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.

Prior antiplatelet therapy and outcome following intracerebral hemorrhage: a systematic review.

OBJECTIVES: Antiplatelet therapy (APT) promotes bleeding; therefore, APT might worsen outcome in patients with intracerebral hemorrhage (ICH). We performed a systematic review and meta-analysis to address the hypothesis that pre-ICH APT use is associated with mortality and poor functional outcome following ICH. METHODS: The Medline and Embase databases were searched in February 2008 using relevant key words, limited to human studies in the English language. Cohort studies of consecutive patients with ICH reporting mortality or functional outcome according to pre-ICH APT use were identified. Of 2,873 studies screened, 10 were judged to meet inclusion criteria by consensus of 2 authors. Additionally, we solicited unpublished data from all authors of cohort studies with >100 patients published within the last 10 years, and received data from 15 more studies. Univariate and multivariable-adjusted odds ratios (ORs) for mortality and poor functional outcome were abstracted as available and pooled using a random effects model. RESULTS: We obtained mortality data from 25 cohorts (15 unpublished) and functional outcome data from 21 cohorts (14 unpublished). Pre-ICH APT users had increased mortality in both univariate (OR 1.41, 95% confidence interval [CI] 1.21 to 1.64) and multivariable-adjusted (OR 1.27, 95% CI 1.10 to 1.47) pooled analyses. By contrast, the pooled OR for poor functional outcome was no longer significant when using multivariable-adjusted estimates (univariate OR 1.29, 95% CI 1.09 to 1.53; multivariable-adjusted OR 1.10, 95% CI 0.93 to 1.29). CONCLUSIONS: In cohort studies, APT use at the time of ICH compared to no APT use was independently associated with increased mortality but not with poor functional outcome.

Do-not-resuscitate orders and predictive models after intracerebral hemorrhage.

OBJECTIVE: To quantify the accuracy of commonly used intracerebral hemorrhage (ICH) predictive models in ICH patients with and without early do-not-resuscitate orders (DNR). METHODS: Spontaneous ICH cases (n = 487) from the Brain Attack Surveillance in Corpus Christi study (2000-2003) and the University of California, San Francisco (June 2001-May 2004) were included. Three models (the ICH Score, the Cincinnati model, and the ICH grading scale [ICH-GS]) were compared to observed 30-day mortality with a chi(2) goodness-of-fit test first overall and then stratified by early DNR orders. RESULTS: Median age was 71 years, 49% were female, median Glasgow Coma Scale score was 12, median ICH volume was 13 cm(3), and 35% had early DNR orders. Overall observed 30-day mortality was 42.7% (95% confidence interval [CI] 38.3-47.1), with the average model-predicted 30-day mortality for the ICH Score, Cincinnati model, and ICH-GS at 39.9% (p = 0.005), 40.4% (p = 0.007), and 53.9% (p < 0.001). However, for patients with early DNR orders, the observed 30-day mortality was 83.5% (95% CI 78.0-89.1), with the models predicting mortality of 64.8% (p < 0.001), 57.2% (p < 0.001), and 77.8% (p = 0.02). For patients without early DNR orders, the observed 30-day mortality was 20.8% (95% CI 16.5-25.7), with the models predicting mortality of 26.6% (p = 0.05), 31.4% (p < 0.001), and 41.1% (p < 0.001). CONCLUSIONS: ICH prognostic model performance is substantially impacted when stratifying by early DNR status, possibly giving a false sense of model accuracy when DNR status is not considered. Clinicians should be cautious when applying these predictive models to individual patients.

Contrast extravasation on CT predicts mortality in primary intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Recent studies of intracerebral hemorrhage (ICH) treatments have highlighted the need to identify reliable predictors of hematoma expansion. The goal of this study was to determine whether contrast extravasation on multisection CT angiography (CTA) and/or contrast-enhanced CT (CECT) of the brain is associated with hematoma expansion and increased mortality in patients with primary ICH. MATERIALS AND METHODS: All patients with primary ICH who underwent CTA and CECT, as well as follow-up noncontrast CT (NCCT) before discharge/death from January 1, 2003, to September 30, 2005, were retrospectively identified. One neuroradiologist reviewed admission and follow-up NCCT for hematoma size and growth. A second neuroradiologist independently reviewed CTA and CECT for active contrast extravasation. Univariate and multivariate logistic regression analyses were performed to evaluate the significance of clinical and radiologic variables in predicting 30-day mortality, designated as the primary outcome. Hematoma growth was considered as a secondary outcome. RESULTS: Of 56 patients, contrast extravasation was seen in 17.9% of patients on initial CTA and in 23.2% of patients on initial CECT following CTA. Univariate analysis showed that the presence of extravasation on CT, large initial hematoma size (>30 mL), the presence of "swirl sign" on NCCT, the Glasgow Coma Scale and ICH scores, and international normalized ratio were associated with increased mortality. On multivariate analysis, only contrast extravasation on CT (P = .017) independently predicted mortality. Contrast extravasation on CT (P < .001) was also an independent predictor of hematoma growth on multivariate analysis. CONCLUSION: Active contrast extravasation on CT in patients with primary ICH independently predicts mortality and hematoma growth.

