Hyperoxia is associated with a greater risk for mortality in critically ill traumatic brain injury patients than in critically ill trauma patients without brain injury.

OBJECTIVE: The role of hyperoxia in patients with traumatic brain injury (TBI) remains controversial. The objective of this study was to determine the association between hyperoxia and mortality in critically ill TBI patients compared to critically ill trauma patients without TBI. DESIGN: Secondary analysis of a multicenter retrospective cohort study. SETTING: Three regional trauma centers in Colorado, USA, between October 1, 2015, and June 30, 2018. PATIENTS: We included 3464 critically injured adults who were admitted to an intensive care unit (ICU) within 24 h of arrival and qualified for inclusion into the state trauma registry. We analyzed all available SpO2 values during the first seven ICU days. The primary outcome was in-hospital mortality. Secondary outcomes included the proportion of time spent in hyperoxia (defined as SpO2 > 96%) and ventilator-free days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In-hospital mortality occurred in 163 patients (10.7%) in the TBI group and 101 patients (5.2%) in the non-TBI group. After adjusting for ICU length of stay, TBI patients spent a significantly greater amount of time in hyperoxia versus non-TBI patients (p = 0.024). TBI status significantly modified the effect of hyperoxia on mortality. At each specific SpO2 level, the risk of mortality increases with increasing FiO2 for both patients with and without TBI. This trend was more pronounced at lower FiO2 and higher SpO2 values, where a greater number of patient observations were obtained. Among patients who required invasive mechanical ventilation, TBI patients required significantly more days of ventilation to day 28 than non-TBI patients. CONCLUSIONS: Critically ill trauma patients with a TBI spend a greater proportion of time in hyperoxia compared to those without a TBI. TBI status significantly modified the effect of hyperoxia on mortality. Prospective clinical trials are needed to better assess a possible causal relationship.

Rapid Activation of Neuroinflammation in Stroke: Plasma and Extracellular Vesicles Obtained on a Mobile Stroke Unit.

BACKGROUND: Neuroinflammation is ubiquitous in acute stroke and worsens outcome. However, the precise timing of the inflammatory response is unknown, hindering the design of acute anti-inflammatory therapeutic interventions. We sought to identify the onset of the neuroinflammatory cascade using a mobile stroke unit. METHODS: The study is a proof-of-concept, cohort investigation of ultra-early blood- and extracellular vesicle-derived markers of neuroinflammation and outcome in acute stroke. Blood was obtained, prehospital, on an mobile stroke unit. Outcomes were biomarker concentrations, modified Rankin Scale score, and National Institutes of Health Stroke Scale score. RESULTS: Forty-one adults were analyzed, including 15 patients treated on the mobile stroke unit between August 2021 and April 2022, and 26 healthy controls to establish biomarker reference levels. Median patient age was 74 (range, 36-97) years, 60% were female, and 80% White. Ten (67%) were diagnosed as stroke, with 8 (53%) confirmed and 2 likely transient ischemic attack or stroke averted by thrombolysis; 5 were stroke mimics. For strokes, median initial National Institutes of Health Stroke Scale score was 11 (range, 4-19) and 6 (75%) received tPA (tissue-type plasminogen activator). Blood was obtained a median of 58 (range, 36-133) minutes after symptom onset. Within 36 minutes after stroke, plasma IL-6 (interleukin-6), neurofilament light chain, UCH-L1 (ubiquitin C-terminal hydrolase L1), and GFAP (glial fibrillary acidic protein) were elevated by as much as 10 times normal. In EVs, MMP-9 (matrix metalloproteinase-9), CXCL4 (chemokine (C-X-C motif) ligand 4), CRP (C-reactive protein), IL-6, OPN (osteopontin), and PECAM1 (platelet and endothelial cell adhesion molecule 1) were elevated. Inflammatory markers increased rapidly in the first 2 hours and continued rising for 24 hours. CONCLUSIONS: The neuroinflammatory cascade was found to be activated within 36 to 133 minutes after stroke and progresses rapidly. This is earlier than observed previously in humans and suggests injury from neuroinflammation occurs faster than had been surmised. These findings could inform development of acute immunomodulatory stroke therapies and lead to new diagnostic tools and improved outcomes.

Pharmacokinetic Evaluation of Cefazolin in the Cerebrospinal Fluid of Critically Ill Patients.

