Title: Is the mechanism of action of hypertonic saline and/or carbocisteine in the treatment of patients with acute respiratory failure due to an increase in mucus hydration?
Funder: Medical Research Council

Abstract: Many patients in the intensive care unit (ICU) need a breathing machine (ventilator) to help them to breathe. However, one problem that can occur from being on a ventilator, is difficulty clearing secretions (sputum) from the lungs. The air we breathe normally is naturally moistened by the body’s respiratory system so that secretions can be cleared easily. Unfortunately, this vital process does not work with a ventilator. As a result, secretions can become thick and dry making breathing harder. The breathing tube from the ventilator can make coughing up secretions even more difficult. Patients may also feel too sleepy from their medication to cough by themselves. This may result in developing an infection in the lungs (ventilator-associated pneumonia)._x000D_ To reduce the problem of thick secretions, air coming from the ventilator can have moisture added to it (humidification). Other treatments include using a suction tube to remove secretions via the breathing tube. Physiotherapists may also use techniques to help clear thick secretions. In some cases, medications called mucoactives may be prescribed. Around one-third of patients in UK ICUs receive a mucoactive at any time. The most common two are called ‘carbocisteine’ and ‘hypertonic saline’. However, we do not know if these medications really help patients with secretions that are difficult to clear._x000D_ We are currently conducting a clinical trial (the MARCH trial) to see whether using one, or both, of these mucoactives helps with clearing thick secretions, and if as a result, patients spend less time on the ventilator. We will also find out if they can improve other important outcomes during the ICU stay. However, although these medications have been used for many years, little is known about the biological way in which they might work to help clear thick secretions. We call this the ‘mechanism of action’. We would therefore like to carry out an additional study, as part of the MARCH trial, to investigate the mechanism of action of carbocisteine and hypertonic saline. We plan to obtain sputum samples, which would otherwise be discarded, from patients taking part in the MARCH trial at three time points – at the start, Day 3, and Day 7. We will then transfer these samples to the laboratory and measure two different features of the sputum. Firstly, how hydrated (wet) the sputum is, secondly, the thickness and stickiness of the sputum and finally measure aspects of inflammation in the sputum. These measurements will mean we can find out if using carbocisteine or hypertonic saline makes sputum less dry, thick, and sticky, and may show us how these medications work. If the MARCH trial is successful, it may explain why secretions are easier to clear in patients receiving these medications. We may also find out if use of mucoactives offer value for money to the NHS. Understanding the mechanism of action of carbocisteine and hypertonic saline will help us plan how best to use these medications with critically ill patients in the ICU and help us plan future studies of these medications better._x000D_ We have an experienced team of people guiding this study. They include scientists, physiotherapists, doctors, former patients and family members, and others with expertise in the study methods. Together they will ensure that this study runs safely and efficiently, as part of the main MARCH trial.

Lay abstract: Research question_x000D_ Is the mechanism of action of carbocisteine and/or hypertonic saline in the treatment of critically ill patients with acute respiratory failure due to an increase in mucus hydration?_x000D_ Background_x000D_ Patients with acute respiratory failure (ARF) experience an increased risk of respiratory tract secretion retention due to altered secretion rheology and impaired mucociliary clearance. The use of carbocisteine and hypertonic saline are now being evaluated in patients with ARF as part of the MARCH trial and in this study we will focus on the mechanistic effects of carbocisteine and hypertonic saline in patients with ARF._x000D_ Hypothesis_x000D_ Treatment of critically ill patients with ARF with carbocisteine, hypertonic saline, or both, will lead to increased mucus hydration and changes in sputum viscosity and elasticity._x000D_ Aim:_x000D_ The aim of this study is to determine if critically ill patients with ARF treated with carbocisteine, hypertonic saline, or both, experience increased hydration of airway mucus (reflected as a reduced percentage mucus solid content)._x000D_ Objectives_x000D_ 1. To measure percentage mucus solid content (dry-to-wet weight ratio) of sputum at following commencement of treatment with carbocisteine, hypertonic saline, or both or usual care airway clearance management alone (no mucoactive)_x000D_ 2. To measure the yield stress (Tc) (derived from sputum viscosity (G’) and elasticity (G’’)) following commencement of treatment with carbocisteine, hypertonic saline, or both or usual airway clearance management alone (no mucoactive)_x000D_ 3. To measure the inflammatory mediators, IL-6, IL-8 and 8-isoprostane following commencement of treatment with carbocisteine, hypertonic saline, or both or usual airway clearance management alone (no mucoactive)_x000D_ Methods_x000D_ We will obtain sputum samples from patients recruited to the MARCH study. Sputum samples will be collected at 3 time-points during the study; baseline (at randomisation), Day 3 and Day 7. The solids concentration of mucus will be measured and dynamic rheology measurements will be recorded including G’ and G” of samples from which the Tc value will be obtained. Inflammatory mediators will be measured by ELISA._x000D_ Delivery of project_x000D_ The MARCH trial is currently in set-up with patient recruitment on target to commence on 1st November 2021. The EME study, if successfully funded, will start in May 2022 with a brief set-up period of 3 months required to develop the sample handling guidelines for the study. Another 15 months will be allocated for collection and analysis of sputum for mucus solid measurements, rheometry and inflammatory mediators. In addition, 6 months will be required for data linking with main trial outcomes and final reporting_x000D_ Impact and Dissemination_x000D_ The primary focus of this project is to show that treatment of ARF with carbocisteine and/or hypertonic saline may increase sputum hydration and reduce sputum viscosity and elasticity and inflammation thus improving mucus clearance from the lungs of patients with ARF. The positive effect of carbocisteine and/or hypertonic saline to changes in any of these parameters may lead to the development of even more effective drugs for the treatment of ARF. The findings of this work will be disseminated through conferences, peer reviewed publications, and through patient and public representatives. The outputs of this work will also be aligned with the outputs of the main MARCH trial.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY