vCSF Danger-associated Molecular Patterns After Traumatic and Nontraumatic Acute Brain Injury: A Prospective Study.

BACKGROUND: Danger-associated molecular patterns (DAMPs) may be implicated in the pathophysiological pathways associated with an unfavorable outcome after acute brain injury (ABI). METHODS: We collected samples of ventricular cerebrospinal fluid (vCSF) for 5 days in 50 consecutive patients at risk of intracranial hypertension after traumatic and nontraumatic ABI. Differences in vCSF protein expression over time were evaluated using linear models and selected for functional network analysis using the PANTHER and STRING databases. The primary exposure of interest was the type of brain injury (traumatic vs. nontraumatic), and the primary outcome was the vCSF expression of DAMPs. Secondary exposures of interest included the occurrence of intracranial pressure ≥20 or ≥ 30 mm Hg during the 5 days post-ABI, intensive care unit (ICU) mortality, and neurological outcome (assessed using the Glasgow Outcome Score) at 3 months post-ICU discharge. Secondary outcomes included associations of these exposures with the vCSF expression of DAMPs. RESULTS: A network of 6 DAMPs (DAMP_trauma; protein-protein interaction [PPI] P=0.04) was differentially expressed in patients with ABI of traumatic origin compared with those with nontraumatic ABI. ABI patients with intracranial pressure ≥30 mm Hg differentially expressed a set of 38 DAMPS (DAMP_ICP30; PPI P< 0.001). Proteins in DAMP_ICP30 are involved in cellular proteolysis, complement pathway activation, and post-translational modifications. There were no relationships between DAMP expression and ICU mortality or unfavorable versus favorable outcomes. CONCLUSIONS: Specific patterns of vCSF DAMP expression differentiated between traumatic and nontraumatic types of ABI and were associated with increased episodes of severe intracranial hypertension.

The Cerebrospinal Fluid Proteomic Response to Traumatic and Nontraumatic Acute Brain Injury: A Prospective Study.

BACKGROUND: Quantitative analysis of ventricular cerebrospinal fluid (vCSF) proteins following acute brain injury (ABI) may help identify pathophysiological pathways and potential biomarkers that can predict unfavorable outcome. METHODS: In this prospective proteomic analysis study, consecutive patients with severe ABI expected to require intraventricular catheterization for intracranial pressure (ICP) monitoring for at least 5 days and patients without ABI admitted for elective clipping of an unruptured cerebral aneurysm were included. vCSF samples were collected within the first 24 h after ABI and ventriculostomy insertion and then every 24 h for 5 days. In patients without ABI, a single vCSF sample was collected at the time of elective clipping. Data-independent acquisition and sequential window acquisition of all theoretical spectra (SWATH) mass spectrometry were used to compare differences in protein expression in patients with ABI and patients without ABI and in patients with traumatic and nontraumatic ABI. Differences in protein expression according to different ICP values, intensive care unit outcome, subarachnoid hemorrhage (SAH) versus traumatic brain injury (TBI), and good versus poor 3-month functional status (assessed by using the Glasgow Outcome Scale) were also evaluated. vCSF proteins with significant differences between groups were compared by using linear models and selected for gene ontology analysis using R Language and the Panther database. RESULTS: We included 50 patients with ABI (SAH n = 23, TBI n = 15, intracranial hemorrhage n = 6, ischemic stroke n = 3, others n = 3) and 12 patients without ABI. There were significant differences in the expression of 255 proteins between patients with and without ABI (p < 0.01). There were intraday and interday differences in expression of seven proteins related to increased inflammation, apoptosis, oxidative stress, and cellular response to hypoxia and injury. Among these, glial fibrillary acidic protein expression was higher in patients with ABI with severe intracranial hypertension (ICH) (ICP ≥ 30 mm Hg) or death compared to those without (log 2 fold change: + 2.4; p < 0.001), suggesting extensive primary astroglial injury or death. There were differences in the expression of 96 proteins between patients with traumatic and nontraumatic ABI (p < 0.05); intraday and interday differences were observed for six proteins related to structural damage, complement activation, and cholesterol metabolism. Thirty-nine vCSF proteins were associated with an increased risk of severe ICH (ICP ≥ 30 mm Hg) in patients with traumatic compared with nontraumatic ABI (p < 0.05). No significant differences were found in protein expression between patients with SAH versus TBI or between those with good versus poor 3-month Glasgow Outcome Scale score. CONCLUSIONS: Dysregulated vCSF protein expression after ABI may be associated with an increased risk of severe ICH and death.

