121 chapter 9 doppler assessment of the fetal and neonatal ... · doppler ultrasound has been used...

Chapter 9 Doppler assessment of the fetaland neonatal brain

K. Brackley, M. Kilby and D. Evans

121

INTRODUCTION

Doppler ultrasound has been used to investigate the humancirculation since 1957 (Satomura 1957), but it was in 1977that Fitzgerald & Drumm developed a Doppler system toobtain velocity waveforms from the umbilical artery andsuggested its use in the evaluation of the fetal condition incases with pre-eclampsia and intrauterine growth restriction.Since that time Doppler ultrasound has become increasinglyutilized as a non-invasive tool to evaluate the hemodynam-ics of the uteroplacental and fetoplacental circulations.Continuing technical developments in Doppler ultrasoundequipment, particularly highly sensitive color flow imagingtechniques, have made it possible to study the fetal circula-tion in even greater detail. Neonatal Doppler studies datefrom 1979 (Bada et al. 1979). Doppler ultrasound has mainlybeen used as a research tool, but a number of clinical appli-cations have been recognized.

Doppler ultrasound is a non-invasive method of measur-ing blood flow velocity, which detects hemodynamicchanges instantly. Repeated measurements can convenientlybe made at the bedside or cotside. However, it is importantto understand the limitations of the method before consider-ing its uses in obstetric and neonatal practice.

DOPPLER MEASUREMENTS

When an ultrasound signal is directed towards a movingobject (e.g. red blood cells within a vessel) the frequency ofthe reflected signal is altered. The size of this change orDoppler shift is directly proportional to the velocity of themoving object (Doppler 1842):

D =

where D is the Doppler shift, F is the transmitted frequency,v is the blood flow velocity (m/s), Θ is the angle ofinsonation and C is the velocity of sound in tissue, which isa constant (1540 m/s). The Doppler-shifted frequenciesreceived by the same ultrasound probe are within the audi-ble range and can be displayed in real-time as a spectral dis-play of repeated flow velocity waveforms. The maximumfrequencies of the waveform envelope or outline are propor-tional to the maximum velocities of erythrocytes within thevessel, usually in the center of the blood vessel. The accu-racy of the technique is partly operator dependent, including

uniform insonation of vessels and the correct setting of hi-pass filters. Doppler waveforms can be assessed eitherquantitatively or qualitatively.

QUANTITATIVE MEASUREMENT

Accurate quantitative assessment of the blood flow dependsupon several variables.

Angle of insonationThe measurement of the blood flow velocity depends uponthe angle between the Doppler beam and the longitudinalaxis of the vessel studied. The angle of insonation should bekept as small as possible. The greater the angle, the lessaccurate the velocity measurement becomes, and an angle ofgreater than 60° should not be used. In neonatal cerebralstudies the angle should be kept as close to zero as possible.Duplex or color Doppler equipment can be used to measurethe angle of insonation to correct blood flow velocitymeasurements (Eik-Nes et al. 1980; Griffin et al. 1983).

Vessel cross-sectional areaThe volume flow depends upon the radius of the vessel stud-ied. Errors in vessel diameter measurement will be doubledin the calculation of absolute blood flow, which is a particu-lar problem when measuring smaller blood vessels such asfetal cerebral arteries. The blood vessel is also assumed to becircular with a constant diameter but this is known to varywith arterial pressure during each cardiac cycle (Eik-Nes etal. 1984):

volume flow = v Πr2,

where v is the time average mean velocity and r is the radiusof the vessel studied.

There is evidence that the neonatal cerebral arteries dochange in diameter (Mchedlishvili 1985; Sonesson & Herin1988). However, if the angle of insonation is fixed, Dopplerultrasound may give a reliable measure of changes in cere-bral hemodynamics but this may not be directly comparablebetween infants.

QUALITATIVE MEASUREMENT

Methods of extracting hemodynamic information fromDoppler signals that avoid the problems associated withmeasurement of absolute velocity and flow have been devel-oped. These methods include the calculation of simple ratiosor indices using certain points on the maximum frequency

2Fv CosΘC

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outline of the waveforms. They have the advantage that theyare angle independent, as the angle of insonation appears inboth the numerator and the denominator of the ratio and itseffect is cancelled out.

The three main indices used in clinical studies are(Fig. 9.1):

A/B (S/D ratio) (Stuart et al. 1980)

=

PI (pulsatility index) (Gosling et al. 1971)

=

RI (resistance index) (Pourcelot 1975)

=

These Doppler indices are generally used as a measure ofdownstream resistance in the circulation, values increasingwith a reduction in end-diastolic flow or higher downstreamresistance. When there is absent end-diastolic velocity(AEDV), PI provides the most useful information since theA/B ratio will be infinity and the RI unity (A/B = A/0 =infinity, RI = (A−0)/A = 1). It should also be noted that com-pletely different alterations in the waveform shape can resultin the same change in ratio. Central circulatory changes cancontribute to alterations in waveform shape, particularly asall the indices are dependent on heart rate or length of thecardiac cycle (Mires et al. 1987; Maulik et al. 1992). It isimportant to recognize that with acute hemodynamicchanges, the measurement of PI can yield misleading results.In a recent report Gunnarson et al. (1998) used cerebralDoppler blood flow velocimetry to study central hemody-namics in the ovine fetus during conditions of hypoxemiaand acidemia. An increase in blood velocities occurredwithin a cerebral vessel during hypoxemia and hypoxic–acidotic periods, whereas PI remained unchanged due to the

effects of a reduced heart rate. This highlights the potentialproblems with the interpretation of PI.

In vitro studies and in vivo cerebral studies in neonatesand animals have shown a good correlation betweenDoppler velocity measurements and cerebral blood flowmeasured by other techniques (Hansen et al. 1983; Greisen etal. 1984, Smith 1984; Raju et al. 1987). The RI is the indexfavored by neonatologists and has been shown to be ofclinical value in asphyxiated infants (see below). Although itmay be assumed to be a measure of cerebral vascularresistance, this has been disputed and its correlation withresistance in animal models is not good.

DOPPLER EQUIPMENT

Continuous-wave Doppler probes transmit ultrasonic wavesand receive the Doppler-shifted frequencies continually.Doppler signals are therefore obtained blindly from all mov-ing structures in the line of the Doppler beam. Visualizationof the vessels cannot be achieved using this equipment,which excludes its use in the fetal cerebral circulation. Inneonatal cerebral studies the two main acoustic windows are transfontanellar for the anterior cerebral arteries andtranstemporal for the middle cerebral arteries (Figs 9.2 and9.3). Continuous-wave Doppler will sample all vessels in thepath of the ultrasound beam, which may confuse the originof the signal. Also, the angle of insonation may be impossi-ble to estimate. These problems reduce the reproducibility ofthe technique and pulsed-wave Doppler is preferred.

Duplex Doppler ultrasound is a combination of pulsed-wave Doppler and real-time ultrasound in which the sametransducer is used both to transmit repetitive ultrasoundpulses and receive the echoes. The depth of the signals can

peak systolic velocity – end-diastolic velocitypeak systolic velocity

peak systolic velocity – end-diastolic velocitymean velocity

peak systolic velocityend-diastolic velocity

Functional assessment of CNS development122

PI =

Forward flow

Reversed flow

Mean

Vein

Artery

Diastole

Systole

A

B

A–BMean

AB =AB

RI =A–BA

+

_

Figure 9.1 Calculation of Doppler velocity waveform indices.

