Archives of Disease in Childhood 1993; 68: 303-307

Pulmonary artery pressure changes in the very lowbirthweight infant developing chronic lung disease

A B Gill, A M Weindling

AbstractPulmonary artery pressure may be esti-mated non-invasively in the prematurenewborn infant because of its negativecorrelation with the time to peak ve-locity:right ventricular ejection time(TPV:RVET) ratio calculated from thepulmonary artery Doppler waveform. Westudied 54 very low birthweight infants ondays 1, 2, 3, 7, 14, 21, and 28 after birth.Thirty four infants developed chroniclung disease (CLD). Twenty did notand acted as controls. After correctingthe TPV:RVET ratio for heart rate(TPV:RVET(c)), during the first 14 daysthe TPV:RVET(c) ratio rose progres-sively in both groups suggesting a fall inpulmonary artery pressure. This occur-red at a significantly slower rate in theCLD group. From days 14 to 28 there wasa significant fall in the ratio in the CLDgroup only, suggesting an increase in pul-monary artery pressure. Using CLD asthe end point, a TPV:RVET(c) ratio <054on day 7 had a predictive value of 78%(sensitivity 73%, specificity 65%). Thisrose to a predictive value of 97% (sensi-tivity 88%, specificity 95%) on day 28.The non-invasive assessment of pul-

monary artery pressure may be useful inthe early clinical management of the verylow birthweight infant at risk of develop-ing CLD.

(Arch Dis Child 1993;68:303-307)

Neonatal IntensiveCare Unit,Department of ChildHealth, University ofLiverpool, LiverpoolMaternity Hospital,Oxford Street,Liverpool L7 7BNA B GillA M Weindling

Correspondence to:Dr Gill.

Accepted 15 September1992

Chronic lung disease (CLD) is mainly con-

fined to the very low birthweight infant,affecting approximately 40%, and is a signifi-cant cause of morbidity and mortality in thefirst two years after birth.1- In infants withCLD, invasive measurements of pulmonaryartery pressure after 6 months of age foundthat pulmonary hypertension was invariablypresent, and the degree of pulmonary hyper-tension correlated with subsequent morbidityand mortality.5-9 These observations are sup-ported by postmortem studies on infantsdying before 28 days of age. These haveshown that the pulmonary vasculature hasundergone changes consistent with an

increase in pulmonary artery pressure. 10-12By using Doppler echocardiography it is

possible to assess non-invasively pulmonaryartery pressure. There are two principlemethods available. The first is triscupidregurgitation and ductal velocity patterns.13 14The advantage of tricuspid regurgitation and

ductal velocity is that it is possible to obtaina quantitative estimate of pulmonary arterypressure. However, these measurements aretechnically quite difficult and are not possiblein all ventilated preterm infants. The dis-appearance of tricuspid regurgitation andclosure of the ductus arteriosus in the majorityof infants by 10 days precludes these methodsfrom use in more prolonged studies. Bycontrast, the second method, measurement ofthe time to peak velocity:right ventricular ejec-tion time (TPV:RVET) ratio,15-18 is possiblein all infants and is relatively straightforwardto measure using a standard ultrasoundmachine and it allows an assessment of thechanges in pulmonary artery pressure. Bothmethods have shown good correlation withinvasive measurements of pulmonary arterypressures in older infants and children.'9-22Researchers using both methods showed thatpulmonary artery pressure fell during theacute and early recovery phase of hyalinemembrane disease. We are, however, unawareof any study that has been confined to thevery low birthweight infant or where resultshave been correlated with the developmentof CLD.The aims of this longitudinal study were

twofold. Firstly, to study pulmonary arterypressure changes using the TPV:RVET ratioin very low birthweight infants with and with-out CLD. Secondly, to study the operatingcharacteristics of this ratio as a means of iden-tifying infants with CLD early in their post-natal course, potentially presenting a windowof opportunity for therapeutic intervention.

