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AJNR Am J Neuroradiol 19:1931–1934, November 1998

Sonographic Ventriculography: A New PotentialUse for Sonographic Contrast Agents in

Neonatal Hydrocephalus

George A. Taylor, Janet S. Soul, and Patricia S. Dunning

BACKGROUND AND PURPOSE: Sonographic identification of communicating and noncom-municating forms of posthemorrhagic hydrocephalus can be difficult. This study evaluates thefeasibility of using sonographic contrast agents to determine ventricular patency in a newbornanimal model.

METHODS: A craniotomy was performed and a catheter was placed under sonographicguidance into the lateral ventricle in five anesthetized newborn piglets. Sonograms wereobtained before and after intraventricular injection of 0.01 mL of a sonographic contrast agent(Imagent, formulation AF0150; Alliance Pharmaceutical Corp, San Diego, CA) diluted in 1 mLnormal saline, and images were assessed for presence and location of echogenic contrastmaterial.

RESULTS: Flow of contrast material was identifiable from the ipsilateral lateral ventricleinto the contralateral lateral ventricle, and through the third and fourth ventricles into thebasal cisterns during real-time sonography in every animal. Ventricular and cistern echoge-nicity remained increased for approximately 4 minutes after injection.

CONCLUSION: Contrast-enhanced sonographic ventriculography has the potential to iden-tify patency of CSF pathways in newborns with hydrocephalus and an indwelling ventricularcatheter.

Intracranial hemorrhage in the premature infant isone of the more common causes of acute hydroceph-alus in the neonatal period (1). Blood may causeimpairment of CSF flow by a variety of mechanisms,including mechanical obstruction of the ventricularsystem, obliterative ventriculitis or arachnoiditis atthe level of the aqueduct of Sylvius, at the outflow ofthe fourth ventricle, or at the level of the subarach-noid space (1–3). Initial medical management of bothslowly and rapidly progressive forms of ventriculardilatation often involves serial lumbar punctures fortemporary improvement of ventricular size (3–5).However, this technique is useful only when there is acommunication between the lateral ventricles and thespinal subarachnoid space, allowing relatively largevolumes of CSF to be removed by this approach.

eived April 21, 1998; accepted after revision August 25.ort for this study was provided by Alliance Pharmaceutical

San Diego, CA, and by Acuson Corp, Mountain View, CA.the Departments of Radiology (G.A.T., P.S.D.) and Neu-

(J.S.S.), Children’s Hospital and Harvard Medical School,, MA.ress reprint requests to George A. Taylor, MD, Departmentiology, Children’s Hospital, 300 Longwood Ave, Boston,115.

erican Society of Neuroradiology

193

Sonographic identification of communicating andnoncommunicating forms of posthemorrhagic hydro-cephalus can be difficult, and techniques to determinepatency of the ventricular system in premature infantsthat are safe, able to be performed at the bedside, andare not user-intensive are currently lacking. Results ofrecent work with experimental microbubble-basedsonographic contrast agents have shown their poten-tial for the creation of regional blood flow maps in theneonatal brain (6). In addition to increasing backscat-ter from blood vessels, these contrast agents alsoproduce a high degree of reflectance in gray-scaleimages. This study evaluates the feasibility of usingcontrast agents for direct sonographic visualization ofventricular patency in a newborn animal model.

MethodsFive newborn Yorkshire piglets were anesthetized with 20

mg/kg of ketamine hydrochloride (Ketalar; Parke-Davis, Mor-ris Plains, NJ) and 5 mg/kg of xylazine (Rompun; Miles, Shaw-nee, KA) by intramuscular injection, followed by 1% halothane(Fluothane; Wyeth-Ayerst, Philadelphia, PA) inhalation anes-thetic until venous access could be secured. Thereafter, a con-tinuous IV infusion of diprivan 1% (Propofol; Stuart Pharma-ceuticals, Wilmington, DE) diluted in 5% dextrose at a dose of0.02 mg/kg per minute was used for the remainder of theexperiment. A heating lamp and warming blanket were used toprevent loss of body temperature during anesthesia.

1

1932 TAYLOR AJNR: 19, November 1998

FIG 1. A–F, Sagittal midline images before (A ) and after (B ) intraventricular contrast administration, coronal images at the level of theanterior horns before (C ) and after (D ) intraventricular contrast administration, and at the level of the occipital horns before (E ) and after(F ) intraventricular contrast administration show improved visibility of the ventricular system and basal cisterns with contrast material.FH, frontal horn; LV, lateral ventricle; 3rd, third ventricle; Aq, aqueduct of Sylvius; 4th, fourth ventricle; PC, prepontine cistern; AC,ambient cistern; BC, basal cistern. Asterisk denotes massa intermedia.

