Cerebral Blood Flow Velocity Changes in Preterm Infants After a Single Dose of Indomethacin: Duration of Its Effect

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Cerebral

Blood

Flow Velocity

Changes

in

Preterm

Infants

After

a Single

Dose

of

Indomethacin:

Duration

of Its Effect

Frank

Van

Bel, MD,

Margot

Van

de Bor, MD, Theo

Stijnen,

PhD,

Jan Baan,

PhD,

and Jan H. Ruys,

MD

From the Departments of Pediatrics and Medical Statistics, University Hospital, Leiden, The Netherlands

ABSTRACT. Indomethacin decreases cerebral blood flow velocity and blood flow in the preterm infant. The

dura-tion of this negative effect has not been established. Cerebral blood flow velocity was evaluated in 24 preterm

infants with symptomatic patent ductus arteriosus before and during the first 12 hours after a single intravenous dose of indomethacin, 0.1 mg/kg. Cerebral blood flow velocity was estimated by serial Doppler investigations of the anterior cerebral arteries. Indomethacin adminis-tration led to an instantaneous decrease of peak systolic flow velocity, temporal mean flow velocity, and end-diastolic flow velocity of the anterior cerebral arteries in all infants, which was maximal between 2 and 40 minutes after indomethacin administration and was followed by a more sustained recovery of all velocities to baseline values. Temporal mean flow velocity was not different from pre-indomethacin values at 3 hours after the admin-istration. It is concluded that indomethacin can impact the cerebral circulation of the preterm infant for at least

2 hours. This may have consequences in preterm infants with unstable hemodynarnics and pulmonary function. Pediatrics 1989;84:802-807; cerebral blood flow, neonate, indomethacin.

Indomethacin is widely used for noninvasive do-sure of symptomatic patent ductus arteriosus in the

preterm infant. Moreover, a protective effect of

indomethacin against periventricular-intraventric-ular hemorrhages have been reported in clinical studies.’ A cerebral blood flow reduction of up to

Received for publication Aug 8, 1988; accepted Dec 7, 1988.

This study has been presented, in part, at the annual meeting of the American Pediatric Society and Society for Pediatric Research, Washington, DC, May 2-5, 1988.

Reprint requests to (F.V.B.) University Hospital Leiden, Dept

of Pediatrics, Neonatal Unit, Bldg 35, P0 Box 9600 2300 RC

Leiden, The Netherlands.

American Academy of Pediatrics.

40% have been reported from animal studies and

studies in adult humans after indomethacin admin-istration, possibly caused by its inhibitory effect on

prostaglandin production.2’3 In newborn babies

treated with indomethacin, a decrease in cerebral blood flow velocity4’5 and in actual cerebral blood

flow determined with the xenon 133 clearance

method6 has been reported. However, the duration of this negative effect on cerebral blood flow in these infants has not yet been established. To an-swer this important question, we studied the

alter-ations in cerebral blood flow during the first 12

hours after a single intravenous dose of indometh-acm, 0.1 mg/kg, in 24 preterm infants treated for patent ductus arteriosus, by serial measurements of the cerebral blood flow velocity using the transcu-taneous Doppler technique.

PATIENTS

AND

METHODS

Twenty-four neonates with a gestational age of

less than 34 weeks, determined by maternal dates

or Ballard score,7 who had patent ductus arteriosus were studied after being given 0.1 mg/kg of indo-methacin intravenously for the first time. The cri-teria for a patent ductus arteriosus diagnosis were based on clinical signs, radiographic characteristics, and Doppler/echocardiographic evidence (left atrial to aortic root ratio 1.158 and a diastolic reverse flow in the pulmonary artery). Infants with abnor-malities that could alter cerebral blood flow (veloc-ity) other than patent ductus arteriosus were

ex-cluded from the study with the exception of the

possible presence of hypercapnia and hypoxia.9”#{176}

Informed parental consent was obtained in all

cases. The study was approved by the scientific board of the department of pediatrics.

