Albumin Versus Balanced Crystalloid for the Early Resuscitation of Sepsis: An Open Parallel-Group Randomized Feasibility Trial. The ABC-Sepsis Trial.

OBJECTIVES: International guidelines recommend IV crystalloid as the primary fluid for sepsis resuscitation, with 5% human albumin solution (HAS) as the second line. However, it is unclear which fluid has superior clinical effectiveness. We conducted a trial to assess the feasibility of delivering a randomized controlled trial comparing balanced crystalloid against 5% HAS as sole early resuscitation fluid in patients with sepsis presenting to hospital. DESIGN: Multicenter, open, parallel-group randomized feasibility trial. SETTING: Emergency departments (EDs) in 15 U.K. National Health Service (NHS) hospitals. PATIENTS: Adult patients with sepsis and a National Early Warning Score 2 greater than or equal to five requiring IV fluids withing one hour of randomization. INTERVENTIONS: IV fluid resuscitation with balanced crystalloid or 5% HAS for the first 6 hours following randomization. MEASUREMENTS AND MAIN RESULTS: Primary feasibility outcomes were recruitment rate and 30-day mortality. We successfully recruited 301 participants over 12 months. Mean (sd) age was 69 years (± 16 yr), and 151 (50%) were male. From 1303 participants screened; 502 participants were potentially eligible and 300 randomized to receive trial intervention with greater than 95% of participants receiving the intervention. The median number of participants per site was 19 (range, 1-63). Thirty-day mortality was 17.9% (n = 53). Thirty-one participants died (21.1%) within 30 days in the 5% HAS arm, compared with 22 participants (14.8%) in the crystalloid arm (adjusted odds ratio, 1.50; 95% CIs, 0.84-2.83). CONCLUSIONS: Our results suggest it is feasible to recruit critically ill patients to a fluid resuscitation trial in U.K. EDs using 5% HAS as a primary resuscitation fluid. There was lower mortality in the balanced crystalloid arm. Given these findings, a definitive trial is likely to be deliverable, but the point estimates suggest such a trial would be unlikely to demonstrate a significant benefit from using 5% HAS as a primary resuscitation fluid in sepsis.

Albumin versus balanced crystalloid for resuscitation in the treatment of sepsis: A protocol for a randomised controlled feasibility study, "ABC-Sepsis".

Background: Patients presenting with suspected sepsis to secondary care often require fluid resuscitation to correct hypovolaemia and/or septic shock. Existing evidence signals, but does not demonstrate, a benefit for regimes including albumin over balanced crystalloid alone. However, interventions may be started too late, missing a critical resuscitation window. Methods: ABC Sepsis is a currently recruiting randomised controlled feasibility trial comparing 5% human albumin solution (HAS) with balanced crystalloid for fluid resuscitation in patients with suspected sepsis. This multicentre trial is recruiting adult patients within 12 hours of presentation to secondary care with suspected community acquired sepsis, with a National Early Warning Score ≥5, who require intravenous fluid resuscitation. Participants are randomised to 5% HAS or balanced crystalloid as the sole resuscitation fluid for the first 6 hours. Objectives: Primary objectives are feasibility of recruitment to the study and 30-day mortality between groups. Secondary objectives include in-hospital and 90-day mortality, adherence to trial protocol, quality of life measurement and secondary care costs. Discussion: This trial aims to determine the feasibility of conducting a trial to address the current uncertainty around optimal fluid resuscitation of patients with suspected sepsis. Understanding the feasibility of delivering a definitive study will be dependent on how the study team are able to negotiate clinician choice, Emergency Department pressures and participant acceptability, as well as whether any clinical signal of benefit is detected.

A Digital Health Intervention for Concussion: Development and Clinical Feasibility Study.

