Early deterioration of cerebrospinal fluid dynamics in a neonatal piglet model of intraventricular hemorrhage and posthemorrhagic ventricular dilation

Laboratory investigation

Restricted access


The optimal management of neonatal intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilation is challenging. The importance of early treatment has been demonstrated in a recent randomized study, involving early ventricular irrigation and drainage, which showed significant cognitive improvement at 2 years. The objective of this study was to define the changes in CSF absorption capacity over time in a neonatal piglet model of IVH.


Ten piglets (postnatal age 9–22 hours) underwent intraventricular injection of homologous blood. A ventricular access device was inserted 7–10 days later. Ventricular dilation was measured by ultrasonography. Serial constant flow infusion studies were performed through the access device from Week 2 to Week 8.


Seven piglets survived long term, 43–60 days, and developed ventricular dilation; this reached a maximum by Week 6. There was no significant difference in baseline intracranial pressure throughout this period. The resistance to CSF outflow, Rout, increased from 63.5 mm Hg/ml/min in Week 2 to 118 mm Hg/ml/min in Week 4. Although Rout decreased after Week 5, the ventriculomegaly persisted.


In this neonatal piglet model, reduction in CSF absorptive capacity occurs early after IVH and accompanies progressive and irreversible ventriculomegaly. This suggests that early treatment of premature neonates with IVH is desirable.

Abbreviations used in this paper:DRIFT = drainage, irrigation, and fibrinolytic therapy; ICP = intracranial pressure; IQR = interquartile range; IVH = intraventricular hemorrhage; PHVD = posthemorrhagic ventricular dilation; Rout = resistance to CSF outflow; SAH = subarachnoid hemorrhage; TGF = transforming growth factor; VEGF = vascular endothelial growth factor.

Article Information

Address correspondence to: Kristian Aquilina, F.R.C.S., Department of Neurosurgery, Frenchay Hospital, Bristol BS16 1LE, England. email: K.Aquilina@bristol.ac.uk.

Please include this information when citing this paper: published online September 28, 2012; DOI: 10.3171/2012.8.PEDS11386.

© AANS, except where prohibited by US copyright law.



  • View in gallery

    A: Coronal brain section, at the level of the atrium of the ventricles, from piglet killed within 24 hours of intraventricular blood injection, showing unclotted blood within the ventricle. B and C: Basal (B) and sagittal (C) views of whole brain from piglet killed 3 days after injection; organized hematoma is evident within the basal cisterns. D: Coronal section, at the level of the temporal horns, of perfused and formaldehyde-fixed brain from piglet killed 8 weeks after injection showing severe dilation of the third and lateral ventricles.

  • View in gallery

    A–C: Ultrasonographic images and intraoperative photograph showing the insertion of ventricular access device. The device is inserted into the lateral ventricle (indicated by asterisk, A) under ultrasound guidance. The intraventricular component (catheter) is indicated by the arrowhead (C). D: Experimental setup for ventricular infusion test—two 25-gauge needles are inserted percutaneously into the reservoir, one connected to the pressure transducer and one to an infusion pump.

  • View in gallery

    A–C: Graphs showing progressive changes in thalamooccipital (A) and maximum frontal difference (B) throughout the survival period and correlation between the 2 parameters (C). Good correlation was demonstrated between the 2 parameters in this model (Spearman r = 0.79, p < 0.0001). D and E: Method of measurement of thalamoocciptal distance (D) and maximum frontal distance (E).

  • View in gallery

    Progressive changes in median (IQR) baseline ICP (upper) and Rout (in mm Hg/ml/min, lower) throughout the survival period. Boxes represent IQR, whiskers full range. (For some of the measurements there were too few observations to allow calculation of IQR.)

  • View in gallery

    A–C: Serial changes in Rout on ventricular infusion testing with corresponding sagittal ultrasound ventricular images on Days 12 (A), 18 (B), and 22 (C) in 1 piglet. A progressive change in Rout was associated with, and preceded, enlargement of the ventricular system.

