Position Paper on the Reporting of Norepinephrine Formulations in Critical Care from the Society of Critical Care Medicine and European Society of Intensive Care Medicine Joint Task Force.

OBJECTIVES: To provide guidance on the reporting of norepinephrine formulation labeling, reporting in publications, and use in clinical practice. DESIGN: Review and task force position statements with necessary guidance. SETTING: A series of group conference calls were conducted from August 2023 to October 2023, along with a review of the available evidence and scope of the problem. SUBJECTS: A task force of multinational and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. INTERVENTIONS: The implications of a variation in norepinephrine labeled as conjugated salt (i.e., bitartrate or tartrate) or base drug in terms of effective concentration of norepinephrine were examined, and guidance was provided. MEASUREMENTS AND MAIN RESULTS: There were significant implications for clinical care, dose calculations for enrollment in clinical trials, and results of datasets reporting maximal norepinephrine equivalents. These differences were especially important in the setting of collaborative efforts across countries with reported differences. CONCLUSIONS: A joint task force position statement was created outlining the scope of norepinephrine-dose formulation variations, and implications for research, patient safety, and clinical care. The task force advocated for a uniform norepinephrine-base formulation for global use, and offered advice aimed at appropriate stakeholders.

The Validity and Applicability of the Revised Delirium Rating Scale (DRS-R98) for Delirium Severity Assessment in a Critical Care Setting.

BACKGROUND: Delirium is a neuropsychiatric syndrome common in critical illness. Worsening delirium severity is associated with poorer clinical outcomes, yet its assessment remains under-reported with most severity assessment tools not validated for critical care. The DRS-R98 is a widely applied and validated tool. The aim of this project is to report the validation and utility of the DRS-R98 in critical illness. METHODS: This prospective, cohort study was conducted in adults with delirium admitted to a critical care unit and predicted to stay for ≥ 24 h. We excluded patients with severe neurological or communication barriers that would have interfered with the DRS-R98 assessment. Patients were screened using a delirium detection algorithm and the Confusion Assessment Method for the Intensive Care Unit. Eligible patient informations were collected and reported to qualified assessor/s before visiting clinical areas, confirming delirium presence and undertaking DRS- R98 assessments. To assess the tool's construct validity, an intensivist completed the Clinical Global Impression-Scale (CGI-S). To calculate the inter-rater reliability (IRR) a subset of patients were simultaneously evaluated by two assessors. RESULTS: We assessed 22 patients, 73% were male, with a median age of 65 years (IQR14). The DRS -R98 mean (SD) severity score was 24 (+/-7.7), total scale was 29 (+/18.0), and CGI-S 3.5 (+/11.5). Assessment duration was 90 min (+/-55) and 15 min (+/-5) for record data extraction and clinical assessment respectively. The CGI-S significantly correlated with DRS-R98 severity (r = 0.626) and total (r = 0.628) scales. The DRS-R98 Cronbach's alpha was 0.896 for severity scale and 0.886 for total scale. The inter-rater reliability (IRR) was assessed in six patients and reported an inter-correlation coefficient of 0.505 (p = 0.124) and 0.565 (p = 0.93) for the severity and total scale respectively. CONCLUSIONS: In critical care, the Delirium Rating Scale R98 had good construct validity, excellent internal consistency, and moderate inter-rater reliability.

The influence of statin exposure on inflammatory markers in patients with early bacterial infection: pilot prospective cohort study.

