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Introduction Valproic acid (VPA) is used for the treatment of seizures and other conditions. Overdose present as central nervous system and respiratory depression, metabolic acidosis, and hyperammonemia. Management is mainly supportive, including activated charcoal, L-carnitine, and hemodialysis. Multiple reports have demonstrated reductions in therapeutic VPA concentrations with carbapenems.Case report 1 A 23-year-old male with bipolar disorder ingested 40 g of VPA. The initial VPA and ammonia concentrations were 300 µg/L and 192 µg/dL, respectively. The peak VPA and ammonia concentrations reached 894 µg/L and 740 µg/dL, respectively. He received multi-dose activated charcoal, L-carnitine, and ertapenem, followed by continuous renal replacement therapy (CRRT). His concentrations decreased rapidly, and he was extubated.Case report 2 A 33-year-old male ingested 10 g of VPA, multiple psychotropics, and alcohol. He had a GCS of 10, hypoxemia, and initial VPA and ammonia of 45 µg/L and 139 µg/dL, respectively. The peak VPA and ammonia were 317 µg/L and 255 µg/L, respectively. He received L-carnitine and ertapenem, with a subsequent decline in concentrations.Discussion Carbapenems may reduce VPA concentrations by 50%–80%. Our cases demonstrate the successful use of ertapenem in the management of severe VPA toxicity. Further studies may establish criteria for the use of carbapenems for treating VPA poisoning and whether they can reduce the need for hemodialysis.

Cardiac glycoside toxicity is primarily a clinical diagnosis. Serum digoxin levels should be obtained to confirm the diagnosis and to guide antidote administration (in the context of pharmaceutical digoxin poisoning).8 Although there is crossreactivity with other cardiac glycosides, the digoxin immunoassay is specific for the detection of digoxin. Because of unpredictable cross-reactivity, the quantitative value has no relation to the degree of toxicity from exposure to nonpharmaceutical cardiac glycosides, and may even be undetectable.8 The serum digoxin level should therefore not be used to guide antidote dosage in cases of nonpharmaceutical cardiac glycoside ingestion. The management of cardiac glycoside poisoning includes supportive care and antidote therapy with digoxin-specific antibody fragments (digoxinFab). Digoxin-Fab is indicated for severe cases of cardiac glycoside toxicity (Box 2). It should be avoided in milder cases because of the theoretical risk of immunogenicity. Currently available commercial preparations include DigiFab and DigiBind (the latter of which is unavailable in North America); each vial, administered intravenously, binds 0.5 mg of digoxin.7 Following administration of digoxin-Fab, serum total digoxin levels should not be measured until the antidote has been eliminated from the body (up to three weeks in patients with impaired kidney function), due to interference with the immunoassay.7 Digoxin-Fab has also proven to be effective as an antidote for poisonings from other cardiac glycosides. A randomized controlled trial involving 66 patients with cardiac glycoside toxicity from ingestion of yellow oleander in Sri Lanka found that digoxin-Fab resulted in a significant resolution of dysrhythmias and hyperkalemia compared with saline placebo.9 Several other observational studies have reported favourable outcomes with use of digoxin-Fab in cases of plant-related cardiac glycoside poisonings.10 Dosing recommendations for symptomatic nondigoxin cardiac glycoside exposure suggest empiric administration of 10 vials of digoxin-Fab.7

Eslicarbazepine is a novel anti-epileptic agent indicated for the treatment of partial-onset seizures. We present the case of an 18 year old female that presented to the Emergency Department four hours after a reported intentional ingestion of an estimated 5600 mg of eslicarbazepine. Although initially hemodynamically stable and neurologically normal, shortly after arrival she developed confusion, rigidity and clonus, followed by recurrent seizures, hypoxemia and cardiac arrest which responded to cardiopulmonary resuscitation and wide complex tachycardia requiring defibrillation. Treatment for refractory seizures included benzodiazepines and eventual intubation and sedation with propofol. Cardiac toxicity responded to sodium bicarbonate. In addition, empiric hemodialysis was performed. In this case report, we discuss the successful management of the first reported overdose of eslicarbazepine using supportive care and hemodialysis. L’eslicarbazépine est un nouvel anticonvulsivant indiqué dans le traitement des crises partielles d’épilepsie. Sera exposé ici le cas d’une femme de 18 ans, conduite au service des urgences quatre heures après, selon son dire, qu’elle eut volontairement consommé environ 5600 mg d’eslicarbazépine. À son arrivée, elle était dans un état hémodynamique stable et un état neurologique normal, mais, peu de temps après, sont apparus de la confusion, de la rigidité et un clonus, suivis de convulsions itératives, d’hypoxémie, d’un arrêt cardiaque qui a cédé à la réanimation cardiorespiratoire et d’une tachycardie à complexes larges qui a nécessité une défibrillation. Le traitement des convulsions réfractaires comprenait de la benzodiazépine, à quoi se sont ajoutées l’intubation et la sédation par le propofol. La toxicité cardiaque de l’anticonvulsivant a été neutralisée par le bicarbonate de sodium. Enfin, on a eu recours à une hémodialyse empirique. Il sera donc question dans l’article de la prise en charge couronnée de succès de la première surdose signalée d’eslicarbazépine par un traitement de soutien et l’hémodialyse.