  • View in gallery

    Basal view of extracted brains from a noninjected piglet (A), a piglet killed 24 hours after intraventricular injection (B), and a piglet killed 2 weeks after injection (C). Extensive subarachnoid blood is still evident at 24 hours (B). This disappears by 2 weeks, when hemosiderin-stained fibrinous adhesions begin to appear (arrow, C).

  • View in gallery

    Left: Photograph showing dense fibrinous adhesions at the caudal surface of the cerebellum and the brainstem, evident at 9 weeks' survival. Right: Photomicrograph of section from area indicated by rectangle in the left panel demonstrating adhesions in the subarachnoid space. H & E, original magnification ×20.



Aquilina KHobbs CCherian STucker APorter HWhitelaw A: A neonatal piglet model of intraventricular hemorrhage and posthemorrhagic ventricular dilation. J Neurosurg 107:2 Suppl1261362007


Black PMTzouras AFoley L: Cerebrospinal fluid dynamics and hydrocephalus after experimental subarachnoid hemorrhage. Neurosurgery 17:57621985


Boon AJTans JTDelwel EJEgeler-Peerdeman SMHanlo PWWurzer HA: Dutch normal-pressure hydrocephalus study: prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid. J Neurosurg 87:6876931997


Böttner MKrieglstein KUnsicker K: The transforming growth factor-betas: structure, signaling, and roles in nervous system development and functions. J Neurochem 75:222722402000


Bradbury MWWestrop RJ: Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit. J Physiol 339:5195341983


Brinker TBeck HKlinge PKischnik BOi SSamii M: Sinusoidal intrathecal infusion for assessment of CSF dynamics in kaolin-induced hydrocephalus. Acta Neurochir (Wien) 140:106910751998


Cherian SThoresen MSilver IAWhitelaw ALove S: Transforming growth factor-betas in a rat model of neonatal posthaemorrhagic hydrocephalus. Neuropathol Appl Neurobiol 30:5856002004


Cosan TEGuner AIAkcar NUzuner KTel E: Progressive ventricular enlargement in the absence of high ventricular pressure in an experimental neonatal rat model. Childs Nerv Syst 18:10142002


Czosnyka MBatorski LLaniewski PMaksymowicz WKoszewski WZaworski W: A computer system for the identification of the cerebrospinal compensatory model. Acta Neurochir (Wien) 105:1121161990


Czosnyka MWhitehouse HSmielewski PSimac SPickard JD: Testing of cerebrospinal compensatory reserve in shunted and non-shunted patients: a guide to interpretation based on an observational study. J Neurol Neurosurg Psychiatry 60:5495581996


Czosnyka ZHCzosnyka MPickard JD: Shunt testing in-vivo: a method based on the data from the UK shunt evaluation laboratory. Acta Neurochir Suppl 81:27302002


Davies MWSwaminathan MChuang SLBetheras FR: Reference ranges for the linear dimensions of the intracranial ventricles in preterm neonates. Arch Dis Child Fetal Neonatal Ed 82:F218F2232000


de Vries LSLiem KDvan Dijk KSmit BJSie LRademaker KJ: Early versus late treatment of posthaemorrhagic ventricular dilatation: results of a retrospective study from five neonatal intensive care units in The Netherlands. Acta Paediatr 91:2122172002


Donovan FMPike CJCotman CWCunningham DD: Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J Neurosci 17:531653261997


Douglas MRDaniel MLagord CAkinwunmi JJackowski ACooper C: High CSF transforming growth factor beta levels after subarachnoid haemorrhage: association with chronic communicating hydrocephalus. J Neurol Neurosurg Psychiatry 80:5455502009


Flood CAkinwunmi JLagord CDaniel MBerry MJackowski A: Transforming growth factor-beta1 in the cerebrospinal fluid of patients with subarachnoid hemorrhage: titers derived from exogenous and endogenous sources. J Cereb Blood Flow Metab 21:1571622001