BACKGROUND: Concussion is a common condition that can lead to a constellation of symptoms that affect quality of life, social integration, and return to work. There are several evidence-based behavioral and psychological interventions that have been found to improve postconcussion symptom burden. However, these are not routinely delivered, and individuals receive limited support during their concussion recovery. OBJECTIVE: This study aimed to develop and test the feasibility of a digital health intervention using a systematic evidence-, theory-, and person-based approach. METHODS: This was a mixed methodology study involving a scoping review (n=21), behavioral analysis, and logic model to inform the intervention design and content. During development, the intervention was optimized with feedback from individuals who had experienced concussions (n=12) and health care professionals (n=11). The intervention was then offered to patients presenting to the emergency department with a concussion (n=50). Participants used the intervention freely and input symptom data as part of the program. A number of outcome measures were obtained, including participant engagement with the intervention, postconcussion symptom burden, and attitudes toward the intervention. A selection of participants (n=15) took part in in-depth qualitative interviews to understand their attitudes toward the intervention and how to improve it. RESULTS: Engagement with the intervention functionality was 90% (45/50) for the symptom diary, 62% (31/50) for sleep time setting, 56% (28/50) for the alcohol tracker, 48% (24/50) for exercise day setting, 34% (17/50) for the thought diary, and 32% (16/50) for the goal setter. Metrics indicated high levels of early engagement that trailed off throughout the course of the intervention, with an average daily completion rate of the symptom diary of 28.23% (494/1750). A quarter of the study participants (13/50, 26%) were classified as high engagers who interacted with all the functionalities within the intervention. Quantitative and qualitative feedback indicated a high level of usability and positive perception of the intervention. Daily symptom diaries (n=494) demonstrated a wide variation in individual participant symptom burden but a decline in average burden over time. For participants with Rivermead scores on completion of HeadOn, there was a strong positive correlation (r=0.86; P<.001) between their average daily HeadOn symptom diary score and their end-of-program Rivermead score. Insights from the interviews were then fed back into development to optimize the intervention and facilitate engagement. CONCLUSIONS: Using this systematic approach, we developed a digital health intervention for individuals who have experienced a concussion that is designed to facilitate positive behavior change. Symptom data input as part of the intervention provided insights into postconcussion symptom burden and recovery trajectories. TRIAL REGISTRATION: ClinicalTrials.gov NCT05069948; https://clinicaltrials.gov/ct2/show/NCT05069948.

Principal results of a randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with a 12 h regimen of N-acetylcysteine for paracetamol overdose (POP trial).

BACKGROUND: The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose. METHODS: Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24 h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n = 6) or NAC alone (n = 2). Calmangafodipir doses were 2, 5, or 10 µmol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395). FINDINGS: All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NAC + calmangafodipir (2 µmol/kg), 4/6; NAC + calmangafodipir (5 µmol/kg), 2/6; NAC + calmangafodipir (10 µmol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT > 100 U/L; with NAC + calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20 h fold change, NAC + calmangafodipir (5 µmol/kg) compared to NAC alone: 0.48 (95%CI 0.28-0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected. INTERPRETATION: Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.

Lactate - Arterial and Venous Agreement in Sepsis: a prospective observational study.

BACKGROUND: Sepsis is a common condition in the emergency department (ED). Lactate measurement is an important part of management: arterial lactate (A-LACT) measurement is the gold standard. There is increasing use of peripheral venous lactate (PV-LACT); however, there is little research supporting the interchangeability of the two measures.If PV-LACT has good agreement with A-LACT, it would significantly reduce patient discomfort and the risks of arterial sampling for a large group of acutely unwell patients, while allowing faster and wider screening, with potential reduced costs to the healthcare system. OBJECTIVE: The aim of this study is to determine the agreement between PV-LACT and A-LACT in septic patients attending the ED. METHODS: We carried out a prospective observational cohort study of 304 consented patients presenting with sepsis to a single UK NHS ED (110 000 adult attendances annually) taking paired PV-LACT and A-LACT. Bland-Altman analysis was carried out to determine agreement. Receiver operating characteristic curves and 2×2 tables were constructed to explore the predictive value of PV-LACT for A-LACT. RESULTS: The mean difference (PV-LACT-A-LACT) is 0.4 mmol/l [95% confidence interval (CI): 0.37-0.45], with 95% limits of agreement from -0.4 (95% CI: -0.45 to -0.32) to 1.2 (95% CI: 1.14-1.27). A PV-LACT of at least 2 mmol/l predicts an A-LACT of at least 2 with 100% sensitivity (95% CI: 89-100%) and 83% specificity (95% CI: 77-87%). CONCLUSION: This study is the largest comparing the two measurements, and shows good clinical agreement. We recommend using PV-LACT in the routine screening of septic patients. A PV-LACT less than 2 mmol/l is predictive of an A-LACT less than 2 mmol/l.

Capillary and Venous Lactate Agreement: a pilot prospective observational study.

BACKGROUND: Blood lactate is a marker of patient illness severity. Capillary lactate (CAP-LACT) measurement can potentially improve patient screening; however, it has poor evidence of clinical utility. AIM: We aimed to investigate agreement between CAP-LACT and peripheral venous lactate (PV-LACT). METHODS: We performed a prospective observational pilot study of 99 patients requiring lactate measurement. Paired CAP-LACT and PV-LACT was recorded. Agreement was determined by Bland-Altman analysis. RESULTS: Bias was 0.2 mmol/L, with 95% limits of agreement from -1.9 to 2.3. CONCLUSIONS: CAP-LACT has poor agreement with PV-LACT. Further research is needed to improve its potential clinical utility.