The CHARTER-Ireland trial: can nebulised heparin reduce acute lung injury in patients with SARS-CoV-2 requiring advanced respiratory support in Ireland: a study protocol and statistical analysis plan for a randomised control trial.

BACKGROUND: COVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia. METHODS: This is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1ß, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1ß/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP. DISCUSSION: This trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT04511923 . Registered on 13 August 2020. Protocol version 8, 22/12/2021 Protocol identifier: NUIG-2020-003 EudraCT registration number: 2020-003349-12 9 October 2020.

Bolus remifentanil for chest drain removal in ICU: a randomized double-blind comparison of three modes of analgesia in post-cardiac surgical patients.

PURPOSE: We compared 1 versus 0.5 microg/kg bolus remifentanil versus placebo in alleviating pain due to chest drain removal. Effects on sedation, respiratory rate (RR), oxygen saturation, heart rate (HR) and blood pressure were also evaluated. METHODS: Sixty patients following cardiac surgery were enrolled in this prospective, randomized, double-blind clinical trial. Patients were randomized to 1 or 0.5 microg/kg remifentanil or placebo. All received standardized analgesia. Visual analog scale (VAS) pain scores and cardio-respiratory data were recorded pre-procedure, at drain removal and at 2 min intervals post procedure. RESULTS: Patients receiving remifentanil had statistically significantly less pain than placebo at drain removal [median (25-75%) VAS: 0.5 microg/kg remifentanil 1 (0-2) versus placebo 5 (3-6), P = 0.001; 1.0 microg/kg remifentanil 0 (0-2) versus placebo 5 (3-6), P = 0.0001]. VAS scores between remifentanil groups were equivalent. Remifentanil 1 microg/kg versus placebo at drain removal revealed significant reductions in HR [mean +/- standard deviation (SD): 76 +/- 15 versus 92 +/- 10, P = 0.01], blood pressure [mean +/- SD: 103 +/- 22 versus 131 +/- 14, P = 0.01] and RR [median (25-75%): 10 (8-12) versus 16 (14-18), P = 0.001]. Remifentanil 0.5 microg/kg versus placebo at drain removal revealed significant reductions in blood pressure [mean +/- SD: 116 +/- 19 versus 131 +/- 14, P = 0.02] and RR [median (25-75%): 12 (10-13) versus 18 (16-18), P = 0.001]. SpO(2) at drain removal was significantly reduced when comparing 1 microg/kg remifentanil versus placebo [median (25-75%): 94 (88-97) versus 97 (96-98), P = 0.049] but not 0.5 microg/kg remifentanil versus placebo. Two patients became apnoeic following 1 microg/kg remifentanil, necessitating respiratory support. Sedation scores in all groups were similar. CONCLUSIONS: Bolus remifentanil at the tested doses delivers excellent analgesia, but 1 microg/kg remifentanil results in respiratory depression. Remifentanil bolus at 0.5 microg/kg is safe and effective for chest drain removal after heart surgery in ICU.