The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) constitutes 10% to 15% of all strokes and remains without a treatment of proven benefit. Despite several existing outcome prediction models for ICH, there is no standard clinical grading scale for ICH analogous to those for traumatic brain injury, subarachnoid hemorrhage, or ischemic stroke. METHODS: Records of all patients with acute ICH presenting to the University of California, San Francisco during 1997-1998 were reviewed. Independent predictors of 30-day mortality were identified by logistic regression. A risk stratification scale (the ICH Score) was developed with weighting of independent predictors based on strength of association. RESULTS: Factors independently associated with 30-day mortality were Glasgow Coma Scale score (P<0.001), age >/=80 years (P=0.001), infratentorial origin of ICH (P=0.03), ICH volume (P=0.047), and presence of intraventricular hemorrhage (P=0.052). The ICH Score was the sum of individual points assigned as follows: GCS score 3 to 4 (=2 points), 5 to 12 (=1), 13 to 15 (=0); age >/=80 years yes (=1), no (=0); infratentorial origin yes (=1), no (=0); ICH volume >/=30 cm(3) (=1), <30 cm(3) (=0); and intraventricular hemorrhage yes (=1), no (=0). All 26 patients with an ICH Score of 0 survived, and all 6 patients with an ICH Score of 5 died. Thirty-day mortality increased steadily with ICH Score (P<0.005). CONCLUSIONS: The ICH Score is a simple clinical grading scale that allows risk stratification on presentation with ICH. The use of a scale such as the ICH Score could improve standardization of clinical treatment protocols and clinical research studies in ICH.

Carbon dioxide reactivity and pressure autoregulation of brain tissue oxygen.

OBJECTIVE: To describe the normal relationships between brain tissue oxygen tension (PbrO2) and physiological parameters of systemic blood pressure and CO2 concentrations. METHODS: Licox Clark-type oxygen probes (GMS mbH, Kiel, Germany) were inserted in the frontal white matter of 12 swine maintained under general anesthesia with a 1.0 fraction of inspired oxygen (FiO2). In seven swine, alterations in end-tidal carbon dioxide (ET-CO2) concentration (range, 13-72 mm Hg) were induced via hyperventilation or instillation of CO2 into the ventilation circuit. In nine swine, mean arterial pressure (MAP) (range, 33-200 mm Hg) was altered; phenylephrine was used to induce hypertension, and a nitroprusside-esmolol combination or systemic hemorrhage was used for hypotension. Quantitative cerebral blood flow (CBF) was measured in two animals by using a thermal diffusion probe. RESULTS: Mean baseline PbrO2 was 41.9 +/- 11.3 mm Hg. PbrO2 varied linearly with changes in ET-CO2, ranging from 20 to 60 mm Hg (r2 = 0.70). The minimum PbrO2 with hypocarbia was 5.9 mm Hg, and the maximum PbrO2 with hypercarbia was 132.4 mm Hg. PbrO2 varied with MAP in a sigmoid fashion suggestive of pressure autoregulation between 60 and 150 mm Hg (r2 = 0.72). The minimum PbrO2 with hypotension was 1.4 mm Hg, and the maximum PbrO2 with hypertension was 97.2 mm Hg. In addition, CBF correlated linearly with PbrO2 during CO2 reactivity testing (r2 = 0.84). CONCLUSION: In the uninjured brain, PbrO2 exhibits CO2 reactivity and pressure autoregulation. The relationship of PbrO2 with ET-CO2 and MAP appears to be similar to those historically established for CBF with ET-CO2 and MAP. This suggests that, under normal conditions, PbrO2 is strongly influenced by factors that regulate CBF.

