Cerebral Doppler studies in the fetus and newborn infant

T H E J O U R N A L OF

PEDIATRICS AUGUST

1991

Volume 119

Number 2

MEDICAL PROGRESS Cerebral Doppler studies in the fetus and newborn infant Tonse N, K, Raju, MD From the Division of Neonatology, Department of Pediatrics, University of Illinois at Chicago In 1979 Bada et al) first reported that cerebral Doppler studies help in the diagnosis of birth asphyxia and intracranial hemorrhage. Much has happened to imaging and Doppler technology since then. In addition to extensive clinical use in cardiology, diagnostic radiology, neurology, and neurosurgery, sophisticated Doppler methods are being applied in hemodynamic research, including studies of the uteroplacental, systemic, and cerebral circulations of the fetus and newborn infant. In this article, I will review briefly some of these applications and discuss their clinical value and limitations. TECHNICAL METHODS

ASPECTS AND DOPPLER

The Doppler principle. In 1842 Christian Johann Doppler published his theory (later known as the Doppler principle), which met with severe skepticism.: Applied to blood flow, the Doppler principle can be stated as follows: When a sound wave of a fixed frequency is transmitted over a blood vessel, the deflected (i.e., the "echoed") frequency is different from that of the transmitted frequency) This frequency "shift" is used to compute the velocity of the moving target (blood) by using the following formula: Velocity = (c • fd)/(2 • ft X COS0), where c is sound wave velocity in human tissue (~1560 m/sec at 37 ~ C); fd = the Supported in part by grants from the Health and Human Services (No. DRR 2528 01 and No. 2525-222) and the University of Illinois College of Medicine Committee on Research (COMCOR No. 87415). Reprint requests: T. N. K. Raju, MD, Department of Pediatrics (m/c 856), 840 South Wood St., Chicago, IL 60612. 9/18/30395

Doppler frequency shift; ft = transmitted frequency; and O = the intercept angle between the vessel and the Doppler insonation. This 0 is one of the major variables affecting the accuracy of measured velocity. When the angle is between 0 and 15 degrees, the error is <4%; it increases to 18% with a 35-degree angle, and to 50% at a 60-degree angle. One must therefore be cautious when interpreting the Doppler results if the angles are large, or if they are not measured. The Doppler instruments, Introduced about 20 years ago, continuous-wave Doppler instruments are small, portable, and inexpensive. A transducer is placed over the plane of the blood vessel's longitudinal axis, while the Doppler signals ACA ECMO ICA ICH MCA Paco2

Anterior cerebral artery Extraeorporeal membrane oxygenation Internal carotid artery Intracranial hemorrhage Middle cerebral artery Arterial carbon dioxide pressure

are transmitted continuously over a wide area. All blood vessels in the path of the insonation contribute to the backscattered echo; however, by adjusting the transducer position, one can study a specific vessel. Audible signals help in detecting flow; and the visual display can be recorded. In most portable continuous-wave Doppler instruments, the velocity data are not provided in real units. Pulsed Doppler systems were developed because of the necessity to localize the vessel with precision. These systems combine conventional ultrasound imaging and Doppler methods. A "sampling volume" is placed in the vessel (or "range gate") to obtain velocity signals within that site. The

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The Journal of Pediatrics August 1991

