Explore the vast range of titles available.

The combination of thiamine, ascorbic acid, and hydrocortisone has recently emerged as a potential adjunctive therapy to antibiotics, infectious source control, and supportive care for patients with sepsis and septic shock. In the present manuscript, we provide a comprehensive review of the pathophysiologic basis and supporting research for each element of the thiamine, ascorbic acid, and hydrocortisone drug combination in sepsis. In addition, we describe potential areas of synergy between these therapies and discuss the strengths/weaknesses of the two studies to date which have evaluated the drug combination in patients with severe infection. Finally, we describe the current state of current clinical practice as it relates to the thiamine, ascorbic acid, and hydrocortisone combination and present an overview of the randomized, placebo-controlled, multi-center Ascorbic acid, Corticosteroids, and Thiamine in Sepsis (ACTS) trial and other planned/ongoing randomized clinical trials.

Acute kidney injury (AKI) is common in patients with sepsis and has been associated with high mortality rates. The provision of thiamine to patients with sepsis may reduce the incidence and severity of sepsis-related AKI and thereby prevent renal failure requiring renal replacement therapy (RRT). To test the hypothesis that thiamine supplementation mitigates kidney injury in septic shock. This was a secondary analysis of a single-center, randomized, double-blind trial comparing thiamine to placebo in patients with septic shock. Renal function, need for RRT, timing of hemodialysis catheter placement, and timing of RRT initiation were abstracted. The baseline creatinine and worst creatinine values between 3 and 24 hours, 24 and 48 hours, and 48 and 72 hours were likewise abstracted. There were 70 patients eligible for analysis after excluding 10 patients in whom hemodialysis was initiated before study drug administration. Baseline serum creatinine in the thiamine group was 1.2 mg/dl (interquartile range, 0.8-2.5) as compared with 1.8 mg/dl (interquartile range, 1.3-2.7) in the placebo group (P = 0.3). After initiation of the study drug, more patients in the placebo group than in the thiamine group were started on RRT (eight [21%] vs. one [3%]; P = 0.04). In the repeated measures analysis adjusting for the baseline creatinine level, the worst creatinine levels were higher in the placebo group than in the thiamine group (P = 0.05). In this post hoc analysis of a randomized controlled trial, patients with septic shock randomized to receive thiamine had lower serum creatinine levels and a lower rate of progression to RRT than patients randomized to placebo. These findings should be considered hypothesis generating and can be used as a foundation for further, prospective investigation in this area.

Given the potential for mitochondrial medicine as a therapy in various illnesses, mitochondrial tests derived from blood samples have gained increasing value. The aim of this study was to perform an in-depth investigation of mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) of healthy adult participants to characterize mitochondrial respiration in health. Adult participants without acute illness were recruited. PBMCs were isolated and quantitative, real-time measurements of mitochondrial oxygen consumption rate were performed using the Seahorse XF Cell Mito Stress Test Kit with Seahorse XFe96 Analyzer. The study included 184 participants without previously diagnosed medical conditions. There was no association between mitochondrial respiration and sex and age groups (≤ 30 years vs. > 30 years). Maximal and Spare respirations were associated with body mass index (BMI). The findings of this study contribute to the growing body of knowledge on mitochondrial bioenergetics in healthy adults and provide further insights into its association with demographic and anthropometric factors.

BackgroundWidespread reports suggest the characteristics and disease course of coronavirus disease 2019 (COVID-19) and influenza differ, yet detailed comparisons of their clinical manifestations are lacking.ObjectiveComparison of the epidemiology and clinical characteristics of COVID-19 patients during the pandemic with those of influenza patients in previous influenza seasons at the same hospitalDesignAdmission rates, clinical measurements, and clinical outcomes from confirmed COVID-19 cases between March 1 and April 30, 2020, were compared with those from confirmed influenza cases in the previous five influenza seasons (8 months each) beginning September 1, 2014.SettingLarge tertiary care teaching hospital in Boston, MAParticipantsLaboratory-confirmed COVID-19 and influenza inpatientsMeasurementsPatient demographics and medical history, mortality, incidence and duration of mechanical ventilation, incidences of vasopressor support and renal replacement therapy, and hospital and intensive care admissions.ResultsData was abstracted from medical records of 1052 influenza patients and 582 COVID-19 patients. An average of 210 hospital admissions for influenza occurred per 8-month season compared to 582 COVID-19 admissions over 2 months. The median weekly number of COVID-19 patients requiring mechanical ventilation was 17 (IQR: 4, 34) compared to a weekly median of 1 (IQR: 0, 2) influenza patient (p=0.001). COVID-19 patients were significantly more likely to require mechanical ventilation (31% vs 8%) and had significantly higher mortality (20% vs. 3%; p<0.001 for all). Relatively more COVID-19 patients on mechanical ventilation lacked pre-existing conditions compared with mechanically ventilated influenza patients (25% vs 4%, p<0.001). Pneumonia/ARDS secondary to the virus was the predominant cause of mechanical ventilation in COVID-19 patients (94%) as opposed to influenza (56%).LimitationThis is a single-center study which could limit generalization.ConclusionCOVID-19 resulted in more weekly hospitalizations, higher morbidity, and higher mortality than influenza at the same hospital.