Fox RJWalji AHMielke BPetruk KCAronyk KE: Anatomic details of intradural channels in the parasagittal dura: a possible pathway for flow of cerebrospinal fluid. Neurosurgery 39:84911996


Fukushima NYokouchi KKawagishi KRen GHigashiyama FMoriizumi T: Proliferating cell populations in experimentally-induced hydrocephalus in developing rats. J Clin Neurosci 10:3343372003


Gjerris FBørgesen SESørensen PSBoesen FSchmidt KHarmsen A: Resistance to cerebrospinal fluid outflow and intracranial pressure in patients with hydrocephalus after subarachnoid haemorrhage. Acta Neurochir (Wien) 88:79861987


Gómez DGDiBenedetto ATPavese AMFirpo AHershan DBPotts DG: Development of arachnoid villi and granulations in man. Acta Anat (Basel) 111:2472581982


Gonzalez-Darder JBarbera JCerda-Nicolas MSegura DBroseta JBarcia-Salorio JL: Sequential morphological and functional changes in kaolin-induced hydrocephalus. J Neurosurg 61:9189241984


Grainger DJWakefield LBethell HWFarndale RWMetcalfe JC: Release and activation of platelet latent TGF-beta in blood clots during dissolution with plasmin. Nat Med 1:9329371995


Guinane JE: Cerebrospinal fluid resistance and compliance in subacutely hydrocephalic cats. Neurology 24:1381421974


Heep AStoffel-Wagner BBartmann PBenseler SSchaller CGroneck P: Vascular endothelial growth factor and transforming growth factor-beta1 are highly expressed in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus. Pediatr Res 56:7687742004


Hochwald GMLux WE JrSahar ARansohoff J: Experimental hydrocephalus. Changes in cerebrospinal fluid dynamics as a function of time. Arch Neurol 26:1201291972


Hochwald GMNakamura SCamins MB: The rat in experimental obstructive hydrocephalus. Z Kinderchir 34:4034101981


Hochwald GMSahar ASadik ARRansohoff J: Cerebrospinal fluid production and histological observations in animals with experimental obstructive hydrocephalus. Exp Neurol 25:1901991969


Jones HCBucknall RM: Changes in cerebrospinal fluid pressure and outflow from the lateral ventricles during development of congenital hydrocephalus in the H-Tx rat. Exp Neurol 98:5735831987


Katzman RHussey F: A simple constant-infusion manometric test for measurement of CSF absorption. I. Rationale and method. Neurology 20:5345441970


Khan OHEnno TLDel Bigio MR: Brain damage in neonatal rats following kaolin induction of hydrocephalus. Exp Neurol 200:3113202006


Kida SPantazis AWeller RO: CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol 19:4804881993


Kim DJCzosnyka ZKeong NRadolovich DKSmielewski PSutcliffe MP: Index of cerebrospinal compensatory reserve in hydrocephalus. Neurosurgery 64:4945022009


Kohn DFChinookoswong NChou SM: A new model of congenital hydrocephalus in the rat. Acta Neuropathol 54:2112181981


Kondziella DLüdemann WBrinker TSletvold OSonnewald U: Alterations in brain metabolism, CNS morphology and CSF dynamics in adult rats with kaolin-induced hydrocephalus. Brain Res 927:35412002


Kosteljanetz M: CSF dynamics in patients with subarachnoid and/or intraventricular hemorrhage. J Neurosurg 60:9409461984


Kosteljanetz M: Pressure-volume conditions in patients with subarachnoid and/or intraventricular hemorrhage. J Neurosurg 63:3984031985


Kuchiwaki HHasuo MFuruse MBrock MDietz H: [Measurement of ventricular fluid pressure and brain tissue pressure in acute experimental communicating hydrocephalus (author's transl).]. No To Shinkei 30:110911131978. (Jpn)