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blood flow, the blood flow velocity in the anterior cerebral artery was determined by transcutaneous

Doppler technique using the anterior fontanel as

an acoustic window. A continuous mode

bidirec-tional Doppler flow meter (Parks 1010) with a 9.6-or 5.0-MHz transducer was used. With this equip-ment, frequency shifts pass through a zero-crossing

detector.”2 The frequency shift was converted to

blood flow velocity using an internal calibration

signal of 5 cm/s and assuming an angle between

the axis of the ultrasound beam and the direction

of flow of 0 degrees. The transducer was placed

over the anterior fontanel and directed toward the left or right anterior cerebral artery until an optimal signal for analysis was obtained. The infants were

in stable condition, not fed, and in a resting state, while lying supine. Maximal arterial pulsations of forward flow (while avoiding a reverse flow) were

always used for recordings. From at least 10

se-quential cardiac cycles, peak systolic flow velocity, end-diastolic flow velocity, and temporal mean flow velocity were determined and averaged. Reproduc-ibility of intracranial Doppler flow velocimetry has proven to be satisfactory in the hands of experi-enced examiner5.’3 Provided cerebral perfusion pressure is relatively constant and hematocrit val-ues are in the physiologic range, blood flow velocity in the anterior cerebral arteries is a qualitative

measure of actual cerebral blood flow’4”5 and is

indicative of changes in cerebral vascular resist-ance, which is largely controlled by the cerebral arterioles situated distally to the anterior cerebral arteries.’6”7

Neonatal data were collected prospectively.

Pac02 was obtained from an indwelling arterial

catheter or from arterial blood samples. Arterial oxygen tensions were derived from

transcutane-ously measured partial oxygen tension (tcPo2).

Blood pressure measurements were made using a

noninvasive oscillometric method (Dinamap).

Hematocrit was measured before the start and

again at the end of the study from venous blood samples. If necessary, packed red blood cell

trans-fusions were given to keep hematocrit values

greater than 40%. Routinely, in every preterm in-fant admitted to our neonatal intensive care unit, serial real-time ultrasound studies of the brain are performed from birth or from admission until dis-charge. To classify periventricular-intraventricular

hemorrhages, the grading system described by Pap-ile et al’8 was used.

The study design was as follows: Doppler meas-urements of the anterior cerebral arteries were per-formed just before, at 2, 4, 6, 8, 10, 20,30, 40, 50, and 60 minutes, and at 2, 3, 4, 8, and 12 hours after indomethacin administration, which was injected

intravenously during 10 to 20 seconds. In most

instances, the transducer was continuously held in place during the first 10 minutes ofthe study period. The rationale for this scheme was based on work of other investigators2’4’ in which a rapid decrease and a more sustained increase of cerebral blood flow was seen after indomethacin administration.

Simultaneously

with the cerebral

Doppler

measure-ments, arterial blood pressure was measured and

tcPo2

values

and heart

rates were registered.

The

Paco2 was measured

just

before and at 4 and 12

hours

after indomethacin medication. At 10 and 30

minutes and at 1, 2, 3, 4, 8, and 12 hours after

indomethacin administration, a brief physical ex-amination was done to assess clinical ductus do-sure. Twenty-four hours after there was clinical evidence that the ductus had closed, closure was reassessed by a pediatric cardiologist, who was

un-aware of the study results, using clinical and

echo-cardiographic examination.

Results are reported as means ± SD or SEM.

Differences between mean values of the variables at different times were assessed by Student’s t test for paired comparisons. To investigate the differ-ence between the global levels of the curves of the group of infants whose ductus

arteriosus

remained open and the group of infants with clinical evidence of ductus closure, we averaged the measurements for each infant during the study period. Next, these mean values were compared between the two groups with Student’s two-sample t test. Correlations were assessed by Spearman’s correlation coefficient. All

P values mentioned are two-sided P < .05 was

considered significant.

RESULTS

The patient characteristics were as follows: birth weight, 1281 ± 348 g (range 800 to

2090

g); gesta-tional age, 29.1 ± 2.4 weeks (range 24 to 33 weeks);

and age at treatment, 6 ± 3 days (range 2 to 12

days). All infants were mechanically ventilated. During the study period, all investigated infants were stable and no major changes in ventilator settings were necessary, which excluded possible influences of artificial ventilation on cerebral blood flow.’9 In 9 infants, periventricular-intraventricular

hemorrhages were diagnosed: grade I in 1, grade II in 4, grade III in 3, and grade IV in 1 infant(s). In eight of nine instances, the periventricular-intra-ventricular hemorrhages were already diagnosed before indomethacin treatment. Periventricular

leukomalacia was diagnosed in 2 infants, in both

(3)

U S U,

C

U >

i 10

0.

