A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess ...whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study.
Randomized prospective clinical trial.
Ten ICUs in the United States.
One hundred nineteen severe traumatic brain injury patients.
Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended.
A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy.
Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.
Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity ...of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244,
ClinicalTrials.gov
).
Using data from the 2000-2004 US Healthcare Cost and Utilization Project National Inpatient Sample, we found that total hospital admissions for skin and soft tissue infections increased by 29% during ...2000-2004; admissions for pneumonia were largely unchanged. These results are consistent with recent reported increases in community-associated methicillin-resistant Staphylococcus aureus infections.
Background. Reports have found a link between vancomycin treatment failure in methicillin-resistant Staphyloccocus aureus (MRSA) bloodstream infections (BSIs) and higher vancomycin minimum inhibitory ...concentrations (MICs), despite MICs being below the susceptibility breakpoint of 2 µg/mL. Consensus guidelines recommend considering use of alternative agents for infections involving a higher vancomycin MIC, despite few data to support this approach. Methods. This retrospective case-control study evaluated the effectiveness and safety of vancomycin, compared with that of daptomycin, in the treatment of MRSA BSIs with a high vancomycin MIC (ie, > 1 µg/mL). Results. A total of 118 vancomycin-treated subjects were compared with 59 daptomycin-treated subjects. Clinical failure, defined compositely as mortality, microbiologie failure, and/or recurrence of infection, was numerically lower in daptomycin-treated subjects (31% vs 17%; P = .084) and was mainly driven by a lower incidence of mortality in the daptomycin group (20% vs 9%; P = .046). Factors independently associated with clinical failure included acute renal failure (odds ratio OR, 3.91 95% confidence interval {CI}, 1.05-14.56) and vancomycin treatment group (OR, 3.13 95%, CI, 1.00-9.76). Right-sided endocarditis was independently associated with clinical success (OR, 0.07 95% CI, .01-. 83). A comparison of 60-day mortality between vancomycin-and daptomycin-treated subjects found a higher probability of survival in the daptomycin-treated group (P = .022). Conclusions. The results demonstrated that daptomycin was associated with a better outcome compared with vancomycin for the treatment of BSIs due to MRSA with higher vancomycin MICs. These findings support the recommendations of recent guidelines, which suggest consideration of the switch to alternative agents when the isolate has a high vancomycin MIC or when patients are not improving during receipt of therapy.
Assess the prevalence of brain tissue hypoxia in patients with severe traumatic brain injuries (TBI), and to characterize the relationship between brain tissue hypoxia and functional outcome.
...Retrospective review of severe TBI patients.
Intensive care unit of a level I trauma center.
Twenty-seven patients with severe TBI requiring intracranial pressure (ICP) monitoring. Median age was 22 yrs, and a majority (63%) had traumatic subarachnoid hemorrhage.
Hourly assessments of ICP, brain tissue oxygen, mean arterial pressure, fraction of inspired oxygen (FiO2), partial pressure of arterial carbon dioxide (PaCO2), and hemoglobin concentration (hemoglobin) were recorded. Outcome was assessed 6-9 months postinjury.
Mean (SD) ICP and BTpO2 were 13.7 (6.6) cm H2O and 30.8 (13.6) mm Hg. A total of 13.5% (379) of the BTpO2 values recorded were < 20 mm Hg, only 86 of which were associated with ICP > or = 20 cm H2O. This prevalence was comparable with episodes of ICP elevations above 20 cm H2O (14.1%, 397). Hypoxic episodes were more common when cerebral perfusion pressure was below 60 mm Hg (relative risk = 3.0, p < 0.0001). We did not find an association in hypoxic risk and hemoglobin in the range of 7-12 g/dL or PaCO2 in the range of 25-40 mm Hg. Subjects with hourly episodes (epochs) of hypoxia > 20% of the time had poorer scores on outcome measures compared with those with fewer hypoxic epochs.
Hypoxic episodes are common after severe TBI, and most are independent of ICP elevations. Most episodes of hypoxia occur while cerebral perfusion pressure and mean arterial pressure are within the accepted target range. There is no clear association between PaCO2 and hemoglobin with BTpO2. The young age and high prevalence of traumatic subarachnoid hemorrhage in this cohort may limit its generalizability. Increased frequency of hypoxic episodes is associated with poor functional outcome.
Catheter-related bloodstream infections are a significant source of morbidity and mortality in the end-stage renal disease population. Although alternative accesses to undergoing renal replacement ...therapy exist, many patients begin hemodialysis with a dialysis catheter due to logistic and physiologic factors involved in arteriovenous fistula creation and maturation. Colonization of catheters via skin flora leads to the production of biofilm, which acts as a reservoir for virulent bacteria. Preventative therapies center on appropriate catheter maintenance, infection control measures, and early removal of devices as patients transition to other access. Despite best efforts, when conservative measures fail to prevent infections in a high-risk population, antimicrobial lock therapy should be considered as an option to combat catheter-related bloodstream infections.