Sample volume envelope enclosing the whole artery

Sample volume envelope in the center of the artery

FiO. t. Laminar blood flow pattern in artery and Doppler waveforms. Concentric layers of blood flow in "laminae," so layers near boundary region hardly move and layers at center movewith maximum velocity;flow velocityprofile becomes parabolic. When Doppler sample volume is placedjust under inner walls envelopingentire artery, spectral display is filled with echo from all moving targets inside sampling site (example A), and mean waveform (heavy line) is nearly half the outer, spectral waveform. When smaller sample volume is placed in vessel center (example B), minimal echo is seen inside spectral display and mean wave is nearly equal to spectral wave. size of the sample volume can be varied, and the signals can be either videotaped or printed. Most commercial pulsed Doppler instruments provide velocity data in centimeters per second. 3 Color-flow imaging Doppler instruments provide information with regard to the Doppler frequency shift at each point in the vessel. The Doppler sampling volume is placed within an artery or vein, and the signals indicate the flow direction relative to the transducer in blue or red. Shades of color reflect relative velocities at different points in the vessel. The most obvious advantage of these instruments is the precision with which anatomic delineations can be achieved, but a major disadvantage is the poorer quality of Doppler velocity information, because only qualitative, not quantitative, velocity data can be obtained.4 Hemoflynamic concepts relevant to Doppler studies. In most peripheral vessels, flow is laminar, so concentric red cell layers in the vessel center have the greatest velocity, whereas those in contact with the vessel wall hardly move3' 5 (Fig. 1). With a pulsed Doppler instrument, one can obtain "spectral" and "mean" velocity waveforms, of which the former contains echo from all sources within the sample volume and the latter provides the instantaneous (spatial) average velocity within the sampling site. By integrating the mean waveform over one cardiac cycle, the time-averaged, instantaneous mean velocity can be obtained.3 Because of the parabolic nature of the blood flow profile,

when the sample volume envelops the inside of an entire artery, the maximum spectral velocity will be twice the mean velocity (Fig. 1, example A). By contrast, when the sample volume is in the center, the differences become smaller (Fig. 1, example B). Thus both the location and size of the sample volume relative to the vessel affect the mean velocity) The velocity profile, however, does not remain constant. Using nuclear magnetic resonance angiography, Meier et al. 6 mapped dramatically different profiles of velocity patterns in the abdominal aorta during a single cardiac cycle (Fig. 2). These findings illustrate one of the many limitations of summarizing mean velocity. For full integration of velocity across the lumen, the Doppler insonation must be constant and uniform, and the sample volume should enclose the entire artery continuously throughout the cardiac cycle, avoiding transducer and patient motion and without recording wall motion. In most commercial systems this is not possible. Because Doppler velocity does not directly reflect volume flow, 0, its computation has been attempted with the following formula: (~ = r / x ~r x r 2, where ~" is the mean velocity, and r is the vessel radius (obtained from diameter measurement). However, some limitations in this approach 315 are listed in Table I. As Poiseuille's law states (the flow is related to the fourth power of diameter), even minor errors in the measured diameter can magnify errors to greater than 50% of computed 0. Attempts are being

Volume 119 Number 2

Cerebral Doppler studies in fetus and neonate

1 67

210 ms s

o

~ "

o --

o

A .......... j...:..

--

9

......... $f

~ g ......./ ........:V

0

~ 390ms

500

1000

Time (ms) Fig, 2. Aortic flow velocity profiles during one cardiac cycle, obtained with nuclear magnetic resonance angiography. Continuously changing velocity profile in abdominal aorta at 90, 150, 210, 270, and 350 msec after electrocardiographic R waves. Graph in center is derived from integrated flow information. (Modified from Meier D, Maier S, B~SsigerP. Magn Rcson Med 1988;8:25-34. Reproduced with permission of Academic Press, lnc.) made to measure vessel distensibility and track wall motion to compute volume flow rates] 2, ~6 The nuclear magnetic resonance angiography and color-flow Doppler (with video digitizer and computers) are being developed to measure velocity and flow rates precisely in human blood vessels and in phantom flow models. 6' 17 Such systems are not yet commercially available for routine clinical use. It is generally assumed that because large arteries act only as "conduit" vessels, pump forces and vascular resistance are the only factors influencing their velocity and volume flow rate. However, recent research has suggested that the diameter of a large artery changes in response to local hemodynamic forces, hematocrit, and arterial carbon dioxide pressure) 3-15' ~8 Up to one third the total cerebral vascular resistance can be attributed to cerebral arteries > 150 ~m diameter) 8 These points must be kept in perspective while evaluating Doppler velocity results. Scanning methods. Because the cranial bones are thin in the perinatal period, virtually any scanning plane can be selected for velocity measurements. The parasagittal scan (Fig. 3, A) is suitable for the study of the internal carotid artery, basilar artery, anterior cerebral artery, and pericallosal artery, particularly because of the very low insonation angles achieved with imaging. 19zz This plane is also chosen in most nonimaging continuous-wave Doppler studies. 1' 23 A coronal scanning via the anterior fontanelle provides access to the vessels in the base of the brain, including those in the circle of Willis24; however, the angle of insonation

