Pressure ulcers in patients with COVID-19 acute respiratory distress syndrome undergoing prone positioning in the intensive care unit: a pre- and post-intervention study

Background: Prone positioning has been widely used to improve oxygenation and reduce ventilator-induced lung injury in patients with severe COVID-19 acute respiratory distress syndrome (ARDS). One major complication associated with prone positioning is the development of pressure ulcers (PUs). Aim: This study aimed to determine the impact of a prevention care bundle on the incidence of PUs in patients with COVID-19 ARDS undergoing prone positioning in the intensive care unit. Study design: This was a single-centre pre and post-test intervention study which adheres to the Standards for Reporting Implementation Studies (StaRI) guidelines. The intervention included a care bundle addressing the following: increasing frequency of head turns, use of an open gel head ring, application of prophylactic dressings to bony prominences, use of a pressure redistribution air mattress, education of staff in the early identification of evolving PUs through regular and rigorous skin inspection and engaging in bedside training sessions with nursing and medical staff. The primary outcome of interest was the incidence of PU development. The secondary outcomes of interest were severity of PU development and the anatomical location of the PUs. Results: In the pre-intervention study, 20 patients were included and 80% (n = 16) of these patients developed PUs, comprising 34 ulcers in total. In the post-intervention study, a further 20 patients were included and 60% (n = 12) of these patients developed PUs, comprising 32 ulcers in total. This marks a 25% reduction in the number of patients developing a PU, and a 6% decrease in the total number of PUs observed. Grade II PUs were the most prevalent in both study groups (65%, n = 22; 88%, n = 28, respectively). In the post-intervention study, there was a reduction in the incidence of grade III and deep tissue injuries (pre-intervention 6%, n = 2 grade III, 6% n = 2 deep tissue injuries; post-intervention no grade III ulcers, grade IV ulcers, or deep tissues injuries were recorded). However, there was an increase in the number of unstageable PUs in the post-intervention group with 6% (n = 2) of PUs being classified as unstageable, meanwhile there were no unstageable PUs in the pre-intervention group. This is an important finding to consider as unstageable PUs can indicate deep tissue damage and therefore need to be considered alongside PUs of a more severe grade (grade III, grade IV, and deep tissue injuries). Conclusion: The use of a new evidence-based care bundle for the prevention of PUs in the management of patients in the prone position has the potential to reduce the incidence of PU development. Although improvements were observed following alterations to standard practice, further research is needed to validate these findings. Relevance to clinical practice: The use of a new, evidence-based care bundle in the management of patients in the prone position has the potential to reduce the incidence of PUs.</p

A randomised, double-blind, placebo-controlled, pilot trial of intravenous plasma purified alpha-1 antitrypsin for SARS-CoV-2-induced Acute Respiratory Distress Syndrome: a structured summary of a study protocol for a randomised, controlled trial

Objectives: The primary objective is to demonstrate that, in patients with PCR-confirmed SARS-CoV-2 resulting in Acute Respiratory Distress Syndrome (ARDS), administration of 120mg/kg of body weight of intravenous Prolastin®(plasma-purified alpha-1 antitrypsin) reduces circulating plasma levels of interleukin-6 (IL-6). Secondary objectives are to determine the effects of intravenous Prolastin® on important clinical outcomes including the incidence of adverse events (AEs) and serious adverse events (SAEs). Trial design: Phase 2, randomised, double-blind, placebo-controlled, pilot trial. Participants: The study will be conducted in Intensive Care Units in hospitals across Ireland. Patients with a laboratory-confirmed diagnosis of SARS-CoV-2-infection, moderate to severe ARDS (meeting Berlin criteria for a diagnosis of ARDS with a PaO2/FiO2 ratio 18 years of age and requiring invasive or non-invasive mechanical ventilation. All individuals meeting any of the following exclusion criteria at baseline or during screening will be excluded from study participation: more than 96 hours has elapsed from onset of ARDS; age < 18 years; known to be pregnant or breastfeeding; participation in a clinical trial of an investigational medicinal product (other than antibiotics or antivirals) within 30 days; major trauma in the prior 5 days; presence of any active malignancy (other than nonmelanoma skin cancer) which required treatment within the last year; WHO Class III or IV pulmonary hypertension; pulmonary embolism prior to hospital admission within past 3 months; currently receiving extracorporeal life support (ECLS); chronic kidney disease receiving dialysis; severe chronic liver disease with Child-Pugh score > 12; DNAR (Do Not Attempt Resuscitation) order in place; treatment withdrawal imminent within 24 hours; Prisoners; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; IgA deficiency. Intervention and comparator: Intervention: Either a once weekly intravenous infusion of Prolastin® at 120mg/kg of body weight for 4 weeks or a single dose of Prolastin® at 120mg/kg of body weight intravenously followed by once weekly intravenous infusion of an equal volume of 0.9% sodium chloride for a further 3 weeks. Comparator (placebo): An equal volume of 0.9% sodium chloride intravenously once per week for four weeks. Main outcomes: The primary effectiveness outcome measure is the change in plasma concentration of IL-6 at 7 days as measured by ELISA. Secondary outcomes include: safety and tolerability of Prolastin® in the respective groups (as defined by the number of SAEs and AEs); PaO2/FiO2 ratio; respiratory compliance; sequential organ failure assessment (SOFA) score; mortality; time on ventilator in days; plasma concentration of alpha-1 antitrypsin (AAT) as measured by nephelometry; plasma concentrations of interleukin-1β (IL-1β), interleukin-8 (IL-8), interleukin-10 (IL-10), soluble TNF receptor 1 (sTNFR1, a surrogate marker for TNF-α) as measured by ELISA; development of shock; acute kidney injury; need for renal replacement therapy; clinical relapse, as defined by the need for readmission to the ICU or a marked decline in PaO2/FiO2 or development of shock or mortality following a period of sustained clinical improvement; secondary bacterial pneumonia as defined by the combination of radiographic findings and sputum/airway secretion microscopy and culture. Randomisation: Following informed consent/assent patients will be randomised. The randomisation lists will be prepared by the study statistician and given to the unblinded trial personnel. However, the statistician will not be exposed to how the planned treatment will be allocated to the treatment codes. Randomisation will be conducted in a 1:1:1 ratio, stratified by site and age. Blinding (masking): The investigator, treating physician, other members of the site research team and patients will be blinded to treatment allocation. The clinical trial pharmacy personnel and research nurses will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set to maintain blinding. Numbers to be randomised (sample size): A total of 36 patients will be recruited and randomised in a 1:1:1 ratio to each of the trial arms. </p

A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for ARDS secondary to COVID-19

Background: Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15).  Methods: Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1β, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints.  Findings: Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1β, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients.  Conclusions: In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic.  Funding: ECSA-2020-009; Elaine Galwey Research Bursary.</p