Thromboembolic Complications After Receipt of Prothrombin Complex Concentrate.

Purpose: Patients presenting with life-threatening bleeding associated with oral anticoagulants (OACs) are challenging with few available treatments. Prothrombin complex concentrate (PCC) is an option for OAC reversal in the setting of life-threatening bleeding with a relatively benign safety profile. Little is known about the risk of developing thromboembolic complications (TEC) in patients receiving PCC who were previously anticoagulated. The aim of this study is to characterize the rate of TEC after receipt of PCC. Methods: All adult patients who received 4-Factor PCC for life-threatening bleeding were retrospectively evaluated over a 2-year time period. Data collected included anticoagulant and indication, bleeding source, PCC dose, INR, and TEC within 14 days of PCC dose, including venous thromboembolism (VTE), acute myocardial infarction, and ischemic stroke. Results: Three hundred thirty-three patients received 383 PCC doses. Of these, 55 (16.5%) patients developed TEC, including VTE, ischemic stroke, and acute myocardial infarction. There was increased rivaroxaban use in patients who developed TEC (25.4% vs 12.2%; P = .011). Additionally, there were more patients who had anticoagulation for a previous TEC in those who developed a new TEC (38.2% vs 23.4%; P = .022). Lastly, there was a higher rate of TEC in those who received >1 dose of PCC (21.8% vs 7.9%; P = .002). Conclusion: PCC administration in the setting of life-threatening bleeding is not benign. Risk of TEC increases in patients who have rivaroxaban reversal, receive a repeat dose of PCC, and have a TEC indication for their anticoagulation and these factors should be further investigated.

Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

Drug Dosing in Patients Undergoing Therapeutic Plasma Exchange.

Therapeutic plasma exchange (TPE) is an extracorporeal process in which a large volume of whole blood is taken from the patient's vein. Plasma is then separated from the other cellular components of the blood and discarded while the remaining blood components may then be returned to the patient. Replacement fluids such as albumin or fresh-frozen plasma may or may not be used. TPE has been used clinically for the removal of pathologic targets in the plasma in a variety of conditions, such as pathogenic antibodies in autoimmune disorders. TPE is becoming more common in the neurointensive care space as autoimmunity has been shown to play an etiological role in many acute neurological disorders. It is important to note that not only does TPE removes pathologic elements from the plasma, but may also remove drugs, which may be an intended or unintended consequence. The objective of the current review is to provide an up-to-date summary of the available evidence pertaining to drug removal via TPE and provide relevant clinical suggestions where applicable. This review also aims to provide an easy-to-follow clinical tool in order to determine the possibility of a drug removal via TPE given the procedure-specific and pharmacokinetic drug properties.

The Curing Coma Campaign: Framing Initial Scientific Challenges-Proceedings of the First Curing Coma Campaign Scientific Advisory Council Meeting.

Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the "grand challenge" of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the "curing coma community" to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients.

Correction to: Standards for Neurologic Critical Care Units: A Statement for Healthcare Professionals from The Neurocritical Care Society.

The authors note that there is a discrepancy between the text of the paper and Table 2 regarding physician subspecialty certification requirements in neurocritical care for Level II centers.

Standards for Neurologic Critical Care Units: A Statement for Healthcare Professionals from The Neurocritical Care Society.

Neurocritical care is a distinct subspecialty focusing on the optimal management of acutely ill patients with life-threatening neurologic and neurosurgical disease or with life-threatening neurologic manifestations of systemic disease. Care by expert healthcare providers to optimize neurologic recovery is necessary. Given the lack of an organizational framework and criteria for the development and maintenance of neurological critical care units (NCCUs), this document is put forth by the Neurocritical Care Society (NCS). Recommended organizational structure, personnel and processes necessary to develop a successful neurocritical care program are outlined. Methods: Under the direction of NCS Executive Leadership, a multidisciplinary writing group of NCS members was formed. After an iterative process, a framework was proposed and approved by members of the writing group. A draft was then written, which was reviewed by the NCS Quality Committee and NCS Guidelines Committee, members at large, and posted for public comment. Feedback was formally collated, reviewed and incorporated into the final document which was subsequently approved by the NCS Board of Directors.

