The Future of Neurocritical Care Research: Proceedings and Recommendations from the Fifth Neurocritical Care Research Network Conference.

The Fifth Neurocritical Care Research Network (NCRN) Conference held in Boca Raton, Florida, in September of 2018 was devoted to challenging the current status quo and examining the role of the Neurocritical Care Society (NCS) in driving the science and research of neurocritical care. The aim of this in-person meeting was to set the agenda for the NCS's Neurocritical Care Research Central, which is the overall research arm of the society. Prior to the meeting, all 103 participants received educational content (book and seminar) on the 'Blue Ocean Strategy®,' a concept from the business world which aims to identify undiscovered and uncontested market space, and to brainstorm innovative ideas and methods with which to address current challenges in neurocritical care research. Three five-member working groups met at least four times by teleconference prior to the in-person meeting to prepare answers to a set of questions using the Blue Ocean Strategy concept as a platform. At the Fifth NCRN Conference, these groups presented to a five-member jury and all attendees for open discussion. The jury then developed a set of recommendations for NCS to consider in order to move neurocritical care research forward. We have summarized the topics discussed at the conference and put forward recommendations for the future direction of the NCRN and neurocritical care research in general.

Multimodal neurologic monitoring.

Neurocritical care has two main objectives. Initially, the emphasis is on treatment of patients with acute damage to the central nervous system whether through infection, trauma, or hemorrhagic or ischemic stroke. Thereafter, attention shifts to the identification of secondary processes that may lead to further brain injury, including fever, seizures, and ischemia, among others. Multimodal monitoring is the concept of using various tools and data integration to understand brain physiology and guide therapeutic interventions to prevent secondary brain injury. This chapter will review the use of electroencephalography, intracranial pressure monitoring, brain tissue oxygenation, cerebral microdialysis and neurochemistry, near-infrared spectroscopy, and transcranial Doppler sonography as they relate to neuromonitoring in the critically ill. The concepts and design of each monitor, in addition to the patient population that may most benefit from each modality, will be discussed, along with the various tools that can be used together to guide individualized patient treatment options. Major clinical trials, observational studies, and their effect on clinical outcomes will be reviewed. The future of multimodal monitoring in the field of bioinformatics, clinical research, and device development will conclude the chapter.

Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: a statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine

Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. The Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine, and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants' collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data

Structural and connectomic neuroimaging for the personalized study of longitudinal alterations in cortical shape, thickness and connectivity after traumatic brain injury.

The integration of longitudinal brain structure analysis with neurointensive care strategies continues to be a substantial difficulty facing the traumatic brain injury (TBI) research community. For patient-tailored case analysis, it remains challenging to establish how lesion profile modulates longitudinal changes in cortical structure and connectivity, as well as how these changes lead to behavioral, cognitive and neural dysfunction. Additionally, despite the clinical potential of morphometric and connectomic studies, few analytic tools are available for their study in TBI. Here we review the state of the art in structural and connectomic neuroimaging for the study of TBI and illustrate a set of recently-developed, patient-tailored approaches for the study of TBI-related brain atrophy and alterations in morphometry as well as inter-regional connectivity. The ability of such techniques to quantify how injury modulates longitudinal changes in cortical shape, structure and circuitry is highlighted. Quantitative approaches such as these can be used to assess and monitor the clinical condition and evolution of TBI victims, and can have substantial translational impact, especially when used in conjunction with measures of neuropsychological function.

Research and technology in neurocritical care.

The daily practice of neurointensivists focuses on the recognition of subtle changes in the neurological examination, interactions between the brain and systemic derangements, and brain physiology. Common alterations such as fever, hyperglycemia, and hypotension have different consequences in patients with brain insults compared with patients of general medical illness. Various technologies have become available or are currently being developed. The session on "research and technology" of the first neurocritical care research conference held in Houston in September of 2009 was devoted to the discussion of the current status, and the research role of state-of-the art technologies in neurocritical patients including multi-modality neuromonitoring, biomarkers, neuroimaging, and "omics" research (proteomix, genomics, and metabolomics). We have summarized the topics discussed in this session. We have provided a brief overview of the current status of these technologies, and put forward recommendations for future research applications in the field of neurocritical care.

Partial recanalization of concomitant internal carotid-middle cerebral arterial occlusions promotes distal recanalization of residual thrombus within 24 h.