Association of cerebrospinal fluid protein biomarkers with outcomes in patients with traumatic and non-traumatic acute brain injury: systematic review of the literature.

BACKGROUND: Acute brain injuries are associated with high mortality rates and poor long-term functional outcomes. Measurement of cerebrospinal fluid (CSF) biomarkers in patients with acute brain injuries may help elucidate some of the pathophysiological pathways involved in the prognosis of these patients. METHODS: We performed a systematic search and descriptive review using the MEDLINE database and the PubMed interface from inception up to June 29, 2021, to retrieve observational studies in which the relationship between CSF concentrations of protein biomarkers and neurological outcomes was reported in patients with acute brain injury [traumatic brain injury, subarachnoid hemorrhage, acute ischemic stroke, status epilepticus or post-cardiac arrest]. We classified the studies according to whether or not biomarker concentrations were associated with neurological outcomes. The methodological quality of the studies was evaluated using the Newcastle-Ottawa quality assessment scale. RESULTS: Of the 39 studies that met our criteria, 30 reported that the biomarker concentration was associated with neurological outcome and 9 reported no association. In TBI, increased extracellular concentrations of biomarkers related to neuronal cytoskeletal disruption, apoptosis and inflammation were associated with the severity of acute brain injury, early mortality and worse long-term functional outcome. Reduced concentrations of protein biomarkers related to impaired redox function were associated with increased risk of neurological deficit. In non-traumatic acute brain injury, concentrations of CSF protein biomarkers related to dysregulated inflammation and apoptosis were associated with a greater risk of vasospasm and a larger volume of brain ischemia. There was a high risk of bias across the studies. CONCLUSION: In patients with acute brain injury, altered CSF concentrations of protein biomarkers related to cytoskeletal damage, inflammation, apoptosis and oxidative stress may be predictive of worse neurological outcomes.

Which Multicenter Randomized Controlled Trials in Critical Care Medicine Have Shown Reduced Mortality? A Systematic Review.

OBJECTIVES: To determine which multicenter randomized controlled trials in critically ill patients have shown that the study intervention was associated with a statistically significant reduction in mortality. Our analysis provides an update to a report published 10 years ago. DATA SOURCES: MEDLINE database and PubMed interface from inception until April 30, 2019. STUDY SELECTION: All adult multicenter randomized controlled trials that evaluated the effects of any intervention or monitoring system in critically ill patients and reported mortality as a primary or secondary outcome were included. DATA EXTRACTION: Numbers of centers and patients, type of intervention, reported mortality outcome, and rate and level of significance were extracted into predefined tables. Included randomized controlled trials were classified as reporting reduced, increased, or no effect of the intervention on mortality. Methodologic quality of trials was evaluated using the updated Consolidated Standards of Reporting Trials statement. DATA SYNTHESIS: A total of 212 trials met the inclusion criteria: 27 (13%) reported a significant reduction in mortality, 16 (7%) an increase in mortality, and 170 (80%) no difference in mortality (one study was reported in 2 groups). Of the 27 trials reporting reduced mortality, six had assessed interventions likely to decrease ventilator-induced lung injury, including low tidal volume, prone position, and neuromuscular blockers, demonstrating the negative effects of mechanical ventilation strategies or improved process of care rather than positive effects of new therapies. Seven of the 27 trials reported beneficial effects of noninvasive ventilation. Results from some positive randomized controlled trials, for example, studies of recombinant activated protein C, talactoferrin, interleukin-1 receptor antagonist in sepsis, and muscle relaxants in severe acute respiratory distress syndrome were not replicated in subsequent randomized controlled trials. Other interventions, for example, gastric tonometry, have been abandoned. CONCLUSIONS: A systematic literature search provided no conclusive evidence of any pharmacologic intervention that has consistently reduced mortality in critically ill patients. Strategies associated with improved or noninvasive mechanical ventilation were associated with reduced mortality.

Is There a Role for Enterohormones in the Gastroparesis of Critically Ill Patients?