Anterior

Anteriorcerebral artery

φ = 0°

Posterior

Corpus callosum

Transducer

Figure 9.2 The transfontanellar approach to the anteriorcerebral artery in a neonate. (Reproduced with permission fromAnthony & Levene 1993.)

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be adjusted to allow visualization and targeting of the vesselstudied, enabling Doppler assessment in a number of fetaland neonatal vessels including the descending aorta, renalartery, common carotid artery, internal carotid artery, andanterior, middle, and posterior cerebral arteries.

Duplex systems can be rather large and cumbersome forneonatal studies and pulsed-wave probes without real timemay offer a good alternative. The facility for altering thedepth of the signal acquisition ‘gate’ allows a defined tissuesample to be taken. As the vessels are very small it is poss-ible to sample across the whole artery, providing more com-plete velocity profiles. Ideally, a fixed probe should be usedto maintain a constant angle of insonation during a study,in which case a change in the frequency shift will reflect achange in velocity (assuming vessel diameter remains thesame). This is not possible in the fetus. Absolute velocityvalues can only be measured if the angle of insonation isknown (see above). Velocity signals are subject to verymarked physiological variations and therefore the record-ings should be gathered over as many cardiac cycles aspossible.

Using color flow imaging, blood flow information iscolor-coded, in terms of direction, velocity and turbulence,and superimposed on the gray-scale real-time image. Thisequipment offers major advantages, especially in the studyof small vessels such as in the fetal cerebral circulation. Itallows rapid visualization and accurate identification of thedesired vessel, which minimizes examination time withreduced exposure to ultrasound energy. It also allows a moreaccurate estimation of the angle of insonation.

More recently, a new technique of detecting blood flowhas been introduced called power Doppler imaging orangiography. Power Doppler displays the intensity or energyof the returning Doppler signal. Although power Dopplerprovides no information on flow direction, velocity, or flowcharacter, it has improved sensitivity compared to colorDoppler imaging in demonstrating slower flow, perfusion insmaller vessels, and continuous imaging of tortuous vessels

as it is angle independent. Its potential value in the investi-gation of fetal cerebral blood flow including intracranialhemorrhage (Guerriero et al. 1997), microcephaly (Pilu et al.1998), vascular malformations (Paladini et al. 1996), andtumors has been suggested, although the increased sensitiv-ity to tissue motion can be problematic in the fetus (Pooh &Aono 1996).

SAFETY OF ULTRASOUND USED IN DOPPLERINVESTIGATIONS

The three main potential mechanisms for damage usingultrasound are heating and cavitation effects and possiblesister chromatid exchange:

1. The heating effect arises from the absorption of theultrasound energy by the tissues through which itpasses (Nyborg 1985). Different tissues have varyingacoustic absorption coefficients, bone having thehighest. All of the studies have been carried out in vitroand they do not take into account the cooling effectthat occurs in perfused tissues. Nevertheless, the highintensity of pulsed-wave Doppler used in certaincircumstances, such as by vaginal probes in earlypregnancy, have the potential to cause significantheating in tissues, a fact underlining the need for care(Ter Haar et al. 1989).

2. Cavitation is the formation of small, gas-filled cavitiescaused by the negative pressures in the acoustic field.Both stable and unstable cavitation are theoreticallypossible although evidence of their effects is notavailable in vivo. However, cavitation is potentiallyharmful, and in vitro models may cause tissuedisruption (O’Brien et al. 1979). No studies suggest thatthe phenomenon occurs at diagnostic intensities in vivo.

3. Sister chromatid exchange remains a theoretical risk; noadverse clinical results have yet been reported.

Follow-up studies of infants scanned in utero have notshown any detrimental neurodevelopmental outcome(Salvesen et al. 1992; Carstensen & Gales 1983), althoughone report suggests an increased incidence of non-right-handedness in those infants exposed to ultrasound in utero(Salvesen et al. 1993).

PRACTICAL GUIDANCE FOR SAFE USE OF DOPPLERULTRASOUND

1. The acoustic power and pulse amplitude should be keptto a minimum commensurate with the production ofwaveforms which can be accurately measured. Theoutput intensity, ISPTA, should be kept below 100 mW/cm2, as advised by the American Institute of Ultrasoundin Medicine (1984).

2. The lowest pulse repetition frequency (PRF) which stillallows measurement of the highest velocities should beused.

Doppler studies of the fetal and neonatal brain 123

Middlecerebral artery

φ = 0°

Transducer

Temporalbone

Figure 9.3 The transtemporal approach to the middle cerebralartery in a neonate. (Reproduced with permission from Anthony& Levene 1993.)


3. If the output of the machine used is not known, thelocal medical physics service should be asked to obtainsuch information.

4. The maximum temperature that may be reached by thetransducer should be ascertained.

5. Particular caution should be taken if the patient has anelevated body temperature.

6. When using duplex Doppler equipment the Dopplerbeam should be turned-off until the vessel required isidentified.

7. The Doppler beam should not be directed towards aparticular point for longer than 1 min.

8. Exposure of tissue–bone interfaces should be minimizedas much as possible.

9. The total duration of exposure to the ultrasound beamshould be minimized.

TECHNIQUE OF MEASURING FETAL CEREBRALBLOOD FLOW

All the cerebral blood flow velocity (CBFV) waveformsshould be obtained using a 3.5 MHz transducer, during fetalapnea and in the absence of fetal movements (see below).The pressure exerted on the maternal abdomen by the ultra-sound transducer should be kept to a minimum. The fetalhead is readily compressed and a significant positive corre-lation between pressure and PI in the middle carotid artery(MCA) and internal carotid artery (ICA) has been noted (Vyaset al. 1990a), potentially giving rise to spurious results. Thevessels studied should be the closest to the Doppler trans-ducer, the angle of insonation always being less than 60°,and the Doppler sample gate length always being 4 mm orless, both to minimize the interference from other smallcerebral vessels and to ensure the production of waveformsthat can be accurately measured. It is important to identifycorrectly each cerebral vessel using color flow imaging, assignificant fetal regional cerebral blood flow differences arepresent in utero (Mari 1994). Downstream resistance is high-est in the MCA and lowest in an intracerebellar artery. In themajority of published fetal cerebral circulation studies, datahave been obtained from the most easily accessible MCA.

Using transabdominal ultrasound, the fetal basal cerebralarteries are visualized in an axial view of the fetal head atthe level of the brain stem. An angled horizontal section ofthe brain including the thalami and cavum septum pellu-cidum is obtained initially (plane where biparietal diameteris usually measured). If the transducer is moved caudally ina parallel plane, the anterior, middle, and posterior fossaeare seen and the circle of Willis can be clearly identifiedusing color flow imaging. This consists of an anastomosis(anterior and posterior communicating arteries) between thepaired internal carotid arteries and the basilar artery.

The ICA divides into the anterior and middle cerebralarteries (Fig. 9.4A). The use of duplex Doppler equipmentallows detection of the ICA pulsations, but color flowDoppler facilitates visualization and confirmation of the

vessel identity as it branches immediately after its exit fromthe bony canal (Fig. 9.4B).

