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based on the observation that asymmetric dilation of the lateral cerebral ventricle occurs with posthemorrhagic hydrocephalus.
REFERENCES 1. Shackelford GD. Neurosonography of hydrocephalus in infants. Neuroradiology 1986;28:452-62. 2. Levene MI. Measurement of the growth of the lateral ventricles in preterm infants with real-time ultrasound. Arch Dis Child 1981 ;56i900-4. 3. Johnson ML, Mack LA, Rumaek CM, et al. B-mode echoencephalography inthe normal and high risk infant. A JR Am J Roentgenol 1979;133:374-81. 4. Rumack CM, Johnson ML. Perinatal and infant brain imaging. Chicago: Year Book Medical Publishers, 1984:157. 5. Brann BS, Wofsy C, Wicks J, Brayer J. The quantification of neonatal cerebral ventricular volume by real-time ultrasonography: derivation and in vitro confirmation of a mathematical model. J Ultrasound Med 1990;9:1-8. 6. Brann BS, Wofsy C, Papile LA, Angelus P, Backstrom C. The quantification of neonatal cerebral ventricular volume by realtime ultrasonography: in vivo validation of the cylindrical coordinate method. J Ultrasound Med 1990;9:9-15. 7. Garrett W J, Kossoff G, Warren PS. Cerebral ventricular size
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in children: a two-dimensional ultrasonic study. Radiology 1980; 136:711-5. London DA, Carroll BA, Enzmann DR. Sonography of ventricular size and germinal matrix hemorrhage in premature infants. AJNR 1980;1:295-300. Sauerbrei EE, Digney M, Harrison PB, Cooperberg PL. Ultrasonic evaluation of neonatal intracranial hemorrhage and its complications. Radiology 1981 ;39:667-85. Quisling RG, Reeder JD, Setzer ES, Kaude JV. Temporal comparative analysis of computed tomography with ultrasound for intracranial hemorrhage in premature infants. Neuroradiology 1983;24:205-11. Naidich TP, Epstein F, Lin JP, Kricheff II, Hochwald GM. Evaluation Of pediatric hydrocephalus by computed tomography. Radiology 1976;119:337-45. Hertzberg BS, Bowie JD, Burger PC, Marshburn PB, Djang WT. The th?ee lines: origin of sonographic landmarks in the fetal head. A JR Am J Roentgenol 1987;149:1009-12. Hakim S, Adams RD. The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure. J Neurol Sci 1965;2:307-27. Geschwind N. The mechanism of normal pressure hydrocephalus. J Neurol Sci 1968;7:481-93. Nagashima T, Tamaki N, Matsumoto S, Horwitz B, Seguchi Y. Biomechanics of hydrocephalus: a new theoretical model. Neurosurgery 1987;21:898-904.
Clinical and laboratory observations Controlled study of the effects of indomethacin on cerebral blood flow velocities in newborn infants Riad Mardoum, MD, Raul Bejar, MD, T. Allen Merritt, MD, a n d Charles Berry, PhD From th e Departments of Pediatrics and of Community and Family Medicine, University of California, San Diego, and the Department of Pediatrics, Mercy Hospital and Medical Center, San Diego, California
Intravenous administration ofindomethacin has been shown to cause a 40% to 50% drop in the cerebral blood flow in adult human subjects a n d up to 30% in newborn pigs. 13 Reduction Of cerebral blood flow velocities has been observed in premature infants receiving indomethacin
Submitted for publication April 16, 1990; accepted Aug. 6, 1990. Reprint requests: Raul Bejar, MD, 225 Dickenson St., San Diego, CA 92103.
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intravenously. 46 However, no prospective double-blind, controlled studies have been published. A reduction of the cerebral blood flow might cause or contribute to ischemic BP BFV tcPco2 tcPo2
Blood pressure Blood flow velocity Transcutaneous carbon dioxide pressure Transcutaneous oxygen pressure
damage of the immature neonatal brain; therefore we designed a placebo-controlled study to assess the effect of indomethacin on the cerebral BFVs in preterm infants. 7
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Table. Mean differences between mean predose and mean postdose values after the first administration of indomethacin or placebo Placebo ( n = 8) Mean BFV (cm/s) Systolic BFV (cm/s) Diastolic BFV (cm/s) Mean BP (ram Hg) Systolic BP (mrn Hg) Diastolic BP (mm Hg)
0.17 + 0.28 0.80 -4- 0.55 0.33 _+ 0.32 0:58 _+ 0.87 0.58 _+ 0.87 0.25 + 0.59
Indomethacin ( n = 7) -4.30 -6.33 -2.49 2.79 5.52 2.31
_+ 1.45 + 2.37 _+ 0.82 +_ 0.84 _+ 1.24 _+ 1.35
p 0.007 0.008 0.005 0.016 0.007 NS
Values(exceptp values)are expressedas the meandifference+ SEM.Predosevalueswerecalculatedby averagingthe valuesmeasuredat 1and 5 minutesbefore administrationof either placeboor indomethacin.Postdosevalueswerecalculatedby averagingthe valuesmeasuredat 1, 5, 10, 15, 25, and 30 minutesafter the administrationof placeboor indomethacin. NS. Not significant.
