Early Experience With Interleukin-6 Receptor Antagonists in Patients With COVID-19 Admitted to a Community Hospital.

Background/objective: The efficacy of interleukin-6 (IL-6) inhibitors in hospitalized patients with severe coronavirus disease 2019 (COVID-19) pneumonitis is unclear. Method: This retrospective, observational cohort study included patients hospitalized at a community hospital with COVID-19 pneumonia from March 2020 to May 2020. All patients were treated with standard of care (SOC), and a nonrandomly selected subset of patients also received an IL-6 inhibitor. The primary outcome was clinical response, defined as an improvement of at least 2 categories relative to baseline on a 7-category ordinal scale up to hospital discharge or 30 days. In adjusted analyses, logistic and linear regression models were conducted, controlling for covariates of hospital length of stay (LOS), intensive care unit (ICU) care, ICU LOS, gender, age, race, and Charlson Comorbidity Index. Results: A total of 133 patients met inclusion criteria. In all, 30 patients received an IL-6 inhibitor plus SOC. There was no statistical difference in clinical outcome between groups as 76.7% in the SOC alone group and 70.0% in the IL-6 inhibitor group met the defined endpoints for clinical response (P = 0.477). In the adjusted analysis, patients treated with IL-6 inhibitors were approximately 4 times more likely to meet the primary endpoint compared with patients with SOC alone (adj. odds ratio = 4.325; P = 0.038, 95% confidence interval = [1.09-17.18]). Conclusions: Compared with SOC alone, IL-6 inhibitors were not associated with a significant clinical response. However, after adjusting for covariates, this study suggests that the initiation of IL-6 inhibitors in patients with early COVID-19 pneumonitis before progression to the ICU may be associated with improved clinical status.

Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial.

Importance: Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients. Objective: To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension. Design, Setting, and Participants: A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019. Interventions: Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307). Main Outcome and Measures: The primary clinical outcome was all-cause mortality at 90 days. Results: Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, -5.0; 95% CI, -7.8 to -2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, -8.7 mg; 95% CI, -12.8 to -4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, -2.85%; 95% CI, -6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33 [2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]). Conclusions and Relevance: Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study. Trial Registration: isrctn.org Identifier: ISRCTN10580502.

Effect of a Nurse-Led Preventive Psychological Intervention on Symptoms of Posttraumatic Stress Disorder Among Critically Ill Patients: A Randomized Clinical Trial.

Importance: A meta-analysis of outcomes during the 6 months after intensive care unit (ICU) discharge indicate a prevalence for clinically important posttraumatic stress disorder (PTSD) symptoms of 25%. Objective: To determine whether a nurse-led preventive, complex psychological intervention, initiated in the ICU, reduces patient-reported PTSD symptom severity at 6 months. Design, Setting, and Participants: A multicenter, parallel-group, cluster-randomized clinical trial with integrated economic and process evaluations conducted in 24 ICUs in the United Kingdom. Participants were critically ill patients who regained mental capacity following receipt of level 3 (intensive) care. A total of 2961 eligible patients were identified from September 2015 to January 2017. A total of 2048 were approached for participation in the ICU, of which 1458 provided informed consent. Follow-up was completed December 2017. Interventions: Twenty four ICUs were randomized 1:1 to the intervention or control group. Intervention ICUs (n = 12; 669 participants) delivered usual care during a baseline period followed by an intervention period. The preventive, complex psychological intervention comprised promotion of a therapeutic ICU environment plus 3 stress support sessions and a relaxation and recovery program delivered by trained ICU nurses to high-risk (acutely stressed) patients. Control ICUs (n = 12; 789 participants) delivered usual care in both baseline and intervention periods. Main Outcomes and Measures: The primary clinical outcome was PTSD symptom severity among survivors at 6 months measured using the PTSD Symptom Scale-Self-Report questionnaire (score range, 0-51, with higher scores indicating greater symptom severity; the minimal clinically important difference was considered to be 4.2 points). Results: Among 1458 enrolled patients (mean [SD] age, 58 [16] years; 599 women [41%]), 1353 (93%) completed the study and were included in the final analysis. At 6 months, the mean PTSD Symptom Scale-Self-Report questionnaire score in intervention ICUs was 11.8 (baseline period) compared with 11.5 (intervention period) (difference, -0.40 [95% CI, -2.46 to 1.67]) and in control ICUs, 10.1 (baseline period) compared with 10.2 (intervention period) (difference, 0.06 [95% CI, -1.74 to 1.85]) between periods. There was no significant difference in PTSD symptom severity at 6 months (treatment effect estimate [difference in differences] of -0.03 [95% CI, -2.58 to 2.52]; P = .98). Conclusions and Relevance: Among critically ill patients in the ICU, a nurse-led preventive, complex psychological intervention did not significantly reduce patient-reported PTSD symptom severity at 6 months. These findings do not support the use of this psychological intervention. Trial Registration: ISRCTN53448131.