BACKGROUND: In the context of infection, progressive illness resulting in acute organ dysfunction is thought to be secondary to inflammatory response. Our aims were to determine risk factors for progressive illness following infection in a low-risk hospitalised cohort, including the impact of prior stain therapy. METHODS: We performed a prospective observational cohort study on two adult acute medical wards of a single tertiary academic hospital. We screened drug prescription charts of all adult acute medical admissions for inclusion criteria of inpatient administration of antibiotics for more than 24 hours for a microbiologically confirmed or clinically suspected infection. Patients were followed until admission to a high dependency unit (HDU) or intensive care unit (ICU), discharge from hospital, or to a maximum of 10 days. Outcomes were evolution of systemic inflammatory response syndrome (SIRS) criteria, white cell count and C-reactive protein measurements, and adverse clinical outcomes. We constructed multivariable models accounting for repeated within-patient measurements to determine associations between a priori selected predictors (days since admission, age, gender, Charlson score, prior statin exposure) and selected outcomes. RESULTS: We enrolled 209 patients; 27.8% were statin users and the commonest infection was pneumonia (51.0%). Most (88.0%) had at least 1 SIRS criterion on admission, and 76 (37.3%) manifested additional SIRS criteria over time. Risks of admission to HDU/ICU (3.3%) and of 30-day mortality (5.7%) were low. The proportion of patients with at least 1 SIRS criterion, mean CRP, and mean WBC all decreased over time. Multivariable regression models identified days since hospital admission as the only variable associated with daily presence of SIRS criteria, WCC, or CRP (adjusted OR <1 and p < 0.0001 in all analyses). Statin exposure was not a significant predictor. CONCLUSIONS: This cohort of ward patients treated for infection had a low risk of clinical deterioration, inflammatory markers improved over time, and statin exposure was not associated with any outcome. Future larger studies may identify risk factors for progression of illness in this population and plausible surrogate endpoints for evaluation in clinical trials.

Critical care pharmacy service provision and workforce in adult extracorporeal membrane oxygenation centres: a multicentre cross-sectional survey.

BACKGROUND: There is good evidence describing pharmacy workforce and service provision in general critical care units. However, no data exist from adult extracorporeal membrane oxygenation (ECMO) centres. AIM: To describe workforce characteristics, pharmacy service provision, and pharmaceutical care activities in critical care units (CCUs) providing an adult ECMO service in the United Kingdom (UK) and compare to national staffing standards for CCUs. METHOD: We conducted a multicentre, cross-sectional electronic survey inviting one pharmacy professional response per UK ECMO centre. We collated information on workforce, service provision, and pharmaceutical care activities provided by pharmacy teams in adult CCUs with an ECMO service. RESULTS: The survey response rate was 90.9%: representatives of 10/11 tertiary hospitals providing ECMO services responded. Median critical care pharmacist to critical care bed was 1:12.1 (IQR: 1:9.4-1:14.9). Most centres (90.0%) did not meet national standards for pharmacy professionals to critical care bed staffing ratios for weekday services. Total critical care beds covered by the critical care pharmacy team varied across the UK: median (IQR) - 45 (37-80) beds. Two centres funded pharmacist time for ECMO activity, and one centre funded a pharmacy technician post. Median peak ECMO activity was 4 ECMO patients in a single day (IQR: 3-5). Most respondents reported reduced pharmacy service at weekends compared to weekday, with limited on-site support. CONCLUSION: Most responding ECMO centres in the UK reported pharmacy staffing ratios below nationally agreed critical care standards. There was high variability in clinical pharmacy services to ECMO patients over 7 days.

Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B trial): protocol for a mixed-methods process evaluation of a randomised controlled trial.

INTRODUCTION: An association between deep sedation and adverse short-term outcomes has been demonstrated although this evidence has been inconsistent. The A2B (alpha-2 agonists for sedation in critical care) sedation trial is designed to determine whether the alpha-2 agonists clonidine and dexmedetomidine, compared with usual care, are clinically and cost-effective. The A2B intervention is a complex intervention conducted in 39 intensive care units (ICUs) in the UK. Multicentre organisational factors, variable cultures, perceptions and practices and the involvement of multiple members of the healthcare team add to the complexity of the A2B trial. From our pretrial contextual exploration it was apparent that routine practices such as type and frequency of pain, agitation and delirium assessment, as well as the common sedative agents used, varied widely across the UK. Anticipated challenges in implementing A2B focused on the impact of usual practice, perceptions of risk, ICU culture, structure and the presence of equipoise. Given this complexity, a process evaluation has been embedded in the A2B trial to uncover factors that could impact successful delivery and explore their impact on intervention delivery and interpretation of outcomes. METHODS AND ANALYSIS: This is a mixed-methods process evaluation guided by the A2B intervention logic model. It includes two phases of data collection conducted during and at the end of trial. Data will be collected using a combination of questionnaires, stakeholder interviews and routinely collected trial data. A framework approach will be used to analyse qualitative data with synthesis of data within and across the phases. The nature of the relationship between delivery of the A2B intervention and the trial primary and secondary outcomes will be explored. ETHICS AND DISSEMINATION: All elements of the A2B trial, including the process evaluation, are approved by Scotland A Research Ethics Committee (Ref. 18/SS/0085). Dissemination will be via publications, presentations and media engagement. TRIAL REGISTRATION NUMBER: NCT03653832.