OBJECTIVES: Delayed gastric emptying occurs in critically ill patients and impairs the delivery, digestion, and absorption of enteral feeding. A pathophysiologic role of the enterohormones peptide YY and ghrelin is supported by preclinical data. To compare the circulating plasma levels of peptide YY and ghrelin in control subjects and in critically ill patients, during feeding and fasting, and to search for a correlation with gastric emptying. DESIGN: A prospective observational trial. SETTINGS: Mixed ICU of an academic hospital. SUBJECTS: Healthy volunteers and patients expected to stay in ICU for at least 3 days in whom enteral nutrition was indicated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma peptide YY and ghrelin (enzyme-linked immunosorbent assay) were measured once in 10 fasting volunteers (controls) and daily from admission until day 5 of the ICU stay in 30 critically ill patients (median [interquartile range] age 63 [57-67] yr, median [interquartile range] Acute Physiology and Chronic Health Evaluation II score 21 [14-24]). Eight patients could not be fed (fasting group). In fed patients, 13 never had a gastric residual volume higher than 250 mL (low gastric residual volume group), in contrast to the high gastric residual volume group (n = 9). The plasma levels of peptide YY did not differ between patients (6.4 [0-18.1] pg/mL) and controls (4.8 [0.3-17.7] pg/mL). Ghrelin levels were lower in patients than in control (213 [54.4-522.7] vs 1,435 [1,321.9-1,869.3] pg/mL; p < 0.05). Plasma peptide YY or ghrelin did not differ between fasting and fed patients or between the high and low gastric residual volume groups. CONCLUSIONS: In critically ill patients, plasma concentration of ghrelin significantly differs from that of controls, irrespective of the feeding status. No correlation was found between the temporal profile of ghrelin or peptide YY plasma concentration with bedside functional assessment of gastric emptying.

Treatment of intraparenchymal hypertension with hyperosmotic therapy: hypertonic saline 7.45% vs. mannitol 20.

BACKGROUND: There is controversy about the superiority of hypertonic saline (HS) over mannitol (M) to treat intracranial hypertension (ICHT). We aim to compare the effects of HS 7.45% vs. M 20% on systemic hemodynamics, intracranial pressure (ICP) and brain regional metabolism or oxygenation during experimental ICHT. METHODS: In 16 sedated and mechanically-ventilated pigs, ICHT was obtained by inflation of a balloon catheter inserted in the right frontal lobe. Ventilation was set to maintain normoxia and normocapnia. Mean arterial pressure was maintained above 80 mmHg by IV isotonic fluids. Animals were randomized to receive a 30-minute IV load of 255 mOsm/dose of either HS 7.45% (N.=7) or M 20% (N.=7). Brain oxygen tension (PbO2) was measured hourly by a parenchymal Clark electrode and cerebral lactate/pyruvate ratio (LPR) was assessed using brain microdialysis. A linear mixed model was used to analyze the time course of considered variables from baseline to 180 minutes after infusion. RESULTS: There was no significant difference in systemic hemodynamics between the two groups over the study period. HS 7.45% administration maintained a lower ICP and a higher cerebral perfusion pressure at 180 minutes, but with no significant difference in PbO2 or LPR. CONCLUSIONS: In this model of ICHT, only small differences were found in maintaining a better cerebral perfusion using HS 7.45% compared to M 20% in the early phase of therapy. These differences were not dependent on changes in systemic hemodynamics and did not result in significant differences in brain regional oxygenation or metabolism.

Modulation of Dietary Lipid Composition During Acute Respiratory Distress Syndrome: Systematic Review and Meta-Analysis.

BACKGROUND: Pharmaconutrition including omega-3 and competitive analogs of omega-6 fatty acids has been used to modulate the inflammatory response during acute respiratory distress syndrome (ARDS). The clinical benefit of this approach when assessed in prospective randomized clinical trials has been inconsistent. We tried to assess the reasons for the conflicting results, including the possible influence of the composition of the control solution. METHODS: We collected data from studies listed in PubMed, Ovid, the Cochrane Database of Systematic Reviews, Embase, the U.S. National Institute of Health database, and the ARDSnet database up to March 2013. We included all trials that evaluated effects of enteral pharmaconutrition vs a control solution on mortality, ventilator-free days, length of stay (LOS) in the intensive care unit (ICU), and ICU-free days. A sensitivity analysis was carried out to study the influence of the lipid content of the control solution. RESULTS: We found 7 eligible studies (802 patients; 405 randomized to pharmaconutrition). The aggregated results showed no overall effect on mortality (risk ratio [RR] = 0.83 [0.55-1.25], P = .37), but there was a mortality benefit when only studies in which pharmaconutrition was compared to a lipid-rich control solution were considered (RR = 0.57 [0.41-0.78], P < .001). ICU LOS was shorter in patients randomized to pharmaconutrition (RR = 0.5 [0.85-0.16]). CONCLUSION: Use of enteral pharmaconutrition in patients with ARDS was associated with decreased mortality only when the comparator solution contained a greater amount of lipid than is currently recommended. Hence, there is insufficient evidence to support the use of enteral pharmaconutrition in ARDS.