Patients and methodsAll infants were studied using an ATLUltramark 4 scanner with a 5 MHz rangegated pulsed wave Doppler probe. Twodimensional imaging was performed with a7.5 MHz probe. The pulmonary artery wasvisualised from the parasternal long axis viewby rotating the probe and angling upwardsuntil the right ventricular outflow tract,pulmonary valve, and main pulmonary arterywere visualised. The sample volume of therange gated Doppler signal was placed distalto the pulmonary valve and the Dopplersignal recorded (fig 1). A sweep speed of100 mm/s made it possible to identify in-dividual Doppler waveforms. A minimumof five waveforms were recorded onto thesystem's computer module for off lineanalysis. Ductal patency and the directionof ductal flow was also assessed.

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4Gill, Weindling

Figure 1 Doppler waveformn from the main pulmonary artety. TPV (sec) and RVET(sec) shown on separate waveforms for clarity. R-R=time difference between successiveR waves on the electrocardiogram (sec). TPV:RVET (c) calculated on five consecutiveDoppler waveforms. X axis represents time in seconds (time shown between two points).Y axis represents Doppler shift in metres/sec (bloodflow is awayfrom the Doppler probeand, therefore, the Doppler trace is below the zero line).

Using the Doppler measurement systemincorporated into the machine, the followingtime intervals were measured. TPV wasmeasured from the onset of ejection to peakvelocity; RVET was measured from the onsetto the cessation of ejection15 (fig 1). TheTPV:RVET ratio was corrected for heart rateby dividing by the square root of the R-Rinterval (TPV:RVET(c)).22 Right ventricularfunction was assessed subjectively at eachechocardiographic study.

Fifty four infants with birth weights below1501 g were studied on days 1, 2, 3, 7, 14,and 28. The fractional inspired oxygen (FiO2)requirement for positive pressure ventilationat the time of scan and the worstalveolar-arterial oxygen (a-A) ratio (a markerof the severity of hyaline membrane disease)on the first three days were recorded.At 28 days of age, two groups of infants

were identified and their TPV:RVET(c) ratioswere compared:

(1) A group with CLD-these were infantswho had been ventilated for hyaline mem-brane disease in the first 48 hours after birthand who were receiving supplemental oxygenat 28 days with characteristic radiographicappearances of CLD.23

Table 1 Demographic and clinical data for CLD and control groupsCLD Control %2 p Value(n=34) (n=20)

Media (range) birth weightin g 850 (512-1452 1214 (814-1496) <0-00001

Median (range) gestation inweeks 27 (23-31) 30 (27-33) <0.00001

No (%) receiving positive pressure ventilation:Day 1 33 (97) 18 (90) 0-2 NSDay 2 32 (94) 10 (50) 13-9 0 0004Day 3 32 (94) 7 (58) 20-1 0 00001Day 7 27 (79) 4 (20) 15-8 0-00002Day 14 21 (62) 1 (5) 14-5 0 00004Day 21 17 (50) 2 (10) 7-2 0 003Day 28 13 (38) 0 8-1 0-00015

X2 using Yates's correction.NS=not significant at 5% level.

(2) A control group-infants who were notreceiving supplemental oxygen or ventilatorysupport at 28 days.

Results are expressed as medians and theinterquartile range. Comparison of databetween groups was performed using theMann-Whitney U test. Matched comparisons,within groups, from one day to anotherwas using the Wilcoxon rank sumtest. Correlations were performed usingSpearman's non-parametric regression; X2(with Yates's correction) was used for analysisof numbers receiving positive pressure ventila-tion, ductal patency, and direction of ductalflow. The significance level was taken at 5%.A peak pulmonary artery pressure of <30

mm Hg is considered to represent the upperlimit of normal pulmonary artery pres-sure. 19-21 Previous studies have shown thatthe lower limit for the TPV:RVET in preterminfants is 0.34.15-16 The average heart rate ofpreterm infants less than 1501 g is 155 (R-Rinterval=0-390). 17 Therefore a TPV:RVET(c)of 0'54 probably represents the lower limit ofpulmonary artery pressure in the preterminfant. Using CLD as the end point, we cal-culated the operating characteristics of aTPV:RVET(c) ratio <054 on each of the daysof study.The study was approved by the Liverpool

Area Health Authority ethics committee andinformed consent was obtained from theparents of each infant studied.