The MCA is the largest branch of the ICA supplyingapproximately 80% of the blood flow to the cerebral hemi-sphere. It passes anterolaterally from the circle of Willis inthe Sylvian fissure, to supply the corpus striatum, basal gan-glia, cortex of the insula, and the inferior frontal gyrus. Thegreater wings of the sphenoid bone, between the anteriorand middle fossae are good reference points for locating theMCA. As the fetal head is often in a lateral position, an acuteangle of insonation (which may reach zero) can be achievedto produce a clear waveform, an advantage for velocitymeasurements. Locci et al. (1992) demonstrated that PI val-ues obtained from the proximal MCA are significantly lower


A

B

Figure 9.4 (A) Diagramatic representation of the cerebralarteries through a cross-section of the fetal head showing thecerebral peduncles (CP), internal carotid (I), and the anterior(A), middle (M) and posterior (P) cerebral arteries. (B) Fetalcerebral circulation shown by color flow Doppler.


than from the distal segment. The MCA is recognized toconsist of four segments: M1, M2, M3, and M4 (Aaslid1986). The M1 segment maintains a more constant diameterand is the preferable site for Doppler studies.

The anterior cerebral artery (ACA) leaves the ICA at theanterior perforating substance and passes forwards, abovethe optic nerve towards the orbital surface of the frontallobe. With color flow imaging the vessel can be easily iden-tified as it leaves the anterior boundary of the circle of Willisand tracks towards the frontal lobe (Fig. 9.4B). Accuratemeasurements of the ACA can sometimes be difficult as theangle of insonation would be greater than 60° when the fetalhead is in the lateral position.

The posterior cerebral artery (PCA) is the terminal branchof the basilar artery and curls back around the cerebralpeduncles before passing backwards above the tentoriumtowards the occipital lobe. The superior cerebellar arteries(SCA) originate from the basilar artery, just before it termi-nates into the PCAs. The SCA can be localized runningparallel and caudal to the PCA (Uerpairojkit et al. 1996).

Transvaginal Doppler assessment has been shown to havesome advantages over transabdominal scanning in that acoronal section of the fetal brain is produced, allowingbetter distinction between the ICA and MCA and producingsignals of equal quality from both cerebral hemispheres(Lewinsky et al. 1991). In addition, it may be superior atearly gestations (Kurjak et al. 1992), in obese patients, andwhen the fetal head is deeply engaged in the pelvis(Lewinsky et al. 1991).

PHYSIOLOGICAL VARIABLES AFFECTING FETALCEREBRAL BLOOD FLOW

A number of physiological variables will influence Dopplermeasurements in the fetal cerebral arteries.

GESTATIONAL AGE

Transvaginal color Doppler imaging has made it possible tovisualize the fetal intracranial circulation earlier in gestationthan with transabdominal ultrasound (Kurjak et al. 1992).Fetal intracranial blood flow has been detected as early as 8weeks’ gestation. End-diastolic frequencies in the Dopplerwaveform become more common with advancing gesta-tional age, being constantly present after 13 weeks’ gesta-tion. Therefore, a significant decrease occurs in the PI duringthe early weeks of pregnancy (Kurjak et al. 1992).

Earlier cross-sectional studies noted a weak paraboliccorrelation of PI with gestational age from intracerebralarteries in normal pregnancy. There was a slight rise in PIbetween 15 and 20 weeks’ and a fall towards term (van denWijngaard et al. 1989; Arduini & Rizzo 1990; Vyas et al.1990b; Mari & Deter 1992). This is in contrast to changes inthe umbilical artery (UA), which indicate a steady fall in thevascular resistance with increasing gestation (Trudingeret al. 1985). However, in a longitudinal study Veille et al.

(1993) found that although the diameter of the MCA, the time velocity integral and the peak flow velocity allincreased progressively with gestational age, the standardDoppler indices did not demonstrate a significant decrease.Only PI showed a weak correlation with gestational age.Blood flow within the MCA ranged between 23 ml/min at19 weeks’ gestation to 133 ml/min at term, paralleling theincrease in fetal weight and total cardiac output. Therefore,the proportion of the cardiac output received by each MCAremained constant throughout gestation, between approxi-mately 3 and 7%.

Other studies have noted a downward trend, but notalways reaching levels of statistical significance, in Dopplerresistance indices within the ICA (Wladimiroff et al. 1986,1987) and the MCA (Meerman et al. 1990; Rizzo & Arduini1991; Harrington et al. 1995; Kurmanavicius et al. 1997) inthe third trimester. However, an increase in cerebral bloodflow velocity with advancing gestational age is a consistentfinding (Meerman et al. 1990; Vyas et al. 1990b; Mari et al.1995). In a cross-sectional study Joern et al. (1996) calcu-lated maximum systolic, mean and maximum end-diastolicvelocities in the MCA after correcting for the angle ofinsonation. The maximum end-diastolic velocity increasedto a relatively greater extent than the maximum systolicvelocity throughout the third trimester and this was inter-preted as a constant decrease in cerebral vascular resistanceup to 42 weeks’ gestation. This illustrates the problems asso-ciated with Doppler waveform analysis in the interpretationof changing downstream resistance or impedance in terms ofabsolute blood velocity or actual blood flow and vice versa.However, it is apparent that under normal circumstances theMCA is a low-resistance, high-capacitance bed, even early ingestation (Wladimiroff et al. 1992).

FETAL BREATHING MOVEMENTS

Wladimiroff (1989) recorded a wide range of PI values in theICA in the presence of fetal breathing movements, demon-strating measurements taken during that time are unreliable.Therefore, all studies of cerebral and other fetal vesselsshould be made during fetal apnea.

FETAL HEART RATE

Measurements of the Doppler velocity waveforms have beenshown to be inversely correlated with fetal heart rate due tothe alteration in end-diastolic frequencies with length ofcardiac cycle. Calculation of the indices can be standardizedfor a particular heart rate of 140 bpm (Mires et al. 1987). Adecrease in the PI was found with increased fetal heart ratesin the ICA, descending aorta and UA in appropriately grownand growth-restricted fetuses (van Eyck et al. 1985, 1986).When the heart rate is within the normal range (110–150 bpm), its influence on the waveform indices is of littleclinical importance. However, fetal heart rate decelerations(Mari et al. 1991) or a fetal tachycardia secondary to rito-drine (Rasanen 1990) will have a significant effect.



FETAL BEHAVIORAL STATES (see p. 94)

Nijhuis et al. (1982) provided clear evidence for the existenceof fetal behavioral states in the human fetus, during the lastfew weeks of pregnancy. Four states were defined based onfetal heart rate patterns, eye movements, and body move-ments. Van Eyck et al. (1987) studied the ICA and the UA inrelation to fetal behavioral states in normal pregnancy at37–38 weeks’ gestation. The PI in the ICA was found to besignificantly lower during the 2F state (active sleep) comparedwith the IF state (quiet sleep) whereas the PI in the UA didnot significantly change. The reduction in PI was not relatedto differences in fetal heart rate and was interpreted as rep-resenting an increase in cerebral blood flow. In pregnanciescomplicated by intrauterine growth restriction (van Eyck etal. 1988), this behavior dependency during the 1F and 2Fstates disappeared in the ICA, the PI being constantly lower.

Interestingly, when Kofinas et al. (1996) investigated theeffect of vibroacoustic stimulation on fetal MCA waveformsin 160 normal pregnant women at various gestations, theynoted a reduction in PI values in fetuses over 28 weeks. Theinfluence of fetal heart rate changes was thought to benegligible and an explanation for the response is not clear.

TECHNIQUE OF MEASURING NEONATAL CBFV

As described above, the ACA and MCA are the most com-monly studied vessels. A pulsed-wave transducer which maybe securely fixed over the anterior fontanelle or temporal areato give a constant angle of insonation is preferred. Collectionof data continuously for up to a minute will allow assessmentof beat-to-beat and cycling variability (see below).

Other vessels which have been studied are the PCA, basi-lar artery and the circle of Willis. Color flow mapping hasalso made it possible to study the internal cerebral veins, thevein of Galen and the sagittal sinus.

