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This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body’s first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin’s anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.

One of the most common questions asked by family members of patients with brain injuries who are in a coma is "will my loved one wake up?". Despite substantial improvements in the care of patients with neurological diseases, the medical and scientific community struggles to answer this simple question. More importantly, the technology and treatment strategies to improve the trajectory of patients with impaired consciousness in the acute setting are limited. The Curing Coma Campaign was developed by the Neurocritical Care Society as a multispecialty, multi-interest community of researchers and caretakers who are focused on patients with disorders of consciousness (DoC) in the acute phase of care. Over the first few years of the group, several publications have focused on identifying the gaps in our knowledge to encourage research in the area. In this review, the current understanding of DoC is reviewed. The work of the Curing Coma Campaign to identify gaps in our knowledge is highlighted.

Guillain-Barre syndrome (GBS) is a peripheral demyelinating neuromuscular disorder occasionally associated with pharmacologically refractory neuropathic pain. We present a case of acute neuropathic pain in a 22-year-old man with GBS managed with percutaneous peripheral nerve stimulation (PNS). Following implantation of leads in the bilateral sciatic, femoral, and brachial plexus nerve distribution, the patient experienced significant pain reduction in both the upper and lower extremities. Analgesic and anxiolytic medications were reduced by 33% on the first day and by 78% on day 21. PNS is a minimally invasive, nonpharmacologic modality for treating acute neuropathic pain in GBS patients.

Background: Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system (CNS) is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences CNS function in SAH. As such, the present project aims to elucidate neutrophil factors and mechanisms mediating CNS injury and cognitive deficits after SAH. Methods: Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. Also, in vitro techniques were used to elucidate how neutrophils affect cellular function of neurons and glia after SAH. Results: Our results show that following SAH, neutrophils infiltrate the meninges, and not the brain parenchyma. Mice lacking functional myeloperoxidase (MPO KO), a neutrophil enzyme, lack both the meningeal neutrophil infiltration and the cognitive deficits associated with SAH. The re-introduction of biologically active MPO, and its substrate hydrogen peroxide, to the cerebrospinal fluid of MPO KO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH. Furthermore, in culture, MPO affects the function of both primary neurons and astrocytes, though not microglia. Neurons exposed to MPO and its substrate show decreased calcium activity at baseline and after stimulation with potassium chloride. In addition, MPO and its substrate lead to significant astrocyte loss in culture, phenocopying a result observed in the brain after SAH. Conclusions: These results implicate MPO as a mediator of neuronal dysfunction in SAH through their effect on both neurons and astrocytes. Finally, these results show that, in SAH, the activity of innate immune cells in the meninges can modulate the activity and function of the underlying brain tissue.

Hemodynamic monitoring is widely used in critical care; however, the impact of such intervention in patients with acute brain injury (ABI) remains unclear. Using PubMed, a systematic review was performed (1966-August 2013), and 118 studies were included. Data were extracted using the PICO approach. The evidence was classified, and recommendations were developed according to the GRADE system. Electrocardiography and invasive monitoring of arterial blood pressure should be the minimal hemodynamic monitoring required in unstable or at-risk patients in the intensive care unit. Advanced hemodynamic monitoring (i.e., assessment of preload, afterload, cardiac output, and global systemic perfusion) could help establish goals that take into account cerebral blood flow and oxygenation, which vary depending on diagnosis and disease stage. Choice of techniques for assessing preload, afterload, cardiac output, and global systemic perfusion should be guided by specific evidence and local expertise. Hemodynamic monitoring is important and has specific indications among ABI patients. Further data are necessary to understand its potential for therapeutic interventions and prognostication.

Background: It is not well understood whether age impacts transcranial Doppler (TCD) mean flow velocities (MFVs) in patients with aneurysmal subarachnoid hemorrhage (SAH) with or without delayed cerebral ischemia (DCI). The aim of our study was to analyze the behavior of TCD MFV during the first 7 days after SAH in patients of different ages and correlate them with the occurrence of DCI. Methods: This study is a databank analysis of patients with SAH admitted between 2010 and 2012 in a single center. We analyzed mean MFV of bilateral middle cerebral arteries (MCAs) in all patients enrolled in the study on days 1, 3 and 7. The correlation between age and TCD MFV was analyzed using a univariate linear regression model. Results: Fifty-five patients were studied. Starting on the third day after the bleeding, increasing age was associated with slower MFVs. This trend was not affected by the interrogation of the right or left MCA. After correction to include only patients who developed DCI, the same findings persisted on days 3 and 7. Conclusion: Older age was correlated with a significant decrease on TCD velocities in patients with SAH, even after correction for patients who developed DCI.

Anemia and bleeding are paramount concerns in neurocritical care and often relate to the severity of intracranial hemorrhage. Anemia is generally associated with worse outcomes, and efforts to minimize anemia through reduced volume of blood sampled are encouraged. Point-of-care-testing reliably detects the use of non-steroidal anti-inflammatory drugs that may worsen bleeding and reduce platelet activity, particularly in patients with intracerebral hemorrhage. How best to monitor the effect of platelet transfusion or platelet-activating therapy is not well studied. For patients known to take novel oral anticoagulants, drug-specific coagulation tests before neurosurgical intervention are prudent.

Methods: We performed an electronic literature search and systematic review of English language articles on cellular/molecular biomarkers associated with outcome and with disease-specific secondary complications in adult patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), and post-cardiac arrest hypoxic ischemic encephalopathic injuries (HIE).Background: Molecular biomarkers have revolutionalized diagnosis and treatment of many diseases, such as troponin use in myocardial infarction. Urgent need for high-fidelity biomarkers in neurocritical care has resulted in numerous studies reporting potential candidate biomarkers.Results: A total of 135 articles were included. Though a wide variety of potential biomarkers have been identified, only neuron-specific enolase has been validated in large cohorts and shows 100% specificity for poor outcome prediction in HIE patients not treated with therapeutic hypothermia. There are many promising candidate blood and CSF biomarkers in SAH, AIS, ICH, and TBI, but none yet meets criteria for routine clinical use.Conclusion: Current studies vary significantly in patient selection, biosample collection/processing, and biomarker measurement protocols, thereby limiting the generalizability of overall results. Future large prospective studies with standardized treatment, biosample collection, and biomarker measurement and validation protocols are necessary to identify high-fidelity biomarkers in neurocritical care.

Intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality. With the aging population, increased use of anticoagulants, and changing racial and ethnic landscape of the United States, the incidence of ICH will increase over the next decade. Improvements in preventative strategies to treat hypertension and atrial fibrillation are necessary to change the trajectory of this increase. Advances in the understanding of ICH at the vascular and molecular level may pave the way to new treatment options. This article discusses the epidemiology, pathophysiology, and current treatment options for patients with ICH. Differences in outcome and treatment between patients taking and not taking anticoagulant therapies are considered.