Evaluation of Bivalirudin During Adult Extracorporeal Membrane Oxygenation: A Retrospective Characterization of Dosing, Efficacy and Bleeding.

Objective: Although heparin is the current standard anticoagulant during venoarterial (VA) and venovenous (VV) extracorporeal membrane oxygenation (ECMO), factors including heparin-induced thrombocytopenia, heparin resistance and drug shortages necessitate alternative anticoagulants such as direct thrombin inhibitors. The aim was to characterize dosing, safety, and efficacy of bivalirudin during ECMO support. Methods: This retrospective single-center study included 24 adults on ECMO support who received ≥6 hours of bivalirudin. The primary endpoint was dose to first therapeutic activated partial thromboplastin time (aPTT). Secondary endpoints included evaluating dosing between ECMO modes, incidence of bleeding and thrombotic events, and time in therapeutic range (TTR). Results: The dose at time of first therapeutic aPTT was bivalirudin 0.05 [0.05-0.1] mg/kg/hour. Bivalirudin dosing requirements were lower in VAECMO compared to VV-ECMO patients and were not impacted by continuous venovenous hemofiltration. Time to therapeutic aPTT was 5.5 [2-13] hours for VA-ECMO and 4.5 [2-8.6] hours for VV-ECMO patients. During any mode of ECMO TTR was 58.3% [39.6-73.1]. Thrombotic events occurred in 3 (13%) patients and major bleeding occurred in 12 (50%) patients. Conclusions: Our findings demonstrated variable bivalirudin dosing requirements based on mode of ECMO and dosing modifications may not be required during CVVH. Factors including mode of ECMO, indication for bivalirudin and concomitant antiplatelet therapy may impact hematologic events. Application of this data can assist with developing a bivalirudin ECMO protocol which provides less variability in initial dosing and TTR.

Prolonged Unconsciousness is Common in COVID-19 and Associated with Hypoxemia.

OBJECTIVE: The purpose of this study was to estimate the time to recovery of command-following and associations between hypoxemia with time to recovery of command-following. METHODS: In this multicenter, retrospective, cohort study during the initial surge of the United States' pandemic (March-July 2020) we estimate the time from intubation to recovery of command-following, using Kaplan Meier cumulative-incidence curves and Cox proportional hazard models. Patients were included if they were admitted to 1 of 3 hospitals because of severe coronavirus disease 2019 (COVID-19), required endotracheal intubation for at least 7 days, and experienced impairment of consciousness (Glasgow Coma Scale motor score <6). RESULTS: Five hundred seventy-one patients of the 795 patients recovered command-following. The median time to recovery of command-following was 30 days (95% confidence interval [CI] = 27-32 days). Median time to recovery of command-following increased by 16 days for patients with at least one episode of an arterial partial pressure of oxygen (PaO2 ) value ≤55 mmHg (p < 0.001), and 25% recovered ≥10 days after cessation of mechanical ventilation. The time to recovery of command-following  was associated with hypoxemia (PaO2 ≤55 mmHg hazard ratio [HR] = 0.56, 95% CI = 0.46-0.68; PaO2 ≤70 HR = 0.88, 95% CI = 0.85-0.91), and each additional day of hypoxemia decreased the likelihood of recovery, accounting for confounders including sedation. These findings were confirmed among patients without any imagining evidence of structural brain injury (n = 199), and in a non-overlapping second surge cohort (N = 427, October 2020 to April 2021). INTERPRETATION: Survivors of severe COVID-19 commonly recover consciousness weeks after cessation of mechanical ventilation. Long recovery periods are associated with more severe hypoxemia. This relationship is not explained by sedation or brain injury identified on clinical imaging and should inform decisions about life-sustaining therapies. ANN NEUROL 2022;91:740-755.

Implementation of a myasthenia gravis drug-disease interaction clinical decision support tool reduces prescribing of high-risk medications.