PHYSIOLOGICAL VARIABLES AFFECTINGNEONATAL CBFV

GESTATIONAL AGE AND POSTNATAL AGE

Several studies of the MCA and ACA have shown that cere-bral blood velocity increases with increasing gestational ageand with each postnatal day, but for each day after birth awide range of velocity values has been reported. The majorchange occurs within the first 12 h of life and is associatedwith a fall in the RI (Archer et al. 1985; Deeg & Rupprecht1988; Horgan et al. 1989, Fenton et al. 1990). These physio-logical changes must be taken into account in recordingsbetween babies or in repeated measurements made in thesame baby (see Table 9.1).

CYCLING VARIATION AND BEAT-TO-BEAT VARIABILITY

Marked beat-to-beat variability of the velocity signal hasbeen recognized for many years (Perlman et al. 1983a).

When recordings were made over periods of one or moreminutes, it became apparent that the cycling variationsoccur at several frequencies (Anthony et al. 1991). Bothpreterm and healthy full-term infants show similar patternsof variation (Anthony et al. 1991). One of the major compo-nents of this variability appears to be respiration (Bignall etal. 1988). The influence of respiration is greatest in preterminfants who are artificially ventilated, presumably represent-ing entrainment to that of the ventilator frequency(Coughtrey et al. 1993). The influence of respiration isaccentuated in hypovolemic states (Rennie 1989).

Ferrar et al. (1994) observed slow frequency CBFV varia-tions of significantly greater amplitude during quiet sleepcompared with active sleep, in full-term infants. The fre-quency was similar to that described in preterm babies andadults, at a similar frequency to Lundberg B waves inintracranial pressure. These may represent vasomotor wavesin the small autoregulatory arteries of the brain. Greatervariability in CBFV has also been described during rapid eyemovement sleep than non-rapid eye movement sleep in bothfull-term and preterm infants (Cowan 1985; Rehan et al.1996). Rehan et al. (1996) also describe greater CBFV vari-ability with periodic and apneic breathing than with regularbreathing.

Therefore, it is important to be aware of such influencesupon CBFV so that observed changes are not necessarilyascribed to pathological states.

OXYGEN, CARBON DIOXIDE AND ARTERIAL PRESSURE

Transient hyperoxia has been shown to induce a small butconsistent reduction in CBFV (Niijima et al. 1988), approxi-mately 3% per 1 kPa rise in PO2 (Menke et al. 1993). Theeffect of carbon dioxide upon CBFV, however, is muchgreater than that of oxygen. There is an approximate rise of30% per 1 kPa rise in PCO2 (Menke et al. 1993). Hypercapniain full-term healthy neonates provokes a rise in diastolicvelocity, due to cerebral vasodilatation (Archer et al. 1986a).On the first day of life, sick preterm infants show a blunted


Table 9.1 Mean velocities for postnatal age in the ACA and MCA in term and preterm infants (Fenton et al. 1990)

Velocity (cm/s)

ACA MCA

Age (hours) Term Preterm Term Preterm

12 6.3 5.524 8.4 3.3 10.0 4.748 8.8 4.6 11.5 6.572 9.7 6.3 11.8 8.1

120 11.5 15.0196 11.0 13.9

Source: Reproduced, with permission, from Anthony & Levene (1993).


CBFV response to increasing carbon dioxide tension, whichbecomes exaggerated after 24 h of age (Levene et al. 1988).The CBFV response to carbon dioxide changes on the firstday of life appears largely dependent on the concomitantchange in arterial pressure (Fenton et al. 1992).

The effects of carbon dioxide changes and changes inarterial blood pressure upon CBFV are difficult to untangleas there is usually interdependence. Using regression analy-sis on observations of arterial pressure, PCO2, and PO2 in 16ventilated preterm infants, Menke et al. (1993) suggest thereis an 8% rise in CBFV per 1 kPa rise in arterial pressure. Thechange is greater in infants below 30 weeks gestation,implying that these infants have immature autoregulatorycontrol of cerebral blood flow (Jorch & Jorch 1987).

PLASMA VISCOSITY

In both adults and neonates, it is known that a low hemat-ocrit is associated with an increased velocity, and the hema-tocrit should therefore be noted in each study (Rosenkrantz& Oh 1982; Brass et al. 1988). Hemodilution in nineneonates resulted in a significant decrease in hematocrit, anincrease in cardiac output and 20% increases in blood flowvelocities of the internal carotid artery and the celiac artery(Mandelbaum et al. 1994).

CEREBRAL BLOOD FLOW IN COMPLICATEDPREGNANCIES

FETAL INTRAUTERINE GROWTH RESTRICTION

In intrauterine growth restriction (IUGR) secondary to pla-cental insufficiency there is an increase in downstream resis-tance in the fetoplacental circulation, with reduced, absentor even reversed end-diastolic flow in the UA Doppler wave-forms (Trudinger et al. 1985; Morrow et al. 1989; Battagliaet al. 1993). Conversely, in the cerebral circulation, earlystudies noted an increase in end-diastolic flow suggesting areduction in downstream resistance (Wladimiroff et al. 1986,1987; van den Wijngaard et al. 1989). These findings areconsistent with the phenomenon of ‘brain-sparing’ or redis-tribution of blood flow in response to fetal hypoxia demon-strated in animal models. Flow is preferentially increased infavor of the vital organs such as the brain, heart, andadrenal glands to maintain adequate oxygen supply, with adecrease in the blood flow to the gut, kidneys, and carcass(Cohn et al. 1974, Peeters et al. 1979). During acute fetallamb asphyxia, induced by obstruction of the maternalaortic blood flow, Malcus et al. (1991) observed significantchanges in vessel diameter using ultrasound. A decrease inthe aortic diameter and aortic blood flow occurred with fetalacidemia whereas in the common carotid artery, vesseldiameter and blood flow significantly increased, i.e. therewas apparent vasodilatation. In the chronic hypoxic state ofthe growth-restricted fetus, a preservation of head growth atthe expense of the abdominal circumference or liver size iswell recognized. In a recent longitudinal study of fetuses

that developed IUGR, Harrington et al. (1999) demonstratedthat a reduction in abdominal circumference mirrored therise in UA PI and preceded waveform changes in the MCAand thoracic aorta. Interestingly, when growth restrictionwas associated with either a structural or chromosomalabnormality, Wladimiroff et al. (1988) noted that PI in theICA was always within the normal range (suggesting theabsence of circulatory redistribution) whereas the PI wasraised in 33% of cases in the UA.

In growth-restricted fetuses the MCA PI demonstrates asignificant inverse correlation with the degree of fetalhypoxemia, measured by cordocentesis (Vyas et al. 1990b;Akalin-Sel et al. 1994). Simultaneous intrapartum pulseoximetry has also shown significantly higher blood flowvelocity in the MCA in the presence of reduced oxygen sat-uration (Sutterlin et al. 1999). However, with severe degreesof hypoxemia (>4 SD below the mean for gestation), Vyas etal. (1990b) noted a tendency for PI to rise (Fig. 9.5). This hasbeen attributed to increased intracranial pressure due tocerebral edema. There appears to be a limit to the adaptivemechanism present in that the severely compromised fetusmay lose its ability to vasodilate the cerebral circulation.