Outcome selection is a critically important aspect of clinical trial design. Alive-and-ventilator free days is an outcome measure commonly used in critical care clinical trials, but has not been fully explored in resuscitation science. A simulation study was performed to explore approaches to the definition and analysis of alive-and-ventilator free days in cardiac arrest populations. Data from an in-hospital cardiac arrest observational cohort and from the Pragmatic Airway Resuscitation Trial were used to inform and conduct the simulations and validate approaches to alive-and-ventilator free days measurement and analysis. Alive-and-ventilator-free days is a flexible outcome measure in cardiac arrest populations. An approach to alive-and-ventilator free days that assigns -1 days when return of spontaneous circulation is not achieved provides a wider distribution of the outcome and improves statistical power. The optimal approach to the analysis of alive-and-ventilator free days varies based on the expected impact of the intervention under study on rates of return of spontaneous circulation, survival, and ventilator-free survival. Alive-and-ventilator free days adds to the armamentarium of clinical trialists in the field of resuscitation science.

Background Ventilator-free days, which combine mortality and duration of mechanical ventilation into a single measure, are often considered as a primary endpoint in clinical trials involving critically ill patients. Despite the composite nature, ventilator-free days are commonly analyzed as continuous or count data with no distinction between a zero score from a patient who dies and a zero score from a patient who is alive but still on ventilator. In this study, we propose a two-part statistical model to compare the effects of two airway management strategies on mortality and duration of mechanical ventilation among patients with out-of-hospital cardiopulmonary arrest in a cluster randomized cross-over clinical trial. Methods In the proposed two-part model, failure to achieve return of spontaneous circulation (ROSC), death after ROSC, and survival are modeled in the first part; the number of ventilator-free days conditional on survival is modeled in the second part. To account for the cluster randomized cross-over design, each part also includes a random cluster effect that is assumed to be either shared or independent across the two parts. We conducted a simulation study to evaluate type I error rates and power of the two-part shared random cluster effect model and the mis-specified two-part model with independent random cluster effects in detecting an overall intervention effect. Results We found that parameter estimates were similar whether the random cluster effects were assumed to be shared or independent across the two parts whereas the shared random cluster effect approach showed higher log-likelihood, but lower Akaike information criterion (AIC) and Bayesian information criterion (BIC). Initial laryngeal tube insertion reduced odds of failing to achieve ROSC and marginally decreased odds of death after ROSC compared with initial endotracheal intubation in Part 1, whereas initial laryngeal tube insertion was not associated with duration of mechanical ventilation among patients alive in Part 2. The shared random cluster effect approach showed higher odds of death associated with lower odds of being ventilator-free. This confirms the expectation that a patient who is less likely to achieve ROSC and survive is more likely to require prolonged mechanical ventilation if the patient indeed survives during hospitalization. Our simulation studies found that the two-part model with a shared random cluster effect yielded type I error rates close to the nominal level. The two-part shared random cluster effect model has better power to detect an overall intervention effect when intervention effects are present in both parts rather than in only one of the two part. Conclusions The proposed two-part model provides a more comprehensive assessment of intervention effects on ventilator-free days in critical care trials. Researchers and clinicians can obtain greater insights with this approach about the direction and magnitude of the intervention effects on mortality, ROSC, and duration of mechanical ventilation.

Incorporating unfamiliar therapies into practice requires effective longitudinal learning and the optimal way to achieve this is debated. Though not a novel therapy, ketamine in critical care has a paucity of data and variable acceptance, with limited research describing intensivist perceptions and utilization. The Coronavirus-19 pandemic presented a particular crisis where providers rapidly adapted analgosedation strategies to achieve prolonged, deep sedation due to a surge of severe acute respiratory distress syndrome (ARDS). How does clinical experience with ketamine impact the perception and attitude of clinicians toward this therapy? We conducted a mixed-methods study using quantitative ketamine prescription data and qualitative focus group data. We analyzed prescription patterns of ketamine in a tertiary academic ICU during two different time points: pre-COVID-19 (March 1-June 30, 2019) and during the COVID-19 surge (March 1-June 30, 2020). Two focus groups (FG) of critical care attendings were held, and data were analyzed using the Framework Method for content analysis. Four-hundred forty-six medical ICU patients were mechanically ventilated (195 pre-COVID-19 and 251 during COVID-19). The COVID-19 population was more likely to receive ketamine (81[32.3%] vs 4 [2.1%], p < 0.001). Thirteen respondents participated across two FG sessions (Pre-COVID = 8, Post-COVID=5). The most prevalent attitude among our respondents was discomfort, with three key themes identified as follows: 1) lack of evidence regarding ketamine, 2) lack of personal experience, and 3) desire for more education and protocols. Despite a substantial increase in ketamine prescription during COVID-19, intensivists continued to feel discomfort with utilization. Factors contributing to this discomfort include a lack of evidence, a lack of experience, and a desire for more education and protocols. Increase in experience with ketamine alone was not sufficient to minimize provider discomfort. These findings should inform future curricula and call for process improvement to optimize continuing education.

