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Study of GSK2862277 in Subjects Undergoing Oesophagectomy Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02221037
Recruitment Status : Terminated (The study was terminated on the basis that protocol defined stopping criteria had been met.)
First Posted : August 20, 2014
Results First Posted : January 11, 2019
Last Update Posted : January 11, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
Lung injury in patients undergoing oesophagectomy may occur during surgery (peri-operatively) as a result of One Lung Ventilation (OLV) and/or during the immediate post-operative period when patients receive intensive care. This is reinforced by the observation that physiological markers of lung injury are most elevated immediately after completion of surgery, and the development of clinical Acute Respiratory Distress Syndrome (ARDS)occurs immediately post-operatively (within 72 hours of surgery), with the majority of cases reported 24-48 hours after completion of surgery. This study is designed to investigate the impact of pre-operative administration of GSK2862277 on biological and physiological markers of lung injury in patients undergoing surgical resection of oesophageal cancer in order to achieve optimal exposure at the site of injury following OLV and lung deflation. This study is a randomized placebo controlled, double-blind, multi-centre, single dose parallel group, design. There will be two treatment groups comprising one active and one placebo arm with approximately 40 patients per group. Patients enrolled in the study will be scheduled to undergo planned/elective trans-thoracic surgery for oesophagectomy. The primary endpoint for this study is the change in pulmonary vascular permeability index (PVPI) from pre-surgical levels to the end of surgery. GSK2862277 will be administered as an orally inhaled aerosol (single nebulized dose) over approximately 3 to 5 minutes (min) 1-3 hours prior to surgery. Subject will be monitored daily until discharge and followed up till day 28.

Condition or disease Intervention/treatment Phase
Lung Injury, Acute and Respiratory Distress Syndrome, Adult Drug: GSK2862277 Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Placebo Controlled, Double-blind, Multi-centre, Single Dose, Parallel Group, Randomised Clinical Trial of GSK2862277 in Patients Undergoing Oesophagectomy Surgery
Actual Study Start Date : April 28, 2015
Actual Primary Completion Date : June 28, 2017
Actual Study Completion Date : June 28, 2017


Arm Intervention/treatment
Experimental: GSK2862277
GSK2862277 will be administered as single orally inhaled aerosol over approximately 3 to 5 minutes; approximately 1-3 hours prior to the subjects scheduled surgery, before the initiation of pre-operative procedures. After surgery subject will undergo either ventilated or collapsed lung BAL procedure. Regular assessments will be conducted until the time of patient discharge. Subjects will be followed up as outpatients at Day 28
Drug: GSK2862277
It is available as 26 milligrams (mg) white to off-white, uniform lyophilized cake that will be reconstituted (using reconstitution fluid formulated with polysorbate 80 in Water for Injection) to 40 mg/vial of Lyophile for reconstitution for inhalation with duration of nebulisation as approximately 3-5 min and will be administered using "Pari eFlow with s30 mesh" device.

Placebo Comparator: Placebo
Placebo will be administered as single orally inhaled aerosol over approximately 3 to 5 minutes; approximately 1-3 hours prior to the subjects scheduled surgery, before the initiation of pre-operative procedures. After surgery subject will be undergo either ventilated or collapsed lung BAL procedure. Regular assessments will conducted until the time of patient discharge. Subjects will be followed up as outpatients at Day 28
Drug: Placebo
It is a clear, colorless to pale yellow liquid, will be administered in volume to match active dose as solution for inhalation with duration of nebulisation as approximately 3-5 min and will be administered using "Pari eFlow with s30 mesh" device.




Primary Outcome Measures :
  1. Baseline Adjusted Change in Pulmonary Vascular Permeability Index (PVPI) on Completion of Surgery [ Time Frame: Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery) ]
    PVPI is a derived value from extra vascular lung water (EVLW), and is considered to be less variable than extra vascular lung water Index (EVLWI). PVPI was measured via single-indicator transpulmonary thermodilution with a patent indwelling Pulse Contour Cardiac Output (PiCCO) catheter. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. Per-Protocol 1 (PP1) Population comprised of all the participants in the Safety population for whom the treatment actually received was the same one when they were randomized to (both study drug and BAL sampling location).


Secondary Outcome Measures :
  1. Baseline Adjusted Change in EVLWI on Completion of Surgery [ Time Frame: Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery) ]
    EVLW refers to the fluid within the lung but outside the vascular compartment. It includes extravasated plasma, intracellular water, lymphatic fluid, and surfactant. EVLWI was measured by trans-pulmonary thermodilution via a PiCCO hemodynamic monitor. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. Only those participants with data available at the specified time points were analyzed.

