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

Laboratory investigation

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Object

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.

Methods

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.

Results

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.

Conclusions

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.

Headings

Figures

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    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.

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