A Randomized Trial of Brief Versus Extended Seizure Prophylaxis After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Seizures occur in 10-20% of patients with subarachnoid hemorrhage (SAH), predominantly in the acute phase. However, anticonvulsant prophylaxis remains controversial, with studies suggesting a brief course may be adequate and longer exposure may be associated with worse outcomes. Nonetheless, in the absence of controlled trials to inform practice, patients continue to receive variable chemoprophylaxis. The objective of this study was to compare brief versus extended seizure prophylaxis after aneurysmal SAH. METHODS: We performed a prospective, single-center, randomized, open-label trial of a brief (3-day) course of levetiracetam (LEV) versus extended treatment (until hospital discharge). The primary outcome was in-hospital seizure. Secondary outcomes included drug discontinuation and functional outcome. RESULTS: Eighty-four SAH patients had been randomized when the trial was terminated due to slow enrollment. In-hospital seizures occurred in three (9%) of 35 in the brief LEV group versus one (2%) of 49 in the extended group (p = 0.2). Ten (20%) of the extended group discontinued LEV prematurely, primarily due to sedation. Four of five seizures (including one pre-randomization) occurred in patients with early brain injury (EBI) on computed tomography (CT) scans (adjusted OR 12.5, 95% CI 1.2-122, p = 0.03). Good functional outcome (mRS 0-2) was more likely in the brief LEV group (83 vs. 61%, p = 0.04). CONCLUSIONS: This study was underpowered to demonstrate superiority of extended LEV for seizure prophylaxis, although a trend to benefit was seen. Seizures primarily occurred in those with radiographic EBI, suggesting targeted prophylaxis may be preferable. Larger trials are required to evaluate optimal chemoprophylaxis in SAH, especially in light of worse outcomes in those receiving extended treatment.

The Implementation of Targeted Temperature Management: An Evidence-Based Guideline from the Neurocritical Care Society.

BACKGROUND: Targeted temperature management (TTM) is often used in neurocritical care to minimize secondary neurologic injury and improve outcomes. TTM encompasses therapeutic hypothermia, controlled normothermia, and treatment of fever. TTM is best supported by evidence from neonatal hypoxic-ischemic encephalopathy and out-of-hospital cardiac arrest, although it has also been explored in ischemic stroke, traumatic brain injury, and intracranial hemorrhage patients. Critical care clinicians using TTM must select appropriate cooling techniques, provide a reasonable rate of cooling, manage shivering, and ensure adequate patient monitoring among other challenges. METHODS: The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacotherapy to form a writing Committee in 2015. The group generated a set of 16 clinical questions relevant to TTM using the PICO format. With the assistance of a research librarian, the Committee undertook a comprehensive literature search with no back date through November 2016 with additional references up to March 2017. RESULTS: The Committee utilized GRADE methodology to adjudicate the quality of evidence as high, moderate, low, or very low based on their confidence that the estimate of effect approximated the true effect. They generated recommendations regarding the implementation of TTM based on this systematic review only after considering the quality of evidence, relative risks and benefits, patient values and preferences, and resource allocation. CONCLUSION: This guideline is intended for neurocritical care clinicians who have chosen to use TTM in patient care; it is not meant to provide guidance regarding the clinical indications for TTM itself. While there are areas of TTM practice where clear evidence guides strong recommendations, many of the recommendations are conditional, and must be contextualized to individual patient and system needs.

Pharmacotherapy Pearls for Emergency Neurological Life Support.

The appropriate use of medications during Emergency Neurological Life Support (ENLS) is essential to optimize patient care. Important considerations when choosing the appropriate agent include the patient's organ function and medication allergies, potential adverse drug effects, drug interactions and critical illness and aging pathophysiologic changes. Critical medications used during ENLS include hyperosmolar therapy, anticonvulsants, antithrombotics, anticoagulant reversal and hemostatic agents, anti-shivering agents, neuromuscular blockers, antihypertensive agents, sedatives, vasopressors and inotropes, and antimicrobials. This article focuses on the important pharmacokinetic and pharmacodynamics characteristics, advantages and disadvantages and clinical pearls of these therapies, providing practitioners with essential drug information to optimize pharmacotherapy in acutely ill neurocritical care patients.

Efficacy, Safety, and Timing of 5% Sodium Chloride Compared With 23.4% Sodium Chloride for Osmotic Therapy.

BACKGROUND: Bolus doses of 23.4% sodium chloride (NaCl) are commonly used for the treatment of intracranial hypertension; however, delays in administration may occur in patients without central intravenous access. At our institution, equiosmolar bolus doses of 5% NaCl have emerged as potential alternatives to 23.4% NaCl because they may be safely administered through peripheral lines. OBJECTIVES: We sought to assess the efficacy in reducing intracranial pressure (ICP), time to administration, and safety of 5% NaCl as compared with 23.4% NaCl for the treatment of intracranial hypertension. METHODS: Patients admitted from July 2012 to June 2014 who received boluses of 5% NaCl or 23.4% NaCl for a sustained ICP >20 mm Hg were included. Data collected included measurements of ICP, time to administration, and adverse events. RESULTS: A total of 44 patients were identified; 11 received 5% NaCl, and 33 received 23.4% NaCl. The median percentage reductions in ICP at 30, 60, and 120 minutes in patients who received 5% versus 23.4% NaCl were 34% versus 26% ( P = 0.850), 48% versus 40% ( P = 0.700), and 46% versus 30% ( P = 0.064), respectively. The median time to administration was shorter in the 5% NaCl group (7 vs 11 minutes, P = 0.364). Both groups had a 27% rate of adverse events and no infusion site reactions. CONCLUSIONS: These data suggest that 5% NaCl may be as effective as 23.4% NaCl at lowering ICP if given at equiosmolar doses, has a shorter time to administration, and has no difference in the prevalence of adverse events.