BACKGROUND: The relative distribution of cefazolin into the cerebrospinal fluid (CSF) remains debated. Determining the distribution of cefazolin into the CSF in noninfected adults may allow for further treatment applications of cefazolin. This prospective pharmacokinetic study aimed to determine the pharmacokinetic parameters of cefazolin in serum and CSF from external ventricular drains (EVDs) in neurologically injured adults. METHODS: Blood and CSF were collected, using a biologic waste protocol, for cefazolin quantification and trapezoidal rule-based pharmacokinetic analysis in a total of 15 critically ill adults receiving 2000 mg intravenously every 8 hours or the renal dose equivalent for EVD prophylaxis. RESULTS: A median (range) of 3 (2-4) blood and 3 (2-5) CSF samples were collected for each patient. The most common admitting diagnosis was subarachnoid hemorrhage (66.7%). The median calculated cefazolin CSF Cmax and Cmin values (interquartile range [IQR]) were 2.97 (1.76-8.56) mg/L and 1.59 (0.77-2.17) mg/L, respectively. The median (IQR) CSF to serum area under the curve ratio was 6.7% (3.7%-10.6%), with time-matched estimates providing a similar estimate (8.4%). Of those receiving cefazolin every 8 hours, the median and minimum directly measured CSF cefazolin concentration ≥4 hours following administration were 1.87 and 0.78 mg/L, respectively. CONCLUSIONS: Cefazolin dosed for EVD prophylaxis achieved CSF concentrations suggesting viability as a therapeutic option for patients with meningitis or ventriculitis due to susceptible bacteria such as methicillin-susceptible Staphylococcus aureus. Further clinical trials are required to confirm a role in therapy for cefazolin. Population-based pharmacokinetic-pharmacodynamic modeling may suggest an optimal cefazolin regimen for the treatment of central nervous system infections.

A quasiexperimental study of targeted normoxia in critically ill trauma patients.

BACKGROUND: Avoidance of hypoxia and hyperoxia may reduce morbidity and mortality in critically ill civilian and military trauma patients. The objective of this study was to determine if a multimodal quality improvement intervention increases adherence to a consensus-based, targeted normoxia strategy. We hypothesized that this intervention would safely improve compliance with targeted normoxia. METHODS: This is a pre/postquasiexperimental pilot study to improve adherence to normoxia, defined as a pulse oximetry (SpO2) of 90% to 96% or an arterial partial pressure oxygen (PaO2) of 60 to 100 mm Hg. We used a multimodal informatics and educational intervention guiding clinicians to safely titrate supplemental oxygen to normoxia based on SpO2 monitoring in critically ill trauma patients admitted to the surgical-trauma or neurosurgical intensive care unit within 24 hours of emergency department arrival. The primary outcome was effectiveness in delivering targeted normoxia (i.e., an increase in the probability of being in the targeted normoxia range and/or a reduction in the probability of being on a higher fraction-inspired oxygen concentration [FiO2]). RESULTS: Analysis included 371 preintervention subjects and 201 postintervention subjects. Preintervention and postintervention subjects were of similar age, race/ethnicity, and sex and had similar comorbidities and Acute Physiologic and Chronic Health Evaluation II scores. Overall, the adjusted probability of being hyperoxic while on supplemental oxygen was reduced during the postintervention period (adjusted odds ratio, 0.74; 95% confidence interval, 0.57-0.97). There was a higher probability of being on room air (FiO2, 0.21) in the postintervention period (adjusted odds ratio, 1.38; 95% confidence interval, 0.83-2.30). In addition, there was a decreased amount of patient time spent on higher levels of FiO2 (FiO2, >40%) without a concomitant increase in hypoxia. CONCLUSION: A multimodal intervention targeting normoxia in critically ill trauma patients increased normoxia and lowered the use of supplemental oxygen. A large clinical trial is needed to validate the impact of this protocol on patient-centered clinical outcomes. LEVEL OF EVIDENCE: Therapeutic/care management, level II.

Anti-neutrophil cytoplasmic antibody associated central nervous system vasculitis with brain and spinal cord subarachnoid hemorrhage: A rare case report and review of the literature.

This case report describes a 48-year old female who presented with altered mental status, lower extremity weakness, low back pain and a recent history of subjective fevers and night sweats found to have posterior parieto-occipital and spinal subarachnoid hemorrhage on imaging. Further work-up revealed vasculitic changes in the intracranial vasculature and the external carotid artery on angiography. She also demonstrated positivity for perinuclear anti-neutrophil cytoplasmic (p-ANCA) antibodies overall consistent with ANCA associated central nervous system vasculitis (AAV). The present case describes a rare and new presentation of AAV that caused both a cerebral and spinal subarachnoid hemorrhage. There has been no documentation of spinal subarachnoid hemorrhage associated with primary or secondary vasculitis in the literature. Ultimately, this case demonstrates the important finding that AAV can have spinal cord manifestations and cervical vasculature involvement along with the more classic intra-cranial vasculitis findings.

A Randomized Pharmacokinetic and Pharmacodynamic Evaluation of Every 8-Hour and 12-Hour Dosing Strategies of Vancomycin and Cefepime in Neurocritically ill Patients.