Hygrothermal monitoring of replacement infill panels for historic timber-frame buildings: initial findings.

Energy retrofits aim to improve the thermal performance of buildings' external envelopes. With buildings of traditional construction there exists the risk that these improvements may lead to interstitial condensation and moisture accumulation. For historic timber-framed buildings, this potentially exposes the embedded historic timbers to conditions favouring fungal decay and insect infestation. Hygrothermal digital simulations can assess this risk, but these have limitations, especially regarding the study of historic and traditional materials, due to a lack of accurate material data. The research presented in this paper therefore uses the monitoring of physical test panels to examine the performance of four different infill solutions. These are, traditional wattle and daub, a composite of wood fibre and wood wool boards, expanded cork board, and hempcrete. The article focuses on the design and construction of the test cell and presents initial results from the first year of monitoring, following the initial drying phase. These showed no evidence of interstitial condensation in any of the panel build-ups, with increases in moisture content correlating directly with climatic measurements of wind-driven rain. Infill materials with low moisture permeability were seen to produce higher moisture contents at the interface with the external render due to the concentration of moisture at this point. Those panels finished in the more moisture permeable lime-hemp plaster, overall present lower moisture contents, with reduced drying times. The use of perimeter, non-moisture permeable, sealants would appear to potentially trap moisture at the junction between infill and historic timber-frame. The monitoring work is ongoing.

Reduced exposure to vasopressors through permissive hypotension to reduce mortality in critically ill people aged 65 and over: the 65 RCT.

BACKGROUND: Vasopressors are administered to critical care patients to avoid hypotension, which is associated with myocardial injury, kidney injury and death. However, they work by causing vasoconstriction, which may reduce blood flow and cause other adverse effects. A mean arterial pressure target typically guides administration. An individual patient data meta-analysis (Lamontagne F, Day AG, Meade MO, Cook DJ, Guyatt GH, Hylands M, et al. Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock. Intensive Care Med 2018;44:12-21) suggested that greater exposure, through higher mean arterial pressure targets, may increase risk of death in older patients. OBJECTIVE: To estimate the clinical effectiveness and cost-effectiveness of reduced vasopressor exposure through permissive hypotension (i.e. a lower mean arterial pressure target of 60-65 mmHg) in older critically ill patients. DESIGN: A pragmatic, randomised clinical trial with integrated economic evaluation. SETTING: Sixty-five NHS adult general critical care units. PARTICIPANTS: Critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension. INTERVENTIONS: Intervention - permissive hypotension (i.e. a mean arterial pressure target of 60-65 mmHg). Control (usual care) - a mean arterial pressure target at the treating clinician's discretion. MAIN OUTCOME MEASURES: The primary clinical outcome was 90-day all-cause mortality. The primary cost-effectiveness outcome was 90-day incremental net monetary benefit. Secondary outcomes included receipt and duration of advanced respiratory and renal support, mortality at critical care and acute hospital discharge, and questionnaire assessment of cognitive decline and health-related quality of life at 90 days and 1 year. RESULTS: Of 2600 patients randomised, 2463 (permissive hypotension, n = 1221; usual care, n = 1242) were analysed for the primary clinical outcome. Permissive hypotension resulted in lower exposure to vasopressors than usual care [mean duration 46.0 vs. 55.9 hours, difference -9.9 hours (95% confidence interval -14.3 to -5.5 hours); total noradrenaline-equivalent dose 31.5 mg vs. 44.3 mg, difference -12.8 mg (95% CI -18.0 mg to -17.6 mg)]. By 90 days, 500 (41.0%) patients in the permissive hypotension group and 544 (43.8%) patients in the usual-care group had died (absolute risk difference -2.85%, 95% confidence interval -6.75% to 1.05%; p = 0.154). Adjustment for prespecified baseline variables resulted in an odds ratio for 90-day mortality of 0.82 (95% confidence interval 0.68 to 0.98) favouring permissive hypotension. There were no significant differences in prespecified secondary outcomes or subgroups; however, patients with chronic hypertension showed a mortality difference favourable to permissive hypotension. At 90 days, permissive hypotension showed similar costs to usual care. However, with higher incremental life-years and quality-adjusted life-years in the permissive hypotension group, the incremental net monetary benefit was positive, but with high statistical uncertainty (£378, 95% confidence interval -£1347 to £2103). LIMITATIONS: The intervention was unblinded, with risk of bias minimised through central allocation concealment and a primary outcome not subject to observer bias. The control group event rate was higher than anticipated. CONCLUSIONS: In critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension, permissive hypotension did not significantly reduce 90-day mortality compared with usual care. The absolute treatment effect on 90-day mortality, based on 95% confidence intervals, was between a 6.8-percentage reduction and a 1.1-percentage increase in mortality. FUTURE WORK: Future work should (1) update the individual patient data meta-analysis, (2) explore approaches for evaluating heterogeneity of treatment effect and (3) explore 65 trial conduct, including use of deferred consent, to inform future trials. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10580502. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 14. See the NIHR Journals Library website for further project information.

