI) was calculated from the equation: PI=(PSFV-EDFV)/PSFV. The TMFV of the ICA was used as a qualitative measure of cerebral blood flow (TMFV-cer) (10,ll) and assumed to be indicative of changes in cerebral vascular resistance. The coefficient of variation of the TMFV-cer (SD[TMFV-cer]/ mean[TMFV-cer] x 100) was used to assess the fluctuation (in Yo)of cerebral blood flow velocity (CV-cer) (12). The PI of the ICA (PI-cer) was used, in association with the PI of the DAo (PI-DAo), to assess whether or not there was evidence for a left-to-right shunt; a left-toright shunt was diagnosed if there was a negative blood flow velocity in the DAo during the diastolic phase of the cardiac cycle (PI > I .OO) (I 3,14) in association with an abnormally high PI of the ICA (PI>0.90) (15). During Doppler measurements, the infants were lying supine and in an anti-Trendelenburg position (1 5"). Neonatal data were collected prospectively. Immediately after birth, including the stabilization period with
VELOCITY WAVE FORM OF DESCENDING THORACIC AORTA
Fig. I. A. Representativereal-time two-dimensional image, using a longitudinal abdominal approach, of the thoracic cavity. Note the sample volume of the Doppler beam (arrow head) placed in the descending thoracic aorta (DAo); B. spectral analysis of a normal velocity waveform of the neonatal DAo.
506
F v a n Be1 er al.
ACTA PEDIATR 81 (1992)
or without surfactant treatment in the resuscitation Table 1. Patient characteristics and clinical data of the investigated room, blood pressure measurements were performed by infants (meansf I SD). oscillometry (Dynamap Criterion, Tampa, Fla) and SF infants (n= 14) Control infants (n= 1 1 ) blood gases and pH were obtained from arterialized I090 f 220 1164f364 blood samples. When the indwelling arterial catheter Birth weight (g) 28.1 f 1.6 28.6* 1.5 was in the correct position, arterial blood pressure was Gestational age (weeks) 2 (n) 6 measured directly and blood collection for blood gases PDA PIVH/PVL (n) and pH was obtained from this arterial catheter. This Grade 1 I was usually the case within one hour after birth. Grade 2 1 Grade 3 1 PIVH and periventricular leucomalacia (PVL) were Grade 4 0 diagnosed using a two-dimensional ultrasound techPVL 0 nique. PIVH was graded using the classification of Air leak (n) 2 Papile et al. (16). Screening for PIVH and PVL was SF= Surfactant, PDA = hemodynamically important patent ductus performed after each Doppler study and afterwards once a week until discharge. The diagnosis of PDA was arteriosus, PIVH = periventricular-intraventricular hemorrhage, based on clinical signs (characteristic murmur, bound- PVL =periventricular leucomalacia. ing pulses and hyperactive precordium), radiographic characteristics (cardiomegaly: cardiothoracic ratio > 0.6 and/or pulmonary plethora) and confirmed by incidence of PDA was not different between groups. No Doppler and two-dimensional echocardiography (left infant had clinical signs of PDA during the first day of atrial/aortic root ratio > 1.15 (17) and a diastolic reverse life and in the majority of infants PDA was diagnosed flow in the pulmonary artery). beyond the fifth day of life. The incidences of PIVH and PVL were also the same for both groups. The occurrence of PIVH or PVL did not appear to be related directly to Study design surfactant treatment in any case. Doppler ultrasound measurements from ICA and DAo were performed directly after birth and stabilization in both groups of infants. In the surf group the blood Ventilation conditions, blood gases and pH, velocity waveform of the ICA was also determined blood pressure and heart rate during the second half of the instillation procedure, and There appeared to be no differences in peak inspiratory then in both groups at 20,30 and 60 min, 6, 12 and 24 h or mean airway pressure (data not shown), pH (data not after birth and then at 24-h intervals until day 5. The shown), Pa02, PaC02 or FiOz between groups at any recordings were stored on hard copy for subsequent postnatal age. Pa02 and PaC02 decreased rapidly analysis. Simultaneously with the ultrasound studies, during the first 30-60 min of life and stabilized within arterial pressure was measured; pH, PaCO2 and Pa02 normal values. Infants who needed surfactant as rescue were determined and TcP02, FiO2, peak inspiratory treatment (Fi02> 0.6) were not included in this study. pressure, mean airway pressure and heart rate were At 6 h after birth, their blood gas values, FiO2 and mean registered. Hematocrit was measured at least every 6 h airway pressures differed significantly from those values and, if necessary, packed red cell transfusions were given of the control infants and those who received surfactant to maintain the hematocrit above 40%. prophylactically. The majority of the infants of both groups remained connected to the ventilator during the entire study period, mostly with minimal ventilator Statistical analysis settings (ventilation frequency: 5-10 cycles pm, peak To investigate possible differences in Doppler and inspiratory pressure: 12-14 cm HzO), as is the policy in clinical variables as a function