INTRODUCTION/AIMS: High-risk medication exposure is a modifiable risk factor for myasthenic exacerbation and crisis. We evaluated whether real-time electronic clinical decision support (CDS) was effective in reducing the rate of prescribing potentially high-risk medications to avoid or use with caution in patients with myasthenia gravis. METHODS: An expert panel reviewed the available drug-disease pairings and associated severity levels to activate the alerts for CDS. All unique alerts activated in both inpatient and outpatient contexts were analyzed over a two-year period. Clinical context, alert severity, medication class, and alert action were collected. The primary outcome was alert override rate. Secondary outcomes included the percentage of unique medication exposures avoided and predictors of alert override. RESULTS: During the analysis period, 2817 unique alerts fired, representing 830 distinct patient-medication exposures for 577 unique patients. The overall alert override rate was 85% (80.3% for inpatient alerts and 95.8% for outpatient alerts). Of unique medication-patient exposures, 19% were avoided because of the alert. Assigned alert severity of "contraindicated" were less likely to be overridden (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.32-0.56), as well as alerts activated during evening staffing (OR 0.69, 95% CI 0.55-0.87). DISCUSSION: Implementation of a myasthenia gravis drug-disease interaction alert reduced overall patient exposure to potentially harmful medications by approximately 19%. Future optimization includes enhanced provider and pharmacist education. Further refinement of alert logic criteria to optimize medication risk reduction and reduce alert fatigue is warranted to support clinicians in prescribing and reduce electronic health record time burden.

Safety and Tolerability of 23.4% Hypertonic Saline Administered Over 2 to 5 Minutes for the Treatment of Cerebral Herniation and Intracranial Pressure Elevation.

BACKGROUND: Hyperosmolar therapy is the cornerstone of medical management of sustained elevated intracranial pressure from cerebral edema. Acute intracranial hypertension and herniation is a medical emergency that requires rapid treatment and stabilization to prevent secondary brain injury or death. Intravenous hypertonic sodium chloride (NaCl) 23.4% is an effective treatment modality commonly used in this setting. Because of its high osmolarity, use has historically been limited primarily to central venous line administration as an intermittent infusion due to concerns about thrombophlebitis, injection site pain, and tissue necrosis or injury with extravasation. The objective of this analysis was to prospectively evaluate the safety of administration of 23.4% NaCl as a rapid intravenous push over 2-5 min. METHODS: A prospective analysis of patients admitted between April 2021 and December 2021 who received 23.4% NaCl intravenous push over 2-5 min in a central or peripheral line was performed. Safety end points included incidence of new onset hypotension [defined as systolic blood pressure (SBP) < 90 mm Hg or SBP decrease of at least 20 mm Hg], bradycardia (defined as heart rate < 50 beats per minute), and infusion site reactions documented within 1 h of administration. For secondary safety outcomes, highest and lowest SBP and lowest heart rates documented within 1 h before 23.4% NaCl administration were compared with values collected within 1 h post administration and evaluated by mixed-design analysis of variance test with adjustment for peripheral versus central line administration. RESULTS: We identified 32 patients who received 79 administrations of 23.4% NaCl through a central line or peripheral line during the study period. An SBP decrease of at least 20 mm Hg was observed in 13% of patients, an SBP < 90 mm Hg occurred in 16% of patients, and bradycardia occurred in 3% of patients who received 23.4% NaCl. Injection site pain was reported by one patient without documented thrombophlebitis, cellulitis, or tissue damage. Pain was not reported during two subsequent administrations in the same patient. There was no documented occurrence of soft tissue injury or necrosis in any patient. Compared with baseline vital signs before 23.4% NaCl administration, no difference in vital signs post administration was observed. CONCLUSIONS: Central and peripheral administration of 23.4% NaCl over 2-5 min was well tolerated, and incidence of hypotension, bradycardia, or infusion site-related adverse events was rare.

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.

Pharmacologic Therapies to Promote Recovery of Consciousness.