would be high for the middle cerebral artery. In the transcranial plane the transducer is placed in front of the ear over the thin temporal window, to obtain a cross-sectional (axial) image of the brain J9, z0 (Fig. 3, B; Fig. 4). Because the vessels are visualized with great clarity and the insonation angles remainvery low, this plane is ideal for the study of the circle of Willis, the MCA, and the posterior cerebral artery. Other views include scanning over the eye to study the ophthalmic artery z5 and scanning via the posterior fontanelle and the foramen magnum to study the posterior cerebral, basilar, and vertebral arteries and the venous structures, z~ Waveform analysis. Doppler studies are generally videotaped for later analysis using the built-in electronic calipers. 19 Because they reflect different components of flow, the velocity measures obtained (Fig. 5) should be properly identified in reporting Doppler results. Velocity acceleration and deceleration slopes, the average rising slope, relative flow rate index, and systolic decay time index are the other Doppler variables that can be measured, all of which reflect the shape of the waveform. These are affected by cardiac (pump) forces, local blood pressure, peripheral vascular resistance, and vessel wall elasticity and compliance.3.7, 26 Measures of resistance, Because of their simplicity and ease of computation, the resistance index of Pource~ot, pulsatility index of Gosling, and systolic/diastolic ratio are the Doppler indexes most reported in the literature (Fig. 5). The

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The Journal of Pediatrics August 1991

Transducer Anterior ~/~f cerebral ~ artery

Internal

arteryJ

Table I. Limitations of resistance and volume flow computations

AI Y

caroti~d~

/ /

Pericallosal artery

|"1~ ~k~ ~/ventr,cle

Basilar/ artery

/ Por~s

Variable

Limitation

Technical

High-pass filter may block low-velocity signals.Signals outside the vessel wall affect Doppler results. Incident angle is high or the angle is unknown.3, 4 Vasomotion of large vessels occurs during cardiac cycle, causing a shift of sample volume location. Velocity profile changes during cardiac cycle and at vessel branching.3, s Sample volume position varies as a result of movement of the operator's hand or the patient's movements (including breathing). 7-1~ Velocity varies with the state of wakefulness and behavior.9, to Because of regional differences in flow, a single vessel velocity cannot be assumed to reflect total cerebral blood flow. Diameter varies 10% to 15% with cardiac cycle) 1, 12 With intact endothelium, the vessel geometry is affected by local shear forces and by hematocrit.~315 Geometry changes in the arterial longitudinal axis. 5 Artery is not perfectly circular, making the formula for the cross-sectional area inaccurate.3, 5 Accurate diameter measurement may be impossible in small arteries. Increasing incident angle may selectively block low-frequency diastolic signals. 8

Velocity

....

CerebeUar vermis

A Transducer ~~.\ ~ __~ Middle cerebral ~ . artery

_ ~

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9 L;ereoral peduncle

Diameter

Circle of / Willis ~

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Fig. 3. Scanning methods. A, Parasagittal scan via anterior fontanelle and, B, transcranial scan via temporal window in front of ear. Note nearly zero-degree insonation 0 achieved for Doppler measurements.