  2. Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [ Time Frame: Up to Day 31 ]
    AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with use of a medicinal product (MP), whether or not considered related to MP. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with use of MP. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia. Safety Population comprised of all participants who received at least one complete dose of study treatment.

  3. Number of Participants With Hematology Abnormalities of Potential Clinical Importance [ Time Frame: Up to Day 8 ]
    Hematology parameters included basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils, neutrophil bands, platelets, red blood cell (RBC) count, segmented neutrophils and white blood cell (WBC) count. The potential clinical concern values were: hematocrit (low: <0.3 fraction and high: >0.54 fraction), Hemoglobin (low: <90 gram per Liter and high: >180 gram per Liter), lymphocytes (low: <0.6 x 10^9 cells/Liter and high: >3.0 x 10^9 cells/Liter), neutrophils: (low: <1.5 x 10^9 cells/Liter and high: >20 x 10^9 cells/Liter), platelets: (low: <100 x 10^9 cells/Liter and high: >600 x 10^9 cells/Liter) and WBC: (low: <3 x 10^9 cells/Liter and high: >20 x 10^9 cells/Liter). Only those participants for which at least one value of potential clinical concern was reported are summarized.

  4. Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance [ Time Frame: Up to Day 8 ]
    Clinical chemistry parameters and their potential clinical concern values were: albumin (low: <25 millimole [mmol]/L and high: >60 mmol/L), calcium (low: <1.8 mmoL/L and high: >2.75 mmol/L), creatinine (low: <30 mmol/L and high: >160 mmol/L), glucose (low: <3 mmol/L and high: >9 mmol/L), potassium (low: <2.5 mmol/L and high: >5.5 mmol/L), sodium (low: <120 mmol/L and high: >160 mmol/L), total carbon dioxide content (low: <16 mmol/L and high: >35 mmol/L) and blood urea nitrogen (low: <3 mmol/L and high: >15 mmol/L). Number of participants with clinical chemistry abnormalities of potential clinical importance are presented.

  5. Number of Participants With Abnormal Urinalysis Parameters [ Time Frame: Day 1 (pre-dose) and Day 8 ]
    Urinalysis included dipstick urine test which was used to screen for glucose, ketones, occult blood and protein on Day 1 (pre-dose) and Day 8. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine glucose, ketones, occult blood and protein can be read as Trace, 1+, 2+ and 3+, indicating proportional concentrations in the urine sample.

  6. Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Importance [ Time Frame: Days 1, 2, 4 and 8 ]
    Single 12-lead ECGs were obtained thereafter during the study, using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, RR and corrected QT (QTc) intervals. Number of participants with ECG values of potential clinical importance are presented.

  7. Number of Participants With Vital Signs of Potential Clinical Importance [ Time Frame: Up to Day 31 ]
    Vital sign measurements included systolic and diastolic blood pressure, pulse rate, temperature and respiratory rate. Vital sign measurements were measured in a semi-recumbent or supine position after 5 minutes rest. The potential clinical concern range for systolic blood pressure: <85 and >160 millimeters of mercury, for diastolic: <45 and >100 millimeters of mercury and heart rate: <40 and >110 beats per minute. Number of participants with vital signs of potential clinical importance are presented.

  8. Baseline Adjusted Change in PaO2/FiO2 on Completion of Surgery [ Time Frame: Baseline (Day 1 [immediately prior to start of surgery]) and Day 1 (on completion of surgery) ]
    Oxygenation and function of gas exchange was assessed by the comparison of partial pressure of oxygen arterially (PaO2) divided by the fraction of oxygen that is being inspired (FiO2), sometimes referred to simply as the 'P to F ratio'. The P to F ratio was assessed at time points during the period of intubation and mechanical ventilation. An arterial blood sample was required for determination of the partial pressure of oxygen and the percentage of O2 which is being inspired was recorded at the corresponding time point. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value.

  9. Levels of BAL Biomarkers on Completion of Surgery [ Time Frame: Day 1 (on completion of surgery) ]
    Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay on Day 1 after completion of surgery. BAL biomarkers included soluble tumor necrosis factor receptor (STNFR) type I, free, STNFR type I, total, tumor necrosis factor alpha, interleukin 6, interleukin 8, interleukin 1 beta, monocyte chemotactic protein-1, macrophage inflammatory protein 1 alpha, macrophage inflammatory protein 1 beta, interleukin 10 and soluble receptor for advanced glycation end (sRAGE) products. Any value below limit of quantification was replaced with half the lower limit of quantification (LLQ) prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