Pharmacologic interventions are commonly used to support rehabilitation efforts of patients with disorders of consciousness (DoC). The 2018 practice guidelines recommend amantadine in adults with traumatic DoC to promote functional recovery, though several other stimulants are used off-label in clinical practice and trials, such as methylphenidate, bromocriptine, levodopa, and zolpidem. Differences in the mechanisms of action, adverse effects, pharmacokinetics, and drug-drug interactions should be considered when selecting the best agent for each individual patient. Overall, pharmacologic stimulants may provide a safe and inexpensive pathway to increased functionality and participation in rehabilitation. This article provides a concise summary of scientific evidence supporting the use of pharmacologic therapies to stimulate recovery of consciousness in patients with DoC.

Volume replacement is associated with a diminished osmolar effect of mannitol in patients with acute brain injury.

INTRODUCTION: Animal experiments recently demonstrated that replacing urinary loses with crystalloid diminishes the therapeutic effect of mannitol by reducing the increase in osmolality. We aimed to investigate whether this effect is similarly seen in in brain-injured patients by studying the association between total body fluid balance (TBB) and the osmolar response to mannitol. METHODS: We performed a retrospective cohort study of adult patients with acute brain injury between 2015 and 2021 who received ≥ 2 doses of mannitol within 8 hours and no intercurrent concentrated saline solution. We analyzed the association between the change in TBB (∆TBB) and change in osmolality (∆Osm) before and after mannitol in a linear model, both as univariate and after adjustment for common confounding factors. RESULTS: Of 6,145 patients who received mannitol, 155 patients met inclusion criteria (mean age 60 ± 17 years, 48% male, 83% white). The mean total mannitol dose was 2 ± 0.5 g/kg and the mean change in plasma osmolality was 7.9 ± 7.1 mOsm/kg. Each 1 L increase in ∆TBB was associated with a change of -1.1 mOsm/L in ∆Osm (95% CI [-2.2, -0.02], p = 0.045). The magnitude of association was similar to that of total mannitol dose and remained consistent in an adjusted model and after excluding outliers. CONCLUSIONS: In patients with acute brain injury, a positive TBB is associated with a diminished mannitol-induced increase in plasma osmolality. Future prospective studies are needed to confirm these findings and their influence on the therapeutic effect of mannitol.

Evaluation of direct thrombin inhibitors during a critical heparin shortage.

A recent heparin shortage related to an outbreak of African Swine Flu in China led to substantial increase in the use of direct thrombin inhibitors (DTI) as an alternative. We evaluated the safety and efficacy of DTIs by assessing the anticoagulation assays within the initial 48 h of therapy comparing before and during shortage. A retrospective evaluation of bivalirudin and argatroban was conducted at a single center before (May 24, 2018 through August 25, 2019) and during heparin shortage (August 26, 2019 through February 20, 2020). The primary outcome was time to first therapeutic activated partial thromboplastin time (aPTT). Secondary outcomes included the percentage of time in therapeutic aPTT range, in-hospital mortality, incidence of recurrent thrombosis, and hemorrhagic events. Of the 204 patients included in the study, 95 patients [bivalirudin (n = 35), argatroban (n = 60)] were included in the pre-shortage cohort and 109 patients [bivalirudin (n = 68), argatroban (n = 41)] were during shortage. No significant difference was observed in the time to first therapeutic aPTT pre- and during shortage (8.9 h ± 10.8 vs 8.8 h ± 10.2, P = 0.62). Compared to pre-shortage cohort, a greater percentage of time was spent in therapeutic aPTT range within the initial 48 h (32% (0-50) vs. 41.6% (0-63), P = 0.04) during shortage without statistically significant differences in the rates of in-hospital mortality, thrombosis, or bleeding. While the optimal DTI protocol is still be determined, the protocols presented in this study allowed for wide-spread utilization of DTIs during a critical heparin shortage without compromising patient safety and effectiveness, likely reflective of the enhancement of DTI protocols, clinician education, and multidisciplinary collaboration and guidance from pharmacy and hematology.

Advances in surgical hemostasis: a comprehensive review and meta-analysis on topical tranexamic acid in spinal deformity surgery.

