Spreading Depolarization and Ketamine Suppression

Cortical spreading depolarizations (CSD) are massive events which recently have been observed
in many types of acute brain injury and likely lead to expansion of injury. These "brain
tsunamis" are unlike any other type of brain electrical event (such as seizures or normal
neuronal transmission) in that they progress very slowly across the surface of the brain
(2-5mm/minute) and involve near complete depolarization of the neurons and other cells. The
only similar event in neurophysiology is an anoxic depolarization, which is the final wave of
loss of cell function preceding death in cells suffering severe, irreversible hypoxia or
ischemia(1). In the case of CSD, the cell is able to recover function, however, at an
enormous metabolic expense. Massive amounts of energy substrate (ATP, glucose, oxygen) as
well as the delivery system to bring these substrates (blood flow) are required to restore
the normal ionic gradient of the cell membrane and cell function. Because of this loss of
function of cells, normal electrocortical (ECog) activity is transiently lost, resulting in a
depression of the high frequency cortical activity, which is why the phenomenon is also
frequently referred to as "cortical spreading depression." CSD has been definitively
documented to occur after many types of acute brain injury including ischemic stroke,
aneurysmal subarachnoid hemorrhage, intracerebral hemorrhage, and severe traumatic brain
injury(2,3). The true incidence is, for the time being, unknown, in that the measurement
technique requires placement of a small cortical electrode at the time of a surgical
procedure. This limits the region of measurement to relatively small area in patients
undergoing surgery, however even in this very small sample, the incidence of delayed SD after
brain injury ranges from 53-88%(4). Efforts are underway to attempt to measure CSD less
invasively(5) or non-invasively(6,7), however these techniques are currently under
exploration and do not have the robust reliability of the cortical electrode system.

Mounting human data coupled with extensive animal data supports the assertion that CSD is not
only a marker in response to severe brain injury, but in fact, plays a causal role in injury
propagation(8). Animal data is fairly definitive in this assertion, in that CSD can be
studied in uninjured brain and inducing CSD leads to neuronal death, particularly with
repeated events. Note the progressive loss of brain electrical activity with repeated CSD in
the figure to the right. In animal models, CSD clearly leads to expansion of injury,
particularly in ischemic stroke models. Human data is unavoidably observational to this
point, however by observing multiple physiologic modalities, the deleterious effects become
clear. A spectrum of local blood flow responses to CSD have been observed, ranging from a
wave of hyperemia (termed the normal hemodynamic response) to a wave of ischemia (termed the
inverse hemodynamic response(9, 10)). The factors that determine the response likely have to
do with the availability of substrate (glucose, oxygen) and delivery (blood flow) coupled
with the baseline metabolic state of the tissue (depressed metabolic state may be more
resistant). When the inverse hemodynamic response is observed, an associated wave of tissue
hypoxia is observed, which becomes linearly more hypoxic with repeated CSD in a short
interval(11). Brain metabolism also can be measured during CSD, and consistent metabolic
challenge is noted, with increased micro dialysis lactate and decreased glucose(12). In the
case of repeated events, this glucose depletion becomes progressive due to inadequate time
for the tissue to recover between these massive events leading to progressive ischemia(12).

From a clinical perspective, the metabolic data can support a deleterious effect, but the
effect on clinical outcome is critical in determining if the events are relevant as a
potential target for therapy. The occurrence and severity of CSD has been closely linked to
both development of new stroke as well as clinical outcome in both retrospective and
prospective series. In subarachnoid hemorrhage, Dreier(13) reported a direct association with
clinical delayed ischemic neurologic defect (DIND) and the presence of a cluster of SD.
Furthermore, in this small series, the patients who went on to develop stroke had markedly
longer periods of depression, indicating inability of the tissue to recover from the event
compared to patients without delayed stroke. The most extensive clinical outcome data is from
traumatic brain injury (TBI)(14,15) where the presence of any CSD showed a non-significant
trend toward predicting worse outcome, however CSD occurring in already dysfunctional tissue
(termed isoelectric spreading depolarization or ISD) was stronger predictor of clinical
outcome than a composite score of most standard variables through to predict outcome (OR 7.58
(95%CI 2.64-21.8) for ISD compared to 1.76(95%CI 1.26-2.46) for the composite prognostic
score)(15).

This mounting observational data as to the deleterious effects of CSD has led to increased
excitement regarding CSD as a novel target for prevention of delayed injury after diverse
types of acute brain injury(16). The optimal target or agent has not been defined, but there
are promising animal data supporting a wide variety of agents, primarily targeting NMDAVR, as
this is thought to be an important factor in propagation of SD(17). Initial clinical case
reports of the effect of ketamine being used as sedation in patients with severe TBI(18) led
to a larger scale effort to retrospectively study the various anesthetics used for standard
clinical care on the frequency of CSD in monitored patients(19). Using only the sedation
medications for which there were >1000 cumulative hours of ECog recording while on that
medication, the effects of propofol, fentanyl, midazolam, ketamine, morphine, and sufentanyl
were examined. The study found a consistent effect of ketamine in decreased probability of
CSD/h per patient. This was nearly linearly dose dependent, and importantly, in multivariate
analysis, ketamine still emerged as having a significant effect on decreasing both occurrence
of CSD as well as the occurrence of the more deleterious clusters of CSD(19).

