J Clin Ultrasound 20:4348, January 1992 CCC 0091-2751192101043-06$04.00 0 1992 by John Wiley & Sons, Inc.

Ophthalmic and Cerebral Blood Flow Velocities in Preterm Infants: Influence of Ambient Lighting Conditions Willem Baerts, MD, Ria A.C. Valentin, MD, and Pieter J.J. Sauer, MD

Abstract: Doppler ultrasound was used to study ophthalmic and middle cerebral artery flow velocities at different ambient lighting conditions in 28 preterm infants in the first week of life. We found significant increases of ophthalmic and middle cerebral artery blood flow velocities when ambient light was increased from moderate to intense. Flow velocities in the ophthalmic artery increased significantly more than in the middle cerebral artery. Doppler ultrasound studies of ophthalmic blood flow velocity may assist in answering the intriguing question whether light-induced changes of ocular perfusion play a role in the development of retinopathy of prematurity. Indexing Words: Doppler ultrasound * Pulsed Doppler * Ophthalmic artery * Retinopathy of prematurity.

Retinopathy of prematurity has been associated with many perinatal problems, particularly those seen in immature infants with respiratory disease.'-' Exposure t o intense light was recently proposed as another possible etiologic factor. Preterm infants who had been exposed to reduced ambient light intensities had a lower incidence of retinopathy than those who had been exposed to standard i l l ~ m i n a t i o n . ~ Studies of the causes of retinopathy have mainly focused on mechanisms by which oxygen may contribute to abnormal retinal vasoproliferation and Surprisingly few studies have attempted to evaluate relationships between ocular perfusion and retinal lesions, possibly because estimation of the circulation in the eye poses many technical problem^.'^^^^ Several groups have reported the results of microsphere studies of ocular perfusion in animal fetal and newborn models.16-20In only one of these studies was exposure to light part of the study protocol. It was shown to result in an increase of ocular blood Department of Pediatrics, Division of Neonatology, Erasmus University, and Sophia Children's Hospital, Rotterdam, The Netherlands. For reprints contact Willem Baerts, MD, Division of Neonatology, Sophia Children's Hospital, Gordelweg 160, NL-3038 GE Rotterdam, The Netherlands.

Useful information about the ocular circulation may be obtained by Doppler ultrasound studies of the flow velocities in the ophthalmic artery.21,22We conducted a Doppler ultrasound study of blood flow velocities in the ophthalmic artery in preterm infants. Flow velocities in the middle cerebral artery were studied simultaneously, for comparison. The aims of this study were (1)to obtain reference values for the arterial blood flow velocities in the ophthalmic and middle cerebral arteries in the first week of life and (2) to evaluate changes in flow velocities in these arteries under different ambient lighting conditions. MATERIALS AND METHODS

Twenty-eight infants were studied. Menstrual ages ranged from 25.9 to 34.0 weeks (mean 29.5, standard deviation 2.1 weeks); birth weights ranged from 570 g to 1740 g (mean 1070 g, standard deviation 315 g). Participating infants were in stable condition. Additional clinical data are presented in Table 1. Two-dimensional and Doppler scans were made with a Diasonics ADA 400 image-directed Doppler scanner (Diasonics Inc, Milpitas CAI, using a sterile, nonirritating coupling gel. For all studies, a 7.5 MHz MS S transducer was used, 43

BAERTS ET AL.

