A randomized controlled trial of nebulized surfactant for the treatment of severe COVID-19 in adults (COVSurf trial).

SARS-CoV-2 directly targets alveolar epithelial cells and can lead to surfactant deficiency. Early reports suggested surfactant replacement may be effective in improving outcomes. The aim of the study to assess the feasibility and efficacy of nebulized surfactant in mechanically ventilated COVID-19 patients. Patients were randomly assigned to receive open-labelled bovine nebulized surfactant or control (ratio 3-surfactant: 2-control). This was an exploratory dose-response study starting with 1080 mg of surfactant delivered at 3 time points (0, 8 and 24 h). After completion of 10 patients, the dose was reduced to 540 mg, and the frequency of nebulization was increased to 5/6 time points (0, 12, 24, 36, 48, and an optional 72 h) on the advice of the Trial Steering Committee. The co-primary outcomes were improvement in oxygenation (change in PaO2/FiO2 ratio) and ventilation index at 48 h. 20 patients were recruited (12 surfactant and 8 controls). Demographic and clinical characteristics were similar between groups at presentation. Nebulized surfactant administration was feasible. There was no significant improvement in oxygenation at 48 h overall. There were also no differences in secondary outcomes or adverse events. Nebulized surfactant administration is feasible in mechanically ventilated patients with COVID-19 but did not improve measures of oxygenation or ventilation.

A prospective multicentre observational study to quantify nocturnal light exposure in intensive care.

Background: Disrupted circadian rhythms can have a major effect on human physiology and healthcare outcomes, with proven increases in ICU morbidity, mortality and length of stay. Methods: We performed a multicentre observational study to study the nocturnal lux exposure of patients in 3 intensive care units. Results: The median light intensity recorded was 1 lux over the 6-hour recording period; however, this is deceptive as it hides short periods of high lux. When looked at in shorter time segments of 30 minutes, there were significant periods of lux higher than a crude median, especially in higher acuity patients. There was a positive correlation between acuity (as estimated by SOFA score) and maximum lux (R = 0.479, p = .0001), median lux (R = 0.35, p = .006) and cumulative lux (R = 0.55, p = .000001). There was no relationship between neighbouring patient acuity and lux. Conclusions: Clinicians should practice vigilance at night to provide optimal environmental conditions for patients to minimise potential harm.

Frailty in the over 65's undergoing elective surgery (FIT-65) - a three-day study examining the prevalence of frailty in patients presenting for elective surgery.

BACKGROUND: Frailty increases the risk of perioperative complications, length of stay, and the need for assisted-living after discharge. As the UK population ages the number of frail patients presenting for elective surgery in the UK is likely to grow. Despite the potential benefits of early diagnosis, frailty is not uniformly screened for in UK elective surgical patients and its prevalence remains unclear. The primary aim of this study was to assess the prevalence of frailty in patients aged over 65 years undergoing elective surgery. METHODS: We performed a prospective cross-sectional observational study in eight UK hospitals. Data were collected over three consecutive days with follow-up at 30 days. HRA approval was obtained (REC 20/SC/0121) and signed informed consent obtained. Participants were eligible for inclusion if they were 65 years or older and undergoing elective surgery. Pre-operative data were collected from hospital notes by anaesthetic trainees. A member of the research team blinded to the pre-operative dataset screened each participant for frailty pre-operatively using the Reported Edmonton Frail Scale (REFS). Post-operative data were collected from the notes on day of surgery and at 30 days. Participants were defined as "frail" if they scored 8 or more on the REFS. RESULTS: Two hundred twenty eight participants were recruited during the study period of whom 218 proceeded to surgery. There were 103 females and 115 males. Median age was 75 years (interquartile range 70-80). Thirty-seven participants (17.0%) were identified as frail. Frail patients were older, had a higher ASA score, were more likely to have carers and were more likely to be anaemic or present with ECG abnormalities. There were no differences in gender, BMI, place of residence or smoking status for patients identified as frail versus non-frail. There was no difference in length-of-stay between frail and non-frail patients, although those identified as frail were less likely to be discharged to their own home. CONCLUSION: We found the prevalence of frailty in a mixed population of elective surgical patients aged 65 or over to be 17.0%. Furthermore, we found the REFS to be a practical tool for pre-operative frailty screening. Frail patients presented for elective surgery with modifiable co-morbidities which could have been optimised pre-operatively. Early screening could highlight frail patients, allowing time for pre-operative planning and evidence-based optimisations of comorbidities. We therefore encourage the adoption of frailty assessment as a routine part of pre-operative assessment.