Controlled ventilation was maintained via an oral endotra-cheal tube, and supplemental oxygen was administered. Poly-vinyl chloride catheters were placed in the left femoral arteryfor continuous blood pressure monitoring and in both femoralveins for administration of IV fluid and medications. A 1 32-cm craniotomy was performed across the midline at the levelof the coronal suture, leaving the dura intact for sonographicaccess. A second 2-mm burr hole was created in the rightoccipitoparietal area, and a 27-G catheter was placed into theoccipital horn of the lateral ventricle under sonographic guid-ance. A 7.0-MHz vector transducer (model 128 XP; AcusonCorp, Mountain View, CA) was used for guidance and imagingstudies.

Arterial blood pressure and heart rate were monitored con-tinuously with a Hewlett Packard model 76 physiological mon-itoring system (Hewlett Packard, Andover, MA). The contrastagent Imagent (formulation AF0150; Alliance PharmaceuticalCorp, San Diego, CA) was reconstituted according to themanufacturer’s directions. A dispersion of surfactant-coatedperfluorohexane/nitrogen–containing microbubbles with a me-dian diameter of approximately 5 mm is formed after reconsti-tution. Elimination from the blood is accomplished by evapo-ration through the lungs (7). Contrast material wasadministered into the occipital horn of the lateral ventriclethrough the indwelling catheter using a tuberculin syringe. Inone animal, three serial intraventricular injections were per-formed using a 0.1-mL, a 0.05-mL, and a 0.01-mL volume ofcontrast agent diluted with sterile water into a total volume of1.0 mL. The smallest dose (0.01 mL) allowed marked echo-genic enhancement without persistent shadowing of deeperstructures by overly echogenic contrast material and was usedfor subsequent studies. Sonograms were obtained in the coro-nal and sagittal planes before and after contrast administrationand were analyzed for presence and location of echogeniccontrast material. Only the fourth ventricle could be confi-dently identified on precontrast images. The exact boundariesof the lateral and third ventricles were not identifiable. As aresult, we were only able to provide subjective estimates of thedegree of ventricular dilatation after contrast injection. Trans-verse measurements of the lateral ventricles were obtained atthe level of the foramen of Monro on postcontrast images.

These studies were performed as part of a related experi-ment on changes in cerebral blood flow during acute elevations

of intracranial pressure. At the conclusion of the study, theanimals were killed using an IV injection of 100 mg/kg ofpentobarbital sodium. This study was approved by our institu-tional Animal Care and Use Committee and complied with theguidelines of the National Institutes of Health for the care andhandling of animals.

ResultsThe presence of contrast material in the ventricular

system was identifiable by a marked increase in echo-genicity and swirling motion at real-time sonography.Flow of contrast material was identifiable from theipsilateral lateral ventricle into the contralateral lat-eral ventricle and through the third and fourth ven-tricles into the basal cisterns in four animals (Fig 1).Ventricular and cistern echogenicity remained in-creased for approximately 4 minutes after injection.Mild (,5 mm Hg) transient elevations in intracranialpressure were observed during injection, but intracra-nial pressure returned to baseline in every animal atthe end of injection. Mild transient dilatation (,4mm transverse dimension) of the lateral ventricleswas observed in all four animals. No dilatation of thefourth ventricle was seen during injection and nodetectable changes in heart rate or mean arterialblood pressure were observed during or after intra-ventricular injection. In one animal, the tip of thecatheter was inadvertently dislodged from the lateralventricle. Serial sonograms showed the rapid appear-ance of echogenic contrast material in the basal cis-terns without ventricular opacification (Fig 2).

DiscussionSeveral imaging methods have previously been de-

scribed for the evaluation of CSF flow dynamics.Winkler (8) has reported that Doppler examination

AJNR: 19, November 1998 NEONATAL HYDROCEPHALUS 1933

FIG 2. A and B, Coronal images at thelevel of the basal ganglia before (A ) andafter (B ) intraventricular contrast adminis-tration show echogenic contrast materialoutlining only the interhemispheric fissure(IHF) and the ambient cisterns (AC). Notethe absence of contrast material in thelateral ventricles.

of the ventricular system during cranial or abdominalcompression may induce movement of CSF detect-able with color or duplex Doppler sonography. Par-ticulate debris within the CSF form reflective surfacesthat cause a transient flash artifact on color Dopplerimages if retrograde flow is present. If no flow ordebris is present, then abdominal compression doesnot result in the expected color flash. These dynamictechniques have been used to show obstruction at theforamina of Monro and the aqueduct of Sylvius. How-ever, the accuracy, sensitivity, and specificity of thismethod have not been reported.

Radionuclide lumbar cisternography and, more re-cently, MR imaging have been used to measure CSFflow direction and velocity and to distinguish betweenobstructive and nonobstructive forms of hydrocepha-lus in preterm infants (8–11). Although these meth-ods are accurate and clinically useful, they are diffi-cult to implement in premature or critically ill infants,or in the operating room.

The findings of this preliminary study show thefeasibility of using newly developed sonographic con-trast agents to outline the ventricular system in anewborn animal model. Patency of the ventricularsystem was easily definable at real-time sonographyby monitoring the progression of echogenic contrastmaterial throughout the ventricular system into thebasal cisterns.