of postnatal age, a our unit when dealing with these extremely preterm multiple linear regression analysis with dummy vari- infants. It took 6-12 h until normal or slightly increased ables was performed using effects coding (18). When FiOz values were obtained (Fig. 2). No relationships significance was found, a Student-Newman-Keuls test were found between pH, blood gases or heart rate on the was performed subsequently for comparison between one hand, and TMFV-cer on the other. In the resuscidifferent postnatal ages. Mean values between groups at tation room we were able to obtain reliable mean a particular postnatal age were compared using Stu- arterial blood pressure (MABP) measurements in only dent’s two-sample t-test. Correlations were assessed by eight infants in the surf group and in seven infants in the Spearman’s correlation coefficient. P < 0.05 was consi- control group. The surf group tended to have higher dered statistically significant. MABP values up to 30 min, but differences between the groups were not statistically significant (Fig. 3). During surfactant instillation, mean heart rate was significantly lower than values obtained immediately before and 10 Results min after the instillation maneuver ( p ~ 0 . 0 1 in ; three Patient characteristics are shown in Table 1. The infants heart rate was below 100). Otherwise, no
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Surfactant treatment and cerebral bloodflow velocity
ACTA PRDIATR 81 (1992)
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Cerebral and aortic blood flow velocity patterns in preterm infants receiving prophylactic surfactant treatment Frank van Bel, Peter J de Winter, Hannie BG Wijnands, Margot van de Bor and Johannes Egberts Departments of Pediatrics and Obstetrics and Gynecology, University Hospital, Leiden. The Netherlad
van Be1 F, de Winter PJ, Wijnands HBG, van de Bor M, Egberts J. Cerebral and aortic blood flow velocity patterns in preterm infants receiving prophylactic surfactant treatment. Acta Paediatr 1992; 81:50410. Stockholm. ISSN 0803-5253 Blood velocity in the internal carotid artery (ICA) and in the descending thoracic aorta (DAo) was investigated used Duplex-Dopplqr ultrasound in 14 infants of < 30 weeks gestation, treated prophylactically with surfactant, and in 1 1 comparable infants with relatively mature lungs who served as controls. After surfactant administration, blood gases, pH or FiOz were not different between the groups. Temporal mean blood velocity in the ICA was used as a relative measure of cerebral flow (TMFV-cer), and its coefficient of variation (CV-cer) was used to assess fluctuations in cerebral blood velocity. The pulsatility index (PI) in the ICA (PI-cer) and DAo (PI-DAo) was used to estimate if a left-to-right shunt was present. During surfactant instillation TMFV-cer was abnormally low and CV-cer indicated a fluctuating cerebral blood velocity. At 10 min after surfactant administration, TMFV-cer of the treated infants was higher compared to the controls, while CV-cer was stable in both groups. PI-cer and PI-DAo were abnormally high during the first hour of life after surfactant treatment, suggesting a left-to-right shunt without, however, clinical signs of a hemodynamically important ductus arteriosus. We suggest that cerebral perfusion is affected during and at 10 min after surfactant instillation. Left-to-right shunting appears to be a common event following surfactant treatment. 0 Aortic, blood velocity, cerebral, neonate, surfactant F van Bel. Department o$ Pediatrics, University Hospital Leiden, Building 35, P.O.Box 9600,2300 RC Leiden. The Netherlands
Most studies of surfactant replacement therapy for the treatment of respiratory distress syndrome in the preterm infant report positive effects on pulmonary function and on mortality and morbidity (1, 2). Despite the positive effects of surfactant therapy, however, no beneficial effects on the incidence of periventricularintraventricular hemorrhage (PIVH) have been found: a recent study of Horbar et al. (3) even reported an increase in the incidence of PIVH. Moreover, an increased incidence of hemodynamically important patent ductus arteriosus (PDA) after surfactant replacement has been reported by several investigators (4, 5). These findings give rise to the question of whether or not the benefit of surfactant replacement therapy may be reduced by introducing risk factors that cannot be controlled properly. Indeed, recent studies suggest that cerebral and systemic hemodynamics are affected after surfactant treatment, which may contribute to the occurrence of these complications (5-9). To investigate the acute and sustained effects of surfactant treatment on neonatal cerebral and systemic circulation we determined the patterns of cerebral blood flow velocity and of blood flow velocity in the descending thoracic aorta (DAo) before, during, and up to the fifth postnatal day after surfactant instillation in 14
preterm babies receiving treatment with surfactant prophylactically at birth. Eleven comparable untreated neonates, but with relatively mature lungs, served as controls.