Pourcelot index is often abbreviated as " P I , " and mistakenly referred to as the "pulsatility index." Adding to the confusion, the Gosling pulsatility index is also often abbreviated as " P I . " Although all three indexes are highly correlated, 7 because their computational formulas and their numeric values differ (Fig. 5), it is important to avoid such errors when reporting them. The three indexes discussed above were introduced as measures of vascular resistance, or more appropriately, of impedance to pulsatile flow. The rationale for their development is rather simple: the end-diastolic velocity is influenced by the peripheral vascular resistance, and the remainder of the waveform by pump forces. Thus their ratio

Resistance measures

provides a measure of impedance, particularly when the angle of insonation is unknown, and when the measured velocities are not in real units. However, this concept should not be stretched too far. Although changes in vascular resistance influence diastolic flow velocity, the contrary is not always true. The Doppler-derived resistance ratios also are influenced by heart rate, local and systemic blood pressure, viscosity, cardiac output, and vascular compliance--all

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Fig. 4. Doppler study of MCA. Upper panel shows transcranial image of region of circle of Willis. Cerebral peduncle is marked by open arrow. Lowerpanel shows two Doppler channels, upper showing spectral waveform and lower showing both spectral and instantaneous mean waveforms. Velocity scale is on right. ANT, anterior; POST, posterior; MAX, maximum.

factors that affect the shape of the entire waveform, including the diastolic component. 7, m, ~6-28Mathematical models of placental circulation show that although the indexes become abnormal with increasing resistance, the relationship is nonlinear. 27 No significant changes occur in the pulsatility index until peripheral vessel obliteration reaches between 60% and 90%. Such modeling of neonatal cerebral circulation is being attempted (Saliba E.: personal communication, 1990). Furthermore, the resistance ratios are not angle independent. Winkler and Helmke 8 showed that with stepwise increments in the angle of incidence, the diastolic velocity frequency was reduced to a greater extent than was the systolic frequency. High-incidence angle and wall-filter setting could selectively eliminate low-frequency diastolic flow signals, providing a spuriously high resistance index. Therefore, for valid comparison of resistance measures between studies, groups of subjects, different time periods, and various blood vessels, the equipment settings and measurement conditions must be virtually identical.

CLINICAL

APPLICATIONS

Normal velocity and resistance findings. From published reports, 19-22,26, 2%31the following conclusions can be drawn: (1) Velocities are higher in the larger proximal intracranial vessels than in the smaller distal vessels; (2) in a given vessel, velocity is about 15% lower in preterm compared with term infants; (3) the mean resistance ratios vary between 5% and 10% (with the standard deviation ranging as high as 15% of the mean) between large and small vessels and between preterm and term infants; (4) for a given vessel, the intersubject coefficient of variation is approximately 25%; (5) there is no substantial side-to-side difference in velocities; (6) velocity increases slightly with postnatal age; (7) level of wakefulness and behavior states affect measured velocity; (8) because of the nearly parabolic nature of the flow profile, instantaneous mean velocities are 40% to 50% &spectral velocitiesZg; (9) the velocity waves are steeper in preterm than in term infants, possibly because of the status of arterial wall maturation26; and (10) up to 15% of the observed variability could be investigator or equipment re-

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The Journal of Pediatrics August 1991

J

\

\

B

Vmax ~Ved DopplerSpectralWaveform

Shaded Area:

Integrating the spectral wave: Spectral Mean Velocity (Vmn-spectral)

InstantaneousMean Wave Integrating the mean wave: Mean Velocity (Vmn-mean)

Fig. 5. Waveform analysis. Method of measuring maximum velocity (Vmax) and end-diastolic velocity (Ved) from spectral (A) and instantaneous mean (B) waves. Time-average velocity can be obtained by integrating either of these waveforms over cardiac cycle. Computational formulas for resistance ratios are as follows: (1) Resistance index = V m a x - V e d / V m a x ; (2) Pulsatility index = Vmax- Vea/Vmn; and (3) Systolic/diastolic ratio = Vmax/Ved.