Low blood pressure is common in patients in intensive care. It is associated with a high risk of death. It can be treated with drugs called vasopressors. These drugs raise blood pressure, but also come with risks and side effects. Usually, a blood pressure target is used to guide how much of the drugs to give to patients. Two previous clinical trials suggested that using a lower blood pressure target (and therefore giving less of the drugs) might reduce the number of deaths among older patients. However, although these results were promising, more research was needed to find out if they were correct. The 65 trial was carried out to test if using a lower blood pressure target really did improve outcomes for older patients. The trial also looked at whether or not it would provide value for money for the NHS. A total of 2600 patients aged ≥ 65 years who had low blood pressure in intensive care joined the trial. Half were randomly assigned to the new lower blood pressure target (less drugs). The other half were assigned to usual care (control group). As we had hoped, patients in the low blood pressure target group received less vasopressor drugs than the usual-care group. After 90 days, 41% of patients in the new low blood pressure target group had died, compared with 44% in the usual-care group. Although fewer patients died in the low blood pressure target group, the difference was small and may have occurred by chance. On average, the new target saved a small amount of money for the NHS. Although we could not prove that use of a lower blood pressure target saves lives for older patients in intensive care, our trial suggests that it might. Receiving less vasopressor drugs appeared safe for patients.

Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Protocol for the 65 randomised clinical trial.

Vasodilatory shock is common in critically ill patients and vasopressors are a mainstay of therapy. A meta-analysis suggested that use of a higher, as opposed to a lower, mean arterial pressure target to guide titration of vasopressor therapy, could be associated with a higher risk of death in older critically ill patients. The 65 trial is a pragmatic, multi-centre, parallel-group, open-label, randomised clinical trial of permissive hypotension (a mean arterial pressure target of 60 -65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial is conducted in 2600 patients from 65 United Kingdom adult, general critical care units. The primary outcome is all-cause mortality at 90 days. An economic evaluation is embedded. The 65 trial received favourable ethical opinion from the South Central - Oxford C Research Ethics Committee and approval from the Health Research Authority. The results will be presented at national and international conferences and published in peer-reviewed medical journals. Trial registration: ISRCTN10580502.

Providing psychological support to people in intensive care: development and feasibility study of a nurse-led intervention to prevent acute stress and long-term morbidity.

OBJECTIVES: Adverse psychological outcomes, following stressful experiences in critical care, affect up to 50% of patients. We aimed to develop and test the feasibility of a psychological intervention to reduce acute stress and prevent future morbidity. DESIGN: A mixed-methods intervention development study, using two stages of the UK Medical Research Council framework for developing and testing complex interventions. Stage one (development) involved identifying an evidence base for the intervention, developing a theoretical understanding of likely processes of change and modelling change processes and outcomes. Stage two comprised two linked feasibility studies. SETTING: Four UK general adult critical care units. PARTICIPANTS: Stage one: former and current patients, and psychology, nursing and education experts. Stage two: current patients and staff. OUTCOMES: Feasibility and acceptability to staff and patients of content and delivery of a psychological intervention, assessed using quantitative and qualitative data. Estimated recruitment and retention rates for a clinical trial. RESULTS: Building on prior work, we standardised the preventative, nurse-led Provision Of Psychological support to People in Intensive Care (POPPI) intervention. We devised courses and materials to train staff to create a therapeutic environment, to identify patients with acute stress and to deliver three stress support sessions and a relaxation and recovery programme to them. 127 awake, orientated patients took part in an intervention feasibility study in two hospitals. Patient and staff data indicated the complex intervention was feasible and acceptable. Feedback was used to refine the intervention. 86 different patients entered a separate trial procedures study in two other hospitals, of which 66 (80% of surviving patients) completed questionnaires on post-traumatic stress, depression and health 5 months after recruitment. CONCLUSION: The 'POPPI' psychological intervention to reduce acute patient stress in critical care and prevent future psychological morbidity was feasible and acceptable. It was refined for evaluation in a cluster randomised clinical trial. TRIAL REGISTRATION NUMBER: ISRCTN61088114; Results.