PURPOSE: Neurocritically ill patients have clinically significant alterations in pharmacokinetic parameters of renally eliminated medications that may result in subtherapeutic plasma and cerebrospinal fluid antibiotic concentrations. METHODS: We conducted a prospective randomized open-label study of adult neurocritically ill patients treated with vancomycin and cefepime. Vancomycin 15 mg/kg and cefepime 2 g were dosed at every-8- or 12-hour intervals. The primary outcomes were the achievement of pharmacodynamic (PD) targets related to time of unbound drug above minimum inhibitory concentrations (MIC) for 60% or more of the dosing interval (fT > MIC ≥ 60%) for ß-lactams and ratio of 24-hour area under the curve (AUC):MIC of 400 or greater for vancomycin. RESULTS: Twenty patients were included in the study. They were divided equally between the every-12-hour and every-8-hour dosing groups. Patients (mean age 51.8 ± 11 yrs) were primarily male (60%) and white (95%), and most had an admission diagnosis of intracranial hemorrhage (80%). Compared with the every-12-hour group, the every-8-hour vancomycin group achieved target trough concentrations (higher than 15 µg/ml) significantly more frequently at initial measurement (0% vs 80%, p<0.01) and at 7-10 days (0% vs 90%, p=0.045) and achieved PD targets more frequently at increasing MICs. Similarly, compared with every-12-hour dosing, the every-8-hour cefepime dosing strategy significantly increased PD target attainment (fT > MIC ≥ 60%) at an MIC of 8 µg/ml (20% vs 70%, p=0.02). CONCLUSIONS: This study demonstrated that more frequent dosing of vancomycin and cefepime is required to achieve optimal PD targets in adult neurocritically ill patients. The need for increased total daily doses is potentially secondary to the development of augmented renal clearance.

Intrathoracic pressure regulation therapy applied to ventilated patients for treatment of compromised cerebral perfusion from brain injury.

BACKGROUND: Reducing intrathoracic pressure in the setting of compromised cerebral perfusion due to acute brain injury has been associated with reduced intracranial pressure and enhanced cerebral perfusion pressure and blood flow in animals. Noninvasive active intrathoracic pressure regulation lowers intrathoracic pressure, increases preload, reduces the volume of venous blood and cerebral spinal fluid in the skull, and enhances cerebral blood flow. We examined the feasibility of active intrathoracic pressure regulation therapy in patients with brain injury. We hypothesized that active intrathoracic pressure regulation therapy would be associated with lowered intracranial pressure and increased cerebral perfusion pressure in these patients. METHODS: At three institutions, active intrathoracic pressure regulation therapy (CirQlator™, ZOLL) was utilized for 2 consecutive hours in five mechanically ventilated patients with brain injury. A 30-minute interval was used to collect baseline data and determine persistence of effects after device use. End-tidal carbon dioxide was controlled by respiratory rate changes during device use. The intracranial pressure, mean arterial pressure, and cerebral perfusion pressure were recorded at 5-minute intervals throughout all three periods of the protocol. Results for each interval are reported as mean and standard deviation. RESULTS: Intracranial pressure was decreased in all five patients by an average of 21% during (15 ± 4 mmHg) compared to before active intrathoracic pressure regulation (19 ± 4) (p = 0.005). This effect on intracranial pressure (15 ± 6) was still present in four of the five patients 30 minutes after therapy was discontinued (p = 0.89). As a result, cerebral perfusion pressure was 16% higher during (81 ± 10) compared to before active intrathoracic pressure regulation (70 ± 14) (p = 0.04) and this effect remained present 30 minutes after therapy was discontinued. No adverse events were reported. CONCLUSIONS: These data support the notion that active intrathoracic pressure regulation, in this limited evaluation, can successfully augment cerebral perfusion by lowering intracranial pressure and increasing mean arterial pressure in patients with mild brain injury. The measured effects were immediate on administration of the therapy and persisted to some degree after the therapy was terminated.

Levetiracetam Pharmacokinetics in a Patient with Intracranial Hemorrhage Undergoing Continuous Veno-Venous Hemofiltration.