Arduini et al. (1992a) performed Doppler velocimetry on36 growth-restricted fetuses at weekly intervals after thediagnosis of a ‘brain-sparing’ effect, until the onset ofantepartum late fetal heart rate decelerations were observed.In the cerebral circulation a nadir of vasodilatation wasreached 2 weeks before the onset of decelerations, whereas afurther dramatic increase in PI occurred within the UA anddescending aorta close to the development of the abnormalheart rate tracing. These results are consistent with data


1

0

2

–1

–2

–3

–4–5 –4 –3 –2 –1 0

∆ PO2 (SD from mean)

∆ M

iddl

e ce

rebr

al a

rter

y pu

lsat

ility

inde

x (S

D f

rom

mea

n)

21

Figure 9.5 Fetal hypoxia and the PI in the MCA. Open circlesrepresent acidemic fetuses and closed circles represent non-acidemic fetuses. (Reproduced with permission from Vyas et al.1990b.)


from fetal lamb experiments, showing that changes in thecerebral circulation take place at an early stage of fetalhypoxemia when only slight alterations in peripheral bloodflow are detected (Peeters et al. 1979). However, in moresevere hypoxemia, there are marked increases in peripheralvascular resistance and minimal increases, or evendecreases, in cerebral blood flow. Individual values of PImay be difficult to interpret due to this variable effect.Indeed, as discussed above, studies on the cerebral circula-tion have shown that velocity is better correlated with brainblood flow than is PI (Rosenberg et al. 1985; Martin et al.1990; Gunnarsson et al. 1998).

The possibility that a reduction in MCA PI can predictadverse perinatal outcome, such as preterm delivery, growthrestriction, Cesarean section for fetal distress and neonatalcomplications, has been investigated. Several studies haveused a ratio of Doppler indices, comparing the MCA or ICAto the umbilical artery or descending thoracic aorta, as abetter indicator of centralization of the fetal circulation andsubsequent perinatal problems (Arduini & Rizzo 1992b;Gramellini et al. 1992; Scherjon et al. 1992; Hecher et al.1995a; Chan et al. 1996; Luzi et al. 1996; Ozcan et al. 1998;Harrington et al. 1999; Ott 1999; Ozeren et al. 1999). In anovine model of acute fetal hypoxia secondary to reducedumbilical or maternal aortic flow, Arbeille et al. (1995) foundthe cerebroplacental ratio (cerebral RI : umbilical RI) to bethe hemodynamic parameter that most closely followed thechanges in PO2. Bahado-Singh et al. (1999) evaluated thescreening efficiency of the cerebroplacental ratio for the pre-diction of IUGR and associated perinatal complications in203 at-risk fetuses. A highly significant increase in perinatalmorbidity and mortality was observed in cases with anabnormal ratio (Fig. 9.6). The cerebroplacental ratio

appeared superior to umbilical artery Doppler in predictingperinatal complications. There was a progressive increase inscreening efficiency as the interval between Doppler studyand delivery fell. An unexplained finding of the study wasthat the ratio did not appear to correlate significantly withoutcome in fetuses over 34 weeks’ gestation. An immaturityof the mechanisms that autoregulate cerebral blood flow inpreterm fetuses was postulated to explain the difference inresults.

The hemodynamic effect appears to be a protective mech-anism to prevent fetal brain hypoxia, as follow-up studies todate have not shown an increase in neurologic problems inthe neonate or up to 3 years of age (Scherjon et al. 1993;Chan et al. 1996; Scherjon et al. 1998). Interestingly,Scherjon et al. (1996) recorded shorter visual-evoked poten-tial latencies at 6 months of age in infants with abnormalratios. They postulated that this accelerated neurophysio-logic maturation could be the result of a beneficial adapta-tion to severe fetal growth restriction. In a cohort of 77growth-restricted fetuses, Yoshimura et al. (1998) found norelationship between abnormal MCA : UA PI ratios and fol-low-up growth at 6 and 12 months of age, despite initiallylower birth weight, increased admission, and length of stayin the neonatal unit. The available evidence suggests that an abnormal cerebroplacental ratio is not an indication tointervene too early and deliver a preterm fetus, but thatincreased surveillance is required. However, the value ofcerebral Doppler velocimetry in improving clinical outcomehas not yet been assessed by a randomized controlled trial.Neither has the issue of cost-effectiveness in clinical practicebeen addressed.

With increasingly adverse conditions there is a preferen-tial shift in cardiac output in favor of the left ventricle (AlGhazali et al. 1989) with increasing right ventricular after-load (Rizzo & Arduini 1991). This has prompted investigatorsto assess the venous side of the fetal circulation as well asthe arterial vessels. As pressure in the right atrium increases,‘a’ wave decelerations are seen in the ductus venosus andthere is an increase in reversed flow within the inferior venacava (Hecher et al. 1995b). Such abnormalities in venousflow are associated with metabolic acidemia whereas arterialredistribution affecting only the MCA does not appear to be associated with acidemia in IUGR (Rizzo et al. 1995).Longitudinal observations in preterm growth-restrictedfetuses have demonstrated that abnormal venous waveformsprecede abnormally reduced short-term variation of fetalheart rate (Hecher & Hackeloer 1997). Short-term heart ratevariation, assessed by computer analysis, is itself considereda better predictor of acidemia compared to decelerations(Guzman et al. 1996).

Using arterial and venous Doppler velocimetry in aprospective study of 19 severely growth-restricted fetuses,Ozcan et al. (1998) found that absent or reversed flow in the ductus venosus was the only significant parameterassociated with perinatal death and 5 min Apgar scores.Randomized controlled trials are needed to determine


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Figure 9.6 Fifth, 10th, 90th and 95th percentile values forcerebroplacental ratio (CPR) morbidity and perinatalcomplications (Doppler imaging-to-delivery interval <2 weeks).Open circles, <10th percentile, no morbidity; filled circles,<10th percentile, with morbidity. (Reproduced with permissionfrom Bahado-Singh et al. 1999.)


whether additional venous Doppler assessment will enableobstetricians to assess more accurately the optimal time fordelivery before the development of abnormal cardiotocogra-phy (Hecher et al. 1995a; Black & Campbell 1997; Hecher &Hackeloer 1997). This is particularly important in the man-agement of the very preterm or growth-restricted fetus,aiming to minimize perinatal morbidity and any subsequentcomplications. It must always be appreciated that there is avariation in fetal responses to adverse intrauterine condi-tions (Hecher & Hackeloer 1997). Long-term follow-up stud-ies are indicated to assess minor differences in neurologicdevelopment. It is also possible that the combined use ofarterial and venous Doppler assessment may allow morewomen to be monitored as outpatients. However, because ofthe requirement for expensive color flow Doppler equipmentand technical expertise, they are likely to be of limited valueas a screening tool in normal pregnancy.

TWIN PREGNANCY

Twin–twin transfusion syndrome (TTTS) is a specific compli-cation of monochorionic diamniotic twin pregnanciesassociated with extremely high perinatal morbidity andmortality. A hemodynamic mismatch is thought to occurbetween the twins because of placental vascular communi-cations between their circulations (Bajoria et al. 1995).Cardiac and venous Doppler studies of the fetal circulationin TTTS are consistent with hypovolemia and increasedplacental resistance in the smaller donor twin and hyper-volemic congestive heart failure in the larger recipient twin(Hecher et al. 1995c). Significantly decreased PI was foundin the MCA of the larger recipient twin but not in the smallerdonor twin (Hecher et al. 1995c). Mean blood flow velocityin the MCA of both twins was normal for gestational agewhereas it was decreased in the thoracic aorta.