Materials Fourteen preterm infants received a single dose of 200 mg/kg (2.5 ml/kg) porcine surfactant (Curosurf) within 10 min after birth (surf group). As controls (control group) we selected infants who did not receive prophylactic surfactant and did not need rescue treatment (if FiOz>0.6 at 6 h of age). These infants had relatively mature lungs and the changes in cerebral and aortic blood flow velocities can be considered normal variations occurring in infants of this selected gestational age group during the first five days of life. All infants were included in the present study after informed parental consent was obtained. All infants were born at the University Hospital of Leiden and participated in a multicenter prophylactic surfactant treatment trial with the following entry criteria: gestational age less than 30 weeks; endotracheally intubated immediately after birth; and no major congenital abnormalities. The study
Surfactant treatment and cerebral blood flow velocity
ACTA PRDIATR 81 (1992)
was approved by the scientific board of the Department of Pediatrics and by the Ethics Committee of the Hospital. The surfactant was administered through a nasogastric tube inserted into the endotracheal tube with the baby's head first turned to the left and then to the right side to instill surfactant to the right and left lung, respectively. Between each instillation we ventilated the infant for 1 min. Ventilator settings were adjusted according to the routines of our department. These imply that, when Pa02 increases, inspired oxygen concentration should be lowered first, then the peak inspiratory pressure, the frequency and the inspiration : expiration ratio. Control infants did not receive a placebo. Cerebral and aortic blood @ow velocity studies Cerebral and aortic blood flow velocity were investigated with a real-time duplex-Doppler ultrasound scanner (Ultramark-4, Advanced Technology Laboratories, Bothell, Wash). All scans were obtained with a 7.5-MHz real-time mechanical sector transducer and a 5-MHz Doppler crystal. The sample volume of the Doppler system ranged from 1.5 to 2.5 mm. A 100 Hz high-pass filter was used to reduce noise from the pulsating arterial wall. For serial investigation of cerebral blood flow, the internal carotid artery (ICA) was insonated, using the anterior fontanel as an acoustic window, just beneath the lateral edge of the sella turcica where it runs straight towards the fontanel. The velocity wave form was then determined at an angle of insonation (angle between Doppler beam and flow direction of the blood) of approximately zero degrees.
505
For serial assessment of changes in aortic blood velocity the DAo was insonated as proximal as possible, but well distal to the origin of the ductus arteriosus to avoid any turbulence of flow, using a longitudinal abdominal approach with the transducer directed in'the anterio-posterior position (Fig. 1). The angle of insonation was always larger than 15" and mostly between 45 and 60". Optimalization of the sample volume position in both instances was obtained by acoustic and visual control. Ten sequential cardiac cycles of the velocity waveforms of ICA and DAo were subjected to real-time spectral analysis. Peak systolic flow velocity (PSFV), temporal mean flow velocity (TMFV: the time mean of the maximum flow velocity envelope curve) and enddiastolic flow velocity (EDFV) were determined and the pulsatility index (PI) was calculated from the equation: PI=(PSFV-EDFV)/PSFV. The TMFV of the ICA was used as a qualitative measure of cerebral blood flow (TMFV-cer) (10,ll) and assumed to be indicative of changes in cerebral vascular resistance. The coefficient of variation of the TMFV-cer (SD[TMFV-cer]/ mean[TMFV-cer] x 100) was used to assess the fluctuation (in Yo)of cerebral blood flow velocity (CV-cer) (12). The PI of the ICA (PI-cer) was used, in association with the PI of the DAo (PI-DAo), to assess whether or not there was evidence for a left-to-right shunt; a left-toright shunt was diagnosed if there was a negative blood flow velocity in the DAo during the diastolic phase of the cardiac cycle (PI > I .OO) (I 3,14) in association with an abnormally high PI of the ICA (PI>0.90) (15). During Doppler measurements, the infants were lying supine and in an anti-Trendelenburg position (1 5"). Neonatal data were collected prospectively. Immediately after birth, including the stabilization period with
VELOCITY WAVE FORM OF DESCENDING THORACIC AORTA
Fig. I. A. Representativereal-time two-dimensional image, using a longitudinal abdominal approach, of the thoracic cavity. Note the sample volume of the Doppler beam (arrow head) placed in the descending thoracic aorta (DAo); B. spectral analysis of a normal velocity waveform of the neonatal DAo.
506
F v a n Be1 er al.
