Background
Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical ...data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty.
Aim
To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities.
Methods
A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants.
Results
Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence.
Conclusion
The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.
Managing traumatic brain injury (TBI) patients with a cerebral perfusion pressure (CPP) near to the cerebral autoregulation (CA)-guided "optimal" CPP (CPPopt) value is associated with improved ...outcome and might be useful to individualize care, but has never been prospectively evaluated. This study evaluated the feasibility and safety of CA-guided CPP management in TBI patients requiring intracranial pressure monitoring and therapy (TBIicp patients). The CPPopt Guided Therapy: Assessment of Target Effectiveness (COGiTATE) parallel two-arm feasibility trial took place in four tertiary centers. TBIicp patients were randomized to either the Brain Trauma Foundation (BTF) guideline CPP target range (control group) or to the individualized CA-guided CPP targets (intervention group). CPP targets were guided by six times daily software-based alerts for up to 5 days. The primary feasibility end-point was the percentage of time with CPP concordant (±5 mm Hg) with the set CPP targets. The main secondary safety end-point was an increase in therapeutic intensity level (TIL) between the control and intervention group. Twenty-eight patients were randomized to the control and 32 patients to the intervention group. CPP in the intervention group was in the target range for 46.5% (interquartile range, 41.2-58) of the monitored time, significantly higher than the feasibility target specified in the published protocol (36%;
< 0.001). There were no significant differences between groups for TIL or for other safety end-points. Conclusively, targeting an individual and dynamic CA-guided CPP is feasible and safe in TBIicp patients. This encourages a prospective trial powered for clinical outcomes.
The initiation of hemodialysis is associated with an accelerated decline of cognitive function and an increased incidence of cerebrovascular accidents and white matter lesions. Investigators have ...hypothesized that the repetitive circulatory stress of hemodialysis induces ischemic cerebral injury, but the mechanism is unclear. We studied the acute effect of conventional hemodialysis on cerebral blood flow (CBF), measured by
OH
O positron emission tomography-computed tomography (PET-CT). During a single hemodialysis session, three
OH
O PET-CT scans were performed: before, early after the start of, and at the end of hemodialysis. We used linear mixed models to study global and regional CBF change during hemodialysis. Twelve patients aged ≥65 years (five women, seven men), with a median dialysis vintage of 46 months, completed the study. Mean (±SD) arterial BP declined from 101±11 mm Hg before hemodialysis to 93±17 mm Hg at the end of hemodialysis. From before the start to the end of hemodialysis, global CBF declined significantly by 10%±15%, from a mean of 34.5 to 30.5 ml/100g per minute (difference, -4.1 ml/100 g per minute; 95% confidence interval, -7.3 to -0.9 ml/100 g per minute;
=0.03). CBF decline (20%) was symptomatic in one patient. Regional CBF declined in all volumes of interest, including the frontal, parietal, temporal, and occipital lobes; cerebellum; and thalamus. Higher tympanic temperature, ultrafiltration volume, ultrafiltration rate, and pH significantly associated with lower CBF. Thus, conventional hemodialysis induces a significant reduction in global and regional CBF in elderly patients. Repetitive intradialytic decreases in CBF may be one mechanism by which hemodialysis induces cerebral ischemic injury.
The majority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are admitted to the Intensive Care Unit (ICU) for mechanical ventilation. The role of multi-organ ...failure during ICU admission as driver for outcome remains to be investigated yet.
Prospective cohort of mechanically ventilated critically ill with SARS-CoV-2 infection.
94 participants of the MaastrICCht cohort (21% women) had a median length of stay of 16 days (maximum of 77). After division into survivors (n = 59) and non-survivors (n = 35), we analysed 1555 serial SOFA scores using linear mixed-effects models.
Survivors improved one SOFA score point more per 5 days (95% CI: 4–8) than non-survivors. Adjustment for age, sex, and chronic lung, renal and liver disease, body-mass index, diabetes mellitus, cardiovascular risk factors, and Acute Physiology and Chronic Health Evaluation II score did not change this result. This association was stronger for women than men (P-interaction = 0.043).
The decrease in SOFA score associated with survival suggests multi-organ failure involvement during mechanical ventilation in patients with SARS-CoV-2. Surviving women appeared to improve faster than surviving men. Serial SOFA scores may unravel an unfavourable trajectory and guide decisions in mechanically ventilated patients with SARS-CoV-2.
RAS pathway mutations have been linked to relapse and chemotherapy resistance in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, comprehensive data on the frequency and ...prognostic value of subclonal mutations in well-defined subgroups using highly sensitive and quantitative methods are lacking. Targeted deep sequencing of 13 RAS pathway genes was performed in 461 pediatric BCP-ALL cases at initial diagnosis and in 19 diagnosis-relapse pairs. Mutations were present in 44.2% of patients, with 24.1% carrying a clonal mutation. Mutation frequencies were highest in high hyperdiploid, infant t(4;11)-rearranged, BCR-ABL1-like and B-other cases (50-70%), whereas mutations were less frequent in ETV6-RUNX1-rearranged, and rare in TCF3-PBX1- and BCR-ABL1-rearranged cases (27-4%). RAS pathway-mutated cells were more resistant to prednisolone and vincristine ex vivo. Clonal, but not subclonal, mutations were linked to unfavorable outcome in standard- and high-risk-treated patients. At relapse, most RAS pathway mutations were clonal (9 of 10). RAS mutant cells were sensitive to the MEK inhibitor trametinib ex vivo, and trametinib sensitized resistant cells to prednisolone. We conclude that RAS pathway mutations are frequent, and that clonal, but not subclonal, mutations are associated with unfavorable risk parameters in newly diagnosed pediatric BCP-ALL. These mutations may designate patients eligible for MEK inhibitor treatment.
