Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00747682 |
| Other study ID # |
18833 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
September 3, 2008 |
| Last updated |
June 22, 2010 |
| Start date |
July 2006 |
| Est. completion date |
August 2009 |
Study information
| Verified date |
June 2010 |
| Source |
University of Utah |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Observational
|
Clinical Trial Summary
The specific aim of the research proposal in preterm infants with IVH and PHH who require
placement of an Omaya reservoir or a shunt is to determine if decreasing ventricular volume
improves, middle cerebral artery flow, cerebral oxygenation, and cortical neuronal
electrical activity. To accomplish this aim, we will simultaneously perform the following
evaluations prior to shunt placement or prior to and after routine CSF aspiration from
reservoir in:
1. middle cerebral artery velocity time integral and resistive index using Doppler
ultrasonography
2. cerebral oxygenation using near infrared spectroscopy (NIRS)
3. background neuronal electrical activity using an EEG. In addition, we will measure
serial CSF concentration of neuroproteins, S100B, GFAP, NSE, TGF-ß, and IL-6, as
evidence of ongoing neuronal damage and correlate the concentration with cerebral
perfusion and activity as measured above.
Description:
Very low birth weight infants are at risk for developing intraventricular hemorrhage (IVH).
Post hemorrhagic hydrocephalus (PPH) is a major complication of IVH and contributes to
long-term developmental delays. Progressive PHH often requires management of ventricular
dilation by adjusting CSF fluid volume. There are 3 methods employed to acutely decrease CSF
volume: 1) serial lumbar puncture, 2) open drain system (continuous CSF removal), and 3)
reservoir system. Serial lumbar puncture is only effective if there is communicating
hydrocephalus. The open drain system is infrequently used as it is cumbersome and there is a
relatively high risk of infection. The method most commonly used to manage CSF volume is the
reservoir system where an in-situ drain is connected to a subcutaneous (Omaya) reservoir
which is periodically aspirated by needle puncture through the scalp. Because the Omaya
system is closed, intraventricular volume and, thus, pressure must necessarily rise prior to
and decrease after CSF aspiration. Ventricular dilation is controlled by the frequency and
volume of CSF aspiration.
When hydrocephalus continues to be a problem despite removal of CSF, a
ventricular-peritoneal (VP) shunt is placed. Approximately 50% of infants with hydrocephalus
treated with removal of CSF resolve their hydrocephalus and do not require VP shunt
placement. Placement of a VP shunt is difficult in extremely preterm infants due to
increased risk of ulceration around the shunt site and the high protein concentration in CSF
which can occlude the valve in the VP shunt requiring revision. Thus, hydrocephalus is
usually treated with serial removal of CSF to allow for identification of those infant's
whose hydrocephalus resolves over time. However, timing and method of CSF management is
controversial because the effect of increasing hydrocephalus on cerebral perfusion,
oxygenation, electrical activity, and neuronal damage has not been established.
Serial removal of CSF causes a change in intracranial volume/pressure that can be
potentially transmitted to intracranial vessels. The caliber of cerebral vessels may be
modified by this balance between intravascular and intracranial pressure, and if the caliber
should change, the blood flow characteristics should also change. In cerebral veins and
capillaries where intraluminal pressure is low, high intraventricular pressure may
significantly affect blood flow and can cause venous stasis. NIRS measures cerebral
oxygenation in capillaries and veins. Intracranial arteries and arterioles may be somewhat
less affected, except when intraventricular pressure greatly increases. The resultant
decrease in the arterial supply can affect tissue perfusion. Arterial flow can be measured
by Doppler ultrasonography. Thus, there is concern that during periods of increasing or
fluctuating ventricular size cerebral arterial perfusion may be compromised and further
cerebral injury may result. Intracranial pressure is further influenced by the
plasticity/deformability of the immature brain and the easy expansibility of the cranial
vault due to the presence of sutures and open fontanelles.
There is indirect evidence from experiments in animals that ventricular distention itself
may cause secondary brain injury. Thus, axonal stretching and disruption secondary to
progressive ventriculomegaly is be associated with gliosis. Periventricular vascular
distortion and compression may decrease cerebral blood flow causing ischemic injury to
periventricular white matter. Inflammation and repair may interfere with CSF flow.
