Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Hospital Course, Confounders, and Medications.

The convergence of an interdisciplinary team of neurocritical care specialists to organize the Curing Coma Campaign is the first effort of its kind to coordinate national and international research efforts aimed at a deeper understanding of disorders of consciousness (DoC). This process of understanding includes translational research from bench to bedside, descriptions of systems of care delivery, diagnosis, treatment, rehabilitation, and ethical frameworks. The description and measurement of varying confounding factors related to hospital care was thought to be critical in furthering meaningful research in patients with DoC. Interdisciplinary hospital care is inherently varied across geographical areas as well as community and academic medical centers. Access to monitoring technologies, specialist consultation (medical, nursing, pharmacy, respiratory, and rehabilitation), staffing resources, specialty intensive and acute care units, specialty medications and specific surgical, diagnostic and interventional procedures, and imaging is variable, and the impact on patient outcome in terms of DoC is largely unknown. The heterogeneity of causes in DoC is the source of some expected variability in care and treatment of patients, which necessitated the development of a common nomenclature and set of data elements for meaningful measurement across studies. Guideline adherence in hemorrhagic stroke and severe traumatic brain injury may also be variable due to moderate or low levels of evidence for many recommendations. This article outlines the process of the development of common data elements for hospital course, confounders, and medications to streamline definitions and variables to collect for clinical studies of DoC.

Ketamine infusion for sedation in a patient on extracorporeal membrane oxygenation (ECMO).

Introduction: we sought to explore the efficacy of ketamine in a patient on extracorporeal membrane oxygenation (ECMO) receiving ketamine for sedation by investigating the utility of plasma ketamine concentrations.Case report: retrospective chart review of one critically ill patient on ECMODiscussion: This was a descriptive review of serial plasma ketamine concentrations in an ECMO patient. Although no reference plasma concentrations exist in ECMO patients, ketamine levels appeared to be lower than those seen in surgical patients not on ECMO.Conclusion: At this point, no reference plasma concentrations exist for ketamine in ECMO patients, further research may help understand the effects of ECMO on ketamine disposition and that lower ketamine concentrations may be used for effective analgesia or sedation.

Prolonged Intra-Sinus Alteplase Infusion in Severe Case of CVST.

Cerebral venous sinus thrombosis (CVST) is an uncommon condition accounting for 0.5-1% of all strokes. It occurs more commonly in women, particularly in the age group of 20-40 years of age due to pregnancy and oral contraceptive use. Systemic anticoagulation is recommended as first line treatment but 10-20% of patients deteriorate despite medical treatment and require surgical or endovascular interventions. We summarize a 41-year-old female with a past medical history of acute disseminated encephalomyelitis who presented with headaches and worsening mental status. Further workup confirmed inferior sagittal sinus thrombus with intraventricular hemorrhage for which she was initiated on heparin continuous infusion. Due to worsening of clot burden and cerebral edema, a right frontal external ventricular drain was placed in addition to medical management of elevated ICP. Intravenous heparin infusion was stopped intermittently for such procedures. However, even when heparin was continued, sub-therapeutic and supra-therapeutic ranges were commonly observed, making anticoagulation management challenging. A new left-sided EVD had to be placed after increased IVH and worsening of hydrocephalus due to clotting. Due to patient's clinical worsening, a microcatheter was placed in the straight sinus and continuous alteplase via intra-sinus catheter was initiated at a rate of 1 mg/hour. This was continued for 72 hours in addition to the continuous heparin infusion. Additionally, she received intraventricular alteplase 1 mg x 3 doses for IVH. Unfortunately, she continued to deteriorate despite maximal medical therapy. She was made comfort care and expired.

Antithrombotic Therapy for Stroke Patients with Cardiovascular Disease.