Tranexamic acid (TXA) is an effective and commonly used hemostatic agent for perioperative blood loss in various surgical specialties. It is being increasingly used in spinal deformity surgery. We aimed to evaluate the safety and efficacy of topical TXA (tTXA) compared to both placebo and/or intravenous (IV) TXA in patients undergoing spinal deformity surgery. We conducted a systematic review of the electronic databases using different MeSH terms from January 1970 to August 2019. Pooled and subgroup analysis was performed using fixed and random-effect model based upon the heterogeneity (I2). A total of 609 patients (tTXA: n = 258, 42.4%) from 8 studies were included. We found that there was a statistically significant difference in terms of (i) postoperative blood loss [mean difference (MD) - 147.1, 95% CI - 189.5 to - 104.8, p < 0.00001], (ii) postoperative hemoglobin level (MD 1.09, 95% CI 0.45 to 1.72, p = 0.0008), (iii) operative time (MD 7.47, 95% CI 2.94 to 12.00, p < 0.00001), (iv) postoperative transfusion rate [odds ratio (OR) 0.39, 95% CI 0.20 to 0.78, p = 0.007], postoperative drain output (MD, - 184.0, 95% CI - 222.03 to - 146.04, p < 0.00001), and (v) duration of hospital stay (MD - 1.14, 95% CI - 1.44 to - 0.85, p < 0.00001) in patients treated with tTXA compared to the control group. However, there was no significant difference in terms of intraoperative blood loss (p = 0.13) and complications (p = 0.23) between the two comparative groups. Furthermore, low-dose (250-500 mg) tTXA (p < 0.00001) reduced postoperative blood loss more effectively compared to high-dose tTXA (1-3 g) (p = 0.001). Our meta-analysis corroborates the effectiveness and safety of tTXA in spinal deformity surgery.

Stress-Related Gastrointestinal Bleeding in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Observational Study.

BACKGROUND/OBJECTIVE: Stress-related mucosal bleeding (SRMB) occurs in approximately 2-4% of critically ill patients. Patients with aneurysmal subarachnoid hemorrhage (aSAH) have a (diffuse) space-occupying lesion, are critically ill, often require mechanical ventilation, and frequently receive anticoagulation or antiplatelet therapy after aneurysm embolization, all of which may be risk factors for SRMB. However, no studies have evaluated SRMB in patients with aSAH. Aims of the study were to determine the incidence of SRMB in aSAH patients, evaluate the effect of acid suppression on SRMB, and identify specific risk factors for SRMB. METHODS: This was a multicenter, retrospective, observational study conducted across 17 centers. Each center reviewed up to 50 of the most recent cases of aSAH. Patients with length of stay (LOS) < 48 h or active GI bleeding on admission were excluded. Variables related to demographics, aSAH severity, gastrointestinal (GI) bleeding, provision of SRMB prophylaxis, adverse events, intensive care unit (ICU), and hospital LOS were collected for the first 21 days of admission or until hospital discharge, whichever came first. Descriptive statistics were used to analyze the data. A multivariate logistic regression modeling was utilized to examine the relationship between specific risk factors and the incidence of clinically important GI bleeding in patients with aSAH. RESULTS: A total of 627 patients were included. The overall incidence of clinically important GI bleeding was 4.9%. Of the patients with clinically important GI bleeding, 19 (61%) received pharmacologic prophylaxis prior to evidence of GI bleeding, while 12 (39%) were not on pharmacologic prophylaxis at the onset of GI bleeding. Patients who received an acid suppressant agent were less likely to experience GI bleeding than patients who did not receive pharmacologic prophylaxis prior to evidence of bleeding (OR 0.39, 95% CI 0.18-0.83). The multivariate regression analysis identified any instance of elevated intracranial pressure, creatinine clearance < 60 ml/min and the incidence of cerebral vasospasm as specific risk factors associated with GI bleeding. Cerebral vasospasm has not previously been described as a risk for GI bleeding (OR 2.5 95% CI 1.09-5.79). CONCLUSIONS: Clinically important GI bleeding occurred in 4.9% of patients with aSAH, similar to the general critical care population. Risk factors associated with GI bleeding were prolonged mechanical ventilation (> 48 h), creatinine clearance < 60 ml/min, presence of coagulopathy, elevation of intracranial pressure, and cerebral vasospasm. Further prospective research is needed to confirm this observation within this patient population.