METHODS The study was approved by the Committee for the Protection of Human Subjects, University of California, San Diego. Preterm infants requiring intravenous indomethaein therapy to constrict a clinically significant patent ductus arteriosus were enrolled in the study if they met the following criteria: (1) first dose of indomethaein, (2) an arterial catheter (umbilical or percutaneous) in place, and (3) continuous monitoring of intraarterial blood pressure and transcutaneous oxygen and carbon dioxide pressure. The effect of the first dose of indomethacin was studied because the drug has a half-life in preterm infants of 14 to 30 hours and because its elimination depends on renal function) Each infant initially received either indomethacin, 0.2 mg/kg administered intravenously in 0.3 ml of saline solution, or placebo, 0.3 ml of saline solution administered intravenously; the alternate agent was administered 30 minutes later. Random allocation was performed by the pharmacists. Each infusion was given via a peripheral vein or central venous line for a period of 15 to 20 seconds. A gate-ranged, pulsed-Doppler, two-dimensional ultrasound scanner (Advanced Technology Laboratories, Inc., Bothell, Wash.) was used to measure the cerebral BFVs. 8, 9 The ultrasound transducer was applied to the anterior fontanelle, with the scanning plane following the coronal suture. A coronal image of the brain anterior to the foramen magnum was obtained to visualize the internal carotid arteries at the base of the skull. After the arteries were seen, the gate of the Doppler scanner was positioned on the internal carotid artery immediately above the skull. A continuous tracing of BFVs was obtained. With this technique the angle of insonation is 0 degrees because the transducer is directly opposed to the carotid arteries. The measurements of the BFVs are therefore independent of this angle, and one of the major disadvantages of the transcutaneous Doppler technique is avoided. This procedure allowed us to make
multiple comparisons of sequential measurements in a single infant and among different infants. Twelve pulsations obtained in three consecutive, but separate, insonations of the left internal carotid artery were analyzed with a computerized system to integrate the mean systolic and diastolic BFVs and the mean cerebral BFVs as a function of time. The BFVs, the systolic, diastolic, and mean arterial BPs, and the tcPo2 and tcPco2 values were obtained at 5 minutes and 1 minute before the first dose (placebo or indomethacin) and then at 1, 5, 10, 15, 25, 29, 31, 35, 40, 45, 55, 60, and 90 minutes after the first dose (placebo or indomethacin). Arterial blood gases were measured at 5 minutes before the first administration and then at 25 and 55 minutes. Serum indomethacin levels were measured at 55 minutes after the administration of the first dose. Infant handling, radiographic studies, and nursing and respiratory therapy procedures (including ventilator and oxygen adjustments and endotracheal suctioning) were avoided during the study period to minimize changes in the cerebral BFVs caused by variables other than administration of indomethacin. Values before indomethacin or placebo administration for each variable were calculated by averaging the values at 5 minutes and 1 minute before administration. Values for each variable were calculated by averaging the values measured at 1, 5, 10, 15, 25, and 30 minutes after the administration of either placebo or indomethacin. The differences between the predose and the postdose values (during the first 30 minutes) for each variable with either placebo or indomethacin were compared by means of an unpaired t test. To account for confounding variables, we used infants as their own control subjects by comparing the mean predose values and the values for all the variables averaged during the first 30 minutes after placebo or indomethacin admin-
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Clinical and laboratory observations
The Journal of Pediatrics January 1991
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Figure. S ystolic flowvelocity (SFV), diastolic flow velocity (DFV), systolic blood pressure (SBP), and diastolic blood pressure (DBP) values (mean _+ 2 SEM) before and after indomethacin. SFV and DFV were significantlylower at 1 minute after indomethacin administration (p