lated, even under the most ideal measurement conditions. These points underscore the need to control measurement conditions rigorously before interpreting Doppler findings, particularly when differences are small among various experimental groups. Doppler studies in disease states. Various changes in Doppler velocity and resistance measures have been reported in abnormal states 32"6e (Table II). The following discussion is limited to some of the more important conditions. Asphyxia and brain death. Bada et al.l reported that the low Pourcelot resistance index seen in babies with perinatal asphyxia reflected postasphyxia luxury perfasion. Archer et al. 32 later demonstrated an abnormally low Pourcelot index (<0.55) in 16 of 27 infants with birth asphyxia, in whom moderate and severe neurologic sequelae were seen on follow-up. However, because of the variability in the disease course, there is considerable overlap in the Pourcelot index among infants affected with asphyxia and normal infants. This index may be useful in extreme cases of birth asphyxia, but it is of limited value in predicting outcome in mild and moderate cases. The Doppler techniques have tceen used to evaluate patients with coma and suspected brain death. Reduced anterograde flow during systole, followed by retrograde flow during the entire diastolic period (thus a net reduction in total flow), is reported to be characteristic of brain death.33,34 These Doppler waveform abnormalities in the MCA and the ICA could be used as an adjunct to other tests in determining brain death, particularly in infants beyond the neonatal period. Intraeranial hemorrhage and hydrocephalus.i, 23, 3>37 Using the continuous-wave Doppler method, Perlman et al. 23 showed that by elimination of beat-to-beat velocity varia-

tions (>10%), the incidence of ICH could be lowered. 23 These fluctuations could be secondary to blood pressure fluctuations from respiratory activity3s but could also be accounted for by movement artifacts, the number of waveforms analyzed, postnatal age, differences in measurement techniques, and ventilatory management. 39, 4o The association between velocity fluctuations and ICH has been questioned) 9 In infants with hydrocephalus the resistance and pulsatility index were markedly increased, reflecting increased intracranial pressure) < 37 After shunt placement and drainage of eerebrospinal fluid, the indexes became normal. Thus cranial Doppler studies could be used as an adjunct to clinical monitoring in infants with hydrocephalus. Vascular malformations. Color-flow and pulsed Doppler studies will be of particular value in the diagnosis of various vascular malformations, including arteriovenous fistulas and aneurysms of the vein of Galen. 4>43 The Doppler flow patterns in the region of malformation will help to differentiate a zone of infarction from that of arteriovenous malformation. The velocity patterns further aid in the differentiation of venous from arterial flow. Extracorporeal membrane oxygenation and the circle of Willis.4g'47 During full ECMO support, the cerebra/artery flow velocity is continuous and nearly nonpulsatile; further, major changes are also seen in velocity and in resistance measures. During the late recovery phase, a 116% to 217% compensatory increase in velocity was seen in the contralateral (left) cerebral vessels.45 Although acute changes do not influence immediate outcome, the long-term effects of the compensatory increase in shear forces on the normal (contralateral) arteries need to be evaluated in ECMO survivors. Doppler studies could be used to test the integrity of the circle of Willis. In healthy babies we found a reversed

Volume 119 Number 2

direction of flow in 4 (5.7%) of 70 first (A 1) segments of the A C A and in 19 (47.5%) of 40 posterior communicating arteries. 47 Another study reported a lower frequency of variant flow patterns. 24 The implication of circle of Willis variants for ECMO candidates also remains to be studied. Other clinical and research applications. Doppler methods have been applied to test the effect of various drugs on the neonatal circulation (Table II). Indomethacin markedly reduces cerebral blood flow velocity.48"49 However, patent ductus arteriosus with large left-to-right shunting also reduces cerebral blood flow velocitY and is associated with an increase in the resistance index. 57 in Spite of extensive use of indomethacin, no major untoward effect has been reported. Thus the clinical significance of the effect of indomethacin on cerebral blood flow velocity in patients with patent ductus arteriosus remains unclear. On the basis of the well-established relationship between the arterial Pat02 and cerebral blood flow, the cerebral vessel reactivity to Pac02 has been tested in human beings and in experimental animals. 28, 55-58Levene et al. 58 reported a 5.9% to 7% change in velocity for each unit (millimeter of mercury) Of Pac02 (44% to 53% per kilopascal) in preterm infants; these values are higher than the 32.6% per kilopascal Pac02 change in cerebral blood flow measured by the xenon technique. 56 Postnatal age and indomethacin therapy in newborn infants, and baseline hematocrit in baboons, have been shown to influence Pat02 reactivity.aS, 55, 58 Because depressed Pat02 responsiveness may signal many conditions with cerebral insult (apnea, sudden infant death, asphyxia, ICH), studies in this area are of great interest. Cerebrovascular resistance is increased and the flow velocity is reduced in newborn infants with polyeythemia and hyperviscosity. These findings become normal after partial plasma exchange transfusion. 61,62 Symptom-free infants with polycythemia could be screened with Doppler methods to determine whether exchange transfusion is needed, and those infants' outcome could be evaluated; however, such studies have not been published. The color-flow Doppler method has demonstrated normal velocity in the vein of Galen. 63 The velocities ranged from 2.3 to 9.5 em/sec; jugular vein compression caused the velocity to drop. Additional studies are needed to determine whether venous flow mapping adds to the understanding of the pathophysiology of ICH. Fetal studies. Literally hundreds of articles have been published related to the study of the uteroplacental circulation using Doppler methods. 9, lO Fetal ICA, MCA, ACA, and the circle of Willis have been studied in a variety of clinical conditions. 6468 To assess cerebral responses in disease states, one can relate placental resistance to the resistance of cerebral vessels. In normal pregnancy, the cere-