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in Figure 1. Middle cerebral arteries were scanned trans-temporally in an axial plane, as reported by Horgan et al.25 The sample volume Number of infants 28 Menstrual ages 25.9-34.0 wks (29.5 i 2.1 wks) was positioned about 10 mm lateral from Willis's Birth weights 570- 1740 g (1070 i 315 g ) circle, catching the artery in the Sylvian fissure. 17 AGA All Doppler tracings were recorded on videotape 11 SGA Asphyxia 7 for later analysis. Mechanical ventilation 24 Light intensities were measured with a PDA 7 " K luxmeter (ABBiMetrowatt GmbH, Metrux Shock L Septicemia 2 Niirnberg, FRG). Normal ambient light had an Decreased 2 intensity of 200 lux-300 lux (about 20 ftc-30 AGA: weight appropriate for menstrual age. SGA: weight l o w for ftc). Increased light amounting to 20,000-30,000 menstrual age. PDA: persistent ductus arteriosus. lux (about 2,000-3,000 ftc) was generated by a Storz 485-B cold light source (Storz & Co GmbH, Tuttlingen, FRG) and applied to the contralatera1 eye. transmitting at 7.5 MHz in 2-D mode and at 6.0 The average study lasted about 15 minutes; MHz in Doppler mode. Two-dimensional brain exposure to increased light never exceeded 3 scans were performed through the anterior fontanel, according t o accepted t e c h n i q ~ e . ~ ~ , ~ ~ minutes. Care was taken that the infant had the eyes closed during the intense illumination. InOphthalmic arteries were scanned trans-ocufants were resting quietly at the beginning of larly, as suggested by Lindner et a1." The transeach study. Most infants showed signs of arousal ducer was placed on the closed eyelids. A sample at first, particularly after starting the ophvolume of 5.4 mm-7.6 mrn was positioned about thalmic examination and after switching on the 5 mm behind the eyeball, catching the artery in light. Habituation usually occurred within 15 its extracranial part. Typical tracings are shown TABLE 1 Clinical Data of the Study Population

v

FIGURE 1. Typical mixed-mode image of ophthalmic artery scan; /upper) image of eye and retrobulbar structures; (lower) part: Doppler tracing of ophthalmic artery flow velocity waveform. JOURNAL OF CLINICAL ULTRASOUND

OPHTHALMIC AND CEREBRAL BLOOD FLOW VELOCITIES

seconds. Only those flow velocity tracings were analyzed that were obtained after stabilization of heart rate and flow velocity. Average flow velocities were calculated by planimetry of the area under the maximum velocity curve of 5 cardiac cycles, and expressed in mm/sec. Changes in velocity were expressed as percent change. For each individual study 3 values were obtained for each artery: basal velocity, velocity at increased light, and percent change. Wilcoxon’s test was used for the statistical analysis of differences between flow velocities and of changes in velocity. The study was approved by the hospital ethical committee for studies on human subjects, and consent was obtained from the parents.

RESULTS

Two-dimensional brain scans were normal in 13 infants, periventricular-intraventricularhemorrhages were seen in 7 infants, periventricular leucomalacia was seen in 5, and other lesions in 3. In 8 Doppler studies no satisfactory tracings could be recorded of the ophthalmic artery; in 5 studies no satisfactory tracings could be recorded of the middle cerebral artery. Under normal lighting conditions average flow velocities in the ophthalmic artery ranged from 18 mm/sec to 146 mmisec (mean 65, standard deviation 23 mm/sec). Average velocities in increased light ranged from 26 mmlsec to 182 mm/sec (mean 79, standard deviation 25 mm/ sec). There was a gradual increase in the aver-

1 c

age velocities over the first few days, both in normal light and in increased light, but the differences were not significant. There were significant differences between velocities in normal light and velocities in increased light. In fact, velocities in increased light were higher than velocities in normal light in all 112 available studies (Figure 2, p = 0). Under normal lighting conditions average flow velocities in the middle cerebral artery ranged from 50 mm/sec to 389 mm/sec (mean 140, standard deviation 59 mm/sec). Average velocities in increased light ranged from 67 mm/sec to 563 mm/sec (mean 159, standard deviation 70 mm/sec). As in the ophthalmic artery, there was a gradual increase in the average velocities over the first few days, both in normal light and in increased light, but the differences were not significant. Again, there were significant differences between velocities in normal light and velocities in increased light. Velocities in increased light were higher than velocities in normal light in 114 of 115 available studies (Figure 3, p = 0). Changes of average flow velocity upon increasing ambient light ranged from +3% to +74% (mean: +24, standard deviation 13%) in the ophthalmic artery, and from -2% to +55% (mean: +15, standard deviation 8%) in the middle cerebral artery. There were no apparent or significant differences between the percent changes in the early days and later in the week. Changes were higher in the ophthalmic artery than in the middle cerebral artery in 78 of the 107 available studies. The latter difference is highly significant (Table 2, p = .00001).

