Spreading Depolarization and Ketamine Suppression
Spreading Depolarization and Ketamine Suppression
Hypothesis: Cortical spreading depolarizations are inhibited by the NMDA receptor antagonist
 Ketamine Aim 1: To demonstrate, in a group of patients with acute severe brain injury
 requiring surgery including traumatic brain injury and aneurysmal subarachnoid hemorrhage,
 whether use of continuous infusion of ketamine decreases frequency of occurrence of cortical
 spreading depolarizations.
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