ResultsThere were 34 infants in the CLD group and20 in the control group. Table 1 shows thedemographic and clinical data for the twogroups. Infants with CLD were of signifi-cantly lower birth weight and gestation whencompared with the control group, p<0Q0001.The number of infants receiving positivepressure ventilation on each day of the studyfell in both groups but there were significantlyfewer ventilated infants in the control groupfrom day 2 onwards.

Table 2 shows the a-A ratio and the FiO2on the day of study. The a-A ratio was signifi-cantly lower in the CLD group over the firstthree days. It was not possible to calculate thea-A ratio after this time as many infants didnot have regular arterial oxygen tensionmeasurements by means of an indwellingarterial catheter. The FiO2 from day 1 was

Table 2 a-A oxygen ratio and FiO2 (%/) on the day ofstudy in the CLD and control groups. All results aremediansDay of CLD Control p Valuestudy (n=34) (n=20)1 a-A ratio 0-16 0-29 0-02

F1O2 70 43 0-0172 a-A ratio 0-16 0-22 0-014

FIO2 50 35 0-0023 a-A ratio 018 0 37 0-0017

FIO2 50 25 0.00017 Fso2 38 21 <0 000114 FIO2 33 21 <0 000121 FIO2 40 21 <0 000128 FIO2 40 21 <0 0001

Analysis using Mann-Whitney U test; significance level 5%.a-A ratio=alveolar-arterial oxygen difference.

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305Pulmonary artery pressure canges in the very low birthweight infant developing chronic lung disease

> 050

0-4

0145 K C 4

0-40

0 7 14 21 28Days after birth

Figure 2 The TPV.RVET(c) ratio in CLD and control group by day of study.X represents medians and closed bars interquartile range. Broken line represents lower limitofpulmonary artery pressure, TPV:RVET(c)=0-54 (correctedfor heart rate).

Table 3 Doppler measurements of TPV (msec), RVET(msec), and heart rate (beats/minute) in the CLD andcontrol groups on the day of study. All results are medians

CLD Control p ValueDay ofstudy (n=34) (n=20)

1 TPV 0 043 0-045 NSRVET 0-172 0-175 NSHeart rate 164 155 NS

2 TPV 0 049 0-051 NSRVET 0-176 0-173 NSHeart rate 164 164 NS

3 TPV 0-048 0-058 0 0009RVET 0-170 0-180 NSHeart rate 171 173 NS

7 TPV 0 049 0-058 0 0007RVET 0-167 0-169 NSHeart rate 170 168 NS

14 TPV 0 050 0-063 0-0005RVET 0-160 0-173 NSDHeart rate 168 164 NS

21 TPV 0 050 0-062 <0 0001RVET 0-170 0-180 NSHeart rate 166 164 NS

28 TPV 0-048 0-069 <0 0001RVET 0-170 0-176 NSHeart rate 168 162 NS

Analysis using Mann-Whitney U test; significance level 5%.Heart rate calculated from the R-R interval on theelectrocardiogram.

Table 4 Number (%o) of infants with patent ductus arteriosus and direction of ductalflowin CLD and control groups by day of study. Direction offlow expressed as the ratio ofleft-right:bidirectionalDay of study CLD (n=34) Control (n=20)

Patency Direction Patency Direction

1 34 (100) 1:2-7* 20 (100) 1:2-32 25 (74) 1:1-3 -14 (70) 1:1-83 19 (56) 38:1 8(40) 3:17 8 (24) 3:1 t2 (10) -

14 3 (9) 2:1 0- -

21 2(6) 1:1 0- -

28 3 (9) 2:1 0- -

* Two infants had pure right-left flow on day 1 only.tBoth infants had left-right flow.Ratios only calculated on those with patent ducts.

Table 5 Operating characteristics of a TPV.RVET(c) ratio <0 54 in identifying infantswith chronic lung disease by day of studyDay ofstudy 1 2 3 7 14 21 28

Sensitivity (%) 97 91 71 73 62 76 88Specificity (%) 15 40 60 65 80 85 95False positive rate (%) 85 60 40 35 20 15 5Predictive value (%) 66 72 75 78 84 89 97

significantly lower in the control group,p=0017. Between day 14 and day 28, therewas a rise in the Fio2 in the CLD group butthis was not significant (p=0 36). There was asignificant negative correlation between theFiO2 and TPV:RVET(c) from day 7 onwards,r increasing from -0-54 on day 7 (p<0-001) to-0-76 on day 28 (p<0.0001).

