Developmental Clinical Studies - development of vitamin D therapy to prevent acute lung injury.
Lead Research Organisation:
University of Birmingham
Department Name: Clinical and Experimental Medicine
Abstract
The aim of this research is to develop vitamin D as a therapy to prevent acute lung injury. Acute lung injury ALI is a major cause of lung failure in critically ill patients. Most patients affected are of working age and survivors experience a significant reduction in health-related quality of life, with 46% unable to return to work within 12 months. Currently, apart from invasive protective ventilation, no therapy has been conclusively proven to reduce mortality or improve functional outcome in survivors. This represents a major unmet health need.
By undertaking this research we will establish if simple and cheap replacement of vitamin D influences the development and severity of acute lung injury.
By undertaking this research we will establish if simple and cheap replacement of vitamin D influences the development and severity of acute lung injury.
Technical Summary
ALI is a major cause of respiratory failure in critically ill patients. Most patients affected are of working age and survivors experience a significant reduction in health-related quality of life, with 46% unable to return to work within 12 months. Currently, apart from protective ventilation strategies, no therapy has been conclusively proven to reduce mortality or improve functional outcome in survivors. Clearly this represents a major unmet health need.
ALI is the final common pathway of response to a variety of direct pulmonary insults such as bacterial /viral pneumonia and gastric aspiration, or indirect insults such as abdominal sepsis or battlefield trauma. However, only a relatively small proportion of patients develop ALI, with research suggesting that genetic, demographic (age), social (smoking, alcohol abuse) and other factors play a role in determining who develops ALI.
Patients undergoing transthoracic oesophagectomy are at significant risk of developing post operative lung injury (~28%), with the development of lung injury associated with a doubling of in hospital stay and significant mortality.Hospital episode statistics show that ~1500 to 2000 oesophagectomies are performed in England annually. There are no current readily available tests that can clearly identify those who are at high risk of ALI following oesophagectomy, and no therapeutic interventions proven to prevent its occurrence.
Epidemiological studies have suggested a role for vitamin D deficiency in the risk of developing both viral and bacterial infection. Vitamin D has profound effects on human immunity acting as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the ?oxidative burst? potential of macrophages, therefore enhancing bacterial killing. In preliminary studies we have found that vitamin D deficiency/ insufficiency is ubiquitous in both patients with ALI and oesophagectomy cases who are at risk of ALI. Severe deficiency is associated with elevated systemic inflammatory response and an increased risk of developing lung injury in the oesophagectomy group.
This proposal aims in a series of clinical studies to determine the proof of concept and optimal dosing strategy for administering cholecalciferol liquid preoperatively to prevent lung injury in oesophagectomy using established markers of bioactivity /efficacy in the setting of ALI.
The proposed treatment is simple and if effective could be easily incorporated into widespread clinical practice. The results from this trial will provide the basis for future clinical studies investigating this and other preventative strategies in broader subject groups known to be at risk of ARDS such as pneumonia and sepsis.
ALI is the final common pathway of response to a variety of direct pulmonary insults such as bacterial /viral pneumonia and gastric aspiration, or indirect insults such as abdominal sepsis or battlefield trauma. However, only a relatively small proportion of patients develop ALI, with research suggesting that genetic, demographic (age), social (smoking, alcohol abuse) and other factors play a role in determining who develops ALI.
Patients undergoing transthoracic oesophagectomy are at significant risk of developing post operative lung injury (~28%), with the development of lung injury associated with a doubling of in hospital stay and significant mortality.Hospital episode statistics show that ~1500 to 2000 oesophagectomies are performed in England annually. There are no current readily available tests that can clearly identify those who are at high risk of ALI following oesophagectomy, and no therapeutic interventions proven to prevent its occurrence.
Epidemiological studies have suggested a role for vitamin D deficiency in the risk of developing both viral and bacterial infection. Vitamin D has profound effects on human immunity acting as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the ?oxidative burst? potential of macrophages, therefore enhancing bacterial killing. In preliminary studies we have found that vitamin D deficiency/ insufficiency is ubiquitous in both patients with ALI and oesophagectomy cases who are at risk of ALI. Severe deficiency is associated with elevated systemic inflammatory response and an increased risk of developing lung injury in the oesophagectomy group.
This proposal aims in a series of clinical studies to determine the proof of concept and optimal dosing strategy for administering cholecalciferol liquid preoperatively to prevent lung injury in oesophagectomy using established markers of bioactivity /efficacy in the setting of ALI.
The proposed treatment is simple and if effective could be easily incorporated into widespread clinical practice. The results from this trial will provide the basis for future clinical studies investigating this and other preventative strategies in broader subject groups known to be at risk of ARDS such as pneumonia and sepsis.