Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03641443 |
| Other study ID # |
aICP Tumor |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 12, 2016 |
| Est. completion date |
December 31, 2019 |
Study information
| Verified date |
February 2020 |
| Source |
Kantonsspital Aarau |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Since decades, neurosurgeons and neurooncologists assumed that the mass effect of brain
tumors with peritumoral edema or intratumoral hemorrhage might lead to increased ICP.
Therefore, decisions on surgical procedures and medical treatments were made based on
clinical and radiological findings suggesting increased ICP. But in fact, no measurement has
ever confirmed increased ICP in brain tumor patients. From an ethical point of view, it is
not justifiable to implant an intraparenchymal ICP probe within an invasive surgical
procedure in a brain tumor patient unless the patient is comatose or present with rapid
impairment of the level of consciousness. Therefore, with the new medical device for
non-invasive ICP measurement presented in this study protocol, we will be able to measure
absolute ICP values in patients with brain tumors.
Description:
Primary brain tumors in adults are less common than metastatic tumors. The most frequent are
glioblastoma multiforme, metastases, anaplastic astrocytoma, meningioma, pituitary tumors and
vestibular schwannoma. 70% of the tumors in adults are supratentorial. The most
infratentorial tumors are metastases, schwannoma, meningioma, epidermoid, hemangioblastoma,
and brainstem glioma. Causes of brain tumors are genetics, radiation, immunosuppression,
viruses and chemotherapy.
Clinically patients present with neurological deficits as hemiparesis, cranial nerve
deficiency or signs of raised ICP such as headache, nausea, vomitus, vigilance disturbance.
After clinical assessment, standard MRI with contrast agent is performed to visualize the
size and structure of the tumor, contrast uptake, peritumoral edema (PTE), and other
radiological findings. Depending on the tumor, size and location, the further procedure must
be defined with either surgical resection, observation, other adjuvant therapies. Mostly, a
histological diagnosis is needed to know the tumor biology and set supplementary treatment.
In patients with brain tumors with mass effect and peritumoral edema with consecutive midline
shift increased intracranial pressure (ICP) is usually considered. During the expansion of an
intracranial mass lesion, there is initially a minimal increase in ICP, but as compensatory
capacity is exhausted the volume pressure curve rapidly steepens, and by further expansion of
the mass a distinct increase in ICP results.
Supratentorial tumors can produce significant mass effect in the brain. In certain tumor
types, especially metastases, high grade gliomas, and meningeomas significant peritumoral
edema that lead to elevation of intracranial pressure might be associated. In cases of
infratentorial tumors with or without edema earlier clinical decompensation with
hydrocephalus, increased ICP and downward herniation are more often due to reduced space
within the posterior fossa. Within the closed bony cranium, increase of volume, such as tumor
with associated edema or hemorrhage, ischemia, occlusion of venous perfusion or hydrocephalus
lead to an increase of ICP and secondary injury to the normal brain. PTE is caused by
vasogenic edema in particular, but also cytotoxic edema, tumor-related-pressure, arterial
blood supply, venous congestion and secretion of angiogenic factors such as vascular
endothelial growth factor (VEGF). VEGF, Aquaporin-4 (AQP4), cyclooxygenase-2 (COX- 2), and
nitric oxide (NO) induce dysfunction of tight junction proteins playing an important role in
the formation of edema. Cerebral edema induced by brain tumor is characterized by an increase
in the permeability of brain capillary endothelial cells and an increase in the brain water
content. Peritumoral vasogenic edema as a result of blood-brain-barrier dysfunction within
the tumor affects neurological function and quality of life, and may even cause
life-threatening raised intracranial pressure.
Cerebral blood flow (CBF) and the carbon dioxide (CO2) reactivity, are known to be reduced in
patients with brain tumor, especially those with pronounced signs of intracranial
hypertension.The study reported by Chang et al. showed, that the mean CBF of both hemispheres
in each group was not significantly different from brain tumor patients with peritumoral
edema to age-matched controls. Cerebrovascular reactivity (CVR) was preserved in patients
with mild peritumoral edema but was significantly reduced in patients with moderate and
severe peritumoral edema. Surgical removal of the tumor significantly improved the impaired
CVR, although the mean CBF did not change.