Figure 2 shows the change in theTPV:RVET(c) ratio on days 1, 2, 3, 7, 14, 21,and 28. Both groups of infants showed a risein the TPV:RVET(c) ratio over the first 14days after birth. However the CLD group hada significantly lower ratio from day 2 onwardswhen compared with the control group,p=0002. The difference in the ratio was dueto a shorter TPV from day 3 onwards,p=0O0009 (table 3), rather than due to differ-ences in RVET or heart rate. The CLD grouphad a significant fall in the TPV:RVET(c)ratio from days 14 to 28, p=00007, whereasthe ratio remained relatively constant inthe control group, p=046. There was nocorrelation between the TPV:RVET(c) ratioon day 1 and birth weight or gestation. Rightventricular function was considered to benormal in all infants throughout the study.

Table 4 shows the ductal patency anddirection of ductal flow in both groups by dayof study. Ductal patency fell from 100% onday 1 to 6% on day 28. In both groups ofinfants bidirectional flow occurred in themajority on day 1 becoming mainly left-rightflow by day 3. There were no significantdifferences in the duration of ductal patencyor direction of ductal flow in the two groupsby day of study. Of the three infants in theCLD group with patent ducts on day 28, twounderwent surgical ligation of the ductusarteriosus.

Table 5 shows the operating characteristicsof a TPV:RVET(c) ratio <0 54 in predictingCLD on the days of study. There was aprogressive rise in the predictive value from65% on day 1 to 97% on day 28. Other ratios(0A49-0-56) were considered in a similar way,but the optimal operating characteristics wereobtained from a ratio of <0 54.

DiscussionAdvances in neonatal intensive care haveimproved the survival of the very low birth-weight infant but there has been an associ-ated increase in the incidence of CLD.24Pulmonary hypertension is invariably presentin infants discharged home on supplementaloxygen5-9 but until now the changes inpulmonary pressure have not been studiedlongitudinally in the very low birthweightinfant during the first 28 days. From thelimited data available it appears thatpulmonary hypertension plays an importantpart in the pathophysiology of this con-dition6 10-11 and has been linked to theincreased incidence of cot death in infantswith CLD.4The TPV:RVET ratio is influenced by

pulmonary artery pressure, myocardial con-tractility, and heart rate.25 Our subjective

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assessment was that all infants had normalright ventricular function. -The TPV, RVETand TPV:RVET are shortened as heart rateincreases and therefore we corrected for thisby dividing the ratio by the square root of theR-R interval.22 23 Kitabatake et al20 and Akibeet al22 showed a close negative correlationbetween this ratio and directly measured pul-monary artery pressure in older infants andchildren. For the purposes of our study weconsidered that a peak pulmonary pressure of30 mm Hg represented the upper limit ofnormal pulmonary artery pressure.21 Usingthe regression equation quoted by Akibe et althis corresponds to a TPV:RVET(c) of 0 53.The infants studied by Evans and Archer'5-17probably resemble our study population moreclosely, and from their results aTPV:RVET(c) of 0 54 being the lower limitof normal in the preterm infant. This figurewas therefore chosen as the lower limit ofnormal pulmonary artery pressure. In fact, theoperating characteristics were not significantlyaltered by using a figure of 053.We found that there was a progressive fall

in pulmonary artery pressure in both groupsof infants over the first 14 days. However therate of decrease was slower in the CLD group.This is probably explained by the fact thatthey had more severe hyaline membranedisease than the control group as reflected bythe significantly lower a-A ratio and higherFiO2 during the first three days. The medianTPV:RVET(c) in the CLD group neverreached the same level as the control groupbut, more importantly, significantly fell fromdays 14 to 28 suggesting a progressive rise inpulmonary artery pressure. The change in thedirection of ductal flow over the first sevendays probably occurred as a result of the fallin pulmonary artery pressure as evidenced bythe rise in the TPV:RVET(c) over the sameperiod. It appeared to have no bearing on thechanges in the TPV:RVET(c) ratio from day14 to day 28.The reason for the rise in pulmonary artery