Prevention of ischemic stroke relies on the use of antithrombotic medications comprising antiplatelet agents and anticoagulation. Stroke risk is particularly high in patients with cardiovascular disease. This review will focus on the role of antithrombotic therapies in the context of different types of cardiovascular disease. We will discuss oral antiplatelet medications and both IV and parental anticoagulants. Different kinds of cardiovascular disease contribute to stroke via distinct pathophysiological mechanisms, and the optimal treatment for each varies accordingly. We will explore the mechanism of stroke and evidence for antithrombotic therapy in the following conditions: atrial fibrillation, prosthetic heart values (mechanical and bioprosthetic), aortic arch atherosclerosis, congestive heart failure (CHF), endocarditis (infective and nonbacterial thrombotic endocarditis), patent foramen ovale (PFO), left ventricular assist devices (LVAD), and extracorporeal membrane oxygenation (ECMO). While robust data exist for antithrombotic use in conditions such as atrial fibrillation, optimal treatment in many situations remains under active investigation.

Inactivated Four-Factor Prothrombin Complex Concentrate Dosing Practices for Reversal of Warfarin-Related Intracranial Hemorrhage.

BACKGROUND/OBJECTIVE: Inactivated four-factor prothrombin complex concentrate (I4F-PCC, Kcentra®) has become an important agent for the urgent or emergent reversal of bleeding associated with vitamin K antagonists such as warfarin. There is recognized inter-institutional variability with the use of I4F-PCC, especially as it relates to dosing practices. We sought to characterize variations in I4F-PCC dosing practices and their impact on patient outcomes and describe overall real-world clinical practice surrounding I4F-PCC utilization in the context of the management of warfarin-related intracranial hemorrhage (ICH). METHODS: This is a multicenter retrospective pragmatic registry study of adult patients admitted at a participating study site between January 1, 2014, and December 31, 2015, who received I4F-PCC for reversal of warfarin-related ICH. Practices around warfarin-related ICH reversal in context of I4F-PCC utilization are described, including repeat I4F-PCC dosing, adjunctive reversal agents, and dose rounding policies (i.e., rounding doses to nearest vial size vs preparing exact/unrounded doses). All research was approved by local human investigation committees at each institution. RESULTS: Seventeen institutions contributed data on 528 patients to this registry. These institutions were primarily urban centers (74%), located in the southeast USA (47%), with Level 1 Trauma designation (79%), and with Comprehensive Stroke Center designation (74%). Most patients included in the study had sustained a non-traumatic ICH (68%), had a median admission GCS of 14 (IQR 7-15), and were receiving warfarin for atrial fibrillation (57.4%). There was substantial time latency between baseline INR and I4F-PCC (median 2.4 h, IQR 1.4-4.5 h). Most patients received adjunctive reversal agents, including vitamin K (89.5%) and fresh frozen plasma (FFP) (31.9%). A smaller proportion (6.0%) of patients received repeat I4F-PCC dosing. The median ICU length of stay (LOS) was 3 days (IQR 2-7 days), median hospital LOS was 6 days (IQR 3-12 days), and overall mortality rate was 28.8%. For institutions rounding doses to the nearest vial size, the first post-I4F-PCC dose INR was statistically but not clinically significantly lower than for institutions without vial size dose rounding, with comparable degrees of INR reduction from baseline. No differences were observed between dose rounding cohorts in adverse effects, ICU or hospital LOS, modified Rankin score at discharge, or mortality rates. CONCLUSIONS: Most patients received single doses of I4F-PCC, with adjunctive reversal agents and rounding doses to vial size. The time difference from baseline INR to factor product administration is a potential opportunity for process improvement in the management of warfarin-related ICH.

Neuro-Interventional Use of Oral Antiplatelets: A Survey of Neuro-Endovascular Centers in the United States and Review of the Literature.