Little research is available that helps answer the primary question involved in clinical
management of ventricular dilation in premature infants: Are there relationships between
ventricular enlargement, cerebral perfusion, brain oxygen delivery, and on-going cerebral
damage?
Doppler ultrasonography has been applied in premature infants to characterize post delivery
changes in arterial and venous cerebral blood flow velocities.[1] Critically low superior
vena cava flow measured by Doppler ultrasonography in the first 24 hours of life has been
associated with intraventricular hemorrhage in premature infants born before 30 weeks
gestation.[2] Using pulsed Doppler ultrasonography, the resistive index can be measured
which is a inversely related to blood flow. In older infants with established hydrocephalus,
cerebral blood flow resistive index appeared to be a good indicator of increased
intracranial pressure.[3] However, in a review article, the value of Doppler indices alone
in predicting increased intracranial pressure was strongly questioned.[4] In a recent
article, the resistive index of the anterior cerebral artery decreased significantly after
CSF drainage in infants with PHH. [5] Although Doppler ultrasonography is easy to perform,
its role in detecting significant changes in cerebral perfusion associated with increased
CSF volume and ventricular dilation is not yet established.
Near infrared spectroscopy (NIRS) is a portable non-invasive technique used to measure
regional cerebral oxygen saturation in cerebral blood.[6] NIRS has been used to evaluate
effect of head [7] and body position [8] on cerebral hemodynamics in preterm infants, and
the effect of certain treatments, such as surfactant administration [9] and suctioning on
conventional or high-frequency ventilation.[10] NIRS measurement of cerebral oxygenation and
hemodynamics shows impairment in those neonates at risk for developing severe brain
ischemia.[11] In premature infants with PHH, CSF fluid aspiration was associated with a
significant increase in cerebral perfusion, cerebral blood volume, and oxidative
metabolism.[12,13] In a small animal model of acute hydrocephalus, NIRS measurement of
global cerebral blood flow using oxygen as a tracer was highly correlated to cerebral blood
flow measured by radioactive microspheres over a wide range of increased intracranial
pressure.[14] As intracranial pressure increased, NIRS measurement and absolute measurement
of cerebral blood flow decreased. NIRS measured cerebral perfusion appears to directly
reflect absolute cerebral blood flow and is sensitive enough to detect significant changes
in cerebral perfusion which occur with evacuation of CSF in infants with PHH.
Amplitude-integrated EEG (aEEG) is a device used for neurologic surveillance. The cortical
electrical activity is transformed into a single signal that represents overall
electrocortical background activity of the brain. Specifically the upper and lower voltage
margins and the amplitude of the tracing and the presence of seizure activity can be
evaluated. In addition, the presence of sleep-wake cycles, a rhythmic sinusoidal variation
in amplitude, can be evaluated. Infants > 34 weeks gestation have predictable aEEG patterns.
The signal depends on gestational age and postnatal age and standards for preterm infants
have been reported.[15,16] In a case report, 2 preterm infants with PHH demonstrated
abnormal sleep-wake cycles and markedly decreased cerebral electrical activity with
increasing ventricular enlargement prior to clinical signs of increased intracranial
pressure. In one infant, aEEG normalized after VP shunt placement.[17] To date, there are no
clinical studies on the effect of aspiration of CSF on aEEG in preterm infants with PHH.
Biomarkers for cerebral injury have been used to predict severity of injury and long-term
outcome, identify patients early at risk for poor neurologic outcomes, and evaluate
effectiveness of therapeutic interventions. Neuronal specific enolase (NSE), a marker for
neuronal damage, and S100B, secreted by astrocytes and a marker of glial/neuronal injury,
have been shown to be increased in children after traumatic brain injury.[18] In preterm
infants with PHH, S100B and glial fibrillary acid protein (GFAP), a structural protein in
astrocytes, were significantly elevated in those infants who had brain parenchymal lesions
and poor neurological outcomes.[19] These biomarkers are quickly metabolized and thus
ongoing elevation would indicate ongoing damage. Transforming growth factor beta (TGF-ß),
produced by fibroblasts and released into the CSF after injury, stimulates production of
extracellular protein which could result in PHH due to a permanent obstruction to CSF
flow.[20] Cytokine IL-6 is a marker of inflammation. There are no longitudinal studies on
the effect of aspiration of CSF on these markers of cerebral damage in preterm infants with
PHH.