  10. Levels of BAL Biomarkers (C-reactive Protein and Total Proteins) on Completion of Surgery [ Time Frame: Day 1 (on completion of surgery) ]
    Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay. BAL biomarkers included C-reactive protein and total proteins. Any value below limit of quantification was replaced with half the LLQ prior to deriving the summary measures. All BAL C-reactive protein samples were below limit of quantification and all were assigned to half the LLQ prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

  11. Levels of BAL Biomarkers (Surfactant Protein and Clara Cell Secretory Protein) on Completion of Surgery [ Time Frame: Day 1 (on completion of surgery) ]
    Samples were collected to determine concentrations of biomarkers in BAL using an appropriately validated assay. BAL biomarkers included surfactant protein D and clara cell secretory protein. Any value below limit of quantification was replaced with half the LLQ prior to deriving the summary measures. Mean levels of BAL biomarkers on completion of surgery are presented. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

  12. Change Over Time in PaO2/FiO2 Post-operatively on Day 2 Through to Day 4 [ Time Frame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4 ]
    Oxygenation and function of gas exchange was assessed by the comparison of PaO2 divided by the FiO2, sometimes referred to simply as the 'P to F ratio'. The P to F ratio was assessed at time points during the period of intubation and mechanical ventilation. An arterial blood sample was required for determination of the partial pressure of oxygen and the percentage of O2 which is being inspired was recorded at the corresponding time point. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value (on completion of surgery on Day 1) minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

  13. Change Over Time in PVPI Post-operatively on Day 2 Through to Day 4 [ Time Frame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4 ]
    PVPI is a derived value from EVLW, and is considered to be less variable than EVLWI. PVPI was measured via single-indicator transpulmonary thermodilution as long as the participant remained in the ICU with a patent indwelling PiCCO catheter. Baseline was Day 1 (immediately prior to start of surgery). Change from Baseline value was the post-Baseline value minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

  14. Change Over Time in EVLWI Post-operatively on Day 2 Through to Day 4 [ Time Frame: Baseline (Day 1 [immediately prior to start of surgery]) to Days 2, 3 and 4 ]
    EVLW refers to the fluid within the lung but outside the vascular compartment. It includes extravasated plasma, intracellular water, lymphatic fluid, and surfactant. EVLWI was measured by trans-pulmonary thermodilution via a PiCCO hemodynamic monitor. Change from Baseline value was the post-Baseline value minus Baseline value. PP1 Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X,X,X in the category titles.

  15. Daily Sequential Organ Failure Assessment (SOFA) Scores on Day 2 Through to Day 4 [ Time Frame: Day 2 to Day 4 ]
    The SOFA score defines the presence and severity of dysfunction within 6 organ systems (cardiovascular, respiratory, coagulation, liver, renal, and nervous system) with a value of "0" for assigned to normal function to a maximum value of "4" for severe dysfunction in each of the organ systems. Each component of the SOFA score was added together, ranging from "0" indicating no organ dysfunction in any of the 6 organ systems, to "24" indicating maximal organ dysfunction across all 6 organ systems. Per-Protocol (PP) 2 Population comprised of all the participants in the Safety population for whom the study drug actually received was the same one they were randomized to (study drug).

  16. Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0 to t]) [ Time Frame: Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose) ]
    Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points. Pharmacokinetic (PK) Population comprised of all participants in the Safety population for whom a pharmacokinetic sample (plasma and/or BAL) was obtained and analyzed.

  17. Maximum Observed Concentration (Cmax) [ Time Frame: Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose) ]
    Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points.

  18. Derived Pharmacokinetic Parameter- Half-life (t1/2) and Time of Occurrence of Cmax (Tmax) [ Time Frame: Day 1 (pre-dose, 1 hour post-dose and on completion of surgery), Day 2 (24 to 26 hours post-dose) and Day 3 (46 to 50 hours post-dose) ]
    Half-life (t1⁄2) is the time required for a quantity to reduce to half its initial value. t1/2 was not determined in all cases due to insufficient data in the terminal phase. Blood samples for pharmacokinetic analysis of GSK2862277 were collected at the indicated time points. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

  19. Ratio of Total Protein Derived From BAL and Plasma Values [ Time Frame: Day 1 (on completion of surgery) ]
    BAL sampling and plasma sampling was done on Day 1 (on completion of surgery). Raw summary statistics for the derived ratio were not produced. Only statistical modeling was performed that produced a posterior distribution for each treatment. Summary measure for the posterior distribution was the median. The quantity being modeled was the mean treatment effect (pooling data from BAL Collapsed and Ventilated Lungs). The standard deviation is capturing the dispersion of the estimate for the mean effect. Ratio of total protein (Ratio was derived from BAL and Plasma values) is presented.