When Pigs Fly: A Multidisciplinary Approach to Navigating a Critical Heparin Shortage.

A recent outbreak of African swine fever (ASF) in China has claimed the lives of millions of pigs, and although this virus has no health impacts on humans, the disruption of the global pig population has far-reaching negative impacts on economic and pork-derived products, including the creation of the critical drug heparin. The active pharmaceutical ingredient in heparin is derived from pig intestines, and because of the ASF outbreak, the U.S. faces an imminent shortage of heparin. This drug shortage has the potential for profound implications, as heparin is used in a substantial and varied number of medical conditions. In response to notification of the heparin shortage crisis, our institution, Massachusetts General Hospital, activated its Hospital Incident Command System to streamline organization of major stakeholders and oversee operational and clinical activities required to mitigate the potential risks and optimize alternative effective strategies. This article describes the essential elements of our institution's emergency response plan, including detailed clinical algorithms developed by our experts for maximal heparin conservation and waste reduction by promoting safe and effective alternative strategies. Through this practice, we have also identified opportunities to change providers' prescribing and utilization behaviors for the better. As the ASF has not yet been contained and this crisis continues, the strategies and policies employed by our institution can provide a framework for other institutions to tackle this ongoing challenge and future drug shortage crises. IMPLICATIONS FOR PRACTICE: A detailed description of how one institution addressed the current heparin crisis, to support heparin conservation and waste reduction, is provided. The strategies used helped decrease heparin use by 80% in less than 2 months of establishing the task force. This accomplishment can be credited to the development of a task force and strategic plan in which experts and stakeholders were quickly identified, offered a part in the decision-making process, and frequently updated. Furthermore, the response system was dynamic, accessible, and one in which challenges were recognized and acted upon. The key to any crisis management is respect for one another and constant and open communication. Heparin is such a widespread drug that this shortage can potentially affect every patient population and provider. Understanding one's institutional needs and the effect of this crisis on those needs is one of the first steps when developing a strategic plan. Continually evaluating and adjusting that approach in response to the needs of the institution are critical to its success. Moreover, as it did for the authors' institution, a constant appraisal of the strategies can lead to opportunities for improvements in organization and practice that can be sustained well beyond the crisis.

A Novel Correction Equation Avoids High-Magnitude Errors in Interpreting Therapeutic Drug Monitoring of Phenytoin Among Critically Ill Patients.

BACKGROUND: Phenytoin has a narrow therapeutic index and the potential of under-treatment or toxicity. Available equations are used to correct for the impact of hypoalbuminemia on unbound (free) phenytoin levels. The authors aimed to determine the accuracy of equations used to estimate free phenytoin in hospitalized patients and assess the impact of using additional clinical data. METHODS: Concurrently measured total and free phenytoin levels in hospitalized patients (2014-2018) were retrospectively evaluated, excluding those from patients on renal replacement therapy and valproic acid. Differences between actual and estimated free phenytoin levels by the original (Original WTZ), Anderson-modified, and Kane-modified Winter-Tozer equations were assessed using Pearson correlations and Bland-Altman analysis. Thereafter, a population-derived formula was developed and validated in a testing cohort. RESULTS: In the 4-year training cohort (n = 81), the Original WTZ equation had the smallest mean difference of all equations. A higher mean difference [-0.362 mcg/mL (95% CI -0.585 to -0.138) vs. -0.054 mcg/mL (95% CI -0.186 to 0.078)] was observed in intensive care unit (ICU) patients compared with non-ICU patients. A cross-validated multivariable model improved the accuracy of free phenytoin estimation in ICU and non-ICU patients, even in the separate testing cohort (n = 52) with respective mean differences of -0.322 mcg/mL (95% CI -0.545 to -0.098) and -0.025 mcg/mL (95% CI -0.379 to 0.329) and was superior to the Original WTZ [mean difference -0.858 mcg/mL (95% CI -1.069 to -0.647) vs. -0.106 mcg/mL (95% CI -0.362 to 0.151), respectively]. CONCLUSIONS: Free phenytoin levels in hospitalized patients cannot be accurately determined using available estimation equations, particularly in critically ill patients. Combining ICU status and other available clinical data can improve therapeutic drug monitoring and prevent high-magnitude errors, particularly when free phenytoin assays are not readily available.