OBJECTIVES: Acute, simultaneous, concomitant internal carotid artery (ICA) and middle cerebral arteries (MCA) occlusions almost invariably lead to significant neurological disability if left untreated. Endovascular therapy is frequently the method of treatment in such situations but there remains a chance of incomplete recanalization. Successful recanalization of the proximal aspect of the occlusion may allow for endogenous thrombolysis and facilitate further endogenous recanalization of any residual MCA occlusion. METHODS: Consecutive patients with acute ischemic stroke undergoing endovascular therapy for tandem extracranial ICA-MCA or contiguous intracranial ICA-MCA occlusions were retrospectively analyzed. Rates of facilitated endogenous recanalization at 24 h (FER(24)) were compared by imaging within the immediate post-intervention 5-24 h period in those with proximal recanalization and in those without. RESULTS: 17 patients were included in the analysis. 12 patients had good initial proximal recanalization but a residual partial or total occlusion of the MCA while five patients failed any recanalization. Seven patients (58.3%) in the first group and none in the second had FER(24) on interval imaging after intervention (p=0.04). The probability of death and disability at discharge was less in patients with FER(24) than those without (p=0.05). CONCLUSIONS: More than half of all patients who present with both ICA and MCA occlusions who are only partially recanalized will undergo facilitated endogenous recanalization within the subsequent 24 h following intervention.

SAH pituitary adrenal dysfunction.

Disruption of the hypothalamic-pituitary-adrenal axis may occur after aneurysmal subarachnoid hemorrhage, resulting in hypopituitarism. An electronic literature search was conducted to identify articles with English-language abstracts published between 1980 and March 2011 that addressed hypothalamic-pituitary-adrenal axis insufficiency and hormone replacement. A total of 18 observational and prospective, randomized studies were selected for this review. Limited data are available evaluating pituitary effects during the acute stage after subarachnoid hemorrhage, with inconsistent results reported. Overall, acutely after subarachnoid hemorrhage, cortisol levels may initially be supranormal, decreasing toward normal levels over time. During the months to years after subarachnoid hemorrhage, pituitary deficiency may occur in up to one in three patients. Limited data suggest modest outcome benefits with fludrocortisone and no benefit or harm from corticosteroids.

High-volume centers.

Outcome from trauma, surgery, and a variety of other medical conditions has been shown to be positively affected by providing treatment at facilities experiencing a high volume of patients with those conditions. An electronic literature search was made to identify English-language articles available through March 2011, addressing the effect of patient treatment volume on outcome for patients with subarachnoid hemorrhage. Limited data were identified, with 16 citations included in the current review. Over 60% of hospitals fall into the lowest case-volume quartile. Outcome is influenced by patient volume, with better outcome occurring in high-volume centers treating >60 cases per year. Patients treated at low-volume hospitals are less likely to experience definitive treatment. Furthermore, transfer to high-volume centers may be inadequately arranged. Several factors may influence the better outcome at high-volume centers, including the availability of neurointensivists and interventional neuroradiologists.

Nonconvulsive seizures after traumatic brain injury are associated with hippocampal atrophy.

OBJECTIVE: To determine if posttraumatic nonconvulsive electrographic seizures result in long-term brain atrophy. METHODS: Prospective continuous EEG (cEEG) monitoring was done in 140 patients with moderate to severe traumatic brain injury (TBI) and in-depth study of 16 selected patients was done using serial volumetric MRI acutely and at 6 months after TBI. Fluorodeoxyglucose PET was done in the acute stage in 14/16 patients. These data were retrospectively analyzed after collection of data for 7 years. RESULTS: cEEG detected seizures in 32/140 (23%) of the entire cohort. In the selected imaging subgroup, 6 patients with seizures were compared with a cohort of 10 age- and GCS-matched patients with TBI without seizures. In this subgroup, the seizures were repetitive and constituted status epilepticus in 4/6 patients. Patients with seizures had greater hippocampal atrophy as compared to those without seizures (21 +/- 9 vs 12 +/- 6%, p = 0.017). Hippocampi ipsilateral to the electrographic seizure focus demonstrated a greater degree of volumetric atrophy as compared with nonseizure hippocampi (28 +/- 5 vs 13 +/- 9%, p = 0.007). A single patient had an ictal PET scan which demonstrated increased hippocampal glucose uptake. CONCLUSION: Acute posttraumatic nonconvulsive seizures occur frequently after TBI and, in a selected subgroup, appear to be associated with disproportionate long-term hippocampal atrophy. These data suggest anatomic damage is potentially elicited by nonconvulsive seizures in the acute postinjury setting.