8

-z;10 S

g

a

. 6B10 20 30 60 50 60 2 3 4 8 12

tndom.thocn Minutes Hours

. p<O.05. .o p(ctO1 t p(O.OO1 ondfl p<O.0001 versus pre-Indomethocn colues

C

:

150#{149}

.- 140

-a a’

I

130-I

x

12 range 1 to 12 hours). Reassessment of ductal status by the pediatric cardiologist 24 hours after indo-methacin administration revealed reopening

asso-ciated with reappearance of clinical signs in 4

pa-tients. Fifteen patients eventually showed definite

ductal

closure.

Heart rate, mean arterial blood pressure, and

tcPo2

values,

determined

simultaneously

with

the

Doppler investigations, are shown in Fig 1 as a

function of time. The mean heart rate steadily

decreased. Mean mean arterial blood pressure was significantly higher 4 minutes after indomethacin administration but did not differ during the

re-mainder of the study period compared with the

baseline value (value before indomethacin admin-istration). tcPo2 was fairly stable throughout the study period. The Paco2 value before indomethacin treatment (46 ± 6 mm Hg) was slightly but signif-icantly higher compared with the values at 4 and

12 hours after treatment (41 ± 6 and 41 ± 7 mm

Hg, respectively, P < .05).

Peak

systolic flow velocity, end-diastolic flow velocity, and temporal mean flow velocity of the anterior cerebral arteries as a function of time are

shown

in Fig 2. All velocities showed the same pattern: a rapid decline in the first 2 minutes after indomethacin administration; lowest values were found between 2 and 40 minutes after indomethacin treatment. Afterward, a sustained recovery of all velocities occurred toward baseline levels. The mean value of the temporal mean flow velocity of the anterior cerebral arteries was no longer

signif-icantly different compared with the baseline value

#{212}246810 2030405060 2 3 6 8

f

Minutes Hours

Indomethocin

. pc 0.05 .. p<O.O1 #{149}t Pt 0.001 ond ti p<O.0001 or$us pre-Indoinethocin cOtu#{149}S Fig 1. Mean values ± SEM of heart rate, mean arterial blood pressure (MABP), and transcutaneous (tc) Po2 in 24 infants

(-)

as a function of time: O#{149}. .0, infants

with clinical evidence of ductus closure (n = 19);

.-

-

-.,

infants whose ductus arteriosus remained open

(n = 5).

Fig 2.

Mean values ± SEM of peak systolic blood flow velocity (PSFV), temporal mean blood flow velocity (MFV), and end-diastolic blood flow velocity (EDFV) of anterior cerebral artery in 24 infants (-) as a function

of time: 0. ‘

.0,

infants with clinical evidence of ductus

closure (n = 19); - - -, infants whose ductus

arterio-st’s remained open (n = 5).

3 hours after indomethacin administration. The

temporal mean end-diastolic flow velocity value 12 hours

after

indomethacin administration was sig-nificantly higher compared with the baseline value. No correlations were found between the following individual data: heart rate, arterial blood pressure,

tcPo2,

and Pac02,

on

the one hand, and peak sys-tolic flow velocity, temporal mean flow velocity, or end-diastolic flow velocity in the anterior cerebral arteries on the other. When the Doppler variables for the infants with clinical ductus closure (19 infants) were compared with those of the infants whose ductus remained open (5 infants), an almost similar time-dependent pattern of all velocities be-tween both subgroups was found (Fig 2). However, infants whose ductus remained open had somewhat higher mean peak systolic flow velocity, temporal mean flow velocity, and end-diastolic flow velocity values in the anterior cerebral arteries throughout

the

first

4 hours, although the differences were not significant. It must be borne in mind, however, that

the subgroup of infants whose ductus remained

open was much smaller than the other subgroup (5

vs 19). After 4 hours the mean end-diastolic flow velocity values of the subgroup with clinical ductal closure were slightly higher. When clinical data measured simultaneously from both subgroups were compared with the cerebral Doppler measurements,

the global level throughout time of the Pao2values

in the 5 infants without clinical ductal closure was

significantly lower throughout

the

study period (P

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8 12

blood pressure, and hematocrit did not differ sig-nificantly between subgroups.