Background Probiotics are live microorganisms that may confer health benefits when ingested. Randomized trials suggest that probiotics significantly decrease the incidence of ventilator-associated pneumonia (VAP) and the overall incidence of infection in critically ill patients. However, these studies are small, largely single-center, and at risk of bias. The aim of the PROSPECT pilot trial was to determine the feasibility of conducting a larger trial of probiotics to prevent VAP in mechanically ventilated patients in the intensive care unit (ICU). Methods In a randomized blinded trial, patients expected to be mechanically ventilated for ≥72 hours were allocated to receive either 1 × 10 10 colony-forming units of Lactobacillus rhamnosus GG or placebo, twice daily. Patients were excluded if they were at increased risk of L. rhamnosus GG infection or had contraindications to enteral medication. Feasibility objectives were: (1) timely recruitment; (2) maximal protocol adherence; (3) minimal contamination; and (4) estimated VAP rate ≥10 %. We also measured other infections, diarrhea, ICU and hospital length of stay, and mortality. Results Overall, in 14 centers in Canada and the USA, all feasibility goals were met: (1) 150 patients were randomized in 1 year; (2) protocol adherence was 97 %; (3) no patients received open-label probiotics; and (4) the VAP rate was 19 %. Other infections included: bloodstream infection (19.3 %), urinary tract infections (12.7 %), and skin and soft tissue infections (4.0 %). Diarrhea, defined as Bristol type 6 or 7 stools, occurred in 133 (88.7 %) of patients, the median length of stay in ICU was 12 days (quartile 1 to quartile 3, 7–18 days), and in hospital was 26 days (quartile 1 to quartile 3, 14–44 days); 23 patients (15.3 %) died in the ICU. Conclusions The PROSPECT pilot trial supports the feasibility of a larger trial to investigate the effect of L. rhamnosus GG on VAP and other nosocomial infections in critically ill patients. Trial registration Clinicaltrials.gov NCT01782755 . Registered on 29 January 2013.

The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear. In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, infection, and patient-important bleeding. A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups. Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.).

Background Pulmonary infections, ranging from mild respiratory issues to severe multiorgan failure, pose a major global health threat. The immune response in community-acquired pneumonia (CAP) and COVID-19 influences disease severity and outcomes, but molecular pathogenesis differs across pathogens. Comparisons of plasma cytokine profiles between CAP and COVID-19 are limited. Analyzing these profiles with machine learning and bioinformatics could reveal subtle patterns and improve our understanding of immune responses in both conditions. Methods We conducted a novel case–control study to profile cytokine levels in patients with CAP and COVID-19. Age- and sex-matched cohorts included 39 patients with CAP, 39 with COVID-19, and 20 healthy controls. We measured 384 plasma cytokine levels using proximity extension assays and analyzed differences between cohorts with conventional statistical methods, bioinformatics and machine learning. Results Median ages of the cohorts were comparable ( P  = 0.797). COVID-19 patients exhibited a higher prevalence of hematologic disease ( P  = 0.047), increased corticosteroid use ( P  = 0.040), and reduced antibiotic use ( P  = 0.012). Clinical outcomes, including mortality, ICU admission, invasive mechanical ventilation, renal replacement therapy, acute respiratory distress syndrome, and acute kidney injury, were similar between groups. Both cohorts showed comparable absolute circulating cytokine profiles but distinct profiles relative to healthy controls. Machine learning identified a model of twelve cytokines that distinguished CAP from COVID-19 with a classification accuracy of 0.71 (SD 0.20). Gene ontology and enrichment analysis revealed differences in cytosolic and nuclear functions, intracellular signaling, stress responses, and cell cycle processes between patient cohorts and healthy controls. Enriched GO pathways showed that CAP pathways were positively associated with leukocyte counts and ARDS development, while COVID-19 pathways were negatively associated with ARDS and positively with platelet counts. Conclusions This case–control study provides insights into cytokine profiles related to CAP and COVID-19 pathogenesis. Although absolute circulating cytokine levels showed no significant differences between the groups, machine learning identified a model of twelve proteins that effectively distinguished the cohorts. Gene ontology and enrichment analyses also revealed distinct dysregulated pathways with differing associations with clinical variables in each cohort. These findings underscore the complexity and variability of cytokine responses in pulmonary infections.