In this study, a 0.01-mL dose of contrast agentdiluted into a total volume of 1.0 mL was sufficient toopacify the entire ventricular system and determineits patency. Echogenic contrast material was detect-able for approximately 4 minutes, after which ventric-ular echogenicity returned to normal. However, ven-tricular volumes and CSF dynamics in infants withhydrocephalus are quite different from those of nor-mal newborn piglets, and it is likely that modificationswill have to be made in both the concentration ofcontrast agent and the total volume of fluid injectedto optimize the degree and duration of ventricularopacification.

An obvious limitation of this technique is that itrequires direct access to the ventricular system. How-ever, a significant proportion of premature infantswith posthemorrhagic hydrocephalus will require aventricular access device for temporary drainage ofobstructed ventricles when medical management ofrapidly progressive ventricular dilatation fails. Ven-tricular access devices are often indicated in prema-

ture infants who are too small to accept a permanentventriculoperitoneal shunt and in infants treated withintraventricular fibrinolytic agents (12). Sonographicventriculography might be useful during initial place-ment of ventricular access devices or before conver-sion to a permanent shunt to assess the presence andlocation of ventricular obstruction by clot or ventric-ulitis. Additional potential applications of this tech-nique include the assessment of ventricular patency ininfants with various forms of hydrocephalus, the iden-tification of potential communication between bilat-eral subdural collections before drainage, and as anintraoperative technique to define the presence ofcommunication between posterior fossa or interhemi-spheric cysts and dilated lateral ventricles to deter-mine the need for additional shunt catheters.

Over the last few years, sonographic contrastagents have steadily evolved to the point where theyare now clinically feasible. Most of the contrast agentscurrently under development consist of a surfactantor otherwise stabilized shell that encapsulates air oran inert gas. These agents exert their effect by in-creased ultrasound backscatter; bubble properties,such as strength and elasticity of the shell, and solu-bility of the encapsulated gas all affect reflectivity andlongevity in the circulatory system (13). Most re-search studies with these agents have concentrated onintravascular enhancement or tissue characterization(7, 13). This class of agent has undergone extensivesafety testing for intravascular use as part of theapproval process by the U.S. Food and Drug Admin-istration for new drugs. Although we know of noinformation on potential adverse effects or reactionsrelated to intrathecal injection of sonographic con-trast agents, additional studies are necessary to de-termine their safety for intraventricular and intrathe-cal use.

Conclusion

Our findings establish the feasibility of using sono-graphic contrast agents for the real-time evaluation ofventricular patency in a newborn animal model. Al-though these results are promising, they are prelimi-nary in nature. Sonographic contrast agents will re-quire extensive safety and efficacy testing before theyare approved for intrathecal use in humans.

1934 TAYLOR AJNR: 19, November 1998

References1. Hanson AR, Snyder EY. Medical management of neonatal pos-

themorrhagic hydrocephalus. Neurosurg Clin N Am 1998;9:95–1042. Papile LA, Burstein J, Burstein R, et al. Posthemorrhagic hydro-

cephalus in low-birth-weight infants: treatment by serial lumbarpunctures. J Pediatr 1980;97:273–277

3. Allan WC, Holt PJ, Sawyer LR, et al. Ventricular dilatation afterneonatal periventricular-intraventricular hemorrhage: natural his-tory and therapeutic implication. Am J Dis Child 1982;136:589–593

4. Volpe JJ. Neurology of the Newborn. 3rd ed. Philadelphia: Saunders;1995:443–452

5. de Vries LS, Larroche J-C, Levene MI. Intracranial sequelae. In:Levene MI, Bennett MJ, Punt J, eds. Fetal and Neonatal Neurologyand Neurosurgery. New York: Churchill-Livingstone; 1988:347–353

6. Greenberg RS, Taylor GA, Stapleton JC, Hillsley CA, Spinak D.Analysis of regional cerebral blood flow in dogs using an experi-mental microbubble-based ultrasound contrast agent. Radiology1996;102:119–123

7. Goldberg BB, Liu J-B, Forsberg F. Ultrasound contrast agents: areview. Ultrasound Med Biol 1994;20:319–333

8. Winkler P. Colour-coded echographic flow imaging and spectralanalysis of cerebrospinal fluid (CSF) in infants, II: CSF-dynamics.Pediatr Radiol 1992;22:31–42

9. Donn SM, Roloff DW, Keyes J. Lumbar cisternography in evalu-ation of hydrocephalus in the preterm infant. Pediatrics 1983;172:670–676

10. Enzmann DR, Pelc NJ. Cerebrospinal fluid flow measured byphase-contrast cine MR. AJNR Am J Neuroradiol 1993;14:1301–1307

11. Hayakawa K, Konishi Y, Kuriyama M, Konishi K, Matsuda T.Cerebrospinal fluid flow void in children. Neuroradiology 1993;35:443–446

12. Hudgins RJ, Boydston WR, Hudgins PA, Alder SR. Treatment ofintraventricular hemorrhage in the premature with urokinase. Pe-diatr Neurosurg 1994;20:190–197

13. Ophir J, Parker KJ. Contrast agents in diagnostic ultrasound.Ultrasound Med Biol 1989;15:319–333