In contrast, small-for-gestational-age fetuses of mono-chorionic diamniotic twin pregnancies unaffected by TTTSare more likely to demonstrate the ‘brain-sparing effect’(with decreased resistance in the MCA) compared to diamni-otic dichorionic twins of similar low birth weights (Gazianoet al. 1998). Joern et al. (1997) compared a non-stress car-diotocograph, ultrasound biometry and Doppler ultrasoundfrom the fetal descending aorta, UA and MCA in the predic-tion of placental insufficiency in 130 multiple pregnancies.Doppler results from all three vessels rather than a singlevessel was the best predictor of IUGR (sensitivity 75.9%) and of an adverse fetal outcome in terms of Apgar score, UA pH < 7.20 and neonatal unit admission.

ABNORMAL AMNIOTIC FLUID VOLUME

Doppler velocity waveforms of the ICA were studied in preg-nancies complicated with prolonged severe oligohydramniosdue to bilateral renal agenesis (van den Wijngaard et al.1988). The end-diastolic velocity was reduced, absent oreven reversed with a raised PI (>2 SD), suggesting very highperipheral vascular resistance, which Van den Wijngaard

and colleagues postulated was due to head compression. The same mechanism was applicable in the newborn whenNewton & Gooding (1975) demonstrated that molding of theskull compressed the superior sagittal sinus, resulting indecreased cerebral blood flow.

In post-term fetuses with oligohydramnios, Weiner et al.found the MCA PI was lower compared to post-term fetuseswith normal amniotic fluid volume or compared to termfetuses, but this was associated with a reduced left cardiacoutput and normal PI in the UA and abdominal aorta(Weiner et al. 1996).

Mari et al. (1992) noted a significant decrease in fetalMCA PI after decompression amniocentesis for symptomaticpolyhydramnios in twin pregnancies, suggesting a possibleimprovement in cerebral perfusion.

FETAL ANEMIA

Vyas et al. (1990c) studied 24 red cell isoimmunized preg-nancies and found mean blood flow velocity in the fetalMCA to be increased with anemia. Although PI wasdecreased in anemic fetuses, there was no significant associ-ation with the difference in hemoglobin concentration.These hemodynamic changes were not significantly associ-ated with the difference in blood PO2. Therefore, the hyper-dynamic circulation was considered to be a consequence ofthe reduced blood viscosity. Mari et al. (1997) noted adecrease in MCA peak systolic velocity with an increase infetal hematocrit after intrauterine transfusion.

The value of blood flow velocity measurements in theMCA for the non-invasive diagnosis of fetal anemia due tomaternal red cell alloimmunization has been recentlyaddressed in a prospective multicenter study involving 111at-risk fetuses (Mari 2000). All of the fetuses with moderateor severe anemia had peak systolic velocity values above 1.5times the median (Fig. 9.7). The multiple of the median ofpeak systolic velocity was a strong predictor of anemiaregardless of the presence or absence of hydrops.Measurements of the peak systolic velocity were found topredict the presence of moderate or severe anemia with asensitivity of 100% and a false positive rate of 12%.Potentially, this could decrease the number of fetuses sub-jected to invasive amniocentesis or cordocentesis for thiscondition.

FETAL BLOOD SAMPLING

A significant decrease in PI occurs within the MCA as wellas the UA and descending aorta following cordocentesis butnot amniocentesis, even when performed transplacentally(Capponi et al. 1996; Chitrit et al. 1997). This may reflect therelease of vasoactive substances (Rizzo et al. 1996a).

LABOR

Conflicting results have been published using MCADoppler in normal labor with some investigators reporting



no significant change in PI (Maesek et al. 1990, 1994;Kurjak et al. 1996) and others noting decreased values(Yagel et al. 1992; Chen et al. 1999). Decreased impedanceto cerebral blood flow may be a protective mechanism toprevent fetal hypoxia during labor, although no significantdifference was detected between downstream resistance inthe MCA during uncomplicated labor and in labor withvariable decelerations (Yagel et al. 1992). Contrary to theirfindings during spontaneous labor, Chen et al. (1999)found no significant change in MCA Doppler indices whenlabor was induced with prostaglandin E1. It may thereforebe significant that these induced labors were more fre-quently associated with abnormal UA pH values.

In pregnancies complicated by preterm labor, significantlylower MCA PI values were also noted in fetuses deliveredwithin 24–48 h compared to fetuses delivered later or atterm (Ghezzi et al. 1995; Rizzo et al. 1996b). Recent ran-domized trials involving tocolysis with sulindac or terbu-taline (Kramer et al. 1999) and indomethacin or magnesiumsulfate (Parilla et al. 1997) have reported no significanteffects of the drug therapy on downstream resistance in theMCA.

CLINICAL ASSOCIATION OF CEREBRAL BLOODFLOW IN THE NEONATE

There have been many studies describing the association of certain disease states and drugs with changes in CBFVmeasurements. Few studies have addressed the clinical consequences and relevance of the associations described.

CBFV AND DRUGS

SURFACTANT ADMINISTRATION

The literature describing the effects of surfactant administra-tion on neonatal CBFV gives conflicting results, withincreased, unchanged, and decreased states being described.These differences may arise from the different types ofsurfactant studied (natural versus synthetic), the differentmethods of delivery (bolus versus slower administration),and the timescale of CBFV measurements.

Jorch et al. (1989a) found no change in CBFV when mea-sured every 10 minutes following bovine surfactant admin-istration to preterm infants in a controlled study. Van de Boret al. (1991) studied 25 preterm infants given syntheticExosurf for respiratory distress syndrome and found thatmean CBFV increased by 33% at 5 minutes, returning tobaseline by 30 minutes. Cowan et al. (1991) used continuousCBFV measurement of 10 preterm infants and found a 36%reduction in CBFV and a 16% reduction in mean arterialpressure, within 2 minutes of administering naturalCurosurf. There was also loss of the end-diastolic velocity,thought to be due to ductal shunting following the fall in thepulmonary vascular resistance. Van Bel et al. (1992) noted afall in CBFV during the instillation of prophylactic naturalCurosurf but the velocities rose to above baseline values 10minutes after administration.

Endotracheal suction and disconnection from the ventila-tor are common procedures during the administration ofsurfactant. Transient airway obstruction will lead to a rapidrise in carbon dioxide, a potent cerebral vasodilator, therebyincreasing cerebral blood flow. Surfactant acts to improvelung compliance and ventilation, leading to a subsequentfall in carbon dioxide and cerebral blood flow. Could theeffects of surfactant on CBFV be due to fluctuations incarbon dioxide? Bell et al. (1994) used the Xenon clearancetechnique to measure cerebral blood flow and concludedthat the observed reduction following natural Curosurf wasdue to the fall in carbon dioxide levels. Saliba et al. (1994)studied different rates of instillation of synthetic Exosurf (5 versus 15 minutes) and, although increases in CBFV andPCO2 were observed following more rapid instillation, theincrease in CBFV could not wholly be explained by the fluc-tuation in PCO2. In this study, there was no evidence thatCBFV changes were mediated by alterations in cardiac out-put, blood pressure, and ductal patency. Rey et al. (1994)demonstrated that the fall in CBFV following naturalCurosurf was more marked at higher doses (200 mg/kg


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Figure 9.7 Peak velocity of systolic blood flow in the middlecerebral artery in 111 fetuses at risk for anemia due to maternalred-cell alloimmunization. Open circles indicate fetuses witheither no anemia or mild anemia (> = 0.65 multiples of themedian hemoglobin concentration). Triangles indicate fetuseswith moderate or severe anemia (<0.65 multiples of themedian hemoglobin concentration). The solid circles indicatethe fetuses with hydrops. The solid curve indicates the medianpeak systolic velocity in the middle cerebral artery, and thedotted curve indicates the 1.5 multiples of the median.(Reproduced, with permission, from Mari 2000 – for thecollaborative group for Doppler assessment of the bloodvelocity in anemic fetuses.)


versus 100 mg/kg). This dose-related effect has also beenseen using near-infrared spectroscopy (NIRS) (Dorrepaal etal. 1993).