Objectives This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH). Background Ambrisentan is an oral, once-daily ...endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH. Methods In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data. Results After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3× the upper limit of normal was ∼2% per year; most of these events were mild and did not lead to discontinuation of drug. Conclusions Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786 )
Still 20% of pediatric acute lymphoblastic leukemia (ALL) patients relapse on or after current treatment strategies. Treatment failure is associated with resistance to prednisolone. We aimed to find ...new druggable targets that modulate prednisolone resistance. We generated microarray gene expression profiles of 256 pediatric ALL patient samples and identified a 3.4-fold increase in epithelial membrane protein 1 (EMP1) expression in in vitro prednisolone-resistant compared with -sensitive patients (P=0.003). EMP1 silencing in six precursor-B ALL (BCP-ALL) and T-ALL cell lines induced apoptosis and cell-cycle arrest leading to 84.1±4.5% reduction in survival compared with non-silencing control transduced cells (non-silencing control short hairpin, shNSC) (P=0.014). Moreover, EMP1 silencing sensitized to prednisolone up to 18.8-fold (P<0.001). EMP1 silencing also abrogated migration and adhesion to mesenchymal stromal cells (MSCs) by 78.3±9.0 and 29.3±4.1% compared with shNSC (P<0.05). We discovered that EMP1 contributes to MSC-mediated prednisolone resistance. Pathway analysis indicated that EMP1 signals through the Src kinase family. EMP1-high BCP-ALL patients showed a poorer 5-year event-free survival compared with EMP1-low patients (77±2 vs. 89±2%, P=0.003). Multivariate analysis taking along white blood cell count, age, prednisolone resistance and subtype identified EMP1 as an independent predictor for poor outcome in BCP-ALL (P=0.004, hazard ratio: 2.36 (1.31-4.25). This study provides preclinical evidence that EMP1 is an interesting candidate for drug development to optimize treatment of BCP-ALL.
Impairments in cerebral autoregulation (CA) are related to poor clinical outcome. Near infrared spectroscopy (NIRS) is a non-invasive technique applied to estimate CA. Our general purpose was to ...study the clinical feasibility of a previously published ‘NIRS-only’ CA methodology in a critically ill intensive care unit (ICU) population and determine its relationship with clinical outcome. Bilateral NIRS measurements were performed for 1–2 h. Data segments of ten-minutes were used to calculate transfer function analyses (TFA) CA estimates between high frequency oxyhemoglobin (oxyHb) and deoxyhemoglobin (deoxyHb) signals. The phase shift was corrected for serial time shifts. Criteria were defined to select TFA phase plot segments (segments) with ‘high-pass filter’ characteristics. In 54 patients, 490 out of 729 segments were automatically selected (67%). In 34 primary neurology patients the median (q1–q3) low frequency (LF) phase shift was higher in 19 survivors compared to 15 non-survivors (13° (6.3–35) versus 0.83° (−2.8–13), p = 0.0167). CA estimation using the NIRS-only methodology seems feasible in an ICU population using segment selection for more robust and consistent CA estimations. The ‘NIRS-only’ methodology needs further validation, but has the advantage of being non-invasive without the need for arterial blood pressure monitoring.
Abstract Dynamic cerebral autoregulation (dCA) estimates require mean arterial blood pressure (MABP) fluctuations of sufficient amplitude. Current methods to induce fluctuations are not easily ...implemented or require patient cooperation. In search of an alternative method, we evaluated if MABP fluctuations could be increased by passive cyclic leg raising (LR) and tested if reproducibility and variability of dCA parameters could be improved. Middle cerebral artery cerebral blood flow velocity (CBFV), MABP and end tidal CO2 (PetCO2 ) were obtained at rest and during LR at 0.1 Hz in 16 healthy subjects. The MABP–CBFV phase difference and gain were determined at 0.1 Hz and in the low frequency (LF) range (0.06–0.14 Hz). In addition the autoregulation index (ARI) was calculated. The LR maneuver increased the power of MABP fluctuations at 0.1 Hz and across the LF range. Despite a clear correlation between both phase and gain reproducibility and MABP variability in the rest condition, only the reproducibility of gain increased significantly with the maneuver. During the maneuver patients were breathing faster and more irregularly, accompanied by increased PetCO2 fluctuations and increased coherence between PetCO2 and CBFV. Multiple regression analysis showed that these concomitant changes were negatively correlated with the MABP–CBFV phase difference at 0.1 Hz Variability was not reduced by LR for any of the dCA parameters. The clinical utility of cyclic passive leg raising is limited because of the concomitant changes in PetCO2 . This limits reproducibility of the most important dCA parameters. Future research on reproducibility and variability of dCA parameters should incorporate PetCO2 variability or find methods to keep PetCO2 levels constant.
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