Long Term Follow up of Children Enrolled in the REDvent Study

Quality of Life Clinical Trial

Official title: The Effect of Intensive Care Unit Therapies and Mechanical Ventilation Strategy on Long Term Outcome in Pediatric ARDS A Follow-up of the Real-time Effort Driven VENTilator Management Study (REDvent)

Status Recruiting

Clinical Trial Summary

This is a prospective observational follow-up study of children enrolled in a single center randomized controlled trial (REDvent).

Nearly 50% of adult Acute Respiratory Distress Syndrome (ARDS) survivors are left with significant abnormalities in pulmonary, physical, neurocognitive function and Health Related Quality of Life (HRQL) which may persist for years.Data in pediatric ARDS (PARDS) survivors is limited. More importantly, there are no data identifying potentially modifiable factors during ICU care which are associated with long term impairments, which may include medication choices, or complications from mechanical ventilator (MV) management in the ICU including ventilator induced lung injury (VILI) or ventilator induced diaphragm dysfunction (VIDD).

The Real-time effort driven ventilator (REDvent) trial is testing a ventialtor management algorithm which may prevent VIDD and VILI. VIDD and VILI have strong biologic plausibility to affect the post-ICU health of children with likely sustained effects on lung repair and muscle strength. Moreover, common medication choices (i.e. neuromuscular blockade, corticosteroids) or other complications in the ICU (i.e. delirium) are likely to have independent effects on the long term health of these children. This proposed study will obtain serial follow-up of subjects enrolled in REDvent (intervention and control patients). 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 (PFTs), neurocognitive function and emotional health, functional status and HRQL after hospital discharge for children with PARDS.

For all domains, the investigators will determine the frequency, severity and trajectory of recovery of abnormalities amongst PARDS survivors after ICU discharge, identify risk factors for their development, and determine if they are prevented by REDvent. They will leverage the detailed and study specific respiratory physiology data being obtained in REDvent, and use a variety of multi-variable models for comprehensive analysis. Completion of this study will enable the investigators to identify ICU related therapies associated with poor long term outcome, and determine whether they can be mitigated by REDvent.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Acute Lung Injury
• Cognitive Dysfunction
• Lung Injury
• Neurocognitive Dysfunction
• Quality of Life
• Respiration Disorders
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn
• Ventilator-Induced Lung Injury

• NCT number: NCT03709199
• Study type: Observational
• Source: Children's Hospital Los Angeles
• Contact: Robinder G Khemani, MD
• Phone: 323-361-2376
• Email: rkhemani@chla.usc.edu
• Status: Recruiting
• Start date: October 1, 2018
• Completion date: May 1, 2026