BACKGROUND: Intra- and postprocedural thrombosis are major complication of aneurysmal coil embolization, stent-assisted coiling, and pipeline embolization. The common but unproven practice of dual antiplatelet therapy with aspirin and a P2Y12 inhibitor in neuro-endovascular patients is inferred from the cardiology literature without large clinical trials to support it in neuro-endovascular patients. OBJECTIVE: We conducted an electronic survey to identify practice variations surrounding the use of oral antiplatelets in patients undergoing endovascular neuro-interventional procedures across neuro-endovascular centers in the United States. METHODS: An electronic survey was distributed via the Web. Any practicing neuro-intensive care unit (ICU), neuro-interventional or stroke physician, pharmacist, physician assistant, or nurse practitioner was eligible to respond to this survey between June and October 2017. RESULTS: A total of 33 responses were collected during the survey period. A response rate of 16% was calculated after taking into account all comprehensive stroke centers in the United States. Aspirin and clopidogrel was the standard-of-care antiplatelet regimen utilized in the majority of institutions (82%). Alternatively, 4 institutions used monotherapy (aspirin [n = 2], clopidogrel [n = 1], either aspirin or clopidogrel [n = 1]) and 2 institutions reported practitioner-dependent practices. Just under half of the centers reported ticagrelor as the primary alternative in clopidogrel nonresponders (48%). CONCLUSION: Dual antiplatelet therapy with aspirin and clopidogrel appears to be standard of care in this setting based on our survey. About half of responding institutions use ticagrelor in cases where clopidogrel resistance is suspected. Large society-wide patient registries are needed to provide data for future safety and efficacy studies.

Therapeutic drug monitoring of valproic acid in extracorporeal membrane oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy for those in cardiopulmonary failure, including post-cardiac arrest. Despite a high volume of ECMO patients using anti-seizure medication, there is a paucity of data concerning the dosing, levels, and clinical scenarios for their use. CASE REPORT: We present three cases of ECMO patients post-PEA arrest who were on valproic acid (VPA) for treatment of seizure and/or myoclonus. The total and free levels of VPA are reported. DISCUSSION: The trough levels are consistent throughout therapy, suggesting VPA is not significantly removed by the ECMO circuitry. Although the total serum levels remained below the toxic range, the free level was elevated in two patients. These patients did not develop signs of toxicity. CONCLUSION: VPA may be an effective anti-seizure medication in ECMO patients. Free VPA levels should be more readily available to better quantify efficacy or toxicity, especially in ECMO patients.

Alcohol Withdrawal Syndrome in Neurocritical Care Unit: Assessment and Treatment Challenges.

Alcohol withdrawal syndrome (AWS) can range from mild jittery movements, nausea, sweating to more severe symptoms such as seizure and death. Severe AWS can worsen cognitive function, increase hospital length of stay, and in-hospital mortality and morbidity. Due to a lack of reliable history of present illness in many patients with neurological injury as well as similarities in clinical presentation of AWS and some commonly encountered neurological syndromes, the true incidence of AWS in neurocritical care patients remains unknown. This review discusses challenges in the assessment and treatment of AWS in patients with neurological injury, including the utility of different scoring systems such as the Clinical Institute Withdrawal Assessment and the Minnesota Detoxification Scale as well as the reliability of admission alcohol levels in predicting AWS. Treatment strategies such as symptom-based versus fixed dose benzodiazepine therapy and alternative agents such as baclofen, carbamazepine, dexmedetomidine, gabapentin, phenobarbital, ketamine, propofol, and valproic acid are also discussed. Finally, a treatment algorithm considering the neurocritical care patient is proposed to help guide therapy in this setting.

Cost-benefit analysis of tranexamic acid and blood transfusion in elective lumbar spine surgery for degenerative pathologies.