Larroche JC: Post-haemorrhagic hydrocephalus in infancy. Anatomical study. Biol Neonate 20:2872991972


Leeds SEKong AKWise BL: Alternative pathways for drainage of cerebrospinal fluid in the canine brain. Lymphology 22:1441461989


Lollis SSHoopes PJKane SPaulsen KWeaver JRoberts DW: Low-dose kaolin-induced feline hydrocephalus and feline ventriculostomy: an updated model. Laboratory investigation. J Neurosurg Pediatr 4:3833882009


Nyberg-Hansen RTorvik ABhatia R: On the pathology of experimental hydrocephalus. Brain Res 95:3433501975


Oi SDi Rocco C: Proposal of “evolution theory in cerebrospinal fluid dynamics” and minor pathway hydrocephalus in developing immature brain. Childs Nerv Syst 22:6626692006


Osaka KHanda HMatsumoto SYasuda M: Development of the cerebrospinal fluid pathway in the normal and abnormal human embryos. Childs Brain 6:26381980


Papaiconomou CBozanovic-Sosic RZakharov AJohnston M: Does neonatal cerebrospinal fluid absorption occur via arachnoid projections or extracranial lymphatics?. Am J Physiol Regul Integr Comp Physiol 283:R869R8762002


Petrella GCzosnyka MSmielewski PAllin DGuazzo EPPickard JD: In vivo assessment of hydrocephalus shunt. Acta Neurol Scand 120:3173232009


Sahar A: Experimental progressive hydrocephalus in the young animal. Childs Brain 5:14231979


Savman KNilsson UABlennow MKjellmer IWhitelaw A: Non-protein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation. Pediatr Res 49:2082122001


Sundström NAndersson KMarmarou AMalm JEklund A: Comparison between 3 infusion methods to measure cerebrospinal fluid outflow conductance. Clinical article. J Neurosurg 113:129413032010


Suzuki SIshii MOttomo MIwabuchi T: Changes in the subarachnoid space after experimental subarachnoid haemorrhage in the dog: scanning electron microscopic observation. Acta Neurochir (Wien) 39:1141977


Thoresen MHaaland KLøberg EMWhitelaw AApricena FHankø E: A piglet survival model of posthypoxic encephalopathy. Pediatr Res 40:7387481996


Ventriculomegaly Trial Group: Randomised trial of early tapping in neonatal posthaemorrhagic ventricular dilatation. Arch Dis Child 65:1 Spec No3101990


Ventriculomegaly Trial Group: Randomised trial of early tapping in neonatal posthaemorrhagic ventricular dilatation: results at 30 months. Arch Dis Child Fetal Neonatal Ed 70:F129F1361994


Wagner KRSharp FRArdizzone TDLu AClark JF: Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 23:6296522003


Whitelaw ACherian SThoresen MPople I: Posthaemorrhagic ventricular dilatation: new mechanisms and new treatment. Acta Paediatr Suppl 93:11142004


Whitelaw AChristie SPople I: Transforming growth factorbeta1: a possible signal molecule for posthemorrhagic hydrocephalus?. Pediatr Res 46:5765801999


Whitelaw AEvans DCarter MThoresen MWroblewska JMandera M: Randomized clinical trial of prevention of hydrocephalus after intraventricular hemorrhage in preterm infants: brain-washing versus tapping fluid. Pediatrics 119:e1071e10782007


Whitelaw AJary SKmita GWroblewska JMusialik-Swietlinska EMandera M: Randomized trial of drainage, irrigation and fibrinolytic therapy for premature infants with posthemorrhagic ventricular dilatation: developmental outcome at 2 years. Pediatrics 125:e852e8582010


Whitelaw AKennedy CRBrion LP: Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation. Cochrane Database Syst Rev 2CD0022702001




All Time Past Year Past 30 Days
Abstract Views 55 55 12
Full Text Views 71 71 18
PDF Downloads 205 205 27
EPUB Downloads 0 0 0


Google Scholar