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Markers of Inflammation and Lung Recovery in ECMO Patients for PPHN (Mi-ECMO)

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ClinicalTrials.gov Identifier: NCT02940327
Recruitment Status : Completed
First Posted : October 20, 2016
Last Update Posted : April 25, 2019
Sponsor:
Collaborators:
University Hospitals, Leicester
Heart Link Children's Charity
British Heart Foundation
Information provided by (Responsible Party):
University of Leicester

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.

Condition or disease
Persistent Pulmonary Hypertension of the Newborn

Detailed Description:

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:

  1. Damage to red cells will result in platelet, leukocyte and endothelial activation.
  2. Markers of platelet, endothelial and leukocyte activation are indicators of lung inflammation and injury severity and hence lung recovery.
  3. Markers of platelet, endothelial and leukocyte activation are indicators of kidney injury severity and hence acute kidney injury.
  4. The level of oxidative stress will correlate with type shifts in pulmonary macrophages, tissue iron deposition and organ injury.
  5. 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.
  6. 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.
  7. 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 pilot feasibility study that will establish the following:

  1. Recruitment rates and patient flows for 24 patients specified as the target population for the feasibility study
  2. Withdrawal rate, and completeness of follow-up and data collection in a paediatric population at high risk for death and major morbidity
  3. The proportions (categorical data) and variance (continuous data) for the primary and secondary outcomes of interest. These will be used to model the sample sizes and outcomes that may be used in a definitive study
  4. Perceptions of family members whose children participate in the study as to the appropriateness of the screening and consent process

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Study Type : Observational
Actual Enrollment : 24 participants
Observational Model: Case-Control
Time Perspective: Prospective
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 Persistent Pulmonary Hypertension of the Newborn (PPHN): Mi-ECMO
Study Start Date : February 19, 2016
Actual Primary Completion Date : July 10, 2017
Actual Study Completion Date : July 10, 2017

Resource links provided by the National Library of Medicine





Primary Outcome Measures :
  1. 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.

  2. 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)


Secondary Outcome Measures :
  1. 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

  2. Clinical and biochemical markers of organ failure [ Time Frame: One year ]
    Time to wean from ECMO

  3. 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


  4. Percentage of patients weaned from ECMO within 7 days [ Time Frame: one year ]
    Clinical and biochemical markers of organ failure

  5. AKI as defined by the KDIGO definition [ Time Frame: one year ]
    Clinical and biochemical markers of organ failure

  6. 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

  7. 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

  8. 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

  9. Non red cell transfusion volume [ Time Frame: one year ]
    Clinical and biochemical markers of organ failure

  10. Time to discharge from ICU [ Time Frame: one year ]
    Clinical and biochemical markers of organ failure

  11. Time to Hospital discharge [ Time Frame: one year ]
    negative prognostic factor

  12. 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

  13. 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

  14. 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)

  15. A questionnaire will assess parents/family/guardians experience of the [ Time Frame: one year ]
    Statistics and demographic study


Biospecimen Retention:   Samples With DNA
Blood samples, Urine samples, Respiratory samples


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 30 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
The study will be conducted at a regional ECMO centre in the UK, the University Hospitals of Leicester NHS Trust. This unit performs over 60 neonatal and paediatric ECMO per year, of which at least 40 are expected to be performed for the treatment of PPHN in infants.
Criteria

Inclusion Criteria:

  1. Patients with a diagnosis of PPHN
  2. Patients that require ECMO support as determined by the ECMO team
  3. Patients aged less than 30 days
  4. Emergency consent obtained within 12 hours from cannulation, and ultimately full consent

Exclusion Criteria:

  1. PPHN is caused by a congenital heart pathology
  2. ECMO is required for a congenital heart disease
  3. Lack of consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02940327


Locations
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United Kingdom
University Hospitals of Leicester NHS Trust
Leicester, United Kingdom, LE3 9QP
Sponsors and Collaborators
University of Leicester
University Hospitals, Leicester
Heart Link Children's Charity
British Heart Foundation

Publications:

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Responsible Party: University of Leicester
ClinicalTrials.gov Identifier: NCT02940327     History of Changes
Other Study ID Numbers: UNLOE 0553
First Posted: October 20, 2016    Key Record Dates
Last Update Posted: April 25, 2019
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: statistical analysis
Keywords provided by University of Leicester:
ECMO
PPHN
Pulmonary Hypertension of the Newborn
Markers of inflammation
Mi-Ecmo
Additional relevant MeSH terms:
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Hypertension, Pulmonary
Persistent Fetal Circulation Syndrome
Hypertension
Inflammation
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Infant, Newborn, Diseases