OBJECTIVE: Blood transfusions are given to approximately one-fifth of patients undergoing elective lumbar spine surgery, and previous studies have shown that transfusions are accompanied by increased complications and additional costs. One method for decreasing transfusions is administration of tranexamic acid (TXA). The authors sought to evaluate whether the cost of TXA is offset by the decrease in blood utilization in lumbar spine surgery patients. METHODS: The authors retrospectively reviewed patients who underwent elective lumbar or thoracolumbar surgery for degenerative conditions at a tertiary care center between 2016 and 2018. Patients who received intraoperative TXA (TXA patients) were matched with patients who did not receive TXA (non-TXA patients) by age, sex, BMI, ASA (American Society of Anesthesiologists) physical status class, and surgical invasiveness score. Primary endpoints were intraoperative blood loss, number of packed red blood cell (PRBC) units transfused, and total hemostasis costs, defined as the sum of TXA costs and blood transfusion costs throughout the hospital stay. A subanalysis was then performed by substratifying both cohorts into short-length (1-4 levels) and long-length (5-8 levels) spinal constructs. RESULTS: Of the 1353 patients who met inclusion criteria, 68 TXA patients were matched to 68 non-TXA patients. Patients in the TXA group had significantly decreased mean intraoperative blood loss (1039 vs 1437 mL, p = 0.01). There were no differences between the patient groups in the total costs of blood transfusion and TXA (p = 0.5). When the 2 patient groups were substratified by length of construct, the long-length construct group showed a significant net cost savings of $328.69 per patient in the TXA group (p = 0.027). This result was attributable to the finding that patients undergoing long-length construct surgeries who were given TXA received a lower amount of PRBC units throughout their hospital stay (2.4 vs 4.0, p = 0.007). CONCLUSIONS: TXA use was associated with decreased intraoperative blood loss and significant reductions in total hemostasis costs for patients undergoing surgery on more than 4 levels. Furthermore, the use of TXA in patients who received short constructs led to no additional net costs. With the increasing emphasis put on value-based care interventions, use of TXA may represent one mechanism for decreasing total care costs, particularly in the cases of larger spine constructs.

Neurocritical Care for Extracorporeal Membrane Oxygenation Patients.

OBJECTIVES: To review the neurocritical care aspects of patients supported by extracorporeal membrane oxygenation, including cerebral physiology, neurologic monitoring, use of sedatives and anti-seizure medications, and prevalence and management of extracorporeal membrane oxygenation associated brain injury. DATA SOURCES: PubMed database search using relevant search terms related to neurologic complications, neurocritical care management, and brain injury management in patients with extracorporeal membrane oxygenation. STUDY SELECTION: Articles included original investigations, review articles, consensus statements and guidelines. DATA EXTRACTION: A detailed review of publications performed and relevant publications were summarized. DATA SYNTHESIS: We found no practice guidelines or management strategies for the neurocritical care of extracorporeal membrane oxygenation patients. Such patients are at high risk for hypoxic-ischemic brain injury, intracranial hemorrhage, cerebral edema, and brain death. Improving clinical outcomes will depend on better defining the neurologic complications and underlying pathophysiology that are specific to extracorporeal membrane oxygenation. Currently, insufficient understanding of the pathophysiology of neurologic complications prevents us from addressing their etiologies with specific, targeted monitoring techniques and interventions. CONCLUSIONS: A large knowledge gap exists in our understanding and treatment of extracorporeal membrane oxygenation-related neurologic complications. A systematic and multidisciplinary approach is needed to reduce the prevalence of these complications and to better manage the neurologic sequelae of extracorporeal membrane oxygenation in a way that will improve patient outcomes.

Impact of antiepileptic drugs for seizure prophylaxis on short and long-term functional outcomes in patients with acute intracerebral hemorrhage: A meta-analysis and systematic review.