100

75

A

.P ._

0

-o

50

F

25 0 1

UZ

2 normal light

3 4 postnatal age

5

6

7

in days increased light

FIGURE 2. Flow velocities in the ophthalmic artery in the first week of life, in normal and increased ambient light. VOL. 20, NO. 1, JANUARY 1992

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BAERTS ET AL.

46 350

300

1

T

0

.250 E E

200

.-C A

150

? i 0

70

100

50

0 3 4 5 postnatal age in days

2

1

normal light

6

7

increased light

FIGURE 3. Flow velocities in the middle cerebral artery in the first week of life, i n normal and increased ambient light.

DISCUSSION

The eye is supplied by branches from the ophthalmic artery. This artery is the first major intracranial branch of the internal carotid artery. It originates from the carotid syphon just before the carotid artery enters Willis’s circle. The ophthalmic artery supplies ocular, orbital, and extraorbital structures. The central retinal artery and the posterior ciliary arteries are the most important ocular branches.26 Blood supply to the developing eye is provided by three vascular system^.^^,^^ The choroid circulation is mainly supplied by the posterior ciliary vessels and perfuses the outer layers of the eye. During early development, the nonvascularised retina is oxygenated by diffusion from the choroid system. The choroid circulation is believed not to be subject to a~toregu1ation.l~ The retinal vascular system evolves from retinal mesenchyma1 elements, starting in the early second trimester of gestation. It develops from the optic

TABLE 2 Percentage Changes of Mean Arterial Blood Flow Velocity in Ophthalmic and Middle Cerebral Arteries, after Increasing Ambient Light ~~

Ophthalmic Artery Range Mean SD

Middle Cerebral Artery

%

010

t3 to +74 24

-2 to +55* 15

13

a

*p = ,00001 (Wilcoxon)

disc toward the periphery and is completed at 8 to 9 months, menstrual age.27’28 The retinal circulation manifests autoregulation, reacting to changes in cardiac output, poz, and pco, much the same as the cerebral circulat i ~ n The . ~ ~ hyaloid vessels, finally, supply the developing lens. They usually degenerate by the end of g e ~ t a t i o n . ~ ~ Eventually, more than 90% of the ocular blood supply may be provided by the choroid system and less than 10% by the retinal arteries.l4,l5 In this study we demonstrated the feasibility of Doppler ultrasound studies of the ophthalmic artery in preterm infants with birth weights from 570 grams and up. We found significant increases of ophthalmic and middle cerebral artery blood flow velocities when ambient light was increased from moderate to intense. Flow velocities in the ophthalmic artery increased significantly more than in the middle cerebral artery. The question is whether measured changes in ophthalmic and middle cerebral artery blood flow velocity accurately reflect changes in ophthalmic and middle cerebral artery flow. In Doppler studies, a linear relationship between blood flow velocity and blood flow does, of course, only exist when the vascular cross-sectional area is constant. The cross-sectional area of the major cerebral arteries does not change significantly under various physiologic conditions, and changes in flow velocity are believed to indicate changes in flow."^-^^ Changes in ophthalmic vascular crossJOURNAL O F CLINICAL ULTRASOUND

