Long Term Follow up of Children Enrolled in the REDvent Study

Background and Significance: Through advancements in critical care, PARDS mortality has
decreased from 50% to less than 20%. Therapeutic strategies for PARDS have sought to improve
survival, but have often ignored morbidity, despite extensive evidence that nearly 50% of
adult ARDS survivors are left with significant abnormalities in pulmonary, physical,
neurocognitive function and HRQL which may persist for years. Recent data highlight that
approximately 20% of children with respiratory failure have low HRQL 6 months after ICU
discharge, and 30% screen positive for post-traumatic stress (PTS). There are virtually no
data regarding pulmonary and neurocognitive deficits in PARDS survivors. More importantly,
there are no data identifying potentially modifiable factors during ICU care which are
associated with long term impairments.

It is increasingly recognized that ARDS ventilator management is associated with VIDD and
VILI, which increase length of MV and failed extubation.REDvent is currently testing whether
a MV strategy which uses esophageal manometry to target physiologic levels of patient effort
can prevent VIDD and shorten length of MV. In addition, the REDvent strategy results in more
lung protective management of Positive End Expiratory Pressure (PEEP), Peak Inspiratory
Pressure (PIP), and Delta Pressure (DP) which may prevent VILI. While the REDvent study is
designed for ICU related outcomes, there is strong biologic plausibility that the REDvent
strategy can improve long-term outcome. The investigators propose serial follow up of
subjects enrolled in the REDvent study (intervention and control patients) which will
leverage the infrastructure and data of an already enrolling clinical trial to fill crucial
knowledge gaps regarding how PARDS survivors recover from critical illness. The central
hypothesis is that preventing VIDD, VILI and shortening time on MV will have a measureable
impact on longer term function by mitigating abnormalities in pulmonary function (PFT),
neurocognitive function and emotional health, functional status and HRQL after ICU discharge
for children with PARDS.

Study Aims:

Specific Aim (SA1): To determine the frequency, severity and trajectory of recovery of PFT
abnormalities amongst PARDS survivors within 6 months of ICU discharge, identify risk factors
for their development, and determine if they are prevented by REDvent.

Specific Aim (SA2): To determine the frequency and severity of impairments in neurocognitive
function and emotional health amongst PARDS survivors in the first year after ICU discharge,
identify risk factors for their development, and determine if they may be improved by
REDvent.

Specific Aim (SA3): To determine the frequency, severity and trajectory of recovery of
respiratory and functional status and HRQL amongst PARDS survivors in the 12 months after ICU
discharge, identify risk factors for their development, and determine if they may be improved
by REDvent.

Study Design: This is a prospective observational follow-up study of children enrolled in a
single center randomized controlled trial (REDvent; RO1 HL134666, PI: Khemani).

Study Measurements and Outcomes: Assessments will be made serially from enrollment up to 1
year after ICU discharge . Data gathered from the parent REDvent study during the original
course of mechanical ventilation will also be used for analysis, to understand whether ICU
specific therapies, management strategies, or severity of illness are associated with long
term outcomes.

Expected Sample Size: REDvent plans to enroll 300 children over 4.5 years. 240 children are
expected to survive to hospital discharge, 200 (83%) are expected to consent for follow-up,
and allowing for 25% dropout, 150 will reach the primary follow-up endpoints.

A1.H1. At least 30% of PARDS survivors will have ventilation inhomogeneity (VI, primary
outcome measured with Lung Clearance Index (LCI)) which will persist 6 months after
discharge.

Analysis: LCI more than 7.5 will be considered abnormal for analysis, and is anticipated to
will occur in at least 30% of patients. This yields a 95% confidence interval from 23 to 38%
assuming 150 patients complete follow-up. Similar analysis is planned for secondary outcomes.
Analyses will be stratified by baseline pulmonary status or history of previous pulmonary
disease.

A1.H2. ICU management of PEEP and transpulmonary driving pressure will be independently
associated with VI after controlling for baseline co-morbidities and PARDS severity.

Analysis: The primary outcome for this sub aim is abnormal LCI 6 (VI) months after discharge,
as above. Analysis will compare median, mean, and extreme (min or max) transpulmonary
pressure at PEEP, plateau, and driving pressure during the acute phase of ventilation (prior
to the first SBT) stratified by normal or abnormal LCI. Length of exposure to these settings
will be modeled by including an interaction between transpulmonary pressure and length of
ventilation. All analyses will be adjusted with multivariable models, controlling for PARDS
severity, co-morbidities, and other ventilator and ancillary therapy management.

A1.H3. REDvent will be independently associated with lower VI and fewer abnormalities in
pulmonary function and respiratory muscle strength.

Analysis: The investigators will first analyze differences in median LCI between REDvent and
control patients using a Mann-Whitney U or t-test. From preliminary data, the investigators
anticipate a power >0.8 to detect > 10% improvement in LCI with the expected enrollment (150
patients). They will subsequently construct a multivariable linear regression model on LCI 6
months after ICU discharge to test whether REDvent management remains independently
associated with less VI after adjusting for short term-ICU outcome variables. In addition,
usual care acute phase arm (lack of REDvent exposure) will be considered as an independent
risk factor for abnormal VI in the multivariable logistic regression model described in
A1.H2.

A2.H1. At least 30% of previously unimpaired PARDS survivors will have impairment in
neurocognitive function 3 months after ICU discharge, and 20% will persist with deficits at 1
year.