PURPOSE: The purpose of this analysis is to assess the effect of antiepileptics (AEDs) on seizure prevention and short and long term functional outcomes in patients with acute intracerebral hemorrhage. METHOD: The meta-analysis was conducted using the PRISMA guidelines. A literature search was performed of the PubMed, the Cochrane Library, and EMBASE databases. Search terms included "Anticonvulsants", "Intracerebral Hemorrhage", and related subject headings. Articles were screened and included if they were full-text and in English. Articles that did not perform multivariate regression were not included. Overall effect size was evaluated with forest plots and publication bias was assessed with the Begg's and Egger's tests. RESULTS: A total of 3912 articles were identified during the initial review. After screening, 54 articles remained for full review and 6 articles were included in the final analysis. No significant association between the use of AEDs after ICH and functional outcome (OR 1.53 [95%CI: 0.81-2.88] P = 0.18, I2 = 81.7%). Only one study evaluated the effect AEDs had in preventing post-ICH seizures. CONCLUSIONS: The use of prophylactic AEDs was not associated with improved short and long outcomes after acute ICH. This analysis supports the 2015 AHA/ASA recommendation against prophylactic AEDs (class III; level of evidence b).

Use of Newer Anticonvulsants for the Treatment of Status Epilepticus.

Status epilepticus (SE) has a high mortality rate and is one of the most common neurologic emergencies. Fast progression of this neurologic emergency and lack of response to traditional antiepileptic drugs (AEDs) in most cases has challenged clinicians to use new agents. This article evaluates the efficacy and safety of AEDs released to the market after 2000 for SE, refractory status epilepticus (RSE), and super-refractory status epilepticus (SRSE). The PubMed database was searched for clinical trials published between January 2000 and July 2018 using the search terms status epilepticus, refractory status epilepticus, super refractory status epilepticus, brivaracetam, clobazam, cannabidiol, eslicarbazepine, lacosamide, perampanel, rufinamide, stiripentol, and zonisamide. Trials that evaluated these agents in adults with SE, RSE, and SRSE were included. Brivaracetam use was identified in two retrospective reviews with success rates of 27% and 57%. One unsuccessful case report of cannabidiol use in SE was found. Four clobazam studies were identified in SE and RSE with success rates ranging from 25-100%. No evidence for the use of eslicarbazepine and zonisamide was found. Using the search terms for lacosamide identified 38 articles: 1 systematic review, 5 prospective studies, 15 retrospective reviews, and 17 case reports. Success rates and dosing varied, but studies that included focal or partial types of SE showed higher success rates. Five articles were identified regarding perampanel use in this setting. Three were retrospective reviews with success rates ranging from 17-60%, and two were case reports. Only one case report regarding the use of rufinamide was found; rufinamide titrated up to 4.4 mg/day allowed discontinuation of barbiturate and clobazam. One case report and two case series of stiripentol were found with reported efficacy between 60% and 100% in SRSE. Evidence is currently insufficient to support the use of these agents in this setting.

Fluids and hyperosmolar agents in neurocritical care: an update.

PURPOSE OF REVIEW: To discuss recent updates in fluid management and use of hyperosmolar therapy in neurocritical care. RECENT FINDINGS: Maintaining euvolemia with crystalloids seems to be the recommended fluid resuscitation for neurocritical care patients. Buffered crystalloids have been shown to reduce hyperchloremia in patients with subarachnoid hemorrhage without causing hyponatremia or hypo-osmolality. In addition, in patients with traumatic brain injury, buffered solutions reduce the incidence of hyperchloremic acidosis but are not associated with intracranial pressure (ICP) alteration. Both mannitol and hypertonic saline are established as effective hyperosmolar agents to control ICP. Both agents have been shown to control ICP, but their effects on neurologic outcomes are unclear. A recent surge in preference for using hypertonic saline as a hyperosmolar agent is based on few studies without strong evidence. SUMMARY: Fluid resuscitation with crystalloids seems to be reasonable in this setting although no recommendations can be made regarding type of crystalloids. Based on current evidence, elevated ICP can be effectively reduced by either hypertonic saline or mannitol.

Voriconazole Autoinduction and Saturable Metabolism After Cessation of Rifampin in a Patient With Invasive Central Nervous System Aspergillus: Importance of Therapeutic Drug Monitoring.

