Clinical trial NCT04064684
Conditions: Acute Respiratory Distress Syndrome
Keywords: Pediatric acute respiratory distress syndrome PARDS Budesonide inhaled steroids
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2020-02-04; Completion date: 2020-03-30
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to show that inhaled steroids in patient with PARDS can decrease the days on mechanical ventilator measured by ventilator-free days,to improve the oxygenation index (OI) or oxygenation saturation index (OSI) in patients receiving inhaled steroids and to show the relevance and feasibility of a larger study by assessing the hypothesis in a small cohort of patients. Patient will be treated for a maximum of 10 days. Secondary objectives are to reduce the length of stay (LOS) in the pediatric intensive care unit (PICU) and hospital admissions; to show less inflammation in the patients receiving inhaled steroids by measuring inflammatory markers from tracheal aspirates like Interleukin (IL6, IL8, tumor necrosis factor (TNF) α, matrix metalloproteinase8 (MMP8) and matrix metalloproteinase9 (MMP9). Lastly, to show that inhaled steroids can improve residual lung disease evaluated by Pulmonary Function Test (PFTs) and Impulse Oscillometry (IOS).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Budesonide intervention 2: Placebo intervention 3: Nebulizer
Intervention descriptions: intervention 1: Enrolled patients will be treated with Pulmicort Respules® (Budesonide inhalation suspension), at a dose of 0.5 mg, nebulized twice daily through the mechanical ventilator. The medication will be administered to the patient by the respiratory therapist with the single-patient-use medication nebulizer attached to the mechanical ventilator circuit. The maximum length of treatment will be 10 days. intervention 2: Enrolled patients will be treated with normal saline.The medication will be administered to the patient by the respiratory therapist with the single-patient-use medication nebulizer attached to the mechanical ventilator circuit. The maximum length of treatment will be 10 days. intervention 3: The medication will be administered to the patient by the respiratory therapist with the single-patient-use medication nebulizer attached to the mechanical ventilator circuit.

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhaled Steroids for the Treatment of Early Pediatric Acute Respiratory Distress 
Syndrome (PARDS), a Randomized Pilot Trial 
 
NCT04064684 
 
Version Date: 12/16/2019 
 
 


IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
Inhaled steroids for the treatment of early Pediatric Acute Respiratory Distress Syndrome 
(PARDS), a randomized pilot trial 
 
A. Coronado Munoz, MD1; R. Mosquera, MD2; M. Nares, MD3; V. Modem, MBBS, MS1; J. Meliones, 
MD1; Jon Tyson, MD, MPH4 
 
1 University of Texas at Houston, Memorial Hermann Children’s Hospital, Division of 
Pediatric Critical Care Medicine 
2 University of Texas at Houston, Memorial Hermann Children’s Hospital, Division of 
Pediatric Pulmonary Medicine 
3 University of Miami, Jackson Memorial Hospital, Division of Pediatric Critical Care. 
4 University of Texas at Houston, Vice Dean Clinical Research, Director Center for Clinical 
Research and Evidence-Based Medicine 
 
ABSTRACT 
Background: 
PARDS has high mortality and has no specific treatment. Inhaled steroids (IS) could help reducing 
the alveolar inflammation. Multiple animal studies examining IS for ARDS show decreased 
inflammation. One pilot trial in adults showed improvement of oxygenation immediately after IS 
administration. We believe that there is enough data to study IS as treatment for PARDS. 
Hypothesis: 
Budesonide 0.5 mg q 12 hours nebulized in mechanical ventilators (started within 72 hours of 
diagnosis of PARDS and administered for up to 10 days while ventilated) increases ventilator- 
free days during the first 28 days. 
Methods: 
Blinded randomized pragmatic trial, intend-to-treat analysis. Inclusion criteria: PARDS by PALICC 
definition [1], 30 days to 18 years old, mechanical ventilation <72 hours. Exclusion criteria: 
alveolar hemorrhage, hospice care or prior steroids use. After informed parental consent, patients 
will be stratified by severity of PARDS mild-moderate versus severe, randomized (random number 
table, block of 10, 1:1) to either nebulized budesonide or normal saline (identical appearance). 
The clinical team will manage the patients with our PARDS protocols. The medication will be 
administered for a maximum of 10 days and it will be stopped if patients have pulmonary bleeding. 
Variables and outcomes will be largely obtained from the EMR. We will aim to enroll 60 patients 
over 2 years. If our hypotheses are confirmed, the trial will justify, facilitate the design, and 
provide an evidence-based hypothesis for multicenter trial. 
 
BACKGROUND 
Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome of non-cardiogenic 
pulmonary edema caused primarily by damage to the alveolar epithelial-endothelial barrier. The 
disruption of this barrier results in accumulation of fluid in the alveolar space and the initiation of 
a complex inflammatory process [1-4]. Despite the numerous therapeutic studies performed for 
ARDS, the only therapy that has shown to improve outcomes is protective mechanical ventilation 
strategies. The clinical management in pediatrics has been historically based on extrapolation 
from adult data [2-4]. Investigated therapies without positive results in pediatrics include the use 
of Nitric Oxide, surfactant replacement, prone positioning and systemic steroids [5-13]. Inhaled 
steroids have been tried in animal studies with positive results and there is a single center pilot 
trial that has used inhaled steroids (IS), budesonide, for the treatment of ARDS in adults, that 
shows improved oxygenation immediate to the administration [14]. 
In June 2015, the Pediatric Acute Lung Injury Consensus Conference published specific 
definitions and evidence on outcomes, management and pathophysiology specific for Pediatric 


IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
Acute Respiratory Distress Syndrome (PARDS). That publication included the use of oxygenation 
measurements to define the severity of PARDS. Severity was divided in mild, moderate and 
severe depending on the Oxygenation Index or Oxygenation Saturation Index. An international 
multicenter prevalence study using those definitions found that patients with severe PARDS have 
a 90 day-mortality of 34%, versus mild 14.3% and moderate 14.5%. The rate of new cases of 
PARDS in that study was 3% of patients treated in the participating critical care units. Majority of 
those cases were secondary to pneumonia (63%) and trauma (19%). [1, 15]. 
Based on animal models of lung injury there are differences in the pathophysiology of 
PARDS with age [16]. These differences may be related to different stages of alveolarization and 
lung development and the maturation of the immune system in children. The inflammation 
produced in the alveolar space is mediated by neutrophils. In children, there are few studies 
looking at the cytokine response in PARDS [17-19]. Two different studies have demonstrated 
elevated levels of interleukins (IL), specifically IL-6 and IL-8 [20-22]. Another study found that 
elevated levels of soluble intercellular adhesion molecule-1 are associated with prolonged 
duration of mechanical ventilation and a higher mortality [23]. Elevated proteases (matrix 
metalloproteinases, MMP) like MMP-8 and MMP-9 have been shown in adult and pediatric studies 
to play key roles in the neutrophilic lung inflammation and are associated with prolonged 
mechanical ventilation [24, 25]. There is, however, poor understanding of the role that these 
mediators play as therapeutic targets and whether decreasing the inflammatory response in the 
alveolar space with the use of corticosteroids would change the clinical course of those patients 
[26, 27]. Inhaled steroids could decrease this inflammatory response in PARDS. 
There is a recently published study in adults using budesonide for ARDS, compared to 
normal saline. 60 patients were divided equally between both cohorts and they showed 
improvement of oxygenation in the group of budesonide but only in the immediate effect post 
administration [14]. Alsara et al. examined the use of preoperative inhaled steroids in adults and 
the occurrence of ALI in the postoperative period. In this patient population and when adjusting 
for COPD, the use of steroids was not associated with the development of early ALI [28]. Festic 
et al. examined the use of pre-hospital inhaled steroid use and the incidence of ALI in at-risk 
patients. The results did not show an association of lower incidence of ALI in patients receiving 
inhaled steroids. The authors concluded that the results could be affected by the population size 
leading to a Type II error [29]. There are several studies evaluating inhaled steroids in animal 
models of ARDS. A systematic review of those studies was presented in the Society of Critical 
Care Medicine conference [30]. The results are varied related to the variability of lung injury 
models. One study showed less pulmonary granulocyte accumulation in the pigs treated with the 
steroids as compared to the placebo group. Two other studies using the same treatment and 
model of lung injury, showed improved oxygenation, pulmonary compliance and survival in the 
steroid group [31-34]. Another study showed that animals receiving budesonide prior to the injury 
had less production of Tumor Necrosis Factor α (TNF α), IL-1, IL-6 and MCP-1. Overall, the use 
of IS in animal models showed less formation of lung edema, better oxygenation, less degree of 
acute lung injury and decreased leukocyte migration [35]. In pediatrics, Drago et al. published a 
pilot-study in 2015 using low dose intravenous methylprednisolone. The results were limited since 
it was a pilot study and it was an underpowered one. There was no statistical significance on the 
main outcome, which was days on mechanical ventilation. The duration of days was similar in 
both groups, 9.74 ± 6.62 versus 9.59 ± 5.21. That study showed the feasibility of developing a 
larger randomized-controlled trial using systemic steroids in pediatric patients with ARDS [9]. 
There are no studies referring to the use of inhaled steroids for PARDS. 
The use of inhaled steroids has been studied in asthma, Chronic Obstructive Pulmonary 
Disease (COPD), Cystic Fibrosis (CF) and neonatal respiratory distress syndrome. Most of the 
studies evaluating inhaled steroids anti-inflammatory effects have been performed in asthmatic 
patients. 
The only inhaled steroid approved for patients younger than 4 years of age is Budesonide 
[36-40]. Another advantage of budesonide is the ability to deliver the medication via nebulization 
in mechanically ventilated patients [41-45]. The immediate anti-inflammatory effects have been 
well described in asthmatic patients [46, 47]. More importantly, the safety profile of inhaled 


IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
steroids has been studied in large pediatric, neonatal 
 including preterm 
, and adult 
populations [36, 37, 48]. Inhaled steroids have also been studied in patients with cystic fibrosis, 
which are at higher risk of pulmonary infections, and have not been associated with a higher risk 
of infection [49, 50]. Recent studies have looked at inhaled steroids in very low birth weight 
preterm neonates for the prevention of chronic lung disease. A recent study in preterm neonates, 
ventilator-dependent infants concluded that the use of inhaled budesonide was associated with 
less incidence of bronchopulmonary dysplasia (BPD). However, there was higher mortality in the 
budesonide group (16.9% vs. 13.6%, gestational age - stratified relative risk 1.24, CI 0.91 – 1.69) 
[51]. A large Cochrane metanalysis, published in 2012, did not find evidence of advantages of 
inhaled steroids over systemic steroids in the management of ventilator-dependent preterm 
infants, but did show fewer side effects than with the use of systemic steroids [52]. Two recent 
Cochrane publications for early < 8 days and late > 7 days systemic steroids use in pre-term 
newborns for prevention of BPD concluded that the use of steroids did not outweigh the adverse 
effects. For both groups there was a faster improvement of the respiratory status assessed by 
weaning-off mechanical ventilation. In the early group, patients that received hydrocortisone had 
a higher survival rate, and for the late group the data suggests that it reduces mortality. Both 
groups had adverse events like gastrointestinal bleeding or perforation and poor neurological 
outcomes [53, 54]. A recent Cochrane publication for the use of inhaled steroids for BPD failed to 
show reduced mortality or BPD. However, this metanalysis was based in eight studies. Further 
studies are necessary to draw conclusions regarding the usefulness or not of inhaled steroids for 
this population [55]. 
We believe there is enough data to conduct a study examining the treatment of PARDS 
with inhaled steroids in a safe manner. This proposal is to perform a pilot study, the largest 
feasible trial in the time proposed, and conduct a Bayesian analysis, to estimate the probability of 
benefits of this treatment, and assess whether a multicenter is warranted [56]. We will examine 
clinical outcomes of pediatric patient with PARDS who will receive inhaled budesonide as a 
therapy. 
 