Practice Patterns of Venous Thromboembolism Prophylaxis in Underweight, Critically Ill Patients with Neurologic Injury.

PURPOSE: Venous thromboembolism (VTE) prophylaxis in underweight patients with neurologic injury remains unaddressed by guidelines and primary literature. This study aimed to describe VTE prophylaxis strategies employed in this population and compare the impact of underweight and non-obese patients on thrombotic and bleeding events. METHODS: A retrospective review of adults admitted with a diagnosis of neurologic injury to a neurology/neurosurgery intensive care unit (ICU) over 6 years. Patients admitted ≥72 h with an order for VTE prophylaxis during admission, and a body mass index (BMI) <30 kg/m2 were included. Patients were stratified to underweight (BMI ≤18.5 kg/m2 or weight ≤50.0 kg) or non-obese (BMI 18.6-29.9 kg/m2) groups and matched, 2:1, on age, diagnosis, and disease severity. RESULTS: The most common regimen in the underweight (n = 107) and non-obese (n = 214) group was unfractionated heparin (UFH) 5000 units subcutaneously Q12 h (69.1 vs. 83.6%; p = 0.003). Only underweight patients received UFH 2500 units subcutaneously Q12 h (17.8 vs. 0.0%; p < 0.0001). The proportion of overall bleeding and thrombotic events while receiving VTE prophylaxis was not significantly different. The proportion of underweight patients developing intracranial hematoma expansion while receiving prophylaxis versus non-obese patients (45.5 vs. 8.3%; p = 0.017) was significant. Patients receiving >150 units/kg/day of UFH displayed a trend toward increased risk of bleeding (9.7 vs. 4.2%; p = 0.064). CONCLUSIONS: Current practice does not reflect dose reductions for neurologically injured, underweight patients. Caution should be considered when using increased doses of UFH in neurologically injured patients that are underweight and/or may be exposed to >150 units/kg/day of UFH. Continued assessment of VTE prophylaxis is needed to confirm these findings.

Treatment of Hyponatremia in Patients with Acute Neurological Injury.

BACKGROUND: Little data exist regarding the practice of sodium management in acute neurologically injured patients. This study describes the practice variations, thresholds for treatment, and effectiveness of treatment in this population. METHODS: This retrospective, multicenter, observational study identified 400 ICU patients, from 17 centers, admitted for ≥48 h with subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), intraparenchymal hemorrhage, or intracranial tumors between January 1, 2011 and July 31, 2012. Data collection included demographics, APACHE II, Glascow Coma Score (GCS), serum sodium (Na+), fluid rate and tonicity, use of sodium-altering therapies, intensive care unit (ICU) and hospital length of stay, and modified Rankin score upon discharge. Data were collected for the first 21 days of ICU admission or ICU discharge, whichever came first. Sodium trigger for treatment defined as the Na+ value prior to treatment with response defined as an increase of ≥4 mEq/L at 24 h. RESULTS: Sodium-altering therapy was initiated in 34 % (137/400) of patients with 23 % (32/137) having Na+ >135 mEq/L at time of treatment initiation. The most common indications for treatment were declining serum Na+ (68/116, 59 %) and cerebral edema with mental status changes (21/116, 18 %). Median Na+ treatment trigger was 133 mEq/L (IQR 129-139) with no difference between diagnoses. Incidence and treatment of hyponatremia was more common in SAH and TBI [SAH (49/106, 46 %), TBI (39/97, 40 %), ICH (27/102, 26 %), tumor (22/95, 23 %); p = 0.001]. The most common initial treatment was hypertonic saline (85/137, 62 %), followed by oral sodium chloride tablets (42/137, 31 %) and fluid restriction (15/137, 11 %). Among treated patients, 60 % had a response at 24 h. Treated patients had lower admission GCS (12 vs. 14, p = 0.02) and higher APACHE II scores (12 vs. 10, p = 0.001). There was no statistically significant difference in outcome when comparing treated and untreated patients. CONCLUSION: Sodium-altering therapy is commonly employed among neurologically injured patients. Hypertonic saline infusions were used first line in more than half of treated patients with the majority having a positive response at 24 h. Further studies are needed to evaluate the impact of various treatments on patient outcomes.