  20. Number of Participants With Positive Immunogenicity Results Post-dosing [ Time Frame: Day 8 and Day 31 ]
    Serum samples were obtained to determine incidence and titers of serum anti-GSK2862277 antibodies at the specified time points. The binding antibody detection assay was performed at the specified time points. Number of participants with positive immunogenicity results post-dosing is presented.

  21. BAL Concentrations of GSK2862277 [ Time Frame: Day 1 (on completion of surgery) ]
    BAL samples were collected on Day 1 (on completion of surgery) and BAL concentrations of GSK2862277 and derived PK parameters were determined. Only those participants available at the specified time points were analyzed.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject has a planned elective transthoracic oesophagectomy
  • Male or female between 18 and 80 years of age inclusive, at the time of signing the informed consent.
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  • A female subject is eligible to participate if she is of:
  • Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 milli-International Units per milliliter and estradiol < 40 picograms per milliliter (<147 picomoles per liter) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
  • Liver parameters according to the thresholds below: Aspartate aminotransferase and Alanine aminotransferase < 5x Upper limit of normal (ULN); alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • QT duration corrected for heart rate by Bazett's formula (QTcB) or QT duration corrected for heart rate by Fridericia's formula (QTcF) <= 480 milliseconds (msec) at screening
  • Either QTcB or QTcF, machine or manual over-read can be used. This applies to both males and females. The QT correction formula used to determine inclusion and discontinuation for an individual subject should be the same throughout the study.
  • Based on average QTc value of triplicate ECGs obtained over a brief recording period.

Exclusion Criteria:

  • Positive screening test for pre-existing antibodies that bind GSK2862277.
  • Current evidence or history of pneumonia within 14 days before dosing.
  • Diagnosis of chronic respiratory disease with a forced expiratory volume in one second (FEV1) less than 50% predicted or resting oxygen saturations of less 92%.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
  • The subject has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Use of corticosteroids (Intravenous, oral or Intramuscular) at a dose of >= 10 Milligrams per day (mg/day) prednisolone (or equivalent) within 14 days prior to dosing, or anti-Tumor Necrosis Factor (anti-TNF) or anti-IL1 within 60 days prior to dosing.

Criteria Based Upon Medical Histories

  • History or current evidence of clinically significant renal disease, diabetes mellitus/metabolic syndrome, hypertension, peripheral vascular disease or any other clinically significant respiratory, cardiovascular, neurological, endocrine, or hematological abnormalities that are uncontrolled on permitted therapy. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the patients at risk through study participation, or which would affect the safety analysis or other analysis if the disease/condition exacerbated during the study.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of regular alcohol consumption within 6 months of the study, defined as: an average weekly intake of >28 units for males or >14 units for females. One unit is equivalent to 8 grams of alcohol: a half-pint [~240 milliliter (ml)] of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits Criteria Based Upon Diagnostic Assessments
  • Screens positive for Hepatitis B surface antigen, Hepatitis C antibody
  • Known Human Immunodeficiency Virus (HIV) positive; testing will be conducted in accordance with local procedures
  • Tests positive for Mycobacterium tuberculosis using QuantiFERON Gold Test. Other Criteria
  • Subject has received a live attenuated vaccine(s) within 3 weeks of randomisation or will require vaccination with a live attenuated vaccine prior to the end of the study (Day 28).
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subject is mentally or legally incapacitated.

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): NCT02221037


Locations
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United Kingdom
GSK Investigational Site
Cottingham, Yorkshire, United Kingdom, HU16 5JQ
GSK Investigational Site
Belfast, United Kingdom, BT9 7AB
GSK Investigational Site
Birmingham, United Kingdom, B15 2TH
GSK Investigational Site
Birmingham, United Kingdom, B9 5SS
GSK Investigational Site
Cambridge, United Kingdom, CB2 0QQ
GSK Investigational Site
Leicester, United Kingdom, LE2 7LX
GSK Investigational Site
Middlesborough, United Kingdom, TS4 3BU
GSK Investigational Site
Nottingham, United Kingdom, NG5 1PB
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] August 23, 2016
Statistical Analysis Plan  [PDF] November 17, 2015

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02221037    
Other Study ID Numbers: 116341
First Posted: August 20, 2014    Key Record Dates
Results First Posted: January 11, 2019
Last Update Posted: January 11, 2019
Last Verified: March 2018
Keywords provided by GlaxoSmithKline:
PaO2/FiO2
Peri-operative lung injury
EVLWI
ARDS
PVPI
SOFA scores
GSK2862277
Oesophagectomy
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Lung Injury
Acute Lung Injury
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Thoracic Injuries
Wounds and Injuries