OPHTHALMIC AND CEREBRAL BLOOD FLOW VELOCITIES sectional area could not be measured in our patients due to the small size of the vessel. The findings of our ophthalmic flow velocity study, however, are in agreement with results of several flow studies. Both in animal models and in the human adult, overall ocular and choroid blood flow were shown to be higher in light than in dark.20,33i34In one ;tudy the increase of choroid perfusion was suggested to have a cooling effect on the light-processing eye.34 Retinal blood flow, incidentally, was shown to be lower in light than in dark in the adult human in several other s t ~ d i e s . Because ~ ~ , ~ ~ our findings are corroborated by the results of flow studies, we assume that observed light-evoked increases of ophthalmic flow velocity reflect increases of ophthalmic flow, and eventually of ocular perfusion. Flow velocities in the middle cerebral artery were also found to be increased at intense light, although relatively less than velocities in the ophthalmic artery. Light-evoked increases of middle cerebral artery flow velocities have been reported previously in adult human subjects. They are believed to reflect increased cerebral activity.37 In one study of light-evoked changes in flow velocities and flows in the middle and posterior cerebral arteries, a relatively large increase in flow was noted in the posterior cerebral artery that perfuses the optical cortex. The ophthalmic artery was not studied.38 When comparing those results to our findings, it seems likely that the relative differences between increases in flow velocities, as were seen in our study, are due to preferential perfusion of ocular structures in response to light.34 The supposed association between retinopathy of prematurity and ambient light in the neonatal intensive care unit raises the intriguing question whether light-induced increases of ocular perfusion may play a role in the development of retinopathy. Recent work on the pathogenesis of retinopathy of prematurity has focused on the effects of local 0, concentrations on retinal vascular development. It is speculated that the relatively high p02’s of the preterm ocular circulation, particularly the choroid circulation, may result in high oxygen concentrations in the developing anterior retina, damaging the mesenchymal precursors of the retinal vascular system.13 We suspect that any increase in ophthalmic/choroid blood flow, light-induced or other and transient or not, may further raise ocular oxygen supply, thus contributing to retinal damage. Although this mechanism may not fully explain the occurrence of retinopathy in preterm VOL. 20. NO. 1, JANUARY 1992

47

infants, it certainly evokes interesting questions for future research. In conclusion, we believe that Doppler ultrasound measurements of flow velocity in the ophthalmic artery may be useful in the assessment of ocular blood flow. We found significant increases of ophthalmic and middle cerebral artery blood flow velocities in preterm infants in the first week of life when ambient light was increased from moderate to intense. Flow velocities showed a significantly higher increase in the ophthalmic artery than in the middle cerebral artery, probably as a result of preferential perfusion of ocular structures. Doppler studies of ophthalmic artery flow velocities may contribute to a further understanding of mechanisms involved in the occurrence of retinopathy or prematurity.

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tors for retrolental fibroplasia: Experience with 3,025 premature infants. Pediatrics 76:339-344, 1985. 5 . Biglan AW, Brown DR, Macpherson TA: Update on retinopathy of prematurity. S e m Perinatol 10:187- 195, 1986. 6. Avery GB, Glass P: Retinopathy of prematurity: What causes it? Clin Perinatol 15:917-928, 1988. 7. Ben Sira I, Nissenkorn I, Kremer I: Retinopathy of prematurity. Surv Ophthalmol 33:l- 16, 1988. 8. Keith CG, Doyle LW, Kitchen WH, et al: Retinopathy of prematurity in infants of 24-30 weeks’ gestational age. Med J A u s t 150:293-296, 1989. 9. Glass P, Avery GB, Siva Subramanian KN, et al: Effect of bright light in the hospital nursery on the incidence of retinopathy of prematurity. N Engl J Med 313:401-404, 1985. 10. Patz A, Eastham A, Higginbotham DH, et al: Oxygen studies in retrolental fibroplasia. 11. The production of the microscopic changes of retrolental fibroplasia in experimental animals. Am J Ophthalmol 36:1511-1522, 1953. 11. Kretzer FL, Hittner HM: Initiating events in the development of retinopathy of prematurity, in Silverman WA, Flynn JT (eds): Contemporary Issues in Fetal and Neonatal Medicine. Volume 2, Retinopathy of Prematurity. Boston, Blackwell Scientific Publications, 1985, p 121.