BACKGROUND Levetiracetam is an antiepileptic drug frequently used in critically ill patients. Levetiracetam is primarily eliminated as a parent compound via glomerular filtration and requires dose adjustment in renal insufficiency, but the literature on patients receiving continuous veno-venous hemofiltration (CVVH) is scant. CASE REPORT We report the levetiracetam pharmacokinetic profile of a patient being treated with levetiracetam 1000 mg intravenously every 12 h who required continuous veno-venous hemofiltration (CVVH). The patient underwent CVVH utilizing a high-flux polyethersulfone membrane filter. The blood flow rate was 250 ml/min, and the predilution replacement therapy fluid flow rate was 2000 ml/h. After achieving presumed steady-state on levetiracetam 1000 mg q12h, serial plasma samples (pre- and post-filter) and effluent samples were drawn at 2, 4, 6, 8, and 10 h. Levetiracetam concentrations were determined utilizing LC-MS/MS. The levetiracetam maximum concentration (Cmax), minimum concentration (Cmin), half-life, area under the concentration-time curve (AUC0-12), clearance (CL), and volume of distribution (Vd) were 30.7 µg/ml, 16.1 µg/ml, 12.9 h, 272 mg·hr/L, 3.68 L/h, and 0.73 L/kg, respectively. The sieving coefficient was 1.03±0.08. CVVH represented 61.3% of the total levetiracetam clearance. The patient was maintained on CVVH for 24 consecutive days and then transitioned to intermittent hemodialysis and remained seizure-free. CONCLUSIONS CVVH is highly effective in removing levetiracetam from circulating plasma. Due to the effective removal, standard doses of levetiracetam are required to maintain adequate plasma concentrations. Dose reductions utilizing HD or estimated creatinine clearance recommendations will likely lead to subtherapeutic levels, especially if higher CVVH flow rates are used.

Intraventricular daptomycin and intravenous linezolid for the treatment of external ventricular-drain-associated ventriculitis due to vancomycin-resistant Enterococcus faecium.

OBJECTIVE: To report the successful treatment of external ventricular-drain (EVD)-associated infection due to vancomycin-resistant Enterococcus faecium (VRE) with intraventricular daptomycin and intravenous linezolid. CASE SUMMARY: A 64-year-old white male with a complicated medical history was admitted to the neurosurgical unit with Scedosporium apiospermum meningitis and hydrocephalus requiring management with a right and left EVD. On day 28, cerebrospinal fluid cultures from the right EVD grew VRE. Despite initiation of intravenous linezolid, cultures from the right EVD remained positive. Intraventricular daptomycin 5 mg daily was initiated and administered into the right EVD for 7 days. Cerebrospinal fluid was collected from EVD outputs and analyzed for daptomycin concentrations. VRE in cultures from the EVD cleared after 1 day of therapy and no adverse effects were noted. Right and left EVD daptomycin concentrations were discordant throughout therapy by at least a 3-fold difference. First-dose peak and trough daptomycin concentrations in the cerebrospinal fluid were 112.2 and 1.34 µg/mL, respectively, for the right EVD and 37.4 and 0.37 µg/mL, respectively, for the left EVD. Daptomycin accumulation was evident after 3 days of therapy. DISCUSSION: Varying doses and frequencies of intraventricular daptomycin have been reported effective for VRE ventriculitis. Intraventricular drug distribution may not be homogeneous throughout the central nervous system. Therefore, daptomycin minimum inhibitory concentration for VRE, cerebrospinal fluid communication throughout the central nervous system, EVD output, and the potential for drug accumulation should be considered when selecting a dose and frequency. CONCLUSIONS: Intraventricular daptomycin may be an option for EVD-associated VRE infections that do not respond to conventional therapy. Intraventricular daptomycin 5 mg is a reasonable initial dose in adults with VRE ventriculitis, based on our experience in this patient.

Recognizing false ischemic penumbras in CT brain perfusion studies.

Computed tomography (CT) plays a pivotal role in the diagnosis of acute stroke and in treatment decision making. CT perfusion imaging performed with intravenous iodinated contrast material allows calculation of the time to peak enhancement, mean transit time, and cerebral blood volume, important parameters for differentiating between an ischemic penumbra, which might benefit from intravascular therapy with thrombolytic agents, and infarcted tissue, which would not benefit from such therapy. Differentiation between the two entities is important because thrombolytic therapy is associated with an increased risk for intracranial hemorrhage. A finding of delay in peak enhancement or increased mean transit time in a region with normal or only slightly abnormal cerebral blood volume is suggestive of an ischemic penumbra; however, accurate interpretation of the CT perfusion parameters may be difficult in the presence of a cerebrovascular anatomic variant or physiologic condition that produces benign oligemia leading to a false appearance of penumbra. For this reason, CT perfusion parameters must be correlated with the clinical history and findings at unenhanced head CT, angiography or CT angiography, and diffusion-weighted magnetic resonance imaging. The authors identify five possible causes of false penumbras, each of which produces a different pattern at imaging: upstream flow restriction, evolution of ischemic change, vascular dysregulation, positioning of the patient's head at an angle during image acquisition, and variant anatomy in the circle of Willis. Familiarity with the imaging patterns and causes of false penumbras may increase the radiologist's confidence in diagnosis and help avoid costly errors in treatment.