Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital

Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies

Noninvasive ventilation in acute cardiogenic pulmonary edema

BACKGROUND Noninvasive ventilation (continuous positive airway pressure [CPAP] or noninvasive intermittent positive-pressure ventilation [NIPPV]) appears to be of benefit in the immediate treatment of patients with acute cardiogenic pulmonary edema and may reduce mortality. We conducted a study to determine whether non invasive ventilation reduces mortality and whether there are important differences in outcome associated with the method of treatment (CPAP or NIPPV). METHODS In a multicenter, open, prospective, randomized, controlled trial, patients were assigned to standard oxygen therapy, CPAP (5 to 15 cm of water), or NIPPV (inspiratory pressure, 8 to 20 cm of water; expiratory pressure, 4 to 10 cm of water). The primary end point for the comparison between noninvasive ventilation and standard oxygen therapy was death with in 7 days after the initiation of treatment, and the primary end point for the comparison between NIPPV and CPAP was death or intubation within 7 days. RESULT A total of 1069 patients (mean [±SD] age, 77.7±9.7 years; female sex, 56.9%) were assigned to standard oxygen therapy (367 patients), CPAP (346 patients), or NIPPV (356 patients). There was no significant difference in 7-day mortality between patients receiving standard oxygen therapy (9.8%) and those undergoing noninvasive ventilation (9.5%, P = 0.87). There was no significant difference in the combined end point of death or intubation within 7 days between the two groups of patients undergoing noninvasive ventilation (11.7% for CPAP and 11.1% for NIPPV, P = 0.81). As compared with standard oxygen therapy, noninvasive ventilation was associated with greater mean improvements at 1 hour after the beginning of treatment in patient-reported dyspnea (treatment difference, 0.7 on a visual-analogue scale ranging from 1 to 10; 95% confidence interval [CI], 0.2 to 1.3; P = 0.008), heart rate (treatment difference, 4 beats per minute; 95% CI, 1 to 6; P = 0.004), acidosis (treatment difference, pH 0.03; 95% CI, 0.02 to 0.04;

The development of a simple risk score to predict early outcome in severe acute acidotic cardiogenic pulmonary edema the 3CPO score

Background-Acute cardiogenic pulmonary edema is a common medical emergency with high early mortality. Initial clinical assessment would benefit from accurate mortality prediction. We aimed to develop a simple clinical score based on presenting characteristics that would predict 7-day mortality in patients with acute cardiogenic pulmonary edema. Methods and Results-We used data from patients recruited to the 3CPO trial (a pragmatic multicenter trial comparing continuous positive airway pressure, noninvasive positive pressure ventilation, and standard oxygen therapy in emergency department patients with acute cardiogenic pulmonary edema) to investigate the association between baseline characteristics and 7-day mortality. Factors associated with mortality (

Mechanistic biomarkers provide early and sensitive detection of paracetamol-induced acute liver injury at first presentation to hospital

Background and Aims: Paracetamol overdose is a common reason for admission to hospital and the most frequent cause of acute liver failure in the western world. Early identification of liver injury would facilitate patient risk stratification. We investigated the potential of novel biomarkers - which demonstrate either enhanced liver expression or have been linked to the mechanism of toxicity - to identify patients with paracetamol-induced acute liver injury at first presentation to hospital when current liver injury markers are still normal. Methods: In plasma samples taken from patients at first presentation to hospital following paracetamol overdose, we measured the following biomarkers: microRNA-122 (miR-122; high liver specificity), High Mobility Group Box-1 (HMGB1; marker of necrosis), full length and caspase-cleaved Keratin-18 (K18; markers of necrosis and apoptosis, respectively) and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic (ROC) curve analysis was used to compare the sensitivity of each marker to report liver injury versus standard liver function test parameters. Results: In all patients (n = 129); the biomarkers (miR-122, HMGB1, necrosis K18, apoptosis K18 and GLDH) at first presentation all correlated with peak hospital stay ALT/INR (all p < 0.0001). In patients with normal ALT/INR at presentation, miR-122, HMGB1 and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy (miR-122, HMGB1 and necrosis K-18: ROC curve AUC values (sensitivity at 90% specificity); 0.93 (0.83), 0.97 (0.91) and 0.94 (0.90), respectively. All p < 0.0001). Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis keratin-18 identify subsequent development of acute liver injury in patients on admission to hospital, soon after paracetamol overdose, and in patients with ALTs in the normal range. The clinical development of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of acute liver injury and in the design and execution of clinical trials for new treatment strategies that aim to refine the management of this common hepatotoxin

Association of baseline hematoma and edema volumes with one-year outcome and long-term survival after spontaneous intracerebral hemorrhage: A community-based inception cohort study

Background Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. Aims In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. Methods We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Results Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42); p = 0.0004). Conclusion Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Data access statement Anonymized summary data may be requested from the corresponding author. </jats:sec