Whole blood thiamine, intravenous thiamine supplementation and delirium occurrence in the intensive care unit: retrospective cohort analyses.

BACKGROUND: Thiamine di-phosphate is an essential cofactor in glucose metabolism, glutamate transformation and acetylcholinesterase activity, pathways associated with delirium occurrence. We hypothesised that a deficiency in whole blood thiamine and intravenous thiamine supplementation could impact delirium occurrence. AIM: To establish whether a deficiency in whole blood thiamine and/or intravenous thiamine supplementation within 72 h of intensive care admission is associated with delirium occurrence. METHOD: The first dataset was secondary analysis of a previous study in an intensive care unit in the Netherlands, reported in 2017. The second dataset contained consecutive intensive care admissions 2 years before (period 1: October 2014 to October 2016) and after (period 2: April 2017 to April 2019) routine thiamine supplementation was introduced within 72 h of admission. Delirium was defined as a positive Confusion Assessment Method-Intensive Care Unit score(s) in 24 h. RESULTS: Analysis of the first dataset (n = 57) using logistic regression showed no relationship between delirium and sepsis or whole blood thiamine, but a significant association with age (p = 0.014). In the second dataset (n = 3074), 15.1% received IV thiamine in period 1 and 62.6% during period 2. Hierarchical regression analysis reported reduction in delirium occurrence in the second period; this did not reach statistical significance, OR = 0.81 (95% CI 0.652-1.002); p = 0.052. CONCLUSION: No relationship was detected between whole blood thiamine and delirium occurrence on admission, at 24 and 48 h. It remains unclear whether routine intravenous thiamine supplementation during intensive care admission impacts delirium occurrence. Further prospective randomised clinical trials are needed.

Precision-based approaches to delirium in critical illness: A narrative review.

Delirium occurs in critical illness and is associated with poor clinical outcomes, having a longstanding impact on survivors. Understanding the complexity of delirium in critical illness and its deleterious outcome has expanded since early reports. Delirium is a culmination of predisposing and precipitating risk factors that result in a transition to delirium. Known risks range from advanced age, frailty, medication exposure or withdrawal, sedation depth, and sepsis. Because of its multifactorial nature, different clinical phenotypes, and potential neurobiological causes, a precise approach to reducing delirium in critical illness requires a broad understanding of its complexity. Refinement in the categorization of delirium subtypes or phenotypes (i.e., psychomotor classifications) requires attention. Recent advances in the association of clinical phenotypes with clinical outcomes expand our understanding and highlight potentially modifiable targets. Several delirium biomarkers in critical care have been examined, with disrupted functional connectivity being precise in detecting delirium. Recent advances reinforce delirium as an acute, and partially modifiable, brain dysfunction, and place emphasis on the importance of mechanistic pathways including cholinergic activity and glucose metabolism. Pharmacologic agents have been assessed in randomized controlled prevention and treatment trials, with a disappointing lack of efficacy. Antipsychotics remain widely used after "negative" trials, yet may have a role in specific subtypes. However, antipsychotics do not appear to improve clinical outcomes. Alpha-2 agonists perhaps hold greater potential for current use and future investigation. The role of thiamine appears promising, yet requires evidence. Looking forward, clinical pharmacists should prioritize the mitigation of predisposing and precipitating risk factors as able. Future research is needed within individual delirium psychomotor subtypes and clinical phenotypes to identify modifiable targets that hold the potential to improve not only delirium duration and severity, but long-term outcomes including cognitive impairment.

Critical care pharmacist research activity, experience and interests: a 2021 United Kingdom survey.