Critical care of acute ischemic stroke.

Advances in neurologic therapeutics and intensive care medicine have expanded the arsenal of treatments available for the critical care of ischemic stroke. Several agents are available for acute reperfusion of the ischemic brain. These include intravenous recombinant tissue-plasminogen activator (rtPA), which is effective in a 3-hour time window, and intra-arterial thrombolytics, which may be effective within 6 hours. In addition, newer agents such as Ancrod and abciximab may be effective within the acute time period. Efforts to prevent secondary brain injury in critically ill patients with stroke often include prevention and reduction of fever, induced hypertension, and mechanical ventilation. Finally, death due to severe brain edema after massive hemispheric infarction can often be prevented with surgical or medical intervention. Unfortunately, there is a critical lack of well-designed clinical studies to guide the clinician in the use of these interventions. In addition, there is concern that some of these interventions may preserve life at the cost of quality of life. This article reviews the evidence behind these approaches to the critical care of ischemic stroke.

Transcranial Doppler ultrasonography in the neurologic intensive care unit.

Transcranial doppler ultrasonography (TCD) is a noninvasive monitoring tool which allows imaging of blood flow velocities in intracranial blood vessels. It is safe, portable, easy to perform and provides accurate information regarding underlying physiology which may help to guide therapy in critically ill neurologic patients. It has significantly contributed to the management of vasospasm related to subarachnoid hemorrhage in the neurologic intensive care unit. TCD is also helpful in the early diagnosis of a variety of complications that can occur in patients with head injury such as vasospasm, elevated intracranial pressure and disordered cerebral autoregulation. Careful performance of the test and experienced interpretation can identify TCD waveforms indicative of cerebral circulatory arrest, an ancillary finding used for the diagnosis of brain death. TCD is likely to play a larger role in evaluation of the patient in the future because of its safety, portability and ability to define moment-to-moment changes in cerebral blood flow velocities and cerebral blood flow.

Cerebral oxygenation during hemorrhagic shock: perils of hyperventilation and the therapeutic potential of hypoventilation.

OBJECTIVES: Prophylactic hyperventilation of patients with head injuries worsens outcome, presumably by exacerbating tissue hypoxia. Oxygen tension in brain tissue (PbrO2) provides a direct measurement of cerebral metabolic substrate delivery and varies with changing end-tidal carbon dioxide tension (ETCO2) and mean arterial pressure. However, the effects of hyperventilation and hypoventilation on PbrO2 during hemorrhagic shock are not known. The aim of this study was to examine the effects of alteration in ventilation on PbrO2 in hemorrhaged swine. METHODS: Clark-type polarographic probes were inserted into the brain tissue of seven swine to measure PbrO2 directly. To examine the effects of alterations in ventilation on hemorrhage-induced hypotension, swine were hemorrhaged to 50% estimated blood volume and PbrO2 was monitored during hyperventilation (RR = 30) and hypoventilation (RR = 4). RESULTS: After the 50% hemorrhage, PbrO2 declined rapidly from 39.8 +/- 4.6 mm Hg to 11.4 +/- 2.2 mm Hg. Hyperventilation resulted in a further 56% mean decrease in PbrO2. Hypoventilation produced a 166% mean increase in PbrO2. These changes were significant (p = 0.001) for absolute and percentage differences from baseline. CONCLUSION: During hemorrhage, alterations in ventilation significantly changed PbrO2: hyperventilation increased brain-tissue hypoxia whereas hypoventilation alleviated it. This finding suggests that hyperventilation has deleterious effects on brain oxygenation in patients with hemorrhagic shock and those with head trauma. Conversely, hypoventilation with resultant hypercapnia may actually help resolve hemorrhagic shock-induced cerebral hypoxia.

Ischemic stroke. Clinical strategies based on mechanisms and risk factors.

Ischemic stroke is a common disorder associated with significant morbidity and mortality. Results of several pivotal clinical trials completed within the last decade have helped refine stroke prevention and treatment strategies. Endarterectomy for symptomatic carotid artery stenosis, anticoagulation in atrial fibrillation, and IV t-PA treatment of hyperacute ischemic stroke may reduce the burden of stroke. Ongoing studies are addressing newly recognized risk factors, such as aortic arch and intracranial atherosclerosis, as well as neuroprotective agents and locally delivered thrombolytics. Successful patient management requires a targeted clinical approach based on vascular localization and risk factor assessment.