Objectives: We sought to determine whether atorvastatin administration attenuates the inflammatory response and improves clinical outcomes in acute influenza. Methods: We conducted a randomized double-blind trial administering atorvastatin 40 milligrams or placebo to adults with confirmed influenza for five days between December 2013–May 2018. Patients were primarily enrolled in the emergency department (ED) at an urban, tertiary-care center. Serum was obtained at enrollment and 72 hours for the primary outcome, change in interleukin (IL-6). Patients reported severity of influenza symptoms over 10 days. We used linear mixed-effects models for the primary comparisons. Results: Of the 116 enrolled patients, 59 received atorvastatin and 57 received placebo. Groups were well-matched including baseline influenza symptom scores and receipt of an antiviral medication. There was no difference between groups in the change in interleukin-6 (IL-6) levels (P=0.468). However, there were significant differences in the overall influenza symptom scores, favoring faster resolution in the atorvastatin group (P=0.05). For patients presenting within 48 hours of symptom onset, resolution was faster for the overall score (P <0.001) and for the fever (P=0.001), sore throat (P=0.005) and headache (P=0.006) components. No safety concerns were identified. Conclusion: Atorvastatin administration in acute influenza appears safe. We did not find attenuation of IL-6 with atorvastatin. Patients receiving atorvastatin reported improvement in their clinical symptoms at a faster rate than those in the placebo group, particularly in patients presenting within 48 hours of symptom onset. This trial is registered at ClinicalTrials.gov, Identifier: NCT02056340.

Background Prescribing pharmacologic therapies for critically ill patients requires a careful balancing of risks and benefits. Defining, monitoring, and reporting harms that occur in clinical trials conducted in critically ill populations, however, is challenging given that the natural history of most critical illnesses includes progressive multiple organ failure and death. In this study, we assessed harms reporting in clinical trials performed in critically ill populations. Methods Randomized, non-industry-sponsored, human clinical trials of pharmacologic interventions in adult critically ill populations published between 2015 and 2018 in high-impact journals were included in this systematic review. Harms data, adherence to Consolidated Standards of Reporting Trials (CONSORT) harms reporting guidelines, and restrictions on harms reporting were recorded. Results A total of 707 abstracts were screened with 40 trials ultimately being included in the analysis. Included trials represent 28,636 randomized patients with a median of 292 (IQR 100–546) patients per trial. The most common disease states were general critical care (33%) and sepsis (28%). Of 18 included CONSORT items, the median number met was 12 (IQR 9, 14). The most commonly missed items were adverse event (AE) severity grading definitions and AE attribution (relationship of AE to study drug), which were only reported in 35 and 38% of manuscripts, respectively. Half of the manuscripts (48%) provided definitions for recorded AEs. There were 5 studies investigating the effects of corticosteroids in sepsis, with the number of AEs reported per analyzed patient ranging from 0.01 to 1.89. AE definitions in studies of similar/equivalent interventions often varied substantially. Study protocols were available for 30/40 (75%) of studies, with 13 (43%) of those not providing any guidance regarding AE attribution. Conclusions Randomized trials of pharmacologic interventions conducted in critically ill populations and published in high impact journals often fail to adequately describe AE definitions, severity, attribution, and collection procedures. Among trials of similar interventions in comparable populations, variation in AE collection and reporting procedures is substantial. These factors may limit a clinician’s ability to accurately balance the potential benefits and harms of an intervention.

IntroductionDiabetic ketoacidosis (DKA) is a potentially life-threatening diabetic complication. Despite the high prevalence of DKA and the substantial associated healthcare burden, limited research on strategies to improve outcomes currently exists.Thiamine (vitamin B1) is a cofactor of pyruvate dehydrogenase, which plays a key role in aerobic glucose metabolism. Thiamine deficiency is common in patients with DKA, resulting in a shift to anaerobic metabolism and hyperlactatemia, which can prolong and complicate recovery. Therefore, we hypothesise that thiamine administration will improve aerobic metabolism and lead to faster resolution of acidemia in patients with DKA.Methods and analysisIn this single centre, double-blind, randomised, placebo-controlled, parallel group interventional trial, 100 patients admitted to the hospital with DKA will be randomised to receive either intravenous thiamine (200 mg in 50 mL 0.9% saline) or placebo (0.9% saline identical in appearance and volume) two times per day for 2 days. The primary outcome will be the change in bicarbonate level over 24 hours as compared between the two treatment groups. Additional secondary outcomes include the change over time in anion gap, lactate levels, oxygen consumption by circulating mononuclear cells, intensive care unit and hospital length-of-stay and hospital resource usage when comparing the two study arms.Ethics and disseminationThis trial was approved by the Committee on Clinical Investigations, the institutional review board of Beth Israel Deaconess Medical Center (protocol number 2018P000475). Findings will be disseminated through peer-reviewed publications and professional conference presentations.Trial registration numberNCT03717896; clinicaltrials.gov.