BACKGROUND: Research and innovation are essential for effective healthcare service delivery, leading to improvements in patient health and wellbeing. National policy dictates that research delivery is embedded into daily practice of United Kingdom (UK) healthcare professionals, including pharmacists. There is a limited understanding of critical care pharmacist research activities, experiences and interests. It is, therefore, important to describe current practice including barriers and facilitators to enable increased engagement. OBJECTIVES: To describe UK critical care pharmacist research activity, experiences, interests and barriers to better engagement. METHOD: An electronic survey was developed, piloted and distributed (June to October 2021) to all critical care pharmacists via UK professional organisations. KEY FINDINGS: The survey was completed by 126 pharmacists, providing a 54% response rate. Few pharmacists reported research capability (postgraduate qualification with a research component, 31% (39/126)) and opportunity (dedicated research time, 28.6% (36/126)), only 12.7% (16/126) have both these influencers. Those that did, produced significantly more research outputs (median 4 (0,9) versus 0 (0,1), P = 0.023) and undertook grant funding applications (X2 (1, n = 126) = 25.8, P < 0.001), compared to those without. The most frequently reported barrier to research was the time (opportunity), (71.4%, 90/126). Few pharmacists reported having a research mentor (13.3%, 16/120). Most pharmacists reported an interest in collaborating on research projects across a broad range of areas. CONCLUSIONS: Critical care pharmacists are motivated to participate in the evaluation continuum including research, although most report capability and opportunity barriers to delivery. We suggest policy recommendations to address limitations and increase pharmacist research involvement.

Opioid, sedative, preadmission medication and iatrogenic withdrawal risk in UK adult critically ill patients: a point prevalence study.

BACKGROUND: Iatrogenic withdrawal syndrome, after exposure medication known to cause withdrawal is recognised, yet under described in adult intensive care. AIM: To investigate, opioid, sedation, and preadmission medication practice in critically ill adults with focus on aspects associated with iatrogenic withdrawal syndrome. METHOD: One-day point prevalence study in UK intensive care units (ICUs). We collected ICU admission medication and/or substances with withdrawal potential, sedation policy, opioid and sedative use, dose, and duration. RESULTS: Thirty-seven from 39 participating ICUs contributed data from 386 patients. The prevalence rate for parenteral opioid and sedative medication was 56.1% (212 patients). Twenty-three ICUs (59%) had no sedation/analgesia policy, and no ICUs screened for iatrogenic withdrawal. Patient admission medications with withdrawal-potential included antidepressants or antipsychotics (43, 20.3%) and nicotine (41, 19.3%). Of 212 patients, 202 (95.3%) received opioids, 163 (76.9%) sedatives and 153 (72.2%) both. Two hundred and two (95.3%) patients received opioids: 167 (82.7%) by continuous infusions and 90 (44.6%) patients for longer than 96-h. One hundred and sixty-three (76.9%) patients received sedatives: 157 (77.7%) by continuous infusions and 74 (45.4%) patients for longer than 96-h. CONCLUSION: Opioid sedative and admission medication with iatrogenic withdrawal syndrome potential prevalence rates were high, and a high proportion of ICUs had no sedative/analgesic policies. Nearly half of patients received continuous opioids and sedatives for longer than 96-h placing them at high risk of iatrogenic withdrawal. No participating unit reported using a validated tool for iatrogenic withdrawal assessment.

Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK.

INTRODUCTION: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care. METHODS AND ANALYSIS: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs. ETHICS AND DISSEMINATION: The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03653832.

Antibiotic dosing in critical illness.

Early and effective antibiotic therapy is essential in the management of infection in critical illness. The loading dose is probably the most important dose and is a function of the volume of distribution of the drug and the desired plasma concentration but independent of renal function. Antibiotics are classified in a number of ways that have implications for dosing. Doses of hydrophilic agents such as ß-lactams should be increased in the early stages of sepsis as the extravascular space increases. For lipophilic agents such as macrolides, the inflammatory process is less important, although factors such as obesity will affect dosing. Classification can also be based on pharmacodynamic properties. Concentration-dependent antibiotics such as aminoglycosides should be administered by extended interval regimens, which maximize bactericidal effect, minimize nephrotoxicity and allow time between doses for the post-antibiotic effect. The critical factor for time-dependent agents, such as ß-lactams, is time above the MIC. Ideally administration of these agents should be continuous, although vascular access availability can restrict infusion time to between 4 and 6 h, which is probably adequate. As well as antibiotic factors, patient factors such as hepatic and renal failure will affect dosing. Hepatic failure will affect antibiotic metabolism, although it is most important in end-stage failure. Renal failure and support will affect drug elimination. Knowledge of these factors is essential. Patient safety and prevention of unnecessary harm is a weighty consideration in critical illness. To ensure effective treatment and minimize adverse effects, therapy should be reviewed daily and adjusted in the light of changes in patient organ function and underlying pathology.