PURPOSE: Optimization of antifungal therapy with voriconazole can be challenging due to inter- and intrapatient variability in voriconazole pharmacokinetics (PK). In this case, we introduce challenges in voriconazole therapy due to drug-drug interactions, autoinduction, and saturable metabolism. SUMMARY: A 32-year-old male on chronic prednisone developed central nervous system (CNS) aspergillosis. He was started on high-dose intravenous (IV) voriconazole 8.5 mg/kg every 12 hours due to concerns for lasting induction effects of recent rifampin therapy. The initial voriconazole trough was 2 µg/mL. Frequent dose adjustments were made to maintain the therapeutic trough goal. On day 24 of voriconazole therapy, his trough was undetectable on IV voriconazole 5.5 mg/kg every 12 hours. His dose was escalated to 8.5 mg/kg every 12 hours to avoid subtherapeutic levels and therapeutic failure. On day 48, his trough level was 1.1 µg/mL on the same dose. His regimen was changed to 6.5 mg/kg every 8 hours at this point. Sixteen days after this regimen on day 74 of voriconazole therapy, his trough was 27.2 µg/mL indicating saturable PK of voriconazole in the absence of interacting drugs. CONCLUSION: Our findings highlight the unpredictable PK of voriconazole and reinforce the importance of continuous therapeutic drug monitoring in critically ill patients.

Use of intraosseous hypertonic saline in critically ill patients.

BACKGROUND: Rapid administration of hypertonic saline 23.4% is crucial in treatment of herniation syndromes. Hypertonic 23.4% saline must be administered via a central line. In cases where central line access is difficult to obtain and leads to delay in therapy, placement of intraosseous access can be lifesaving. MAIN BODY: The purpose of this case series is to describe the use of intraosseous administration of 23.4% saline in critically ill patients and to assess feasibility. CONCLUSION: Intraosseous administration of 23.4% saline in 6 adult patients with neurological emergencies was feasible and should be considered in cases where obtaining intravenous access is time consuming.

Hypothermia and brain inflammation after cardiac arrest.

The cessation (ischemia) and restoration (reperfusion) of cerebral blood flow after cardiac arrest (CA) induce inflammatory processes that can result in additional brain injury. Therapeutic hypothermia (TH) has been proven as a brain protective strategy after CA. In this article, the underlying pathophysiology of ischemia-reperfusion brain injury with emphasis on the role of inflammatory mechanisms is reviewed. Potential targets for immunomodulatory treatments and relevant effects of TH are also discussed. Further studies are needed to delineate the complex pathophysiology and interactions among different components of immune response after CA and identify appropriate targets for clinical investigations.

Antiepileptic drugs in critically ill patients.

BACKGROUND: The incidence of seizures in intensive care units ranges from 3.3% to 34%. It is therefore often necessary to initiate or continue anticonvulsant drugs in this setting. When a new anticonvulsant is initiated, drug factors, such as onset of action and side effects, and patient factors, such as age, renal, and hepatic function, should be taken into account. It is important to note that the altered physiology of critically ill patients as well as pharmacological and nonpharmacological interventions such as renal replacement therapy, extracorporeal membrane oxygenation, and target temperature management may lead to therapeutic failure or toxicity. This may be even more challenging with the availability of newer antiepileptics where the evidence for their use in critically ill patients is limited. MAIN BODY: This article reviews the pharmacokinetics and pharmacodynamics of antiepileptics as well as application of these principles when dosing antiepileptics and monitoring serum levels in critically ill patients. The selection of the most appropriate anticonvulsant to treat seizure and status epileptics as well as the prophylactic use of these agents in this setting are also discussed. Drug-drug interactions and the effect of nonpharmacological interventions such as renal replacement therapy, plasma exchange, and extracorporeal membrane oxygenation on anticonvulsant removal are also included. CONCLUSION: Optimal management of antiepileptic drugs in the intensive care unit is challenging given altered physiology, polypharmacy, and nonpharmacological interventions, and requires a multidisciplinary approach where appropriate and timely assessment, diagnosis, treatment, and monitoring plans are in place.