RESEARCH AIMS 
Primary Hypothesis: Budesonide 0.5 mg q 12 hours nebulized in mechanical ventilators 
(started within 72 hours of diagnosis of PARDS and administered for up to 10 days while 
ventilated) increases ventilator-free days during the first 28 days 
 
AIMS: 
− 
To show that inhaled steroids in patient with PARDS can decrease the days on mechanical 
ventilator measured by ventilator-free days. 
− 
To improve the oxygenation index (OI) or oxygenation saturation index (OSI) by 30% in 
patients receiving inhaled steroids, by day 10 or the last day of mechanical ventilation if 
this happen before day 10, starting the treatment within 72 hours of diagnosis. 
− 
To show the relevance and feasibility of a larger study by assessing the hypothesis in a 
small cohort of patients. 
− 
To show that inhaled steroids can improve residual lung disease evaluated by Pulmonary 
Function Test (PFTs) and Impulse Oscillometry (IOS) 
− 
To reduce inflammatory markers (IL6, IL8, TNF α, MMP 8 and MMP9) and neutrophil 
counts from tracheal aspirates. 
− 
To reduce the length of stay (LOS) in the PICU and hospital admissions. 
 
STUDY DESIGN AND METHODS 
Blinded randomized pragmatic pilot trial. We will include pediatric patients with Pediatric Acute 
Respiratory Distress Syndrome, diagnosed <72 hours, on mechanical ventilation. The severity of 
ARDS will be determined using established PALICC criteria determined by Oxygenation Index 


IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
(OI) and Oxygenation saturation index (OSI) [1]. The definitions are presented in Figure 1. This 
study is pending IRB approval, University of Texas, HSC at Houston. 
 
 
Inclusion Criteria: 
- 
Pediatric patients older than 30 days and up to 18 years of age admitted to the 
PICU with a diagnosis of PARDS enrolled within 72 hours of diagnosis. 
- 
Patients requiring invasive mechanical ventilation. 
- 
Criteria of PARDS as defined by the Pediatric Acute Lung Injury Consensus 
Conference (PALICC), on June 2015 in Pediatric Critical Care Journal [1] Figure 1. 
 
Exclusion Criteria: 
- 
Patients with diffuse alveolar hemorrhage. 
- 
Patients terminally ill with limitation of care or in hospice care. 
- 
Patients receiving inhaled steroids or systemic steroids as chronic therapy before 
admission. 
- 
Patients with high dose systemic steroids for anti-inflammatory purposes. We will 
not exclude patients receiving hydrocortisone for shock. 
- 
Patients with hypersensitivity reactions documented to budesonide or other 
inhaled steroids like fluticasone, beclomethasone or others or other systemic steroids like 
prednisone, hydrocortisone, prednisolone and methylprednisolone. 
Enrollment: 


IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
Patients with PARDS will be identified in the PICU of Memorial Hermann Children’s Hospital. 
PICU attendings, fellows and nurses will be informed about the study and they will inform the 
research team about potential patients. One person for the research team will be on-call to review 
daily admissions to the PICU to identify potential patients. Parents or legal guardians of eligible 
patients will be approached for consent. Once consent is obtained the patients will be 
stratified by severity of PARDS OI < 16 (mild or moderate) and OI > 16 (severe). The 
randomization will be generated by a computer and the random number table will be 
performed by the Memorial Hermann Research Pharmacy. The patients will be blocked 
randomized, blocks of ten patients, 1:1, two blinded groups: budesonide vs placebo 
(normal saline). The research pharmacy of Memorial Hermann Hospital will deliver the 
medication according to the randomization list. They will distribute the medication to the patient’s 
bin in the Automated Medication Cabinet in the PICU. The medications will be distributed in 
identical syringes, identical label with the number of the study and patient information. 
Medication delivery: 
Enrolled patients will be treated with Pulmicort Repsules®, Budesonide inhalation suspension 
[57], at a dose of 0.5 mg, nebulized twice daily through the mechanical ventilator. That budesonide 
dose is the one recommended for treatment of pediatric asthmatic patients [40]. Normal saline is 
commonly used as a solution to dilute secretions and facilitate suctioning of those secretions. 
There are no trials of normal saline in patients with PARDS but it is thought to be harmless and it 
is currently used for clearing respiratory secretions. Studies In vitro for hypertonic saline have 
showed that sodium chloride in the airway does not get absorbed systemically [58, 59]. The 
research team, medical management team, bedside nurse and respiratory therapist will be 
blinded to the medication versus placebo. Both are clear liquids of similar consistency. They are 
also stable medications and can be distributed bedside by research pharmacy in identical 
syringes. The medication will be ordered in the Electronic Medical Record (EMR) as a research 
medicine. The medication will be administered to the patient by the respiratory therapist with the 
single-patient-use medication nebulizer attached to the mechanical ventilator circuit. The 
maximum length of treatment will be 10 days. If the patient improves and can be weaned-off 
mechanical ventilation, invasive or non-invasive, prior to 10 days of therapy the medication will 
be discontinued on the last day of ventilatory support [60]. If the patients require reintubation, we 
will continue the study medication until completing the 10-day treatment. If the patient has 
pulmonary bleeding the treatment will be discontinued. All these patients will be included in an 
intention-to-treat analysis. 
Risk 
The risks associated with this treatment are not considered clinically relevant taking in 
consideration the evidence described in susceptible subjects as described in the Background 
section. The short time duration of the treatment proposed also minimizes the risk of side effects. 
General side effects associated to steroids use are discussed in the following paragraph 
explaining why these effects are not considered to pose a risk to our patients. 
Inhaled steroids have been associated with Candida albicans in the oral mucosa. However, this 
medication is going to be administered directly in the lungs. There is a known and well described 
immunosuppressant effect of steroids. However, this risk has only been described in studies 
involving long term treatment with systemic steroids. There is no data that demonstrates an 
immunosuppressive effect of budesonide in patients with asthma that use it chronically. Another 
risk associated with steroids is the possibility adrenal suppression. However, this risk has not 
been demonstrated in inhaled steroids. Finally, effects on growth have been demonstrated in 
pediatric patient receiving inhaled steroids like budesonide but these studies have been done in 
patients with prolonged treatments with budesonide. 
Medical management: 
The management of the mechanically ventilated patients with PARDS will be at the discretion of 
the on-service team. This includes the use of open lung strategy, permissive hypercapnia and low 
tidal volume ventilation. The standard of care of the patients with ARDS in our unit is evidence- 
based: Tidal volumes between 6-8 ml/kg (ideal body weight), permissive hypercapnia tolerating 
pCO2 as high as 70 Torr as long as the pH is 7.25 or higher and FiO2 titrated to maintain 


IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
oxygenation saturations between 92 – 94% and adjusting Positive end-expiratory pressure 
(PEEP) and inspiratory : expiratory ratios accordingly. [61-64] The extubation is decided by the 
Extubation readiness trial protocol of our unit [65]. All that information will be variables 
recorded for each patient enrolled along with the outcomes. The physicians, faculty and 
fellows, of the pediatric critical care division will adhere to PARDS management recommendation 
for mechanical ventilation lung protection and to the extubation readiness trial protocols. This will 
be reminded during our weekly patient discussion meetings and monthly research meetings. 
Fellows will be available to help with data collection and will be invited to directly participate in the 
trial. 
Data and outcomes: 
The clinical information will be largely extracted from the EMR. Ventilator-free days (VFD): The 
number of days between weaning off the mechanical ventilation and day 28 after enrollment in 
study. If the patient dies before day 28 or if the patient requires mechanical ventilation for more 
than 28 days the value VFD will be 0. It will be measured two ways: for IMV and for a combination 
of IMV + NIMV. For patients reintubated within 48 hours it will be considered a continuous 
ventilation [15, 66]. The secondary outcome is Oxygenation index and Oxygenation 
saturation index are routinely measured in ventilated patients. We will obtain the measurements 
twice a day while the patients continue requiring invasive mechanical ventilation (IMV) and non- 
invasive mechanical ventilation (NIMV) up to 28 days. Length of stay in PICU and in hospital 
will be also measured until patients are transferred, discharged or decease. Tracheal aspirates 
will be obtained on day 1, day 3 and on the last day of treatment or last day of invasive mechanical 
ventilation. It will be processed in the critical care research laboratory with the use of custom 
ordered commercial laboratory assays compatible with EPOCH microplates [67]. This will include 
ELISA test for TNF α levels, IL-1, IL-6, IL-8 and MMP-8 and MMP-9. A cell count will be 
performed in each sample to obtain a neutrophil count. A vial of tracheal aspirate will be stored 
for genetic testing on protein expression for future translational research; these samples will be 
stored in a subzero freezer. The values obtained will be recorded daily since enrollment until 
completion of treatment or until discontinuation of mechanical ventilation or for 28 days if patients 
remain on mechanical ventilation (IMV or NIMV). The values will be obtained daily and a 4 am 
and 4 pm value will be included for every day of treatment. Before discharge from PICU patients 
will be referred to the High-Risk Clinic at one month after PICU discharge to evaluate for residual 
lung disease measured by PFTs and IOS. These studies will be performed by the Pediatric 
Pulmonary Division research team. [68] The rest of the variables to be collected are listed in 
Appendix A. 
 
DATA ANALYSIS PLAN 
Sample size: largest feasible study in 2 years; 60 patients expected, and we commit to enrolling 
60 even if three years are required 
Since this is a pilot single center trial, we propose performing a Bayesian analysis for 
the primary outcome and for the ventilator free days outcome [56]. This will allow us to enroll 
the maximum number of patients feasible in two years. According to the number of admissions in 
the PICU at Children’s Memorial Hermann (around 1200 patients per year) and incidence of 
PARDS, we estimate we could enroll 60 patients 
This will be a pilot study and will estimate the probability of benefits and assess whether 
a multicenter trial is warranted. Bayesian analysis will be performed using a neutral prior 
(50% probability of benefit). Bayesian posterior probability of benefit ≥ 75%, showing increased 
VFDs, will be required to propose a larger multicenter trial. These analyses will be performed by 
Claudia Pedroza, PhD, a Bayesian statistician. 
The rest of variables will be analyzed with frequentist statistics and will include t-test for 
continuous variables, chi-square for categorical, Mann Whitney U test for nonparametric statistics. 
 
DATA MANAGEMENT COMMITTEE 


IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
A Data Safety Monitoring Board (DSMB) will review this study yearly. They will perform an 
unblinded review of patients for possible unforeseen complications associated to the treatment 
arm including worst clinical outcomes for any of the groups. The composition of this board will 
have Doctor Konstantinos Boukas, Medical Director Pediatric Critical Care, as chair and doctor 
Syed Hashmi, statistician, and doctor Ankur Kamdar, rheumatologist, expert on steroid 
medications. The DSMB report will be sent to the principal investigator and to the IRB. All the 
detailed information is attached in the document called DSMB charter. 
 
Additionally, the progress on the execution, data collection, safety and data analysis of this project 
will be supervised monthly by doctor Jon Tyson, doctor Jon Meliones, doctor Claudia Pedroza 
and doctor Ricardo Mosquera. This group will supervise and receive updates from the PI and will 
review the data collected and evaluate the safety of the study. The progress will also be discussed 
with the directors of the Center for Clinical and Translational Sciences KL2 program at UTH every 
3 months. A review document will be completed at the time of the continuous reviews by the IRB 
and it will include Adverse Events. Serious Adverse Events will be informed to the IRB within 7 
days. 
 