The literature therefore suggests that synthetic surfactantis associated with increases in CBFV (van de Bor et al. 1991;Saliba et al. 1994), whereas natural surfactants appear toreduce CBFV (Cowan et al. 1991; Rey et al. 1994; van Bel et al. 1992). This was tested by Murdoch & Kempley (1998)in a randomized controlled trial of 20 ventilated preterminfants undergoing surfactant treatment (synthetic Exosurfversus natural Curosurf ). There was a slow and sustained risein CBFV with synthetic surfactant. In contrast, with naturalsurfactant, there was an abrupt fall in CBFV. This was max-imal at 1 minute and had largely resolved by 15 minutes. Therapid recovery in CBFV may explain why other groups usingNIRS have not observed such changes (Edwards et al. 1992),as the technique requires that stability in oxygenation isachieved before measurements are carried out.

Most investigators who claim surfactant has an effect oncerebral blood flow independent of changes in PCO2 andarterial blood pressure have endeavored to measure theseparameters. However, fluctuations in PCO2 and arterial pressure may be rapid and go undetected (Halley et al. 1995).

The observed changes in CBFV following surfactant instil-lation have led to fears that surfactant therapy may be asso-ciated with an increased risk of intraventricular hemorrhage(IVH). The evidence suggests that these fears are unfounded.A meta-analysis of the randomized controlled trials evaluat-ing the efficacy of surfactant therapy in the treatment ofrespiratory distress syndrome shows a reduction in the riskof all IVH (relative risk 0.88; 95% CI 0.77 to 0.99) (Soll1999).

ANALGESIA, SEDATION, AND PARALYSIS

A bolus of 0.1 mg/kg midazolam produces a minor reductionin CBFV, associated with a transient fall in blood pressure(Harte et al. 1997; van Straaten et al. 1992). Diazepam alsoappears only to produce minor changes in CBFV (Jorch et al.1989b). Neuromuscular blockade and, to a lesser extent,morphine sedation decrease fluctuations in CBFV in preterminfants (Perlman et al. 1985; Colditz et al. 1989). Perlman et al. (1985) suggest that using paralysis to reduce CBFVfluctuations results in a decreased risk of intraventricularhemorrhage in ventilated preterm infants.

SEIZURES AND ANTICONVULSANTS

Seizures in adults and children produce a substantialincrease in cerebral blood flow. Perlman & Volpe (1983b)studied clinical seizures in 12 preterm infants and found thatCBFV, blood pressure, and intracranial pressure all rose dur-ing seizure activity. The increase in CBFV appears indepen-dent of motor activity, as it has also been observed in EEGseizures during paralysis (Bode 1992). Boylan et al. (1999)found an increase in CBFV during both electroclinical andelectrographic (clinically silent) seizures; regression analysis

suggested that the increase in CBFV was not whollyexplained by changes in blood pressure or PCO2 during theseizure. A regional increase in cerebral perfusion has beendemonstrated by SPECT, but it was not possible to correlatethe area of hyperperfusion with the epileptiform focus(Borch et al. 1998).

Phenobarbitone does not produce any significant changein CBFV when given as a 20 mg/kg loading dose (Saliba etal. 1991a) and appears not to reduce CBFV fluctuations(Kuban et al. 1988).

INDOMETHACIN

When used as treatment for patent ductus arteriosus (PDA)at doses of 0.1 and 0.2 mg/kg, indomethacin is associatedwith a 20–50% reduction in mean CBFV. The effect appearsmaximal around 30–40 minutes after giving indomethacinand persists for 120 minutes (Laudignon et al. 1988; van Belet al. 1989b; Saliba et al. 1991b; Austin et al. 1992; van Belet al. 1993). A slow infusion over 30 minutes produces amore gradual fall but the overall magnitude is similar tobolus administration (Austin et al. 1992). Other methods,such as NIRS and Xe clearance, show a similar magnitudeand timescale of reduced cerebral blood flow (Pryds et al.1988, Edwards et al. 1990).

A PDA can have profound effects upon CBFV. It is asso-ciated with a raised RI and a decrease in CBFV (Lipman etal. 1982, Martin et al. 1982). In some cases retrograde cere-bral blood flow velocities can occur (Perlman et al. 1981).Nevertheless, the action of indomethacin appears to be adirect effect of the drug. There is no evidence of ductalclosure in studies that have used echocardiographic assess-ment (Austin et al. 1992) and surgical ligation tends toincrease CBFV by increasing end-diastolic flow (Saliba etal. 1991c). Indomethacin given prophylactically for intra-ventricular hemorrhage prevention, i.e. in the absence of apatent ductus, causes a reduction in CBFV end-diastolicflow (Yanowitz et al. 1998). Indomethacin leads to a reduc-tion in vascular reactivity to changes in CO2 (Levene et al.1988, Saliba et al. 1991b) and its effect appears not to bemediated by alterations in prostaglandin concentration(van Bel et al. 1993).

METHYLXANTHINES

In adults, cerebral blood flow is known to decrease after asingle bolus injection of aminophylline. Rosenkrantz & Oh(1984) demonstrated a 21% reduction in anterior cerebralartery CBFV, 60 minutes following aminophylline adminis-tration to nine infants. A substantial reduction in PCO2 wasalso seen, suggesting that CBFV changes may be mediatedvia CO2 changes. Two studies also demonstrated a fall inCBFV following aminophylline but the magnitude of the fallwas too great to be explained solely by CO2 changes (Chang& Gray 1994, Goven et al. 1995). These findings have beenconfirmed by NIRS (McDonnell et al. 1992; Bucher et al.1994) and Xe clearance (Pryds & Schneider 1991).



Aminophylline at steady state, therapeutic concentrationsdoes not appear to alter CBFV (Ghai et al. 1989).

Caffeine therapy has not been shown to reduce CBFV,despite causing a reduction in CO2 (Saliba et al. 1989a, b;van Bel et al. 1989c), although it has not been compareddirectly with aminophylline.

DEXAMETHASONE

Cabanas et al. (1997) measured CBFV around the first, third,and fifth doses of dexamethasone given to ten ventilatedinfants with chronic lung disease. There was a short-termincrease in CBFV over one to two hours, accompanied by arise in mean arterial pressure. Progressive doses of dexa-methasone produced larger increases in CBFV. Using NIRS,the same group confirmed the increase in CBFV and foundthat the effect was independent of changes in mean arterialpressure and CO2 (Pellicer et al. 1998).

CBFV AND PREDICTION

HYDROCEPHALUS

Many investigators have documented the associationbetween higher CBFV resistivity index (RI) values andhydrocephalus in neonates and children (Hill & Volpe 1982;Alvisi et al. 1985). Following CSF drainage in neonates withhydrocephalus, the RI falls and the mean CBFV rises (Hill &Volpe 1982; van Bel et al. 1988; Seibert et al. 1989; Goh etal. 1991a, b, 1992; Kempley & Gamsu 1993).