Safety and Effectiveness of Intravenous Chlorpromazine for Agitation in Critically Ill Patients.

BACKGROUND: Agitation is common in the intensive care unit (ICU). Although antipsychotics are frequently used as first-line therapy, chlorpromazine has fallen out of favor due to risk of cardiovascular complications and severe hypotension. Although chlorpromazine is used anecdotally, there is a lack of data regarding its safety and effectiveness. The objective of this study was to investigate the use of intravenous (IV) chlorpromazine for agitation in the ICU setting. METHODS: A retrospective review was performed at a tertiary care academic medical center. Patients were included if they received IV chlorpromazine in the ICU for agitation, infused at a rate of 1 mg/min. Primary end points were change in systolic blood pressure (SBP), heart rate (HR), and mean arterial pressure (MAP) within 4 hours of administration. Secondary end points included change in vasopressor and adjunct sedative medication requirements, achievement of Richmond-Agitation Sedation Scale (RASS) 0 to -1, and incidence of cardiac arrhythmias. RESULTS: A total of 39 patients encompassing 107 IV chlorpromazine administrations were included. The median dose was 25 mg. Median vital signs prior to infusion were SBP 129 mm Hg, HR 90 beats/minute, and MAP 88 mm Hg. Over the subsequent 4 hours, SBP and HR did not change significantly (P = .83 and P = .10, respectively). Mean arterial pressure decreased from a median of 88 to 83 mm Hg (P = .04). There were no significant changes in vasopressor requirements, adjunct sedative medication requirements, or achievement of RASS goal. No patients developed symptomatic cardiac arrhythmias. CONCLUSION: In our small retrospective study, the use of IV chlorpromazine at routine doses did not result in clinically significant hemodynamic changes when infused at a rate of 1 mg/min. Intravenous chlorpromazine may be considered as a potential treatment option for agitation in ICU patients with appropriate monitoring.

Stimulant Therapy in Acute Traumatic Brain Injury: Prescribing Patterns and Adverse Event Rates at 2 Level 1 Trauma Centers.

BACKGROUND/OBJECTIVE: Pharmacological stimulant therapies are routinely administered to promote recovery in patients with subacute and chronic disorders of consciousness (DoC). However, utilization rates and adverse drug event (ADE) rates of stimulant therapies in patients with acute DoC are unknown. We aimed to determine the frequency of stimulant use and associated ADEs in intensive care unit (ICU) patients with acute DoC caused by traumatic brain injury (TBI). METHODS: We retrospectively identified patients with TBI admitted to the ICU at 2 level 1 trauma centers between 2015 and 2018. Patients were included if they were stimulant naive at baseline and received amantadine, methylphenidate, or modafinil during ICU admission. Stimulant dose reduction or discontinuation during ICU admission was considered a surrogate marker of an ADE. Targeted chart review was performed to identify reasons for dose reduction or discontinuation. RESULTS: Forty-eight of 608 patients with TBI received pharmacological stimulant therapy (7.9%) during the study period. Most patients were diagnosed with severe TBI at presentation (60.4%), although stimulants were also administered to patients with moderate (14.6%) and mild (25.0%) TBI. The median time of stimulant initiation was 11 days post-injury (range: 2-28 days). Median Glasgow Coma Scale score at the time of stimulant initiation was 9 (range: 4-15). Amantadine was the most commonly prescribed stimulant (85.4%) followed by modafinil (14.6%). Seven (14.6%) patients required stimulant dose reduction or discontinuation during ICU admission. The most common ADE resulting in therapy modification was delirium/agitation (n = 2), followed by insomnia (n = 1), anxiety (n = 1), and rash (n = 1); the reason for therapy modification was undocumented in 2 patients. CONCLUSIONS: Pharmacological stimulant therapy is infrequently prescribed but well tolerated in ICU patients with acute TBI at level 1 trauma centers. These retrospective observations provide the basis for prospective studies to evaluate the safety, optimal dose range, and efficacy of stimulant therapies in this population.

Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit.

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.

CAR T-Cell-Associated Neurotoxicity: Current Management and Emerging Treatment Strategies.

Axicabtagene ciloleucel and tisagenlecleucel are 2 chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 for the treatment of B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma. Two commonly recognized complications associated with CAR T-cell therapies are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS can occur in isolation or concomitantly with CRS following CAR T-cell therapy and may be due to disruption of the blood-brain barrier and the effects of elevated cytokine levels on the central nervous system. Presently, the optimum management of ICANS remains elusive, as there lacks consensus guidelines. The objective of this review is to provide a comprehensive summary of ICANS and strategies for prompt identification and management of patients presenting to the intensive care unit with this syndrome.

Evaluation of Medication Exposure on Exacerbation of Disease in Patients With Myasthenia Gravis.

Background and Purpose: In patients with myasthenia gravis (MG), worsening of symptoms poses a risk of respiratory failure which can be precipitated by medication use. Although purported, the risks associated with administration of certain medications are not fully elucidated. Thus, clinical decision support involving a best practice alert was executed to caution providers of drug-disease interactions when ordering a potentially harmful medication. We performed an analysis of the alert overrides with subsequent medication exposure to determine the incidence of MG exacerbations. Methods: This retrospective chart-review evaluated adult patients with MG at 2 large academic medical centers via electronic health records between November-2019 and November-2021 who received a medication following override of the clinical decision support tool. The primary outcome was proportion of patient encounters complicated by myasthenic exacerbations after potentially harmful medication administration. Secondary outcomes included changes in motor strength, length of stay, discharge disposition, unplanned level-of-care escalations, and changes to immunosuppressant therapy following medication administration. Results: A total of 70 orders were assessed in 38 patients across 55 encounters. Medications administered during these encounters included macrolides, fluoroquinolones, ß-blockers, calcium channel blockers, and magnesium sulfate. Exacerbation of disease occurred in 7 patient encounters (12.7%) and occurred after intravenous magnesium or intravenous labetalol. In 5/7 events, at least 1 other risk factor associated with a myasthenic exacerbation was present. Conclusions: Of the medications reported to potentially worsen MG, intravenous labetalol and intravenous magnesium were the 2 agents associated with myasthenic exacerbations with a higher incidence in patients harboring additional risk factors.

Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions.

Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem. However, the relative contributions of monoaminergic, glutamatergic, cholinergic, GABAergic, and orexinergic neurotransmitter systems to recovery of consciousness after severe brain injury are unknown, and personalized approaches to targeted therapy have yet to be developed. This review summarizes the state-of-the-science in the neurochemistry and neurobiology of neurotransmitter systems involved in conscious behaviors, followed by a discussion of how pharmacologic therapies may be used to modulate these neurotransmitter systems and promote recovery of consciousness. We consider pharmacologic modulation of consciousness at the synapse, circuit, and network levels, with a focus on the mesocircuit model that has been proposed to explain the consciousness-promoting effects of various monoaminergic, glutamatergic, and paradoxically, GABAergic therapies. Though fundamental questions remain about neurotransmitter mechanisms, target engagement and optimal therapy selection for individual patients, we propose that pharmacologic therapies hold great promise to promote recovery and improve quality of life for patients with severe brain injuries.

Intravenous Ganaxolone: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability in Healthy Adults.

Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median Tmax of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median Tmax of approximately 1 and 3 hours, respectively. Cmax was dose and administration-time dependent, ranging from 73.8 ng/mL (10 mg over 5 minutes) to 1240 ng/mL (30 mg over 5 minutes). Bolus doses above 10 mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.