The risk of acute radiocontrast-mediated kidney injury following endovascular therapy for acute ischemic stroke is low.

BACKGROUND AND PURPOSE: Endovascular therapy is an alternative for the treatment of AIS resulting from large intracranial arterial occlusions that depends on the use of iodinated RCM. The risk of RCM-mediated AKI following endovascular therapy for AIS may be different from that following coronary interventions because patients may not have identical risk factors. MATERIALS AND METHODS: All consecutive patients with large-vessel AIS undergoing endovascular therapy were prospectively recorded. We recorded the baseline kidney function, and RCM-AKI was assessed according to the AKIN criteria at 48 hours after RCM administration. We compared the rate of RCM-AKI 48 hours after the procedure and sought to determine whether any preexisting factors increased the risk of RCM-AKI. RESULTS: We identified 99 patients meeting inclusion criteria. The average volume of contrast was 189 ± 71 mL, and the average creatinine change was -4.6% at 48 hours postangiography. There were 3 patients with RCM-AKI. Although all 3 patients died as a result of their strokes, return to baseline creatinine levels occurred before death. There was a trend toward higher rates of premorbid diabetes mellitus, chronic renal insufficiency, preadmission statin and NSAID use, and a higher serum creatinine level on admission for the RCM-AKI group. The volume of procedural contrast was similar between groups (those with and those without RCM-AKI) (P = .5). CONCLUSIONS: In this small study, the rate of RCM-AKI following endovascular intervention for AIS was very low. A much larger study is required to determine its true incidence.

Higher rates of mortality but not morbidity follow intracranial mechanical thrombectomy in the elderly.

BACKGROUND AND PURPOSE: Mechanical thrombectomy is a promising means of recanalizing acute cerebrovascular occlusions in certain situations. We sought to determine if increasing age adversely affects prognosis. MATERIALS AND METHODS: We reviewed all Merci thrombectomy cases and compared patients younger than 80 years of age with older individuals. We compared these 2 age groups with respect to recanalization rates, hospital LOS, hemorrhagic transformation, and death and disability on discharge. RESULTS: Elderly patients were more likely to die from their stroke than those younger than 80 years of age, regardless of recanalization success (48% versus 15%; OR, 5.5; 95% CI, 2.1-14.1). Among survivors, there was no difference in the probability of having a good functional outcome (mRS,

Metabolic crisis after traumatic brain injury is associated with a novel microdialysis proteome.

BACKGROUND: To examine if the metabolic distress after traumatic brain injury (TBI) is associated with a unique proteome. METHODS: Patients with severe TBI prospectively underwent cerebral microdialysis for the initial 96 h after injury. Hourly sampling of metabolism was performed and patients were categorized as having normal or abnormal metabolism as evidenced by the lactate/pyruvate ratio (LPR) threshold of 40. The microdialysate was frozen for proteomic batch processing retrospectively. We employed two different routes of proteomic techniques utilizing mass spectrometry (MS) and categorized as diagnostic and biomarker identification approaches. The diagnostic approach was aimed at finding a signature of MS peaks which can differentiate these two groups. We did this by enriching for intact peptides followed by MALDI-MS analysis. For the biomarker identification approach, we applied classical bottom-up (trypsin digestion followed by LC-MS/MS) proteomic methodologies. RESULTS: Five patients were studied, 3 of whom had abnormal metabolism and 2 who had normal metabolism. By comparison, the abnormal group had higher LPR (1609 +/- 3691 vs. 15.5 +/- 6.8, P < 0.001), higher glutamate (157 +/- 84 vs. 1.8 +/- 1.4 microM, P < 0.001), and lower glucose (0.27 +/- 0.35 vs. 1.8 +/- 1.1 mmol/l, P < 0.001). The abnormal group demonstrated 13 unique proteins as compared with the normal group in the microdialysate. These proteins consisted of cytoarchitectural proteins, as well as blood breakdown proteins, and a few mitochondrial proteins. A unique as yet to be characterized peptide was found at m/z (mass/charge) 4733.5, which may represent a novel biomarker of metabolic distress. CONCLUSION: Metabolic distress after TBI is associated with a differential proteome that indicates cellular destruction during the acute phase of illness. This suggests that metabolic distress has immediate cellular consequences after TBI.

Recanalization rates decrease with increasing thrombectomy attempts.