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12. Kremer I , Kissun R, Nissenkorn I, et al: Oxygen induced retinopathy in newborn kittens: A model for ischemic vasoproliferative retinopathy. Invest Ophthalmol V i s Sci 28:126-130, 1987. 13. Kretzer FL, Hittner HM: Retinopathy of prematurity: Clinical implications of retinal development. Arch Dis Child 63:1151-1167, 1988. 14. Bill A: Blood circulation and fluid dynamics in the eye. Physiol Rev 55:383-417, 1975. 15. Hill DW: Ocular and retinal blood flow. Acta Ophthalmol 67 suppl 191:15-18, 1989. 16. O’Day DM, Fish MB, Aronson SB, et al: Ocular blood flow measurement by nucleide labeled microspheres. Arch Ophthalmol 86:205-209, 1971. 17. Peeters LLH, Sheldon RE, Jones MD, et al: Retinal and choroidal blood flow in unstressed fetal and neonatal lambs. Pediatr Res 14:1047- 1052, 1980. 18. Milley Jr, Rosenberg AA, Jones MD: Retinal and choroidal blood flows in hypoxic and hypercarbic newborn lambs. Pediatr Res 18:410-414, 1984. 19. Stiris T, Odden J-P, Hansen TWR, et al: The effect of arterial pco, variations on ocular and cerebral blood flow in the newborn piglet. Pediatr Res 25:205-208, 1989. 20. Stiris T, Hansen TWR, Odden J-P, et al: Effect of light and hyperoxia on ocular blood flow in the newborn piglet. Biol Neonate 55191- 196, 1989. 21. Canning CR, Restori M: Doppler ultrasound studies of the ophthalmic artery. Eye 2:92-95, 1988. 22. Lindner W, Schaumberger M, Versmold HT: Ophthalmic artery blood flow velocity in healthy term and preterm neonates. Pediatr Res 24:613-616, 1988. 23. Pape KE, Blackwell RJ, Cusick G , et al: Ultrasound detection of brain damage in preterm infants. Lancet 1:1261- 1264, 1979. 24. Cooke RWI: Ultrasound examination of neonatal heads. Lancet II:38, 1979. 25. Horgan JG, Rumack CM, Hay T, et al: Absolute intracranial blood-flow velocities evaluated by duplex Doppler sonography in asymptomatic preterm and term neonates. A J R 152:1059-1064, 1989.

26. Hayreh SS: The ophthalmic artery: 111. branches. B r J Ophthalmol46:212-247, 1962. 27. Smith CG, Gallie BL, Morin JD: Normal and abnormal development of the eye, in Crawford JS, Morin J D (eds): The eye i n childhood. New York, Grune and Stratton, 1983, p 1. 28. Flower RW: Perinatal retinal vascular physiology, in Silverman WA, Flynn J T (eds): Contemporary issues i n fetal and neonatal medicine, Volume 2: Retinopathy ofPrematurity. Boston, Blackwell Scientific Publications, 1985, p 97. 29. Alm A, Bill A: The oxygen supply to the retina: I . Effects of changes in intraocular and arterial pressures, and in arterial PO, and pcoz on the oxygen tension in the vitreous body of the cat. Acta Physiol Scand 84:261-274, 1972. 30. Volpe J J , Perlman JL, Hill A: Cerebral blood flow velocity in the human newborn: The value of its determination. Pediatrics 70:147- 152, 1982. 31. Perlman JL. Neonatal blood flow velocity measurement. Clin Perinatol 12:179- 193, 1985. 32. Greisen G, Johansen K, Ellison PH, et al. Cerebral blood flow in the newborn infant: Comparison of Doppler ultrasound and 133xenon clearance. J Pediatr 101:411-418, 1984. 33. Parver LM, Auker CR, Carpenter DO, et al. Choroidal blood flow: 11. Reflexive control in the monkey. Arch Ophthalmo~100:1327- 1330, 1982. 34. Parver LM, Auker CR, Carpenter DO. Choroidal blood flow: 111. Reflexive control in human eyes. Arch Ophthalmol 101:1604-1606,1983. 35. Feke GT, Zuckerman R, Green GJ, et al. Response of human retinal blood flow to light and dark. Invest Ophthalmol V i s Sci 24:136-141, 1983. 36. Riva CE, Grunwald J E , Petrig BL. Reactivity of the human retinal circulation to darkness: A laser Doppler velocimetry study. Invest Ophthalmol V i s Sci 24:737-740, 1983. 37. Lassen NA, Ingvar DH, Skinhoj E. brain function and blood flow. Scient Am 239:50-59, 1978. 38. Aaslid R. Visually evoked dynamic flow response of the human cerebral circulation. Stroke 18:771775, 1987.

JOURNAL OF CLINICAL ULTRASOUND

Ophthalmic and cerebral blood flow velocities in preterm infants: influence of ambient lighting conditions.

Doppler ultrasound was used to study ophthalmic and middle cerebral artery flow velocities at different ambient lighting conditions in 28 preterm infa...
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