This is a randomized controlled trial to determine the safety and feasibility of external
lumbar drainage (ELD) of cerebrospinal fluid (CSF) as an adjunct to existing treatments
to lower brain pressure, in select patients suffering severe traumatic brain injury
(TBI). This trial is funded by the Department of Defense, Uniformed Services University
of Health Sciences, Center for Neuroscience and Regenerative Medicine (CNRM).
Following a severe TBI, the brain swells and the pressure in the cranium rises causing
further brain injury, The goal of treatment of such patients is to use treatments that
lower brain swelling or pressure - directly by removing blood clots or indirectly by
trying to lower the volume of contents in the cranium, viz. CSF or blood. Routinely a
drain is placed in the skull to drain CSF out to provide space for brain swelling, thus
keeping intracranial pressure (ICP) low. In some instances, all treatments available are
unable to control swelling and the skull may need to be removed from one side, and in
spite of this patients may die or suffer severe neurological injury and remain disabled.
Several non-randomized studies have shown that ELD is very effective in lowering
intracranial pressure (ICP) in an immediate and lasting manner. While historical concerns
remain that the brain may shift downwards causing herniation, this is not supported by
recent studies. However, due to the historic nature of such teachings, some physicians
may not use this potentially effective treatment in treating severe TBI patients with
high ICP.
Therefore, in this trial we will determine the safety ELD in treating severe TBI
patients, in a randomized controlled manner, whereby two-thirds of the patients will be
randomized to routine usual treatments and either early or late ELD, and a third to only
routine usual treatments. The patient randomized to ELD will receive this in addition to
all other usual treatments, and no available treatment will be withheld
The secondary objectives are to determine if routine quantitative pupillometry can be
used for safety determination and monitoring of ELD by evaluating:
Correlation with ELD safety score
Temporally changes prior to occurrence of any 'critical neuro-worsening events
Comparison / Usual treatment All participants will undergo usual treatment as per
evidence- and guidelines-based Seattle International Severe Traumatic Brain Injury
Consensus Conference (SIBICC) algorithm (36, 71). Routine non-invasive automated
infra-red pupillometry will be performed bilaterally every hour as part of routine
neurological checks for neuro-worsening in addition to hourly Glasgow Coma Scale (GCS)
score checks and other routine intensive care unit (ICU) protocols. No treatment will be
withheld. ICP monitoring will be performed with intra-parenchymal monitor or external
ventricular drainage (EVD) as per local protocols.
RISKS TO HUMAN SUBJECTS:
The assessments for this study involve risk and benefits to patients in excess of routine
standard of care treatment. The risks related to the intervention i.e. placement of
lumbar drain and drainage of CSF, are critical neurological worsening events related to
cerebral herniation such as decrease in GCS score, development of new motor deficit, or
rarely death. These events will be recorded for all patients and prompt treatment will be
instituted accordingly, including an emergent computed tomography (CT) scan (36).
Clinical protocols exist at all neurotrauma ICUs for such neuro-worsening events and
neurointensivists and neurotrauma surgeons are well placed to manage them medically or
surgically in routine care of severe TBI patients.
Background 'Event rate' for critical neuro-worsening events with usual treatment: To
estimate background 'event rate' of critical neuro-worsening events, we analyzed the
Brain Trauma Foundation (BTF)-New York State TBI-trac® registry from 1997-2004, with 4789
TBI patients, of which 3590 had CT data and 2616 were between the age of 18-65 years.
When inclusion / exclusion criteria for age and CT findings were applied, 50.3% of these
were eligible for the study. The mean incident risk of having new pupillary asymmetry at
any point after admission was 22.0% (95% confidence intervals (CI): 19.9-24.3%), risk of
motor worsening was 18.0% (95% CI: 12.6-25.0%) for those with motor score 1-4, and 16.4%
(95% CI: 12.1-21.9%) for all motor scores with deterioration. Finally, risk of 2-week
mortality was 22.4% (95% CI 20.2-24.8%). This data provides us with an expected event
rate, though the comparison will still be made between control and intervention arms of
the study, per protocol. Given the high incidence of these events occurring as natural
history of the disease, they will be classified as anticipated Serious adverse events
(SAEs).
Human Subjects Protections:
Pressure and Volume protected lumbar CSF drainage: In the studies reviewed, ELD was set
to drain at 0-20 mmHg or drained at fixed volume. In order to increase safety, we will
perform ELD in patients without high ICP at 15 mmHg and those with high ICP at 20 mmHg
and additionally volume-limit drainage to 10 ml/hour.
Procedure safety:
Indication:
ELD will be utilized as the first intervention in the 2nd tier of SIBICC protocol, which
will invariably be preceded by gradual increase in ICP. As per SIBICC protocol, a CT scan
will be obtained prior to advancement to 2nd tier and ELD placement.
Contra-indications:
ELD will NOT be utilized to lower ICP during sudden ICP crises associated with
neuro-worsening. Hypertonic saline, mannitol, hyperventilation, and review for surgery
will be utilized as per clinical routine.
ELD will NOT be placed in lieu of an EVD. ELD will NOT be performed in patients
undergoing hemicraniectomy.
Safety Monitoring: Given the greatest risk of neuro-worsening from herniation is soon
after drainage is commenced, all patients will undergo automated pupillometry for
pupillary size, symmetry, light reactivity and neurological pupillary index (NPI) every
15 minutes for 1 hour following ELD placement and start of CSF drainage. Following the
first hour, pupillometry will be performed hourly. If NPI drops by 1 point within the 1st
hour, a head CT may be obtained to review any craniocaudal shift.
SAFETY REPORTING: All unanticipated SAEs will be reported to the steering committee,
local site institutional research boards (IRBs) as well as the overall IRB, within 24
hours. Anticipated SAE and adverse events (AEs) will be reported in annual reports.
Data Safety and Monitoring Board (DSMB):
A DSMB of a pool of 7 experienced trauma neurosurgeons and neurointensivists of
international standing, will review every neuro-worsening events, as defined above, in
each arm of the study. The DSMB will meet every 6 months to review anticipated SAEs. DSMB
will review unanticipated SAE including deaths within 48 hours, and will make
determinations of association of unanticipated adverse events with interventions.
Potential benefits of the proposed research to participants:
As this is an interventional study, the research participants may gain direct benefit or
suffer harm. At conclusion of the study, the overall results will be included in a
summary report mailed to all participants. In the field of TBI management, this study has
potential benefits in treating post-traumatic intracranial hypertension, which is the
main mechanism of neurological deterioration following severe TBI and improving
functional outcome for participants.