Clinical Trial: Markers of Inflammation and Lung Recovery in ECMO Patients for PPHN
Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational
Official Title: A Feasibility Study to Consider the Relationship Between Markers of Red Cell Damage, Inflammation and the Recovery Process of Newborns Requiring Extracorporeal Membrane Oxygenation (ECMO) for
Brief Summary: Respiratory failure in newborns is common and has high rates of death. Where conventional intensive care strategies have failed, newborn children are referred to treatment with Extra- Corporeal Membrane Oxygenation (ECMO). This involves connecting children via large bore cannulas placed in their heart and major blood vessels to an artificial lung that adds oxygen to their blood and removes waste gases (carbon dioxide). Although this treatment saves lives, it still has some limitations. In particular, severe complications like bleeding, or damage to the kidneys can occur. These complications can lead to death in some cases and long-term disability in others. Based on ongoing research in adults and children undergoing cardiac surgery the investigators have identified a new process that may underlie some of the complications observed in ECMO. The investigators have noted that when transfused blood is infused in an ECMO circuit, this results in the accelerated release of substances from the donor cells that cause organ damage; at least in adults. There are treatments that can reverse this process. Before the investigators explore whether these treatments should be used in newborn children on ECMO, the investigators must first demonstrate that they can measure the complex inflammatory processes that occur in these critically ill children. The investigators therefore propose to conduct a feasibility study to identify the practical issues and challenges that would need to be overcome in order to perform a successful trial in this high-risk population.
Detailed Summary:
The primary hypothesis is that damage to red blood cells by the exposure to the ECMO circuit will result in inflammatory responses that mitigate against successful weaning from Extra-Corporeal Membrane Oxygenation (ECMO) for Persistent Pulmonary Hypertension of the Newborn (PPHN).
The secondary hypothesis are:
- Damage to red cells will result in platelet, leukocyte and endothelial activation.
- Markers of platelet, endothelial and leukocyte activation are indicators of lung inflammation and injury severity and hence lung recovery.
- Markers of platelet, endothelial and leukocyte activation are indicators of kidney injury severity and hence acute kidney injury.
- The level of oxidative stress will correlate with type shifts in pulmonary macrophages, tissue iron deposition and organ injury.
- Ability to raise anti-oxidative response, measured by Heme Oxigenase-1 (HMOX 1) expression, will correlate with shorter intubation times and less severe kidney and lung injury.
- Granulocyte and platelets activation are secondary to rising redox potential and the levels of activation will correlate with longer intubation times and more severe organ injury.
- Markers of anti-oxidative response, platelet, endothelial and leukocyte activation, as well as oxidative stress levels have diagnostic and prognostic utility for the prediction of key clinical events including delayed time to recovery, acute kidney injury in paediatric patients undergoing Extra-Corporeal Membrane Oxygenation (ECMO) for Persistent Pulmonary Hypertension of the Newborn (PPHN).
This is a
Sponsor: University of Leicester
Current Primary Outcome:
- Change of markers of platelet and leukocyte activation in arterial blood [ Time Frame: 2-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Platelets and leukocyte activation, as well as platelets—leukocyte aggregates will be determined with specific antibodies (CD41, PAC-1 and CD62P for platelets, CD64, CD163 and CD11a for leukocytes and CD14, CD16, CD41 for the aggregates) and analysed by flow cytometry. Full blood count will be measured.
- Change of markers of endothelial cell activation in arterial blood [ Time Frame: 2-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Cytokines and chemokines important in monocyte/macrophage differentiation and renal injury, e.g. IL-6, -8, TNFα, MCP-1 and MIP-1, as well as markers of endothelial injury (circulating ICAM or E-selectin) may be measured from serum on the Luminex MAGPIX Analyser (Oosterhout, NL)
Original Primary Outcome: Same as current
Current Secondary Outcome:
- Change of serum haemoglobin levels [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]biochemical markers of organ failure
- Clinical and biochemical markers of organ failure [ Time Frame: One year ]Time to wean from ECMO
- Pulmonary inflammation as determined qualitatively by analysis of bronchial aspirates lysates [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]
Bronchial aspirates samples will be spun and the pelleted cells washed with PBS. Iron deposition will be assessed using ferrocyanide method where BA smears are stained with Prussian Blue and analysed by light microscopy.