PRIVACY AND SECURITY 
The information will be obtained from EMR Care4. The relevant clinical identifiers as MRN, date 
of birth and date of admission will be linked with a code. This code will be assigned and recorded 
in the Linking log document. This document will be stored in a separate locked cabinet, in a safe 
locked office and password and privacy protected computer. The data will be collected in Red 
Cap as demonstrated in CRF. 
 
 
 
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patients at risk. J Crit Care, 2013. 28(6): p. 985-91. 
30. 
Munoz, A.C., et al., 1144: INHALED STEROIDS FOR THE TREATMENT OF ACUTE RESPIRATORY 
DISTRESS SYNDROME IN ANIMAL STUDIES. Critical Care Medicine, 2018. 46(1): p. 556. 
31. 
Walrther, S., et al., Corticosteroid by aerosol in septic pigs - effects on pulmonary function and 
oxygen transport. Intensive Care Medicine, 1993. 19: p. 155 - 160. 
32. 
Walther, S., et al., Nebulized corticosteroid improves pulmonary function and outcome in 
experimental porcine septicemia. Acta Anaesthesiologica Scandinavica, 1991. 35: p. 635 - 641. 
33. 
Walther, S., et al., Pulmonary Granulocyte accumulation is reduced by nebulized corticosteroid in 
septic pigs. Acta Anaesthesiologica Scandinavica, 1992. 36: p. 651 - 655. 
34. 
Yan, Y.M., et al., Therapeutic effects of inhaling aerosolized surfactant alone or with 
dexamethasone generated by a novel noninvasive apparatus on acute lung injury in rats. J 
Trauma Acute Care Surg, 2012. 73(5): p. 1114-20. 
35. 
Jansson, A.H., C. Eriksson, and X. Wang, Effects of budesonide and N-acetylcysteine on acute 
lung hyperinflation, inflammation and injury in rats. Vascul Pharmacol, 2005. 43(2): p. 101-11. 
36. 
Sheffer, A., et al., Long-term safety of once-daily budesonide in patients with early-onset mild 
persistent asthma: results of the Inhaled Steroid Treatment as Regular Therapy in Early Asthma 
(START) study. Annals of Allergy, Asthma and Immunology, 2005. 94: p. 48 - 54. 
37. 
Silverman, M., et al., Safety and tolerability of inhaled budesonide in children in the Steroid 
Treatment As Regular Therapy in early asthma (START) trial. Pediatric Allergy and Immunology, 
2006. 17(Suppl 17): p. 14 - 20. 
38. 
Vikre-Jørgensen, J., L. Agertoft, and S. Pedersen, Dose Titration of Nebulized Budesonide in 
Young Children. Pediatric Pulmonology, 1997. 23: p. 270 - 277. 
39. 
Volovitz, B. and M. Nussinovitch, Effect of High Starting Dose of Budesonide Inhalation 
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40. 
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diagnosis and management of asthma. . U.S. Dept. of Health and Human Services, National 
Institutes of Health, National Heart, Lung, and Blood Institute. , 2007. 
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Miller, D.D., et al., Aerosol delivery and modern mechanical ventilation: in vitro/in vivo 
evaluation. Am J Respir Crit Care Med, 2003. 168(10): p. 1205-9. 
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Hess, D., et al., Medication Nebulizer Performance Effects Of Diluent Volume, Nebulizer Flow, 
and Nebulizer Brand. Chest, 1996. 110: p. 498-505. 
43. 
Longest, P.W., et al., Improving Aeorol Drug Delivery During Invasive Mechanical Ventilation 
With Redesigned Components. Respiratory Care, 2014. 59(5): p. 686-698. 
44. 
Longest, P.W., M. Azimi, and M. Hindle, Optimal delivery of aerosols to infants during 
mechanical ventilation. J Aerosol Med Pulm Drug Deliv, 2014. 27(5): p. 371-85. 
45. 
Longest, P.W. and G. Tian, Development of a new technique for the efficient delivery of 
aerosolized medications to infants on mechanical ventilation. Pharm Res, 2015. 32(1): p. 321-36. 
46. 
Mendes, E.S., et al., Immediate antiinflammatory effects of inhaled budesonide in patients with 
asthma. Ann Am Thorac Soc, 2014. 11(5): p. 706-11. 
47. 
Volovitz, B., et al., Rapid induction of clinical response with a short-term high-dose starting 
schedule of budesonide nebulizing suspension in young children with recurrent wheezing 
episodes Journal of Allergy and Clinical Immunology, 1998. 101(4): p. 464 - 469. 
48. 
DiSantostefano, R.L., et al., Risk of pneumonia with inhaled corticosteroid/long-acting beta2 
agonist therapy in chronic obstructive pulmonary disease: a cluster analysis. Int J Chron Obstruct 
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Balfour-Lynn, I.M. and K. Welch, Inhaled corticosteroids for cystic fibrosis. Cochrane Database 
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50. 
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Chronic Bronchopulmonary Pseudomonas aeruginosa Infection. American Journal of Respiratory 
and Critical Care Medicine, 1997. 156(4): p. 1190-1196. 
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Bassler, D., et al., Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia. N 
Engl J Med, 2015. 373(16): p. 1497-506. 
52. 
Shah, S., et al., Inhaled versus systemic corticosteroids for preventing chronic lung disease in 
ventilated very low birth weight preterm neonates. Cochrane Database of Systemic Reviews, 
2012(5). 
53. 
Doyle, L.W., et al., Early (< 8 days) systemic postnatal corticosteroids for prevention of 
bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev, 2017. 10: p. 
CD001146. 
54. 
Doyle, L.W., et al., Late (> 7 days) systemic postnatal corticosteroids for prevention of 
bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev, 2017. 10: p. 
CD001145. 
55. 
Onland, W., M. Offringa, and A. van Kaam, Late (>/= 7 days) inhalation corticosteroids to reduce 
bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev, 2012(4): p. 
CD002311. 
56. 
Amrhein V, Greenland S, and M. B, Scientists rise up against statistical significance. Nature, 
2019. 567(7748): p. 305-307. 
57. 
AstraZeneca, Pulmicort Repsules ®, (budesonide, inhalation suspension), in 
http://www.azpicentral.com/pulmicort-respules/pulmicortrespules.pdf#page=1. 2010. 
58. 
Zhang, L., et al., Nebulised hypertonic saline solution for acute bronchiolitis in infants. Cochrane 
Database of Systematic Reviews, 2017(12). 
59. 
Elkins, M.R. and P.T.P. Bye, Mechanisms and applications of hypertonic saline. Journal of the 
Royal Society of Medicine, 2011. 104 Suppl 1(Suppl 1): p. S2-S5. 
60. 
Kurachek, S.C., et al., Extubation failure in pediatric intensive care: a multiple-center study of risk 
factors and outcomes. Crit Care Med, 2003. 31(11): p. 2657-64. 
61. 
THE ACUTE RESPIRATORY DISTRESS SYNDROME NETWORK, A., Ventilation With Lower Tidal 
volumes As Compares With Traditional Tidal volumes For Acute Lung Injury And the Acute 
Respiratory Distress Syndrome. The New England Journal of Medicine, 2000. 342(18): p. 1301-8. 
62. 
Britos, M., et al., The value of positive end-expiratory pressure and Fio(2) criteria in the definition 
of the acute respiratory distress syndrome. Crit Care Med, 2011. 39(9): p. 2025-30. 
63. 
Thompson, B.T., et al., Clinicians' Approaches to Mechanical Ventilation in Acute Lung Injury and 
ARDS. Chest, 2001. 120: p. 1622-1627. 
64. 
Chacko B, et al., Pressure-controlled versus volume-controlled ventilation for acute respiratory 
failure due to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Cochrane 
Database of Systematic Reviews, 2015(1). 
65. 
Khemani, R.G., et al., Pediatric extubation readiness tests should not use pressure support. 
Intensive Care Med, 2016. 42(8): p. 1214-22. 
66. 
Schoenfeld, D.A.B., GR.; for the ARDS Network, Statistical evaluation of ventilator-free days as 
an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. 
Critical care medicine, 2002. 30(8): p. 1772-1777. 
67. 
Biotek Intruments, I. Epoch Microplate Spectrophotometer. 2012; Available from: 
http://daytam.atauni.edu.tr/uploads/dosya/3ac576d0f36adc27e263009054d53719.pdf. 
68. 
Ward, S.L., et al., Long-Term Pulmonary Function and Quality of Life in Children After Acute 
Respiratory Distress Syndrome: A Feasibility Investigation. Pediatr Crit Care Med, 2017. 18(1): p. 
e48-e55. 
69. 
Wong, J.J., et al., Risk Stratification in Pediatric Acute Respiratory Distress Syndrome: A 
Multicenter Observational Study. Crit Care Med, 2017. 45(11): p. 1820-1828. 


IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix A 
 
Variable 
Unit 
Range of Scale 
Subject ID 
1 – x 
Subject age 
Months 
1 – 264 
Date of admission 
Date format 
Mm/dd/yy 
Gender 
Nominal 
1 Male 
2 Female 
Weight 
(kg) 
Days in PICU 
Days 
0 – x 
Days in Hospital 
Days 
0 – x 
Primary Diagnosis – etiology 
of ARDS Sepsis/ Pneumonia 
Dichotomy 
1 Sepsis 
2 Pneumonia 
Secondary Diagnosis 
Nominal 
Each 
coded 
diagnosis 
will 
be 
Day of diagnosis of ARDS 
(documented on chart, day 1 
control group) 
Date format 
Mm/dd/yy 
Disposition after PICU 
Nominal 
1 Transfer to floor 
2 Discharge home 
3 Deceased 
PRISM III Admission score 
to PICU: 
Continuous 
0-72 
Date 
of 
first 
dose 
of 
intervention 
Date format (dd/mm/yy) 


IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
Days on treatment 
Numeric 
All following values will be 
recorded from 4 am and 4 
pm measurements on 
days 1 – 5 
Oxygenation index 
[FiO2 
x 
Mean 
Airway 
Pressure x 100] / PaO2 
4 – 8 mild 
8 – 16 moderate 
> 16 severe 
PEEP 
cmH2O 
Tidal volume 
Volume per breath per kilo, 
ideal weight (ml/Kg) 
pH 
Continuous 
pCO2 
Continuous Torr 
pO2 
Continuous Torr 
O2 sat (blood gas) 
Continuous Percentage 
 

ICF_001.pdf: 
Telephone: (713)7047921 / (| |)|||||| 
IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 08/15/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhaled Steroids for the Treatment of Early Pediatric Acute Respiratory Distress 
Syndrome (PARDS), a Randomized Pilot Trial 
 
NCT04064684 
 
Version Date: 08/15/2019 
 
 


Telephone: (713)7047921 / (| |)|||||| 
IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 08/15/2019 
 
 
 
 
PARENTAL PERMISSION TO TAKE PART IN RESEARCH 
 
 
Simple Study Title: 
Inhaled steroids for PARDS 
 
Full Study Title: 
Inhaled steroids for the treatment of early Pediatric Acute Respiratory Distress 
Syndrome (PARDS), a randomized pilot trial. 
 
Principal Investigator: Alvaro Coronado Munoz, MD; Assistant professor UTHealth 
 
Study Contact: 
(713) 704-7921 / (| |)| |-|
| 
6431 Fannin St ||||||||  Houston Tx, 77030 
 
The purpose of this study is to see if Budesonide can be useful to treat PARDS. If you choose to allow 
your child to take part in this study, your child could receive either Budesonide or normal saline 
nebulized on the mechanical ventilator to treat PARDS. The total amount of time your child will be in 
this study is a maximum of 10 days. 
 
There are potential risks involved with this study that are described in this document. Some known risks 
include worsening on the course of the disease. There may be potential benefits to your child such as 
improving your child’s condition by decreasing the ventilator and decreasing the inflammation in the 
lungs. 
 