An earlier study on measurements of intratumoral and peritumoral blood flow as well as within
the hemispheres indicated, very low flow values in the peritumoral edematous area. These
findings suggest that the hypodense area surrounding brain tumor may actually represent tumor
pressure ischemia.
Certain risk factors for increased edema, such as age, sex, tumor size, neurological
symptoms, seizures, location, histology, and contrast enhancement, have been identified. The
extend of PTE has been demonstrated as a predictor of favorable overall survival time in
patients with larger PTE in metastases, but on the contrary smaller PTE was a statistically
significant predictor of longer survival in high-grade gliomas. On the other hand it has been
shown, that postoperative complications were more frequent and duration of intensive care
treatment was longer in patients with PTE. Outcome was significantly better in patients
without PTE.
Steroids are in use since 1960's and play a substantial role in the management of brain tumor
and increased ICP associated with perilesional edema. Vasogenic edema responds very well to
corticosteroids, although they have important side effects. Corticosteroids should be used in
a low dose daily to avoid serious side effects such as myopathy, diabetes, hypertonia,
osteoporosis, psychiatric alterations, skin thinning and an increased risk for some
opportunistic infections.
In the study of Skjoeth et al., brain tumor patients with a substantial amount of edema were
included. The effect of steroids was monitored during 5 days by clinical examination and
epidural ICP measurement. ICP reduction was found only in 4 of 13 patients, another 4
patients with meningioma had a significant increase of ICP and none of them experienced
clinical improvement.
Cerebral swelling through the craniotomy can seriously threaten surgical access and increase
the risk of cerebral ischemia with potential worsening of outcome. Rasmussen et al. observed
that subdural ICP is the strongest predictor of intraoperative brain swelling. In addition
midline shift, diagnosis of glioblastoma multiforme and metastasis were significant risk
factors of intraoperative brain swelling. With an intraoperative ICP greater than 13 mmHg,
supra- and infratentorial brain swelling occurred with 95% probability and at an ICP greater
than 26 mmHg, severe brain swelling occurred with 95% probability.
Cold et al. reported subdural ICP measurements in 29 patients during supra- and
infratentorial craniotomies. The authors observed, that at subdural ICP < 6 mmHg
intraoperative brain herniation never occurred. Patients with a subdural ICP greater than 7
mmHg some brain herniation was documented in all cases, and if subdural ICP was greater than
11 mmHg, pronounced brain swelling/herniation occurred in all patients. In a follow-up study,
including patients receiving supratentorial craniotomy cerebral herniation did not occur at
subdural ICP < 7 mmHg. On the other hand, at ICP >10 mmHg cerebral herniation occurred with
high probability. These thresholds were independent of anesthetic agent used and the level of
partial pressure of carbon dioxide (PCO2). Jorgensen et al. reported results of posterior
fossa craniotomies where at an ICP < 10 mmHg, brain swelling/herniation rarely occurred,
while at ICP ≥10 mmHg some degree of brain swelling/herniation was always present.
Interestingly neurosurgeons' tactile estimation of dural tension correlated poorly with any
tendency to brain swelling/herniation.
Peritumoral edema is considered to decrease after surgical resection, but there are cases
where the edema enlarges postoperatively. Ono and other authors presented cases with
postoperative progressive edema. Correlating to this results, it has been proven, that
postoperative sustained ICP elevation occurs and the rise in ICP occurred before any
neurological deterioration was noticed. Similarly, studies showed, that edema increases after
radiotherapy or radiosurgery.
Although it is suspected that intracranial lesion with mass effect might cause increased ICP,
there is no clinical evidence proven yet. Raised ICP can cause clinical manifestations and
symptoms such as headache, nausea, vomiting, and neurological deficits. These signs, which
are known as intracranial hypertension signs, are variable and have not been validated due to
the lack of technological tools to measure ICP non-invasively. To date, only intra- and
postoperative measurements of increased ICP have been shown with intraparenchymal ICP probes
or intraventricular catheters.