Remaining cells will be lysed and frozen at -80C for WB analysis with HMOX-1 antibodies to estimate oxidative stress response and iNOS and Arginase (Arg-1) antibodies to assess macrophage/T-cells M1/Th1 and M2/Th2 responses in lungs
- Percentage of patients weaned from ECMO within 7 days [ Time Frame: one year ]Clinical and biochemical markers of organ failure
- AKI as defined by the KDIGO definition [ Time Frame: one year ]Clinical and biochemical markers of organ failure
- Heart injury as determined by serum troponin levels [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- Renal inflammation as determined by urine NGAL concentrations [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- Allogenic red cell transfusion volume [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- Non red cell transfusion volume [ Time Frame: one year ]Clinical and biochemical markers of organ failure
- Time to discharge from ICU [ Time Frame: one year ]Clinical and biochemical markers of organ failure
- Time to Hospital discharge [ Time Frame: one year ]negative prognostic factor
- Measures of haemoglobin metabolism [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- Levels of inflammatory cytokines in serum [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- MV levels [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]MV will be isolated by centrifugation (1,500 g, 15 min ×2 at 4°C). MV size will be evaluated using the Nanosight. Mean size and particle concentration values will be calculated using Nanoparticle Tracking Analysis software using the manufacturer's instructions. Antigen expression on MV, indicative of the cell of origin will be determined using flow cytometry (Beckman Coulter MCL-XK or a Cyan ADP 9 colour instrument)
- A questionnaire will assess parents/family/guardians experience of the [ Time Frame: one year ]Statistics and demographic study
Original Secondary Outcome:
- Change of serum haemoglobin levels [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]biochemical markers of organ failure
- Clinical and biochemical markers of organ failure [ Time Frame: discharge ]Time to wean from ECMO
- Pulmonary inflammation as determined qualitatively by analysis of bronchial aspirates lysates [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]
Bronchial aspirates samples will be spun and the pelleted cells washed with PBS. Iron deposition will be assessed using ferrocyanide method where BA smears are stained with Prussian Blue and analysed by light microscopy.
Remaining cells will be lysed and frozen at -80C for WB analysis with HMOX-1 antibodies to estimate oxidative stress response and iNOS and Arginase (Arg-1) antibodies to assess macrophage/T-cells M1/Th1 and M2/Th2 responses in lungs
- Percentage of patients weaned from ECMO within 7 days [ Time Frame: one year ]Clinical and biochemical markers of organ failure
- AKI as defined by the KDIGO definition [ Time Frame: one year ]Clinical and biochemical markers of organ failure
- Heart injury as determined by serum troponin levels [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- Renal inflammation as determined by urine NGAL concentrations [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- Allogenic red cell transfusion volume [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- Non red cell transfusion volume [ Time Frame: one year ]Clinical and biochemical markers of organ failure
- Time to discharge from ICU [ Time Frame: one year ]Clinical and biochemical markers of organ failure
- Time to Hospital discharge [ Time Frame: one year ]negative prognostic factor
- Measures of haemoglobin metabolism [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- Levels of inflammatory cytokines in serum [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]Clinical and biochemical markers of organ failure
- MV levels [ Time Frame: 12-24-48 and 72 hours after ECMO commencement and 24 hours after ECMO is discontinued ]MV will be isolated by centrifugation (1,500 g, 15 min ×2 at 4°C). MV size will be evaluated using the Nanosight. Mean size and particle concentration values will be calculated using Nanoparticle Tracking Analysis software using the manufacturer's instructions. Antigen expression on MV, indicative of the cell of origin will be determined using flow cytometry (Beckman Coulter MCL-XK or a Cyan ADP 9 colour instrument)
- A questionnaire will assess parents/family/guardians experience of the [ Time Frame: one year ]Statistics and demographic study
Information By: University of Leicester
Dates:
Date Received: October 13, 2016
Date Started: February 2016
Date Completion: February 2017
Last Updated: October 20, 2016
Last Verified: October 2016