Endovascular therapy of traumatic injuries of the intracranial cerebral arteries.

Traumatic intracranial arterial injuries represent uncommon complications of both closed-head injury and penetrating head trauma. These injuries include arterial dissections, pseudoaneurysms, and fistulas, both direct and indirect. Although these lesions may be identified while still asymptomatic, they usually present in a delayed fashion with intracranial hemorrhage, focal cerebral ischemia, or, occasionally, severe epistaxis. Endovascular therapy has assumed a major role in the management of this diverse group of lesions. Embolization of pseudoaneurysms with balloons or detachable coils, the use of embolic particles for small arterial injuries, and large vessel occlusion with detachable balloons represent current treatment strategies that have evolved over the past three decades. Angioplasty and stent deployment may have a future role to play in the management of arterial dissection. Principles of neurologic critical care that minimize secondary brain injury are essential adjuncts in the management of these patients before, during, and after endovascular treatment.

Application of a rheolytic thrombectomy device in the treatment of dural sinus thrombosis: a new technique.

We present a novel application of a transvascular rheolytic thrombectomy system in the treatment of symptomatic dural sinus thrombosis in a 54-year-old woman with somnolence and left-sided weakness. The diagnosis of bilateral transverse and superior sagittal sinus thrombosis was made and the patient was treated with anticoagulant therapy. After an initial period of improvement, she became comatose and hemiplegic 8 days after presentation. After excluding intracerebral hemorrhage by MR imaging, we performed angiography and transfemoral venous thrombolysis with a hydrodynamic thrombectomy catheter, followed by intrasinus urokinase thrombolytic therapy over the course of 2 days. This technique resulted in dramatic sinus thrombolysis and near total neurologic recovery. Six months after treatment, the patient showed mild cognitive impairment and no focal neurologic deficit. Our preliminary experience suggests that this technique may play a significant role in the endovascular treatment of this potentially devastating disease.

New treatments for stroke.

Stroke is the third leading cause of death and the leading cause of adult disability in the United States. With an annual incidence of over 500,000, stroke has enormous social and economic consequences. Ischemic stroke comprises over 80% of all strokes, with strokes caused by intracerbral hemorrhage and subarachnoid hemorrhage making up the rest. Recent advances in the understanding of stroke risk factors and the mechanisms of nervous system damage in acute stroke, especially ischemic stroke, have led to new therapies for both prevention and treatment. Anticoagulation with warfarin can prevent cardioembolic stroke resulting from atrial fibrillation. Carotid endarterectomy can prevent stroke caused by internal carotid artery stenosis. Tissue plasminogen activator, a clot-dissolving medication, has recently been proven effective in acute ischemic stroke if administered within three hours of onset. Despite these advances, stroke remains common, and most acute stroke unfortunately remains untreatable. Current and future approaches emphasize educating the public and healthcare professionals regarding stroke warning signs and the need for emergent care. Active clinical research is exploring even newer treatments based on the scientific basis of stroke neurobiology.

Neurologic manifestations of spinal epidural arteriovenous malformations.

Eight patients with spinal epidural arteriovenous malformations presented with progressive myelopathy (3), hemorrhage (3), and tinnitus/bruits (2). MRI suggested a vascular malformation in four (of seven) patients. Spinal angiography was necessary for diagnosis. Treatment by endovascular embolic occlusion (with balloons, particles, or coils) (7 patients) or surgical resection (4 patients), or both, temporarily arrested progression of neurologic symptoms, but recurrence of symptoms in two patients was associated with development of collateral arterial supply to the malformation.

Screening clinics for the homeless: evaluating outcomes.

The study evaluated the outcomes of a series of health-screening clinics specifically developed to target the homeless population. Problems screened during this study were selected because of the high prevalence of each among the homeless and included hypertension, diabetes, anemia, tuberculosis, and foot problems. Screening clinics were developed and implemented by faculty and senior baccalaureate nursing students. Data were collected with a screening form that focused on risk factors and individual health history and by chart review. Two hundred fourteen clients were screened in 17 different screening clinics. Participation in the clinics ranged from 33 clients at a hypertension-screening clinic to 0 at one of the foot-screening clinics. Abnormalities were identified in 22% of the clients who were screened, and documentation was found that 80% of those with abnormalities received follow-up. Overall, the screening clinics appear to be an effective approach to disease prevention in a homeless population.