Though ongoing observational data is still clearly needed to better characterize the
susceptibility and effects of CSD, in order to move toward trial of CSD directed therapy, a
prospective trial of the effect of ketamine on the occurrence of CSD is necessary to confirm
these retrospective observations and establish the precedent for future therapeutic trials.
The SAKS trial will provide important confirmatory pilot data to direct the implementation of
future trials.

This is a prospective, randomized, controlled, multiple cross-over trial evaluating the
efficacy of ketamine in the suppression of CSDs. This multiple crossover design was chosen in
order to be able to develop preliminary data which could guide implementation of future
multicenter trials. Because of the significant variability between patients, a study
randomized by patients would be subject to a large amount of potential bias. Because factors
such as time of day or hospital day also are known to affect CSD, a brief crossover period of
6 hours was chosen. The study will be registered with clinicaltrials.gov prior to enrollment
of patients. Patients with severe traumatic brain injury or subarachnoid hemorrhage who fit
the inclusion/exclusion criteria will be approached by either research coordinators or study
investigators who will consent the LAR for the study prior to clinically indicated
craniotomy. It is not expected that patients will be able to independently consent given the
severity of the condition, however, if the patient is conscious, attempts will be made to
discuss the study with him or her as well.

The patient's surgical procedure will be carried out as planned. The only alteration of the
surgical procedure will be the placement of a subdural electrode strip (1x6 cortical strip:
Integra: Plainsboro, NJ) on the brain cortex adjacent to the operative site at the end of the
procedure. These strips are standard, FDA approved, disposable, pre-sterilized devices used
routinely for epilepsy monitoring. In addition, the investigators have used these strips as
part of our post-injury IRB approved protocol (10-159) for many days after surgery. The
cortical strip (plus a dermal reference electrode on the mastoid or apex of the skull) will
be monitored with a Moberg CNS monitor. (Moberg Research, Ampler, PA).The Moberg monitor is a
modified version of a standard clinical use multiparametric monitoring system shown below
which was cleared by the FDA in 2008. The only difference is the ECog amplifier, which allows
for direct full frequency spectrum DC recording.

Upon arrival, post-operatively, to the Neurosciences Intensive Care Unit, the patient will
have randomization completed via online randomization program. Randomization will be to
allocate patients to either of two groups: 1) Ketamine first or 2) Propofol/other first. No
secondary randomization criteria are thought to be necessary given the small sample size for
this pilot trial. Initiation of the protocoled sedation regimen will begin on the next hour
divisible by 6 (i.e. 06:00, 12:00, 18:00, 24:00). The randomization will determine which
sedative to start, and after that the ketamine and propofol/other infusions will be
alternated every 6 hours on the above schedules.

Dosages of these sedating medications will not be standardized, but rather titrated to
clinical effect. The clinical effect will be determined by the attending intensivist based on
the patient's clinical needs. This level of sedation will be communicated to nursing via the
Riker Sedation-Agitation Score(20). A minimal dose of ketamine (0.1mg/min or 6mg/hr) will be
infused during the ketamine periods, which is lower than required to induce sedation. No
minimal sedation requirements will exist for the propofol or other regimen period. This will
be done to test the effect of ketamine (which is hypothesized to affect frequency of SD)
compared to other sedations regimens (which are not thought to affect SD.) Each period of
adjustment of the sedation regimen will be treated as a "spontaneous breathing trial" which
is a common standard of care procedure for nursing which involves holding sedation to
determine a patient's neurologic exam and respiratory ability with subsequent titration back
to appropriate clinical effect. These sedation breaks are very common in the ICU and
titration to the desired clinical effect will be performed with the appropriate drug per the
standard ICU nursing protocols. In the event that the patient no longer needs invasive
positive pressure ventilation prior to discontinuation of ] neuromonitoring, propofol/other
sedation intervals will not have mandatory sedative infusions, however, ketamine intervals
will have a basal dose of 0.1mg/min (6mg/hr). 'The sedation protocol will end when the strip
is removed. This is determined by the patients critical care needs. The strip is checked
daily for function as well as any sign of problem such as leak of CSF. Once other critical
care monitoring is discontinued (such as ventricular drains and invasive monitoring) the
strip will be removed. Other endpoints will include any sign of CSF leak, adverse event
reported, or treating intensivist does not think alternating sedation is safe.

During the sedation protocol, cortical electroencephalographic monitoring with the cortical
electrodes will be continuously recording. Other physiologic data obtained clinically
(including, but not limited to, vital signs, arterial wave forms, laboratory values, video
EEG) will be subject to review and data collection for correlation with occurrence of SD.
This data is obtained as part of standard of care and stored in a departmental server in an
anonymous fashion. Clinical video EEG will be obtained on the majority of patients (if not
all patients) as part of standard multimodal monitoring. This video will be reviewed to look
for any external stimuli that might induce cortical spreading depressions.

Inclusion Criteria:

- GCS <8

- SAH or severe traumatic brain injury requiring craniotomy

- Consent obtainable (via legal representative)

- Ictus (bleed or injury) within 48 hours of enrollment

- Clinically appropriate for multimodality monitoring

Exclusion Criteria:

- Anticipated survival <48 hours

- No craniotomy

- Infratentorial craniotomy only•Unable to obtain consent

- Absence of clinically used multimodality monitoring

- Prisoners

- Pregnant