Parenteral thiamine for prevention and treatment of delirium in critically ill adults: a systematic review protocol.

BACKGROUND: Delirium is an acute confusional state, common in critical illness and associated with cognitive decline. There is no effective pharmacotherapy to prevent or treat delirium, although it is scientifically plausible that thiamine could be effective. Thiamine studies in dementia patients are inconclusive. Aside from small numbers, all used oral administration: bioavailability of thiamine is poor; parenteral thiamine bypasses this. In the UK, parenteral thiamine is administered as a compound vitamin B and C solution (Pabrinex®). The aim of this review is to evaluate the effectiveness of parenteral thiamine (alone or in a compound solution) in preventing or treating delirium in critical illness. METHODS: We will search for studies in electronic databases (MEDLINE (Pro-Quest), EMBASE, CINAHL, LILACS, CNKI, AMED, and Cochrane CENTRAL), clinical trials registries (WHO International Clinical Trials Registry, ClinicalTrials.gov, and Controlled-trials.com), and grey literature (Google Scholar, conference proceedings, and Index to Theses). We will perform complementary searches of reference lists of included studies, relevant reviews, clinical practice guidelines, or other pertinent documents (e.g. official documents and government reports). We will consider quasi-randomised or randomised controlled trials in critically ill adults. We will include studies that evaluate parenteral thiamine versus standard of care, placebo, or any other non-pharmacological or pharmacological interventions. The primary outcomes will be the delirium core outcome set, including incidence and severity of delirium and cognition. Secondary outcomes are adapted from the ventilation core outcome set: duration of mechanical ventilation, length of stay, and adverse events incidence. Screening, data extraction, and risk of bias assessment will be undertaken independently by two reviewers. If data permits, we will conduct meta-analyses using a random effects model and, where appropriate, sensitivity and subgroup analyses to explore sources of heterogeneity. DISCUSSION: This review will provide evidence for the effectiveness of parental thiamine in the prevention or treatment of delirium in critical care. Findings will contribute to establishing the need for a multicentre study of parenteral thiamine in the prevention and treatment of critical care delirium. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019118808.

Adverse events and clinical outcome associated with drotrecogin alfa-activated: a single-center experience of 498 patients over 8 years.

PURPOSE: Licensed in 2002 for severe sepsis, drotrecogin alfa-activated (DAA) remains a much debated therapy particularly with respect to outcomes and a potentially increased risk of serious bleeding events (SBEs). Recent publications have suggested a significantly increased incidence of SBEs and death in those with baseline bleeding risks (BBRs). Our center is one of the highest prescribers of DAA worldwide; we describe our experience of SBEs and other clinical outcomes. METHODS: Prospectively collected data using a clinical guideline audit tool and database to track outcome and adverse events of DAA-treated severe sepsis patients were analyzed. RESULTS: Four hundred ninety-eight patients received DAA over an 8-year period. Hospital, critical care, and 28-day mortalities were 46.2%, 39.6%, and 35.1%, respectively. Contraindications were identified for 40 (8.0%) patients, of whom 24 (4.8%) had BBRs. Hospital mortality was 47.5% (19/40) for patients with any contraindication and 45.8% (11/24) for those with a BBR. Seventy-six (15.3%) bleeding events were reported; 22 (4.4%) were considered serious. Hospital mortality was 60.5% for patients with any bleeding event and 77.3% for those with SBEs. CONCLUSIONS: This large single-center case series demonstrates that DAA has an incidence of SBEs similar to initial clinical trials. As expected, SBEs were associated with a poor outcome.