Clinical Experience With Pharmacological Venous Thromboembolism Prophylaxis in the Underweight and Critically Ill.

BACKGROUND: The optimal regimen for pharmacological prophylaxis of venous thromboembolism (VTE) in underweight, critically ill patients is unknown. OBJECTIVE: To describe prescribing patterns for VTE prophylaxis in underweight (≤50 kg or body mass index ≤18.5 kg/m(2)), critically ill patients and identify the prevalence of VTE and bleeding. METHODS: This was a retrospective cohort study that included patients who received standard- or reduced-dose VTE prophylaxis for ≥48 hours. RESULTS: A total of 295 individuals were included in the study. The majority of underweight patients in this study (79.7%) received unfractionated heparin, 5000 units 3 times daily. No statistically significant difference in the prevalence of clinically relevant VTEs between the reduced- and standard-dose groups was observed (4.4% vs 5.6%, P = 1.00), but a higher proportion of bleeding events was identified within the standard-dose group (6.7% vs 11.2%, P = 0.4). CONCLUSIONS: Empirical dose reductions of VTE prophylaxis are infrequently used in underweight, critically ill patients. Further studies need to be conducted that assess the safety and efficacy of reduced-dose VTE prophylactic regimens in this population to determine if acceptable efficacy can be achieved, with lower risks of bleeding.

Emergency Neurological Life Support: Pharmacotherapy.

The appropriate use of medications during Emergency Neurological Life Support (ENLS) is essential to optimize patient care. Important considerations when choosing the appropriate agent include the patient's organ function and medication allergies, potential adverse drug effects, drug interactions, and critical illness and aging pathophysiologic changes. Critical medications used during ENLS include hyperosmolar therapy, anticonvulsants, antithrombotics, anticoagulant reversal and hemostatic agents, anti-shivering agents, neuromuscular blockers, antihypertensive agents, sedatives, vasopressors and inotropes, and antimicrobials. This article focuses on the important pharmacokinetic and pharmacodynamics characteristics, advantages and disadvantages, and clinical pearls of these therapies, providing practitioners with essential drug information to optimize pharmacotherapy in acutely ill neurocritical care patients.

Adverse neurologic effects of medications commonly used in the intensive care unit.

Adverse drug effects often complicate the care of critically ill patients. Therefore, each patient's medical history, maintenance medication, and new therapies administered in the intensive care unit must be evaluated to prevent unwanted neurologic adverse effects. Optimization of pharmacotherapy in critically ill patients can be achieved by considering the need to reinitiate home medications, and avoiding drugs that can decrease the seizure threshold, increase sedation and cognitive deficits, induce delirium, increase intracranial pressure, or induce fever. Avoiding medication-induced neurologic adverse effects is essential in critically ill patients, especially those with neurologic injury.

Response to a bolus of conivaptan in patients with acute hyponatremia after brain injury.

PURPOSE: The aim of the study was to analyze the response to the vasopressin-receptor antagonist conivaptan in a large cohort of brain-injured patients with acute hyponatremia. MATERIALS AND METHODS: The natremic response (rise in serum sodium) to an initial bolus of conivaptan was retrospectively evaluated in 124 patients over a 3-year period in our neurosciences intensive care unit. Variables associated with this response were identified using linear regression. RESULTS: Median pretreatment sodium was 132 mEq/L, and duration of hyponatremia before dose was 1 day. Median natremic response was +4 mEq/L (interquartile range, 2-7 mEq/L), measured a median of 9 hours (interquartile range, 6-12 hours) after conivaptan administration. This was associated with significant urine output (median, 2.6 L over 12 hours), with degree of aquaresis associated with natremic response (regression coefficient, B = 1.8 change in sodium per liter; 95% confidence interval, 1.3-2.4; P < .001). Seventy-four patients (60%) responded with a rise of at least 4 mEq/L. Response was predicted by higher baseline urine output (B = 0.018 per mL; 0.004-0.032; P = .01) and lack of oral fluid intake (B = 2.06; 0.44-3.68; P = .01) but not tonicity of intravenous fluids or creatinine clearance. CONCLUSIONS: Conivaptan given as a bolus can effectively treat acute hyponatremia in brain-injured patients.

Central nervous system complications after transplantation.

The incidence of serious neurologic complications after organ and stem cell transplantation can be as high as 20% to 30%, with most occurring in the early posttransplant period. Encephalopathy often results from metabolic disturbances and immunosuppressant drug neurotoxicity but can also occur with central pontine myelinolysis and other lesions of the central nervous system (CNS). Seizures are also common and can be related to drug toxicity or herald CNS disorders. A thorough evaluation of any patient who develops seizures or mental status changes after transplantation is warranted to distinguish transient reversible causes from serious CNS disorders.