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Table II. Cerebral Doppler changes in various diseases

Condition

Change

Asphyxia

Low pulsatility index, low resistance index; related to long-term outcome 1,32 Diastolic.fl0w reversal3~,34 Brain death ICH Increased pulsatility and resistance indexes, reduced blood flow~,3~ Increased beat-to-beat variation--risk factor for ICH; reduction of ICH risk when variation is eliminated 23 No relation between beat-to-beat variation and ICH risk39 Hydrocephalus Increased resistance index; reversal after drainage36,37 Vascular Abnormal flow; turbulent pattern in malformations arteries; arterial and VenOus flow patterns in mass lesions41-43 ECMO Reduced pulsatility index; related to ECMO flow rate; variable velocity changes44-46 Reduced ipsilateral velocity during acute phase, compensatory increase during recovery in contralateral vessels45 After ECMO, retrograde direction of flow in contralate/ral ACA A1 segment and in ipsilateral ICA; anter0grade flow in iPsilateral MCA44,45 Drug effects Indomethacin: acute reduction in velocity; increased resistance index~8,49 Aminophylline: no change when Pac02 changes are controlled 5~ Caffeine: no effect51; acetazolamide: no effect (in piglets) s2 Maternal Cocaine abuse: increase in mean velocity on first day after birth s3 Exogenous surfactant: transient increase in mean velocity54 COz reactivity Increase of 5.9%-7% veloc!ty per mm Hg Pac02 change in preterm babies; lower values in baboons and lambs28,55,57,58 Influenced by baseline hematocrit, 28 postnatal age, and indomethacin 58 Patent ductus Reduced or reversed diastolic velocity; arteriosus increased pulsatility and resistance indexess9 Shock Markedly reduced systolic and diastolic velocity in MCA; improved velocity during recovery6~ Polycythemia Increased resistance index and reduced and hyperviseosity velocity, which become normal after partial plasma exchange transfusion 61,62

brovascular resistance always remains higher than placental resistance; both resistance values drop as the pregnancy nears term, and the cerebral/placental resistance ratio remains substantially greater than 1. However, in pregnancies complicated by severe intrauterine growth retardation, pla-

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The Journal of Pediatrics August 1991