Traumatic cerebral vascular injury (TCVI) is a frequent, but under-recognized, endophenotype of traumatic brain injury (TBI). It likely contributes to functional deficits after TBI and TBI-related ...chronic disability, and represents an attractive target for targeted therapeutic interventions. The aim of this prospective study is to assess microvascular injury/dysfunction in chronic TBI by measuring cerebral vascular reactivity (CVR) by 2 methods, functional magnetic resonance imaging (fMRI) and functional Near InfraRed Spectroscopy (fNIRS) imaging, as each has attractive features relevant to clinical utility.
42 subjects (27 chronic TBI, 15 age- and gender-matched non-TBI volunteers) were enrolled and underwent outpatient CVR testing by 2 methods, MRI-BOLD and fNIRS, each with hypercapnia challenge, a neuropsychological testing battery, and symptom survey questionnaires.
Chronic TBI subjects showed a significant reduction in global CVR compared to HC (p < 0.0001). Mean CVR measures by fMRI were 0.225 ± 0.014 and 0.183 ± 0.026 %BOLD/mmHg for non-TBI and TBI subjects respectively and 12.3 ± 1.8 and 9.2 ± 1.7 mM/mmHg by fNIRS for non-TBI versus TBI subjects respectively. Global CVR measured by fNIRS imaging correlates with results by MRI-BOLD (R = 0.5). Focal CVR deficits seen on CVR maps by fMRI are also observed in the same areas by fNIRS in the frontal regions.
Global CVR is significantly lower in chronic TBI patients and is reliably measured by both fMRI and fNIRS, the former with better spatial and the latter with better temporal resolution. Both methods show promise as non-invasive measures of CVR function and microvascular integrity after TBI.
Diffuse traumatic axonal injury (TAI) is a type of traumatic brain injury (TBI) characterized predominantly by white matter damage. While TAI is associated with cerebral atrophy, the relationship ...between gray matter volumes and TAI of afferent or efferent axonal pathways remains unknown. Moreover, it is unclear if deficits in cognition are associated with post-traumatic brain volumes in particular regions. The goal of this study was to determine the relationship between markers of TAI and volumes of cortical and subcortical structures, while also assessing the relationship between cognitive outcomes and regional brain volumes. High-resolution magnetic resonance imaging scans were performed in 24 patients with TAI within 1 week of injury and were repeated 8 months later. Diffusion tensor imaging (DTI) tractography was used to reconstruct prominent white matter tracts and calculate their fractional anisotropy (FA) and mean diffusivity (MD) values. Regional brain volumes were computed using semi-automated morphometric analysis. Pearson's correlation coefficients were used to assess associations between brain volumes, white matter integrity (i.e., FA and MD), and neuropsychological outcomes. Post-traumatic volumes of many gray matter structures were associated with chronic damage to related white matter tracts, and less strongly associated with measures of white matter integrity in the acute scans. For example, left and right hippocampal volumes correlated with FA in the fornix body (r = 0.600, p = 0.001; r = 0.714, p < 0.001, respectively). In addition, regional brain volumes were associated with deficits in corresponding neuropsychological domains. Our results suggest that TAI may be a primary mechanism of post-traumatic atrophy, and provide support for regional morphometry as a biomarker for cognitive outcome after injury.
Infection is the second leading cause of death in hemodialysis patients. Catheter-related bloodstream infection and infection-related mortality have not improved in this population over the past two ...decades. This study evaluated the impact of a prophylactic antibiotic lock solution on the incidence of catheter-related bloodstream infection and mortality.
This prospective, multicenter, observational cohort study compared the effectiveness of two catheter locking solutions (gentamicin/citrate versus heparin) in 555 hemodialysis patients dialyzing with a tunneled cuffed catheter between 2008 and 2011. The groups were not mutually exclusive. Rates of catheter-related bloodstream infection and mortality hazards were compared between groups.
The study population (n=555 and 1350 catheters) had a median age of 62 years (interquartile range=41-83 years), with 50% men and 71% black. There were 427 patients evaluable in the heparin period (84,326 days) and 322 patients evaluable in the antibiotic lock period (71,192 days). Catheter-related bloodstream infection in the antibiotic lock period (0.45/1000 catheter days) was 73% lower than the heparin period (1.68/1000 catheter days; P=0.001). Antibiotic lock use was associated with a decreased risk of catheter-related bloodstream infection compared with heparin (risk ratio, 0.23; 95% confidence interval, 0.13 to 0.38 after multivariate adjustment). Cox proportional hazards modeling found that antibiotic lock was associated with a reduction in mortality (hazard ratio, 0.36; 95% confidence interval, 0.22 to 0.58 in unadjusted analyses; hazard ratio, 0.32; 95% confidence interval, 0.14 to 0.75 after multivariate adjustment). The rate of gentamicin-resistant organisms decreased (0.40/1000 person-years to 0.22/1000 person-years) in the antibiotic lock period (P=0.01).
The results of this study show that the use of a prophylactic, gentamicin/citrate lock was associated with a substantial reduction in catheter-related bloodstream infection and is the first to report a survival advantage of antibiotic lock in a population at high risk of infection-related morbidity and mortality.
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