Caring for COVID-19 patients through a pandemic in the intensive care setting: A narrative review.

Since the declaration of the novel SARS-CoV-2 virus pandemic, health systems/ health-care-workers globally have been overwhelmed by a vast number of COVID-19 related hospitalizations and intensive care unit (ICU) admissions. During the early stages of the pandemic, the lack of formalized evidence-based guidelines in all aspects of patient management was a significant challenge. Coupled with a lack of effective pharmacotherapies resulted in unsatisfactory outcomes in ICU patients. The anticipated increment in ICU surge capacity was staggering, with almost every ICU worldwide being advised to increase their capacity to allow adequate care provision in response to multiple waves of the pandemic. This increase in surge capacity required advanced planning and reassessments at every stage, taking advantage of experienced gained in combination with emerging evidence. In University Hospital Southampton General Intensive Care Unit (GICU), despite the initial lack of national and international guidance, we enhanced our ICU capacity and developed local guidance on all aspects of care to address the rapid demand from the increasing COVID-19 admissions. The main element of this success was a multidisciplinary team approach intertwined with equipment and infrastructural reorganization. This narrative review provides an insight into the approach adopted by our center to manage patients with COVID-19 critical illness, exploring the initial planning process, including contingency preparations to accommodate (360% capacity increment) and adaptation of our management pathways as more evidence emerged throughout the pandemic to provide the most appropriate levels of care to our patients. We hope our experience will benefit other intensive care units worldwide. This article is categorized under: Infectious Diseases > Genetics/Genomics/Epigenetics.

Perioperative Risk Stratification and Modification.

This article discusses the important topic of perioperative risk stratification and the interventions that can be used in the perioperative period for risk modification. It begins with a brief overview of the commonly used scoring systems, risk-prediction models, and assessments of functional capacity and discusses some of the evidence behind each. It then moves on to examine how perioperative risk can be modified through the use of shared decision making, management of multimorbidity, and prehabilitation programs, before considering what the future of risk stratification and modification may hold.

Compassionate use of Pulmonary Vasodilators in Acute Severe Hypoxic Respiratory Failure due to COVID-19.

BACKGROUND: There have been over 200 million cases and 4.4 million deaths from COVID-19 worldwide. Despite the lack of robust evidence one potential treatment for COVID-19 associated severe hypoxaemia is inhaled pulmonary vasodilator (IPVD) therapy, using either nitric oxide (iNO) or prostaglandins. We describe the implementation of, and outcomes from, a protocol using IPVDs in a cohort of patients with severe COVID-19 associated respiratory failure receiving maximal conventional support. METHODS: Prospectively collected data from adult patients with SARS-CoV-2 admitted to the intensive care unit (ICU) at a large teaching hospital were analysed for the period 14th March 2020 - 11th February 2021. An IPVD was considered if the PaO2/FiO2 (PF) ratio was less than 13.3kPa despite maximal conventional therapy. Nitric oxide was commenced at 20ppm and titrated to response. If oxygenation improved Iloprost nebulisers were commenced and iNO weaned. The primary outcome was percentage changes in PF ratio and Alveolar-arterial (A-a) gradient. RESULTS: Fifty-nine patients received IPVD therapy during the study period. The median PF ratio before IPVD therapy was commenced was 11.33kPa (9.93-12.91). Patients receiving an IPVD had a lower PF ratio (14.37 vs. 16.37kPa, p = 0.002) and higher APACHE-II score (17 vs. 13, p = 0.028) at ICU admission. At 72 hours after initiating an IPVD the median improvement in PF ratio was 33.9% (-4.3-84.1). At 72 hours changes in PF ratio (70.8 vs. -4.1%, p < 0.001) and reduction in A-a gradient (44.7 vs. 14.8%, p < 0.001) differed significantly between survivors (n = 33) and non-survivors (n = 26). CONCLUSIONS: The response to IPVDs in patients with COVID-19 associated acute hypoxic respiratory failure differed significantly between survivors and non-survivors. Both iNO and prostaglandins may offer therapeutic options for patients with severe refractory hypoxaemia due to COVID-19. The use of inhaled prostaglandins, and iNO where feasible, should be studied in adequately powered prospective randomised trials.