There are alternatives to taking part in this research study, such as continuing with the current care that 
it does not include any specific treatment for this condition. 
 
Participation in this research study is voluntary. You may choose not to allow your child to take part in 
this research study or may choose to leave the research study at any time. Your decision will not affect 
the clinical care your child receives at the University of Texas Health Science Center at Houston 
(UTHealth) or Memorial Hermann Healthcare System. 
 
If you are interested in participating, please continue to read below. 
 
What is the purpose of this research study? 
The purpose of this study is to see how well Budesonide works at treating people with Pediatric Acute 
respiratory distress syndrome (PARDS). This condition is a severe inflammation in the lungs. Children 
with PARDS have to be in the critical care unit connected to a mechanical ventilator. This study will test 
the safety of the Budesonide to treat PARDS. Budesonide has been approved by the Food and Drug 
Administration (FDA) but not for this specific condition; therefore, it is called an investigational drug. 
This study is called a pilot study since it will only include a small number of patients and will help us 
design a larger study with more patients in the future. 
 
 
Contact: Alvaro Coronado Munoz, MD 


Informed Consent Budesonide for PARDS 
Page 2 
Contact: Alvaro Coronado Munoz, MD 
Telephone: (713)7047921 / (| |)|||||| 
IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 08/15/2019 
 
 
 
 
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by U.S. 
Law. This will not include information that can identify your child. After the study has ended, website 
will include a summary of the results. You can search this website at any time. 
 
Who is being asked to take part in this study? 
You are being asked to allow your child to take part in this research study because your child has PARDS. 
This study is being conducted only in our hospital. About 60 people will take part in the study in this city 
at UTHealth and Memorial Health System. 
 
What will happen if your child takes part in this study? 
If you allow your child to take part in this study your child will be randomized (similar to flipping a coin) 
to receive Budesonide or normal saline. It is not known whether Budesonide will be of benefit. Normal 
saline is currently used in patients with this and other conditions that require mechanical ventilator to 
help clearing the lung secretions.   For this reason, some study participants must receive normal saline 
to compare. Normal saline is what we call a placebo: a thought to be harmless medication that will allow 
a careful comparison to study the benefits and side effects of the investigational drug. There is a 50% 
chance your child will receive Budesonide and a 50% chance that your child will receive normal saline. 
Neither you, your child nor your doctor will know if your child is receiving Budesonide or normal saline, 
as both will look the same. 
 
The only additional test we are going to perform additional to routine standard of care test is samples 
from the lungs taken out during routine suctioning of your child’s airway. These samples will be analyzed 
for the purpose of the study only and won’t affect the treatment of your child. Routine exams, tests, and 
procedures that need to be done to monitor your child’s safety and health will be ordered by the 
primary team taking care of your child. We will record this information to carefully follow the effects of 
the study treatment, including preventing and managing side effects. 
 
How long will your child be in the study? 
If your child takes part in the study, his or her participation will last for 10 days. We would like to add 
additional measurements to your child’s lung recovery called Pulmonary function tests, free of charge, 
90 days after the first day of participation in this study. These measurements will be done by the 
pulmonary team research team. 
 
What choices does your child have, other than this study? 
You may select other options than being in this research study. Currently we allow the patients to 
recover from PARDS with time and with supportive measure to their breathing and oxygen levels. 
 
What are the risks of taking part in this study? 
There are both risks and benefits to taking part in this study. It is important for you to think carefully about 
these as you make your decision. 
 
If you choose to allow your child to take part in this study, there is a risk that Budesonide may result in 
worse outcomes such as lower oxygen levels or longer time on the ventilator. 


Informed Consent Budesonide for PARDS 
Page 3 
Contact: Alvaro Coronado Munoz, MD 
Telephone: (713)7047921 / (| |)|||||| 
IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 08/15/2019 
 
 
 
 
 
There is also a risk that your child could have side effects from the Budesonide. These side effects may 
be worse and may be different than you would get with the usual treatment. 
 
Some of the most common side effects that the study doctors know about are that prolonged used of 
prolonged steroids are associated to risk of infections like fungal infections. That risk has not been 
described in the maximum period planned for this study (10 days). Even though Budesonide is intended 
to decreased the inflammation in the lungs and therefor improve the condition of your child any 
medication delivered to critically ill lungs can worsen their condition prolonging the days that 
mechanical ventilation is needed. There may be some risks that the study doctors do not yet know 
about. Children receiving inhaled steroids have less growth by around 0.5 inch than patients that do not 
received inhaled steroids. These numbers have been calculated in patients with asthma that receive 
inhaled steroids for more than 12 weeks. Patients that receive steroids could also have less function on 
the “adrenal gland” in the body. That gland is in charge of producing our own body’s corticoid, called 
cortisol. There are no studies demonstrating that patients receiving inhaled steroids for short periods of 
time have that risk. 
 
What are the benefits to taking part in this study? 
There is one small pilot study in adult patients with ARDS treated with Budesonide. The results were 
encouraging for reducing inflammation and improving oxygenation but it didn’t address the number of 
days on mechanical ventilator as we are planning to do in our study. We do not know if to the same 
results will be seen in children with ARDS as they saw with the adults. This study may help the study 
doctors learn things that may help other people in the future. 
 
Can you stop taking part in this study? 
You may decide to stop your child from taking part in the study at any time. To withdraw from the study, 
please contact Alvaro Coronado Munoz, MD at (| |) | |-|
| or (713) 704-7921. 
 
Your doctor or the sponsor can stop the study at any time. Your doctor or the sponsor may stop your 
child’s participation in the study if his or her condition worsens, the study is stopped, the study drug is 
no longer available, your child does not meet all the requirements of the study, or the study is not in 
your child’s best interest. If your child’s participation in the study is stopped, your doctor will discuss 
other options for his or her treatment. 
 
If your child stops participating in this study, the information already collected will still be used in the 
data analysis. However, no further information will be collected without your permission. 
 