BACKGROUND AND PURPOSE: Use of the Merci retriever is increasing as a means to reopen large intracranial arterial occlusions. We sought to determine whether there is an optimum number of retrieval attempts that yields the highest recanalization rates and after which the probability of success decreases. MATERIALS AND METHODS: All consecutive patients undergoing Merci retrieval for large cerebral artery occlusions were prospectively tracked at a comprehensive stroke center. We analyzed ICA, M1 segment of the MCA, and vertebrobasilar occlusions. We compared the revascularization of the primary AOL with the number of documented retrieval attempts used to achieve that AOL score. For tandem lesions, each target lesion was compared separately on the basis of where the device was deployed. RESULTS: We identified a total of 97 patients with 115 arterial occlusions. The median number of attempts per target vessel was 3, while the median final AOL score was 2. Up to 3 retrieval attempts correlated with good revascularization (AOL 2 or 3). When >or=4 attempts were performed, the end result was more often failed revascularization (AOL 0 or 1) and procedural complications (P = .006). CONCLUSIONS: In our experience, 3 may be the optimum number of Merci retrieval attempts per target vessel occlusion. Four or more attempts may not improve the chances of recanalization, while increasing the risk of complications.

Endovascular mechanical clot retrieval in a broad ischemic stroke cohort.

BACKGROUND AND PURPOSE: Our aim was to describe an expanded experience with endovascular mechanical embolectomy in a broad group of patients, including those not meeting entry criteria for the MERCI multicenter trials. METHODS: We performed an analysis of all patients with ischemic stroke treated with the Merci Clot Retrieval Device at a single academic center outside of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trials. RESULTS: Twenty-four patients were treated with the device. Nine were MERCI trial ineligible: 4 received intravenous (IV) tissue plasminogen activator (tPA), 1 received IV tPA and was younger than 18 years of age, and 4 had time-to-treatment of longer than 8 hours. Mean age was 64 years (range, 14-89 years; 42% women). Median National Institutes of Health Stroke Scale (NIHSS) score was 21 (range, 11-30). Median symptoms-to-procedure-start time was 303 minutes (range, 85-2385 minutes). Recanalization (Thrombolysis in Myocardial Infarction, 2-3) was achieved in 15/24 (63%). In device-only patients, recanalization occurred in 10/16. In patients who failed IV tPA undergoing rescue embolectomy, recanalization was achieved in 4/5. Three patients unresponsive to device therapy received rescue intra-arterial tPA/abciximab; recanalization was achieved in 2/3. Recanalization was achieved in 3/4 patients in whom treatment was started longer than 8 hours after symptom onset. Asymptomatic hemorrhage occurred in 38%; symptomatic hemorrhage, in 8%. Three device fractures occurred; none worsened clinical outcome. In-hospital mortality was 17%; 90-day mortality, 29%. Good 90-day functional outcome (modified Rankin Scale,

Influence of gender on outcomes after intra-arterial thrombolysis for acute ischemic stroke.

Recent data suggest that women obtain greater benefit than men from IV fibrinolysis for acute ischemic stroke. It is unknown whether this gender-thrombolysis advantage extends to those treated with intra-arterial (IA) thrombolysis. The authors evaluated the independent effect of gender among ischemic stroke patients treated with IA fibrinolysis and found no differences in short-term clinical and angiographic outcomes between men and women who received IA thrombolysis for acute ischemic stroke.

Assessment of cerebral blood flow by means of blood-flow-volume measurement in the internal carotid artery: comparative study with a 133xenon clearance technique.

BACKGROUND AND PURPOSE: We sought to evaluate a new, angle-independent ultrasonic device for assessment of blood flow volume (BFV) in the internal carotid artery (ICA). METHODS: Nineteen patients and 4 healthy volunteers were enrolled in a comparative study conducted in the Care Unit of the Division of Neurosurgery at UCLA Medical Center. All patients had been admitted because of severe brain injury: 15 patients with severe head trauma (Glasgow Coma Scale score< or =8) and 4 patients with subarachnoid hemorrhage due to aneurysm rupture. In all patients and subjects, cerebral blood flow (CBF) values obtained with the 133xenon-clearance technique were compared with BFV measurements in the ipsilateral ICA. RESULTS: Hemispheric CBF values showed a close and linear correlation with BFV measurements (r=0.76, P<0.0001). Global CBF values showed a higher correlation with the total BFV value obtained from both ICAs (r=0.84, P<0.0001). With 37 mL x min(-1) x 100 g(-1) as a cutoff value for the ischemic range, a BFV value of 220 mL/min would yield a positive predictive value of 91.7% and a negative predictive value of 82.6% (sensitivity 73.3%, specificity 95%). Conversely, BFV sensitivity and specificity were 60% and 96%, respectively, for the hyperemic range defined by a CBF value >55 mL x min(-1) x 100 g(-1) (positive predictive value of 85.7% and negative prediction value of 85.7%). CONCLUSIONS: BFV measurements with this new technology proved to accurately correlate with CBF values evaluated by the 133xenon-clearance technique. These results support the implementation of this technique for bedside assessment of cerebral hemodynamics in critically ill neurosurgical patients.

Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome.

OBJECTIVE: To determine whether early seizures that occur frequently after intracerebral hemorrhage (ICH) lead to increased brain edema as manifested by increased midline shift. METHODS: A total of 109 patients with ischemic stroke (n = 46) and intraparenchymal hemorrhage (n = 63) prospectively underwent continuous EEG monitoring after admission. The incidence, timing, and factors associated with seizures were defined. Serial CT brain imaging was conducted at admission, 24 hours, and 48 to 72 hours after hemorrhage and assessed for hemorrhage volume and midline shift. Outcome at time of discharge was assessed using the Glasgow Outcome Scale score. RESULTS: Electrographic seizures occurred in 18 of 63 (28%) patients with ICH, compared with 3 of 46 (6%) patients with ischemic stroke (OR = 5.7, 95% CI 1.4 to 26.5, p < 0.004) during the initial 72 hours after admission. Seizures were most often focal with secondary generalization. Seizures were more common in lobar hemorrhages but occurred in 21% of subcortical hemorrhages. Posthemorrhagic seizures were associated with neurologic worsening on the NIH Stroke Scale (14.8 vs 18.6, p < 0.05) and with an increase in midline shift (+ 2.7 mm vs -2.4 mm, p < 0.03). There was a trend toward increased poor outcome (p < 0.06) in patients with posthemorrhagic seizures. On multivariate analysis, age and initial NIH Stroke Scale score were independent predictors of outcome. CONCLUSION: Seizures occur commonly after ICH and may be nonconvulsive. Seizures are independently associated with increased midline shift after intraparenchymal hemorrhage.

PET investigation of post-traumatic cerebral blood volume and blood flow.

Hemodynamic changes following traumatic brain injury (TBI) may reflect cellular damage leading to secondary injury. The purpose of this study was to investigate the regional hemodynamic parameters acutely after TBI among regions in and around contusions. Sixteen patients (11 male, 5 female) showing evidence of contusion on CT and 18 normal volunteers (12 male, 6 female) underwent positron emission tomography (PET) with O-15 CO and O-15 H2O to estimate cerebral blood volume (CBV) and cerebral blood flow (CBF), respectively. A flow to volume ratio (FVR = CBF/CBV) was also calculated as an index of vasodilatation. The hemodynamic parameters were compared among contusion, pericontusion, and remote areas. Globally, hemodynamic parameters did not differ between patients and normal volunteers, and did not correlate with intracranial pressure (ICP). Regionally, contusional and pericontusional areas showed significantly lower CBF and FVR compared with normal volunteers, while CBV did not differ significantly. The correlation between CBF and CBV was significant (r = 0.37, p < 0.01). Remote areas did not show a significant difference in any of the PET parameters. In conclusion, regional brain edema is likely to occur in contusion and pericontusion areas, while some of the contusional tissue may show vascular engorgement.

Delayed increase in extracellular glycerol with post-traumatic electrographic epileptic activity: support for the theory that seizures induce secondary injury.

Early post-traumatic seizures occur commonly and may have adverse clinical consequences. In order to determine the significance of post-traumatic seizures, we performed a prospective assessment of the consequences of epileptic activity by assessing the change in extracellular glycerol levels. Glycerol is a marker of cellular membrane breakdown. Thirteen patients underwent combined electroencephalography (EEG) and cerebral microdialysis monitoring. Two patients had seizures on EEG with associated delayed elevations of glycerol associated with the seizure activity. Higher mean levels of glycerol were present in those patients with seizures compared to those without seizures (p < 0.001). Preliminary evidence suggests that post-traumatic seizures lead to additional membrane injury as reflected by elevated extracellular glycerol levels.