These findings have prompted several groups to identify avalue of RI, above which would be an indication of therequirement for CSF drainage. Pople et al. (1991) studiedchildren with shunted hydrocephalus. An abnormally raisedRI predicted a blocked shunt with a sensitivity of 56% and aspecificity of 97%. The RI correlated with intracranial pres-sure in patients with confirmed shunt blockage. These resultswere not confirmed in infants. Anderson & Mawk (1988)studied infants with hydrocephalus and found that RI wasraised in 31% of those who subsequently required a shuntand in 36% of those who did not. Seibert et al. (1989) foundwide variation in RI values in infants with hydrocephalusthat limited predictive ability.

When compared with intracranial pressure (ICP) measure-ment, there is an association between a raised RI and raisedICP (Goh et al. 1991a, b, 1992). The change in RI occurs earlyin the evolution of hydrocephalus (Quinn et al. 1992) andthus, the correlation between RI and ICP is too weak for RIto be predictive (Goh et al. 1991a; Quinn et al. 1992;Kempley & Gamsu 1993).

In infants with hydrocephalus, compression of the ante-rior fontanelle (using the ultrasound transducer) duringDoppler ultrasound examination for a brief period (3–5 sec-onds) was found to result in a transient increase in RI onlyin those infants who subsequently required surgical inter-vention. An increase in RI during compression of >40% frombaseline was predictive of subsequent shunt placement

(Taylor & Madsen 1996). Westra et al. (1998) applied thistechnique to infants and children referred for possible tap-ping or shunt placement. Using an RI > 0.90 during trans-ducer pressure, they predicted raised ICP with a specificity of100% and sensitivity of 76%.

PRETERM BRAIN INJURY

Calvert et al. (1988) undertook serial CBFV measurement in 29 preterm infants. Three infants, who had evidence ofintraventricular hemorrhage on cranial ultrasound, had sim-ilar CBFV compared with the infants with no evidence ofhemorrhage. Two infants died with evidence of periventric-ular leukomalacia at autopsy, both of whom had had a pro-longed period of low CBFV.

Shortland et al. (1990) studied 120 preterm infants andfound no association between CBFV and intracranial lesions.Van Bel et al. (1989a) found that preterm infants who werelater found to have major impairment at two years of agehad a consistently higher RI in the first week of life,although the predictive ability of RI was not formally tested.Rennie et al. (1995) performed CBFV measurements in 74very low birth weight infants and found no association withsubsequent outcome when formally assessed at 18 months ofage.

Thus, the absolute values of RI or CBFV do not appearuseful in the prediction of preterm brain injury or neuro-developmental outcome. Baenziger et al. (1999) found nocorrelation with outcome when cerebral blood flow wasmeasured during the neonatal period using Xe clearance.The lack of predictive ability when considering the absolutevalues of CBFV has prompted investigators to examine therelationship between fluctuations in CBFV and outcome.Perlman et al. (1983a) studied 50 preterm infants and con-cluded that a fluctuating pattern of CBFV was associatedwith a risk of developing intraventricular hemorrhage (like-lihood ratio 8; 95% CI 2 to 31). No such association was seenby Coughtrey et al. (1997) or Kuban et al. (1988). The reac-tivity of CBFV to a CO2 challenge was also found not to beassociated with ultrasound evidence of neurologic injury(Fenton et al. 1992).

Therefore, CBFV measurement is not a proven and reliablemethod of predicting brain injury or long-term outcome inpreterm infants.

HYPOXIC–ISCHAEMIC INJURY IN TERM INFANTS

The original Doppler study in neonates after intrapartumhypoxic–ischaemic injury demonstrated a low RI, due to anincrease in end-diastolic velocity, which was thought torepresent impairment in cerebrovascular autoregulation(Bada et al. 1979). Archer et al. (1986b) performed repeatedDoppler measurements on infants after intrapartum hypoxia–ischemia and related the findings to the neurodevelopmentaloutcome at follow-up. Of the 18 infants with an abnormal RI(<0.55), 12 died or were severely handicapped. All theabnormal results were apparent between 24 and 62 hours of



age. All the infants with normal RI values were normal atfollow-up. A RI < 0.55 gives a likelihood ratio of 5.1 (95% CI2.5 to 10.6) for the prediction of death or neurodevelop-mental handicap. The association of reduced RI and pooroutcome after hypoxia–ischemia has been confirmed byother workers (Deeg et al. 1990; Stark & Seibert 1994).

The abnormalities in Doppler waveform take 24 hours toemerge and are usually normal in the first 6 hours, despitesignificant injury (Eken et al. 1995). Levene et al. (1989)have shown that an increase in CBFV (absolute value asopposed to RI) in the second 24 hours and a lack of reactiv-ity to PCO2 predicted a poor outcome. An increase in globalcerebral blood flow has also been demonstrated with Xeclearance (Pryds et al. 1990) and NIRS techniques (Meek etal. 1999).

Therefore, measurement of CBFV and estimation of RI canbe of some prognostic value, provided it is performed 24hours after the hypoxic–ischemic insult.

CONCLUSION

It is possible that Doppler assessment of the fetal cerebralcirculation could identify the extent of fetal compromise andaid in judging the time of delivery of such pregnancies.However, the problem of implementing such a policy issubstantial. Not only is the equipment expensive, but themeasurements are sometimes difficult, even in skilled hands.Nevertheless, tertiary referral centers may eventually estab-lish that abnormal venous Doppler in the presence of redis-tributed cerebral blood flow is a clear indication for delivery.Further long-term follow-up studies must be performed toensure that by this time cerebral damage has not alreadyoccurred.

The limitations in using Doppler indices to assess cerebralhemodynamics, particularly acute changes in blood flow,should be recognized. However, the potential of peaksystolic velocity measurements in the MCA to predict fetalanemia will hopefully improve our management of allo-immunized pregnancies.

In the neonate, Doppler measurements have been shownto have a clinical role in the prediction of outcome follow-ing hypoxic–ischemic injury in term infants. There is no

convincing proof that CBFV measurements are likely to beof clinical use in the prediction of outcome in preterminfants. Although initially promising, the use of CBFVassessment to detect infants with raised intracranial pressurelikely to require surgical CSF drainage procedures has beendifficult to apply in the clinical arena. There are manystudies reporting CBFV changes with different physiologicalstates and pharmacological interventions. As yet, theseremain research interests with little clinical application.Techniques for continuous measurement of the CBFV andanalysis of variability may be a useful non-invasive researchtool for studying neonatal cerebral hemodynamics.


Key Points

• The interpretation of changes in Doppler indices and cerebralblood flow velocity in terms of actual cerebral blood flow hascertain limitations.

• The observation of trends rather than individual Dopplermeasurements from the MCA may be of more clinical value.

• An increase in end diastolic flow occurs in the MCA Dopplerwaveform during fetal and neonatal hypoxia.

• An abnormal cerebroplacental ratio is associated with asignificant increase in perinatal morbidity and mortality but thevalue of cerebral Doppler velocimetry in improving clinicaloutcome has not yet been assessed by a randomized controlledtrial.

• The non-invasive measurement of peak systolic velocity in theMCA has been shown to predict moderate or severe fetal anemiain maternal red cell alloimmunization. The potential to decreasethe number of invasive procedures performed for this conditionrequires further study.

• Following intrapartum hypoxia–ischemia, an abnormalResistance Index (RI < 0.55) in the term neonate is predictive ofadverse outcome (death or neurodevelopmental handicap), whenthe examination is performed 24–60 hours of age (Likelihoodratio 5.1; 95% CI 2.5 to 10.6).

• Doppler CBFV measurement is not a proven and reliable methodfor the prediction of neurodevelopmental outcome followingpreterm brain injury.

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121 chapter 9 doppler assessment of the fetal and neonatal ... · doppler ultrasound has been used...

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