ACTA PEDIATR 81 (1992)
or without surfactant treatment in the resuscitation Table 1. Patient characteristics and clinical data of the investigated room, blood pressure measurements were performed by infants (meansf I SD). oscillometry (Dynamap Criterion, Tampa, Fla) and SF infants (n= 14) Control infants (n= 1 1 ) blood gases and pH were obtained from arterialized I090 f 220 1164f364 blood samples. When the indwelling arterial catheter Birth weight (g) 28.1 f 1.6 28.6* 1.5 was in the correct position, arterial blood pressure was Gestational age (weeks) 2 (n) 6 measured directly and blood collection for blood gases PDA PIVH/PVL (n) and pH was obtained from this arterial catheter. This Grade 1 I was usually the case within one hour after birth. Grade 2 1 Grade 3 1 PIVH and periventricular leucomalacia (PVL) were Grade 4 0 diagnosed using a two-dimensional ultrasound techPVL 0 nique. PIVH was graded using the classification of Air leak (n) 2 Papile et al. (16). Screening for PIVH and PVL was SF= Surfactant, PDA = hemodynamically important patent ductus performed after each Doppler study and afterwards once a week until discharge. The diagnosis of PDA was arteriosus, PIVH = periventricular-intraventricular hemorrhage, based on clinical signs (characteristic murmur, bound- PVL =periventricular leucomalacia. ing pulses and hyperactive precordium), radiographic characteristics (cardiomegaly: cardiothoracic ratio > 0.6 and/or pulmonary plethora) and confirmed by incidence of PDA was not different between groups. No Doppler and two-dimensional echocardiography (left infant had clinical signs of PDA during the first day of atrial/aortic root ratio > 1.15 (17) and a diastolic reverse life and in the majority of infants PDA was diagnosed flow in the pulmonary artery). beyond the fifth day of life. The incidences of PIVH and PVL were also the same for both groups. The occurrence of PIVH or PVL did not appear to be related directly to Study design surfactant treatment in any case. Doppler ultrasound measurements from ICA and DAo were performed directly after birth and stabilization in both groups of infants. In the surf group the blood Ventilation conditions, blood gases and pH, velocity waveform of the ICA was also determined blood pressure and heart rate during the second half of the instillation procedure, and There appeared to be no differences in peak inspiratory then in both groups at 20,30 and 60 min, 6, 12 and 24 h or mean airway pressure (data not shown), pH (data not after birth and then at 24-h intervals until day 5. The shown), Pa02, PaC02 or FiOz between groups at any recordings were stored on hard copy for subsequent postnatal age. Pa02 and PaC02 decreased rapidly analysis. Simultaneously with the ultrasound studies, during the first 30-60 min of life and stabilized within arterial pressure was measured; pH, PaCO2 and Pa02 normal values. Infants who needed surfactant as rescue were determined and TcP02, FiO2, peak inspiratory treatment (Fi02> 0.6) were not included in this study. pressure, mean airway pressure and heart rate were At 6 h after birth, their blood gas values, FiO2 and mean registered. Hematocrit was measured at least every 6 h airway pressures differed significantly from those values and, if necessary, packed red cell transfusions were given of the control infants and those who received surfactant to maintain the hematocrit above 40%. prophylactically. The majority of the infants of both groups remained connected to the ventilator during the entire study period, mostly with minimal ventilator Statistical analysis settings (ventilation frequency: 5-10 cycles pm, peak To investigate possible differences in Doppler and inspiratory pressure: 12-14 cm HzO), as is the policy in clinical variables as a function of postnatal age, a our unit when dealing with these extremely preterm multiple linear regression analysis with dummy vari- infants. It took 6-12 h until normal or slightly increased ables was performed using effects coding (18). When FiOz values were obtained (Fig. 2). No relationships significance was found, a Student-Newman-Keuls test were found between pH, blood gases or heart rate on the was performed subsequently for comparison between one hand, and TMFV-cer on the other. In the resuscidifferent postnatal ages. Mean values between groups at tation room we were able to obtain reliable mean a particular postnatal age were compared using Stu- arterial blood pressure (MABP) measurements in only dent’s two-sample t-test. Correlations were assessed by eight infants in the surf group and in seven infants in the Spearman’s correlation coefficient. P < 0.05 was consi- control group. The surf group tended to have higher dered statistically significant. MABP values up to 30 min, but differences between the groups were not statistically significant (Fig. 3). During surfactant instillation, mean heart rate was significantly lower than values obtained immediately before and 10 Results min after the instillation maneuver ( p ~ 0 . 0 1 in ; three Patient characteristics are shown in Table 1. The infants heart rate was below 100). Otherwise, no
MABP lmm Hg)
pC02 IkPa) 10
I
rn surfactant In-14) o controls In-1 1)
I
. 9 i 8-
507
Surfactant treatment and cerebral bloodflow velocity
ACTA PRDIATR 81 (1992)
I
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