Nebulised surfactant for the treatment of severe COVID-19 in adults (COV-Surf): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: SARS-Cov-2 virus preferentially binds to the Angiotensin Converting Enzyme 2 (ACE2) on alveolar epithelial type II cells, initiating an inflammatory response and tissue damage which may impair surfactant synthesis contributing to alveolar collapse, worsening hypoxia and leading to respiratory failure. The objective of this study is to evaluate the feasibility, safety and efficacy of nebulised surfactant in COVID-19 adult patients requiring mechanical ventilation for respiratory failure. TRIAL DESIGN: This study is a dose-escalating randomized open-label clinical trial of 20 COVID-19 patients. PARTICIPANTS: This study is conducted in two centres: University Hospital Southampton and University College London Hospitals. Eligible participants are aged ≥18, hospitalised with COVID-19 (confirmed by PCR), who require endotracheal intubation and are enrolled within 24 hours of mechanical ventilation. For patients unable to consent, assent is obtained from a personal legal representative (PerLR) or professional legal representative (ProfLR) prior to enrolment. The following are exclusion criteria: imminent expected death within 24 hours; specific contraindications to surfactant administration (e.g. known allergy, pneumothorax, pulmonary hemorrhage); known or suspected pregnancy; stage 4 chronic kidney disease or requiring dialysis (i.e., eGFR < 30); liver failure (Child-Pugh Class C); anticipated transfer to another hospital, which is not a study site, within 72 hours; current or recent (within 1 month) participation in another study that, in the opinion of the investigator, would prevent enrollment for safety reasons; and declined consent or assent. INTERVENTION AND COMPARATOR: Intervention: The study is based on an investigational drug/device combination product. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactant formulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilled syringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13% phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5% cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lyso-phosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, an investigational device based on the Aerogen® Solo vibrating mesh nebulizer. The timing and escalation dosing plans for the surfactant are as follows. Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and 30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention. Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240 mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls. 2 controls with no placebo intervention. The trial steering committee, advised by the data monitoring committee, will review trial progression and dose escalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached) based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinued on the basis of lack of efficacy. The trial may be stopped early on the basis of safety or feasibility concerns. Comparator: No placebo intervention. All participants will receive usual standard of care in accordance with the local policies for mechanically ventilated patients and all other treatments will be left to the discretion of the attending physician. MAIN OUTCOMES: The co-primary outcome is the improvement in oxygenation (PaO2/FiO2 ratio) and pulmonary ventilation (Ventilation Index (VI), where VI = [RR x (PIP - PEEP) × PaCO2]/1000) at 48 hours after study initiation. The secondary outcomes include frequency and severity of adverse events (AEs), Adverse Device Effects (ADEs), Serious Adverse Events (SAEs) and Serious Adverse Device Events (SADEs), change in pulmonary compliance, change in positive end-expiratory pressure (PEEP) requirement of ventilatory support at 24 and 48 hours after study initiation, clinical improvement defined by time to one improvement point on the ordinal scale described in the WHO master protocol (2020) recorded while hospitalised, days of mechanical ventilation, mechanical ventilator free days (VFD) at day 21, length of intensive care unit stay, number of days hospitalised and mortality at day 28. Exploratory end points will include quantification of SARS-CoV-2 viral load from tracheal aspirates using PCR, surfactant dynamics (synthesis and turnover) and function (surface tension reduction) from deep tracheal aspirate samples (DTAS), surfactant phospholipid concentrations in plasma and DTAS, inflammatory markers (cellular and cytokine) in plasma and DTAS, and blood oxidative stress markers. RANDOMISATION: After informed assent, patients fulfilling inclusion criteria will be randomised to 3:2 for the treatment and control arms using an internet-based block randomization service (ALEA tool for clinical trials, FormsVision BV) in combination with electronic data collection. Randomisation will be done by the recruiting centre with a unique subject identifier specific to that centre. BLINDING (MASKING): This is an open-labelled unblinded study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The total sample size is 20 COVID-19 mechanically ventilated patients (12 intervention; 8 control). TRIAL STATUS: Current protocol version is V2 dated 5th of June 2020. The recruitment is currently ongoing and started on the 14th of October 2020. The anticipated study completion date is November 2021. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04362059 (Registered 24 April 2020), EUDAMED number: CIV-GB-20-06-033328, EudraCT number: 2020-001886-35 (Registered 11 May 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).