pressure is unclear but may be explainedby the following pathological studies.Tomashefski et al I I found that in those infantswith hyaline membrane disease who diedduring the first two weeks after birth, thepulmonary vascular tree showed changesconsistent with adaptation to extrauterine lifeby thinning of the smooth muscle lining thepulmonary arterioles and remodelling of thepulmonary vasculature, but the changes wereat a slower rate than in the term infant. After4 weeks of age, Taghizadeh et al'0 andTomashefski et al II found that in infants whodeveloped CLD, there was significant muscu-larisation of the smaller pulmonary arteriolesthat progressively increased the longer CLDwas present before death occurred. It waspostulated that the changes in the pulmonaryvasculature were secondary to persistentstimuli, such as hypoxia. From cardiaccatheter data we know that hypoxia is a potentpulmonary vasoconstrictor and persistenthypoxic episodes will have a deleterious effecton the pulmonary vasculature. Our results

appear to show that the normal cardiovascularadaptation to extrauterine life occurs in thevery low birthweight infant over the first 14days despite severe hyaline membrane disease.However, persistent impairment in lungfunction and parenchymal damage appears toreverse these changes leading to an increase inpulmonary artery pressure.We also found that there was a progressive

increase in the correlation between theTPV:RVET(c) and FiO2 from day 7 today 28. This is in contrast to the observationsof Evans and Archer who were unable to findany correlation, but in their study, infantswere only studied if the FiO2 remained above0o5.1' However, our results showed an associ-ation between the pulmonary artery pressureand the severity of chronic lung disease.Invasive measurements in small groups ofinfants with CLD by Berman et al.,7 Bush etaL,8 and Goodman et al9 also showed thatraised pulmonary artery pressure was in-variably present and correlated with the levelof supplemental oxygen. In those studiesfailure to reduce pulmonary artery pressureafter exposure to 100% oxygen was associatedwith a poor outcome. The importance of thisis that it is more difficult to prevent hypoxicperiods the higher the oxygen requirement.Recurrent hypoxia will have further dele-terious effects on the pulmonary vasculaturepotentially leading to persistent pulmonaryhypertension.The second part to our study was to

assess the operating characteristics of theTPV:RVET(c) ratio in identifying infants whowere most likely to develop CLD early in theirpostnatal course. We found that if theTPV:RVET(c) was <054, we were able topredict CLD in the majority of patients(table 5) even by 7 days of age. The presentmanagement of infants with CLD is limited tosupplemental oxygen, nutritional supplemen-tation to increase growth and diuretics.3 24 Byestimating pulmonary artery pressure, usingthe TPV:RVET(c) ratio, infants at risk ofdeveloping CLD could be identified early intheir postnatal course. This presents anopportunity for early therapeutic intervention.Interestingly, older infants with severepulmonary hypertension secondary to CLDhave been treated with calcium antagonists,such as nifedipine, in an attempt to reducethe pulmonary artery pressure. Brownlee eta126 and Johnson et a127 studied the clini-cal, pharmacokinetic, and pharmacodynamicshort term effects of intravenous nifedipine ona small group of infants who had invasivemeasurements of pulmonary artery pressure.There was a significant short lived fall inpulmonary artery pressure and pulmonaryvascular resistance and the pharmacologysuggested first order kinetics. In addition topresent therapeutic manoeuvres, we speculatethat in order to influence CLD severity,treatment could be aimed at trying to preventthe rise in pulmonary artery pressure early inthe postnatal course. This could be doneeither indirectly by attempting to minimise theparenchymal lung damage or directly by using

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Pulmonary artery pressure changes in the very low birthweight infant developing chronic lung disease 307

pulmonary vasodilators. This might improvepulmonary perfusion, improve oxygenation,and break the cycle where hypoxia leads tofurther increases in vascular resistance.

Further studies are required to determinethe extent to which this non-invasive assess-ment of pulmonary artery pressure can beused in the clinical management of the verylow birthweight infant with CLD.

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