cental resistance increases while the cerebral resistance begins to drop; thus the ratio becomes less than 1. This might be one of the "brain protective" phenomena of redistribution of blood flow. 65"67 It has been suggested that the ratio of cerebral-placental resistance indexes could be used to predict fetal compromise. 67 Doppler studies could help in monitoring the progress of fetal hydrocephalus. Compared with normal values, the Gosling pulsatility index is 40% to 100% higher in fetuses with congenital hydrocephalus, and the side-to-side difference exceeds 50% in those with asymmetric ventricular dilation.68 Other fetal cerebral Doppler applications include the recognition of cerebral vascular malformations, measures of cerebral damage, and the studies of effects of maternal vasoactive drugs on fetal cerebrovascular hemodynamics. Bioeffects of ultrasound and safety issues. It is beyond the scope of this review to summarize the numerous studies on ultrasound bioeffects and equipment safety (see reference 69 for details). Two mechanistic factors are of concern regarding the bioeffects of ultrasound. As ultrasound propagates through tissues, part of its energy is absorbed and converted into heat, which could have a biologic effect. The American Institute of Ultrasound in Medicine has proposed safe thermal threshold values for equipment and for clinical use. 69 The second issue is that of cavitational effect from short ultrasound pulses, particularly seen in experiments on the larva of fruit flies (Drosophila). However, extremely high intensity pulses are required to produce cavitational effect in mammalian tissue. Furthermore, despite widespread clinical use for more than 25 years, no specific adverse effects have been shown to arise from exposure to diagnostic ultrasonography. Numerous epidemiologic studies have shown no causal association of diagnostic ultrasonography with any adverse fetal outcome. Nonetheless, an inability to find a convincing proof of an ill effect does not rule out a remote possibility of risk. Therefore the American Institute of Ultrasound in Medicine recommends that when ultrasound studies are to be conducted for purposes other than direct medical benefit, the subject be informed of the anticipated exposure conditions and other theoretical risks (69). The manufacturers of ultrasound equipment also are required to provide users with information regarding exposure energy and other technical data related to the bioeffects of their equipment. SUMMARY

AND CONCLUSIONS

The goal of developing reliable commercial Doppler systems for measuring vessel diameter and velocity changes during the cardiac cycle appears to be near. Reaching this goal would enable us to obtain volume-flow information

continuously. In animal experiments, continuous measurements of Doppler velocity, pressure, and flow add important insights into hemodynamic measurements. Incorporating Doppler methods in microcirculatory research could also provide a link between the microcirculatory and the macrocirculatory hemodynamie research. Although Doppler methods have been validated, Doppler findings in clinical research (using commercial systems) must be considered at best to reflect qualitative circulatory alterations indicating directions of change], 8, 70 Because of inherent technologic limitations and considerable intersubject and intrasubject variability, direct extrapolation of the numeric findings from one study to the other can lead to misleading conclusions. The Doppler results are also influenced by measurement conditions and equipment settings. However, Doppler-derived information can be used as an adjunct to clinical management in many of the diseases discussed above. As with any physiologic variable, serial measurements probably are of greater value than single measurements. With continued improvement in technology, Doppler methods hold promise of becoming an important adjunct in cerebral hemodynamic monitoring in perinatalneonatal intensive care units. I thank Drs Margaret Go, Evangelia Zikos, Vivek Ghai, Laurie Chapman, Edward Co, Otto Aldana, and Shin Y. Kim for their collaboration in various Doppler studies during the past decade. Dr. Kristine McCulloch has helped in editing most of my manuscripts, including this one. REFERENCES

1. Bada HS, Hajjar W, Chua C, Sumnar DS. Noninvasive diagnosis of neonatal asphyxia and intraventricular hemorrhage by Doppler ultrasound. J PEDIATR1979;95:775-9. 2. White DN. Johann Christian Doppler and his effect: a brief history. Ultrasound Meal Biol 1982;8:583-91. 3. Hatle L, Angelsen B. Physics of blood flow measurements. In: Hatle L, Angelsen B, eds. Doppler ultrasound in cardiology: physical principles and clinical applications. 2nd ed. Philadelphia: Lee & Febiger, 1985:8-73. 4. Zwiebel WJ. Color duplex imaging and Doppler spectrum analysis: principle, capabilities, and limitations. Semin Ultrasound CT MR 1990;11:84-96. 5. Milnor WR. Steady fl0w. In: Milnor WR. Hemodynamics. 2nd ed. Baltimore: Williams & Wilkins, 1989:11-50. 6. Meier D, Maier S, B6siger P. Quantitative flow measurements on phantoms and on blood vessels with MR. Magn Reson Med 1988;8:25-34. 7. Thompson RS. Blood flow velocity waveforms. Semin Perinatol 1987;11:300-10. 8. Winkler P, Helmke K. Major pitfalls in Doppler investigations with particular reference to the cerebral vascular system. I. Sources of error, resulting pitfalls and measures to prevent errors. Pediatr Radiol 1990;20:219-28.