Analysis: As with the previous aim, the primary outcomes are expressed as binary variables
for ease of interpretation. The investigators anticipate 100 previously unimpaired children
will complete this aim. The primary outcome is neurocognitive function using Batelle-2 or
WISC-5. They estimate approximately 40% of children will have impaired neurocognitive
function at 3 month follow-up, resulting in a 95% confidence interval from 30% to 50%.
Descriptive analysis will be provided by specific domain both as continuous data and
categorized as above. Emotional health assessments and PTS analysis will mimic what is
presented above for the subset with data available.

A2.H2. Duration of delirium while in the ICU will be independently associated with impaired
neurocognitive function.

Analysis: The primary outcomes will be categorical, evaluated 3 months after discharge. The
primary predictor variable is days with delirium (as identified by CAPD score > 9) modeled as
an ordinal variable. Additional confounding variables will be considered including length of
MV, illness severity, sedation doses, with selection as described in the previous aims.
Secondary analysis will generate a linear regression model on the continuous outcome of
normalized neurocognitive score from Batelle-2 or WISC-5, and will consider an interaction
term based on the tool used for measurement.

A2.H3. Lack REDvent exposure will be independently associated with impaired neurocognitive
function.

Analysis: The investigators will directly examine normalized neurocognitive score between
REDvent and control groups using a t-test or MWU test. The percentage of children with
abnormal values at 3 months will be compared between the groups with a Chi-Square test. In
multivariable linear regression modeling they will examine the independent relationship
between REDvent intervention arm and normalized neurocognitive score, using similar methods
as detailed above. In addition, usual care acute phase arm (lack of REDvent exposure) will be
considered as an independent risk factor in the multivariable logistic regression models
described in A2.H2.

A3.H1. At least 25% of PARDS survivors will have a new respiratory requirement, and 40% will
have a decline in overall functional status or a significant decrease in HRQL from baseline
at 3 months after ICU discharge, and at least 20% of children will persist with a deficit in
one of these domains at 12 months.

Analysis: As with the previous aims, the primary outcomes are expressed as binary variables
for ease of interpretation. However, additional analysis will consider all outcomes as
continuous variables. The primary outcomes under this aim consider 3 domains: 1) Functional
Status decline: FSS 2 or more points above (worse than) baseline 2) HRQL decline: PEDsQL 5
points or more below (worse than) baseline 3) New respiratory requirement (oxygen, positive
pressure, respiratory medications, and respiratory therapies). Based on the research
presented above, they estimate 40% of children will have impaired HRQL or functional status
at 3 month follow-up, with 95% CI ranging from 32% to 48%, and 25% of children will have a
new respiratory requirement, with 95% CI ranging from 18.5 to 32.4%. The same analysis will
be repeated at 12 month follow-up.

A3.H2. Cumulative exposure to neuromuscular blockade, corticosteroids, length of MV, and
delirium will be independently associated with decline in 1) functional status 2) HRQL and 3)
new respiratory requirement 3 months after ICU discharge after controlling for PARDS
severity, co-morbidities, and other confounding variables.

Analysis: The primary outcomes will be categorical, as described in the section above
(A3.H1), evaluated 3 months after discharge. The primary predictor variables include: days of
neuromuscular blockade, days receiving corticosteroids, days with delirium (CAP-D > 9120-124)
and days on MV, modeled as ordinal variables. Additional confounding variables will be
considered with selection as described in the previous aims. Multiplicative interaction terms
will be considered for inclusion (i.e. corticosteroids*neuromuscular blockade).

A3.H3. REDvent will be independently associated with improved recovery to baseline
respiratory status, functional status, and HRQL recovery 3 months after ICU discharge.

Analysis: The investigators will directly examine PEDsQL change from baseline and FSS change
from baseline at 3 month follow up in REDvent and control patients using Mann Whitney U
tests. The percentage of children reaching baseline pulmonary requirement at 3 months will be
compared between the previously stated groups with a Chi-Square test. In multivariable linear
regression modeling the investigators will examine the independent relationship between
REDvent intervention arms and change in FSS and HRQL outcomes using the methods detailed in
the previous aims. In addition, usual care acute phase arm (lack of REDvent exposure) will be
considered as an independent risk factor in the multivariable logistic regression models
described in A3.H2 on the categorical outcomes described above.

Inclusion Criteria:

1. Children > 1 month (at least 44 weeks Corrected Gestational Age) and ≤ 18 years of age
AND

2. Supported on mechanical ventilation for pulmonary parenchymal disease (i.e.,
pneumonia, bronchiolitis, Pediatric Acute Respiratory Distress Syndrome (PARDS)) with
Oxygen Saturation Index (OSI) ≥ 5 or Oxygenation Index (OI) ≥4 115 AND

3. Who are within 48 hours of initiation of invasive mechanical ventilation (allow for up
to 72 hours for those transferred from another institution) AND

4. Enrolled in the REDvent Study

Exclusion Criteria (1-5 are REDvent exclusion):

1. Contraindications to use of an esophageal catheter (i.e. severe mucosal bleeding,
nasal encephalocele, transphenoidal surgery) OR

2. Contraindications to use of RIP bands (i.e. omphalocele, chest immobilizer or cast) OR

3. Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall defects,
pregnancy) OR

4. Conditions precluding conventional methods of weaning (i.e., status asthmaticus,
severe lower airway obstruction, critical airway, intracranial hypertension, Extra
Corporeal Life Support (ECLS), intubation for UAO, tracheostomy, DNR, severe chronic
respiratory failure, spinal cord injury above lumbar region, cyanotic heart disease
(unrepaired or palliated)) OR

5. Primary Attending physician refuses (will be cleared with primary attending before
approaching the patient) OR

6. Death in the ICU OR

7. New DNR orders during acute illness in ICU OR

8. Primary Language not English or Spanish OR

9. Children in foster care or a ward of the state.