The inspection of the ocular fundus would be an option to detect papilledema as a sign of
intracranial hypertension. Nevertheless, papilledema is considered to have a late onset since
it takes some time to be developed and not all patients with brain tumors present with fundus
abnormalities. Moreover, if the patient has a preexisting condition such as high blood
pressure causing intracranial hypertension and chronic papilledema, it will be difficult to
assess the changes.
Currently, ICP can be measured and registered only using invasive techniques. The two ICP
measurement methods available - intraventricular and intraparenchymal - require both a
neurosurgical procedure, in order to implant the catheter and probes within the brain
parenchyma and ventricles. Thus, these measures include themselves a risk for the subject.
Infections and intracranial bleedings related to invasive ICP measurement techniques are
considered frequent complications. In addition, invasive recording of ICP requires
neurosurgical expertise and intensive care unit (ICU) facilities. Present review articles
conclude that there is still a lack of non-invasive techniques for accurate measurement of
the ICP.
Intracranial pressure (ICP) measurement is clinically important in several pathophysiology
conditions. Cerebrospinal fluid (CSF) pressure is the reference for the "gold standard"
invasive ICP measured via a brain ventriculostomy or by lumbar puncture in patients with free
CSF circulation. Elevated ICP is a critical indication for treatment of patients with acute
neurologic condition, and the best approach to management is considered to be different
depending on the underlying pathophysiology. ICP can only be measured using invasive methods
in routine clinical practice. The most common application of ICP monitoring is in the
management of patients with severe closed head injury or some other neurologic disorders.
The concept of non-invasive ICP measurement has been discussed since the 1980s. Numerous
methods for finding the objects or physiological characteristics of cerebrospinal system that
would be related to the ICP and its monitoring have been postulated by many authors. Most of
the proposed technologies were based on ultrasound and were capable of monitoring blood flow
in intracranial or intraocular vessels, cranium diameter, or acoustic properties of the
cranium. Broad research has extended into sonography of optic nerve sheath and its relation
with elevated ICP. However, most of these correlation-based methods had the same problem -
the need of individual patient specific calibration.
Seeking to measure absolute ICP values, researchers from Kaunas University of Technology
created a non-invasive method, which does not need a patient specific calibration. The method
is based on direct comparison of ICP value with the value of pressure Pe that is externally
applied to the tissues surrounding the eyeball. Intracranial segment of ophthalmic artery
(OA) is used as a natural sensor of ICP and extracranial segment of OA is used as a sensor of
Pe. A special two depth transcranial Doppler (TCD) device is used as a pressure balance
indicator when ICP = Pe. Accuracy, precision, sensitivity, specificity, and diagnostic value
of this method were proven with patients with mild neurological diseases. This device has not
yet been used in clinical studies to investigate ICP in brain tumor patients. A study of our
neurosurgical department to validate the accuracy of non-invasive ICP measurement compared to
invasive measurement techniques is ongoing.
Since decades, neurosurgeons and neurooncologists assumed, that the mass effect of brain
tumors with peritumoral edema or intratumoral hemorrhage might lead to increased ICP.
Therefore, decisions on surgical procedures and medical treatments were made based on
clinical and radiological findings suggesting increased ICP. But in fact, no measurement has
ever confirmed increased ICP in brain tumor patients. From an ethical point of view, it is
not justifiable to implant an intraparenchymal ICP probe within an invasive surgical
procedure in a brain tumor patient unless the patient is comatose or present with rapid
impairment of the level of consciousness. Therefore, with the new medical device presented in
this study protocol, we will be able to measure absolute ICP values in patients with brain
tumors. The aim of the study is to correlate absolute ICP values with clinical and
radiological (tumor size, midline shift and peritumoral edema) parameters which are defined
as intracranial hypertension signs in brain tumor patients. The observations obtained in this
study have important clinical implications to neurosurgeons, neurologists, and
neurooncologists in order to define the timing of surgical procedures, medical treatments
such as steroids and osmotic agents and indications for monitoring in the ICU.