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9. Maulik D. Basic principles of Doppler ultrasound as applied in obstetrics. Clin Obstet Gynecol 1989;32:628-44. 10. Gill RW. Parameters and standardization of obstetric Doppler. Echocardiography 1990;7:573-81. 11. Caro CG, Parker KH. Mechanics and imaging of the macarocireulation. Magn Reson Med 1990;14:179-86. 12. Hocks APG, Brands P J, Smeets FAM, Reneman RS. Assessment of the distensibility of superficial arteries. Ultrasound Med Biol 1990;16:121-8. 13. Brant AM, Teoclori MF, Kormos RL, Borovetz HS. Effect of variations in pressure and flow on the geometry of isolated canine carotid arteries. Biomechanics 1987;20:831-8. 14. Melkumyants AM, Balashov SA, Khayutin VM. Endothelium dependent control of arterial diameter by blood viscosity. Cardiovasc Res 1989;23:741-7. 15. Melkumyants AM, Balashov SA. Effect of blood viscosity on arterial flow induced dilator response. Cardiovasc Res 1990; 24:165-8. 16. Wilson LS, Dadd MJ, Gill RW. Automatic vessel tracking and measurement for Doppler studies. ULtrasound Med Biol 1990; 16:645-52. 17. Kitabatake A, Tanouchi J, Yoshida Y, Masuyama T, Uematsu M, Kamada T. Quantitative color flow imaging to measure the two-dimensional distribution of blood flow velocity and the flow rate. Jpn Circ J 1990;54:304-8. 18. Faraci FM, Heistad DD, Mayhan WG. Role of large arteries in regulation of blood flow to brain stem in cats. J Physiol 1987;387:115-23. 19. Raju TNK, Zikos E. Regional cerebral velocity in infants: a transcranial and fontanellar pulsed Doppler study. J Ultrasound Med 1987;6:497-507. 20. Bode H. Results. In: Bode H. Pediatric applications of transcranial Doppler sonography. New York: Springer-Verlag, 1988: 25-75. 21. Deeg KH, Ruppreeht Th. Pulsed Doppler sonographic measurement of normal values for the flow velocities in the intracranial arteries of healthy newborns. Pediatr Radiol 1989;19: 71-8. 22. Fenton AC, Shortland DB, Papathoma E, Evans DH, Levene MI. Normal range for blood flow velocity in cerebral arteries of newly born term infants. Early Hum Dev 1990;22:73-9. 23. Perlman JM, Goodman S, Kreusser KL, Volpe JJ. Reduction in intraventrieular hemorrhage by elimination of fluctuating cerebral blood-flow velocity in preterm infants with respiratory distress syndrome. N Engl J Med 1985;312:1353-7. 24. Mitchell DG, Merton DA, Mirsky P J, Needleman L. Circle of Willis in newborns: color Doppler imaging of 53 healthy fullterm infants. Radiology 1989;172:201-5. 25. Linder W, Schaumberger M, Versmold HT. Ophthalmic artery blood flow velocity in healthy term and preterm neonates. Pediatr Res 1988;24:613-6. 26. Raju TNK, Kim SY. Cerebral artery flow velocity acceleration and deceleration characteristics in newborn infants. Pediatr Res 1989;26:588-92. 27. Thompson RS, Trudinger BJ. Doppler waveform pulsatility index and resistance, pressure and flow in the umbilical placental circulation: an investigation using a mathematical model. Ultrasound Med Biol 1990;16:449-58. 28. Raju TNK, Kim SY. The effect of hematocrit alterations on cerebral vascular Pco2 reactivity in newborn baboons. Pediatr Res 1991;29:385-390.

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