When looking for a different effect of indometh-acm on cerebral blood flow velocity based on

ges-tational age, we found that the pattern and

mag-nitude ofpeak systolic flow velocity, temporal mean

flow velocity, and end-diastolic flow velocity

changes in the anterior cerebral arteries were sim-ilar when infants born after 28 weeks’ gestation or less (n = 12) were compared with those born after a gestation of more than 28 weeks.

Seven infants were slightly hypercapnic (Pac02 > 50 mm Hg) at the beginning of the study. How-ever, there was no significant difference in the maximal decrease in temporal mean flow velocity of the anterior cerebral arteries after indomethacin administration between hyper- and normocapnic infants (48% vs 42%).

DISCUSSION

Results of our study indicate that temporal mean flow velocity of the anterior cerebral arteries was significantly lower for 2 hours after a therapeutic intravenous dose of indomethacin, 0.1 mg/kg,

com-pared

with the value before indomethacin treat-ment. This decrease indicates a decrease in cerebral blood flow during this time and a concomitant increase in cerebral vascular resistance, as illus-trated in Fig 3, showing a relative measure of this quantity. To our knowledge this is the first study to assess the duration of the effect of intravenous indomethacin administration on neonatal cerebral circulation. Although none of our 24 (relatively stable) infants showed clinical signs of impaired cerebral function after indomethacin treatment, its effect on cerebral metabolism remains uncertain. In experimental studies in adult and newborn ani-mals, the decrease in cerebral blood flow after

in-domethacin administration was accompanied by a

a,

C

:

a

.

a

o io io c

Minutes Indomethocn

Hours

Fig 3. Pattern of relative cerebral vascular resistance during study period expressed by mean arterial blood pressure divided by temporal mean blood flow velocity of the anterior cerebral artery. Mean arterial blood pressure is taken as a measure of effective pressure difference over cerebrovascular bed and mean flow velocity as a relative measure of total cerebral blood flow.

compensatory enhancement of oxygen extraction

from the blood to maintain cerebral metabolism.20’2’

However, the same studies showed that, if cerebral

perfusion pressure was changed, cerebral oxygen

consumption at lower mean arterial blood pressure

was reduced from baseline values, indicating a

de-crease in metabolism.#{176}’’ Clinical studies, in which

preterm

infants

received

indomethacin for preven-tion of periventricular-intraventricular hemor-rhages or for noninvasive closure of patent ductus arteriosus, have shown no adverse

neurodevelop-mental

effects

of neonatal

indomethacin

medica-tion.’

Also,

in our study population, which

con-sisted of infants who were relatively stable at the time of the investigations, it was not probable that cerebral damage was related to indomethacin treat-ment. Eight of nine infants already had periven-tricular-intraventricular hemorrhages before the start of the study. Moreover, one of the two infants in whom periventricular leukomalacia subsequently developed had been severely asphyxiated

perina-tally, which probably accounts for the detected

cerebral damage. The other infant with periventric-ular leukomalacia had a severe gastric hemorrhage

with a period of profound hypotension: the unusual

late first echographic appearance of the periven-tricular leukomalacia fits well with this event. How-ever, the possibility cannot be excluded that, in

preterm infants with unstable hemodynamics and

pulmonary function, an indomethacin-induced

de-crease in cerebral perfusion will harm brain tissue and function.

In the infants without clinical ductus closure, a similar pattern of peak systolic flow velocity, tem-poral mean flow velocity, and end-diastolic flow velocity of the anterior cerebral arteries with the rapid decrease and sustained recovery after indo-methacin administration was present. However, ab-solute velocities in this subgroup were higher, prob-ably because of the vasodilatory effect on the cere-bral arterioles of the consistently lower Po2 values

(Fig 1).24 Therefore, it is unlikely that indometha-cm-induced ductal closure plays a role in the initial lowering of the blood flow velocities in the anterior cerebral arteries. The same can be said with regard to the change in Pac02 values after indomethacin administration: the initial decrease of blood flow velocities of the anterior cerebral arteries was too large to be explained by the slightly lower values of

PacO2 found at 4 and 12 hours after indomethacin

administration compared with the baseline

valueY Moreover, no correlation was found

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cere-bral circulation is caused by inhibition of the

vas-odilatory effects of prostaglandins, analogous to its

action on the ductus arteriosus.27 But the instan-taneous effect of indomethacin on the cerebral cir-culation as compared to the more sustained effect on ductal closure suggests the presence of other mechanisms possibly involving scavenging free rad-icals or effects on calcium transport in smooth muscle. In fact, Eriksson et al26 showed that the indomethacin effect on cerebral blood flow was independent of prostaglandin activity.