While taking part in this study, the study team will notify you of new information that may become 
available and could affect your willingness to allow your child to stay in the study. 
 
What happens if your child is injured during the study? 
If your child suffers an injury as a result of taking part in this research study, please understand that 
nothing has been arranged to provide free treatment of the injury or any other type of payment. 
However, necessary facilities, emergency treatment, and professional services will be available to your 
child, just as they are to the general community. You should report any such injury to Alvaro Coronado 


Informed Consent Budesonide for PARDS 
Page 4 
Contact: Alvaro Coronado Munoz, MD 
Telephone: (713)7047921 / (| |)|||||| 
IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 08/15/2019 
 
 
 
 
 
Munoz, MD at (| |) | |-|
|. You will not give up any of your child’s legal rights by signing this consent 
form. 
 
What are the costs of taking part in this study? 
The sponsor will pay for the special tests and examinations that are required by this study and not 
otherwise part of your child’s standard medical care. 
However, many of the tests, procedures, and exams your child will receive are believed to be part of 
standard medical care, and may or may not be covered by your medical insurance. If your medical 
insurance does not pay for your child’s care you will be responsible for the cost of the medical care 
related to your child’s condition including laboratory tests, deductibles, co-payments, physician and 
clinic fees, hospitalization and procedures. 
 
If you receive a bill that you believe is related to your child’s taking part in this research study, please 
contact Alvaro Coronado Munoz, MD (| |) | |-|
| with any questions. 
 
How will privacy and confidentiality be protected? 
Your child’s privacy is important and your child’s participation in this study will be kept confidential. 
However, absolute confidentiality cannot be guaranteed. 
 
If you sign this document, you give permission to UTHealth or Memorial Hermann Healthcare System to 
use and disclose (release) your child’s health information. The health information that we may use or 
disclose for this research includes your child’s age, diagnosis, days of illness, the indications for 
mechanical ventilator and laboratory results decided by the primary team. Please understand that 
health information used and disclosed may include information relating to HIV infection, drug abuse, 
alcohol abuse, behavioral health, and psychiatric care. 
We will also collect respiratory sample that are routinely collected in patients with your child’s 
condition. We will analyze these samples in the UTHealth Pediatric Critical Care Laboratory for markers 
of inflammation in the lungs. These results will be only used for the research study but won’t affect the 
clinical care of your child. These samples are routinely collected in patients with your child condition and 
there are no additional risks to your child when we collect these samples. 
 
Personal identifiers such as your child’s name and medical record number will be removed from the 
information and samples collected in this study. After we remove all identifiers, the information or 
samples may be used for future research or shared with other researchers without your additional 
permission. 
 
People who receive your child’s health information may not be required by Federal privacy laws (such as 
the Privacy Rule) to protect your child’ health information and may share your child’s information with 
others without your permission, if permitted by laws governing them. Your child will not be personally 
identified in any reports or publications that may result from this study. If all information that does or 
can identify your child is removed from your child’s health information, the remaining information will 
no longer be subject to this authorization and may be used or disclosed for other purposes. 


Informed Consent Budesonide for PARDS 
Page 5 
Contact: Alvaro Coronado Munoz, MD 
Telephone: (713)7047921 / (| |)|||||| 
IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 08/15/2019 
 
 
 
 
 
Representatives of the organizations listed below will see your child’s name and other personal 
identifiers when they review your child’s research records and medical records for the purposes of 
verifying study data: 
• 
Representatives of UTHealth and/or Memorial Hermann Health System 
• 
Representatives from the U.S. Food and Drug Administration (FDA) 
• 
Representatives of the sponsor of this research including contract research organizations 
• 
Companies engaged with the UTHealth for the commercialization of the results of the research 
study 
 
Please note that you do not have to sign this Authorization, but if you do not, your child may not 
participate in this research study. UTHealth and Memorial Hermann Health System or Harris Health 
System may not withhold treatment or refuse treating your child if you do not sign this Authorization. 
 
You may change your mind and revoke (take back) this Authorization at any time. Even if you revoke this 
Authorization, researchers may still use or disclose health information they already have obtained about 
your child as necessary to maintain the integrity or reliability of the current research. To revoke this 
Authorization, you must contact Alvaro Coronado Munoz, MD in writing at 6431 Fannin St |||||||| 
Houston Tx 77030. 
 
This Authorization will expire 15 years after the end of the study. 
 
Whom can you contact if you have questions about the study? 
If you have questions at any time about this research study, please feel free to contact Alvaro Coronado 
Munoz, MD at (| |) | |-|
|, as they will be glad to answer your questions. You can contact the study 
team to discuss problems, report injuries, voice concerns, obtain information in addition to asking 
questions about the research. 
 
The Committee for Protection of Human Subjects at the University of Texas Health Science Center has 
reviewed this research study. You may contact them for any questions about your rights as a research 
subject, and to discuss any concerns, comments, or complaints about taking part in a research study at 
(713) 500-7943. 
 
What will happen when my child becomes a legal adult? 
If your child will reach the legal age of majority (18 in the state of Texas) and is able to provide his or her 
own consent while enrolled as a participant in this study, the study team will contact him or her to 
obtain his or her adult consent. 


Informed Consent Budesonide for PARDS 
Page 6 
Contact: Alvaro Coronado Munoz, MD 
Telephone: (713)7047921 / (| |)|||||| 
IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 08/15/2019 
 
 
 
 
 
SIGNATURES 
Sign below only if you understand the information given to you about the research and you choose to 
allow your child to take part in this research study. Make sure that all your questions have been 
answered. If you decide to allow your child to take part in this research study, a copy of this signed 
consent form will be given to you. 
 
 
 
Name of Child 
 
 
 
 
 
 
 
Name of Parent/ 
Guardian 
Relationship to Child 
Signature 
Date 
 
 
 
 
 
 
Name of Person 
Obtaining Consent 
Signature of Person Obtaining Consent 
Date