It has been reported that indomethacin’s

ability

to reduce cerebral blood flow is greater in the

pres-ence of hypercapnia-induced

vasodilation.2’3

The

absence of a larger decrease in temporal mean flow velocity of the anterior cerebral arteries after in-domethacin administration

found

in our seven in-fants with initial hypercapnia, compared with nor-mocapnic infants, may be explained by the

circum-stance that in some of these seven infants a

prolonged hypercapnia existed with concomitant reduction of vasodilation and normalization of cer-ebral blood flow.

Finally, our study appears to give some evidence

for a vasoconstrictive action of indomethacin on

the systemic circulation as well: in so far as changes in heart rate reflect similar changes in cardiac output,#{176} it can be inferred from Fig 1 that cardiac output decreases from 4 minutes after indometha-din administration. Except for one mean arterial

blood

pressure measurement (at 4 minutes after indomethacin), this quantity essentially remained unchanged. Total peripheral resistance, defined as mean arterial

blood

pressure divided by cardiac output, appears to be significantly increased, as-suming no changes in central venous pressure.

In conclusion, we found an instantaneous

in-crease in cerebral vascular resistance and a conse-quent decrease in cerebral blood flow after admin-istration of an intravenous dose of indomethacin, 0.1 mg/kg, which lasted for about 2 hours after administration. This effect of indomethacin seems

to be largely independent of ductus closure.

Atten-tion must be paid to these alterations in cerebral

perfusion

in view of the risk for ischemic damage in preterm infants with unstable hemodynamics

and pulmonary function.

REFERENCES

1. Ment LR, Duncan CC, Ehrenkranz RA, et al. Randomized

indomethacin trial for prevention of intraventricular

hem-orrhage in very low birth weight infants. J Pediatr.

1985;107:937-943

2. Dahlgren N, Nilsson B, Sakabe T, et al. The effect of

indomethacin on cerebral blood flow and oxygen consump-tion in the rat at normal and increased carbon dioxide

tensions. Acta Physiol Scand. 1982;111:475-485

3. Wennmalm A, Eriksson 5, Wahren J. Effect of indometha-cin on basal and carbon dioxide stimulated cerebral blood flow in man. Clin Physiol. 1981;1:227-234

4. Cowan F. Indomethacin, patent ductus arteriosus, and cer-ebral blood flow. J Pediatr. 1986;109:341-343

5. Lundell BPW, Sonesson SE, Cotton RB. Ductus closure in

preterm infants: effects on cerebral hemodynamics. Acta Paediatr Scand. 1986;329(suppl):140-147

6. Pryds 0, Greisen G, Johansen KH. Indomethacin and cer-ebral blood flow in premature infants treated for patent

ductus arteriosus. Eur J Pediatr. 1988;147:315-316

7. Ballard JL, Kazmaier-Novak K, Driver M. A simplified

score for assessment of fetal maturation of newly born

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8. Ellison RC, Peckham GJ, Lang P, et al. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics.

1987;71:364-372

9. Martin CG, Snider AR, Katz SM, et al. Abnormal cerebral blood flow pattern in preterm infants with a large patent

ductus arteriosus. J Pediatr. 1982;1O1:587-593

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meas-urement. Clin PerinatoL 1985;17:179-193

11. Sumner DS. Ultrasound. In: Kempczinsky RF, Yao JST,

eds. Practical Noninvo.sive Vascular Diagnosis. Chicago, IL:

Yearbook Medical Publishers; 1982:21-47

12. Wladimiroff JW, Van Bel F. Fetal and neonatal cerebral blood flow. Semin PerinatoL 1987;11:335-346

13. Winberg P, Dahistrom A, Lundell B. Reproducibility of intracranial Doppler flow velocimetry. Acta Paediatr Scand.

1986;329(suppl):134-139

14. Barton DC, Hellmann J, Hernandez MJ, et al. Regional

cerebral blood flow, cerebral blood flow velocity, and pulsa-tility index in newborn dogs. Pediatr Res. 1983;17:908-912 15. Greisen G, Johansen K, Ellison PH, et al. Cerebral blood

flow in the newborn infant: comparison of Doppler

ultra-sound and “xenon clearance. J Pediatr. 1984;104:411-418 16. Huber P, Hands JH. Effect of contrast material,

hypercap-nia, hyperventilation, hypertonic glucose and papaverine on

the diameter of the cerebral arteries. Invest RO4iOL 1967;2:17-32

17. Greenberg JH, Noordergraaf A, Reivich M. Control of cer-ebral blood flow: models and experiments. In: Baan J,

Noor-dergraaf A, Raines J, eds. Cardiovascular System Dynamics.

Cambridge, MA: MIT Press; 1978:391-398

18. Papile LA, Burstein J, Burstein R, et al. Incidence and

evolution of subependymal and intraventricular hemor-rhage: a study of infants with birthweights less than 1500

gm. J Pediatr. 1978;92:529-533

19. Leahy FAN, Durand M, Cates D, et al. Cranial blood volume changes during mechanical ventilation and spontaneous breathing in newborn infants. J Pediatr. 1982;101:984-987

20. Pickard JD, MacDonell LA, Mackenzie ET, et al. Response

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dose of indomethacin on the cerebral circulation of newborn pigs. Pediatr Res. 1987;21:188-192

22. Setzer F, Duenas L, Rodriguez, et al. Prophylactic indo-methacin for prevention of intraventricular hemorrhage: neurodevelopmental follow-up. Pediatr Res. 1987;21:391A.

Abstract

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25. Lassen NA. Control of cerebral circulation in health and disease. Circ Res. 1974;34:749-760

26. Eriksson 5, Hagenfeldt L, Law D, et al. Effect of prosta-glandin synthesis inhibitors on basal and carbon dioxide

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28. Leffler CW, Busjja DW, Fletcher AM, et al. Effects of 30. Rudolph AM. Circulatory changes during the perinatal

indomethacin upon cerebralhemodynamics ofnewborn pigs. period. Pediatr CardioL 1983;4(suppl II):17-20

ANNOUNCEMENT

OF 1990 PEDIATRIC

CRITiCAL

CARE MEDICINE

EXAMINATiON

The Sub-board of Pediatric Critical Care Medicine of the American Board of

Pediatrics will administer its next certifying examination on Friday, July 20, 1990.

The following criteria must be met to be eligible to sit for the examination:

1. Certification by the American Board of Pediatrics 2. Subspecialty Training or Experience

Three

years of training in pediatric critical care medicine is required for

physicians

who began training on or after January 1, 1988. Two years of training in pediatric critical care medicine is required for physicians who began training

before January 1, 1988. No foreign training will be accepted.

OR

Certification in pediatric cardiology, neonatal-perinatal medicine, pediatric

pulmonology,

or anesthesiology based upon completion of residency training plus two years of training in critical care medicine. Physicians who entered

training in pediatric critical care medicine prior to January 1, 1988, will need

only

one year.

OR

Five years of broadly based pediatric critical care medicine. A minimum of 50%

of full-time professional activities must be spent in pediatric critical care

medicine to receive credit.

OR

Combination

of training and experience. (Please see Eligibility Criteria.) 3. Verification of training and recommendation by Program Director.

Each application will be considered individually and must be acceptable to the

Sub-board of Pediatric Critical Care Medicine.

Registration will extend from September

1, 1989,

to

November 30, 1989.

Requests

for applications received prior to September 1, 1989, will be held on file. The application fee is $1000. Applications postmarked after November

30,

1989, must include a $200 late fee. New applications postmarked after

December

30,

1989, cannot be

accepted

for

the

1990

examination.

Please direct inquires to the American Board of Pediatrics, 111 Silver Cedar

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1989;84;802

Pediatrics

Frank Van Bel, Margot Van de Bor, Theo Stijnen, Jan Baan and Jan H. Ruys

Indomethacin: Duration of Its Effect

Cerebral Blood Flow Velocity Changes in Preterm Infants After a Single Dose of

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