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Real-time Effort Driven VENTilator Management (REDvent)

Primary Purpose

Ventilation Therapy; Complications, Diaphragm Disease, Pediatric Respiratory Diseases

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Computerized Ventilator Protocol
Esophageal Manometry
Respiratory Inductance Plethysmography (RIP)
Diaphragm Ultrasound
Maximal Inspiratory Pressure
Sponsored by
Children's Hospital Los Angeles
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Ventilation Therapy; Complications

Eligibility Criteria

30 Days - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Children > 1 month (>44 weeks CGA) and ≤ 18 years of age AND
  2. Supported on mechanical ventilation with pulmonary parenchymal disease (i.e., pneumonia, bronchiolitis, Pediatric Acute Respiratory Distress Syndrome (PARDS)) with Oxygen Saturation Index (OSI) ≥ 5 or Oxygenation Index (OI) ≥) 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)

Exclusion Criteria:

  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 on enrollment that preclude conventional methods of weaning (i.e., status asthmaticus, severe lower airway obstruction, critical airway, intracranial hypertension, Extra Corporeal Life Support (ECLS), intubation for UAO, 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).

Sites / Locations

  • Children's Hospital Los AngelesRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

REDvent-acute

Control-acute

REDvent-weaning

Control-weaning

Arm Description

Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Patients will be managed with pressure control plus pressure support ventilation using a computerized decision support tool that will recommend changes to ventilator settings approximately every 4 hr (with or without a new blood gas). If the patient is spontaneously breathing, it will incorporate real-time measures of effort of breathing (esophageal manometry) to keep it in a target range.

Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Ventilator management will be per usual care until the patient meets weaning criteria and passes the oxygenation test.

Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Patients will be managed in a pressure support/CPAP mode of ventilation with assessments or changes to the level of pressure support every 4 hours, targeting maintaining effort of breathing (esophageal manometry) in a normal range. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT.

Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Ventilator management will be per usual care. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT.

Outcomes

Primary Outcome Measures

Median Duration of Weaning
Time from first attempted SBT until SBT passage or extubation [whichever comes first]

Secondary Outcome Measures

Median Ventilator Free Days
Days alive and not on mechanical ventilation
Number of Participants with Extubation Failure
re-intubation or use of non invasive ventilation
Number of Participants with Mortality
Death
Median Maximal Inspiratory Airway Pressure During Airway Occlusion (aPiMax)
Measured during standardized airway occlusion maneuvers
Median Maximal Inspiratory Esophageal Pressure During Airway Occlusion (ePiMax)
Measured during standardized airway occlusion maneuvers
Median Change in diaphragm thickness on Exhalation (Dte) from baseline
From daily ultrasound measurement

Full Information

First Posted
August 23, 2017
Last Updated
August 28, 2023
Sponsor
Children's Hospital Los Angeles
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Children's Hospital of Philadelphia
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1. Study Identification

Unique Protocol Identification Number
NCT03266016
Brief Title
Real-time Effort Driven VENTilator Management
Acronym
REDvent
Official Title
Identifying and Preventing Ventilator Induced Diaphragm Dysfunction in Children
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 21, 2017 (Actual)
Primary Completion Date
May 31, 2024 (Anticipated)
Study Completion Date
June 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital Los Angeles
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Children's Hospital of Philadelphia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is a Phase II controlled clinical trial that will obtain comprehensive, serial assessments of respiratory muscle strength and architecture to understand the evolution of ventilator-induced respiratory muscle weakness in critically ill children, and test whether a novel computer-based approach (Real-time Effort Driven ventilator management (REDvent)) can preserve respiratory muscle strength and reduce time on MV. REDvent offers systematic recommendations to reduce controlled ventilation during the acute phase of MV, and uses real-time measures from esophageal manometry to adjust supported ventilator pressures such that patient effort of breathing remains in a normal range during the ventilator weaning phase. This phase II clinical trial is expected to enroll 276 children with pulmonary parenchymal disease, anticipated to be ventilated > 48 hrs. Patients will be randomized to REDvent-acute vs. usual care for the acute phase of MV (interval from intubation to first spontaneous breathing trial (SBT)). Patients in either group who fail their first Spontaneous Breathing Trial (SBT), will also be randomized to REDvent-weaning vs. usual care for the weaning phase of MV (interval from first SBT to passing SBT). The primary clinical outcome is length of weaning (time from first SBT until successful passage of an SBT or extubation (whichever comes first)). Mechanistic outcomes surround multi-modal serial measures of respiratory muscle capacity (PiMax), load (resistance, compliance), effort (esophageal manometry), and architecture (ultrasound) throughout the course of MV. Upon completion, this study will provide important information on the pathogenesis and timing of respiratory muscle weakness during MV in children and whether this weakness can be mitigated by promoting more normal patient effort during MV via the use of REDvent. This will form the basis for a larger, Phase III multi-center study, powered for key clinical outcomes such as 28-day Ventilator Free Days.
Detailed Description
Study Aims: SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the duration of weaning from MV (Primary outcome). SA2: To determine if changes to direct measures of respiratory muscle strength, load, effort, and architecture throughout the duration of MV are related to weaning outcomes. SA3: To determine if patient effort of breathing during both acute and weaning phases of MV is independently associated with the development of respiratory muscle weakness. Study Design: Single-center randomized controlled trial (138 children per arm) using REDvent (intervention arm) as compared with usual care ventilator management including a standardized daily SBT (control arm). Acute phase randomization will occur upon study enrollment, and patients who fail the first SBT will undergo a weaning phase randomization. The investigators will obtain serial measurements of respiratory system capacity, load, effort of breathing, and diaphragm architecture throughout the course of MV. Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Intervention Arm (REDvent-acute): Patients will be managed with pressure control plus pressure support ventilation using a computerized decision support tool that will recommend changes to ventilator settings approximately every 4 hr (with or without a new blood gas). If the patient is spontaneously breathing, it will incorporate real-time measures of effort of breathing (esophageal manometry) to keep it in a target range. Control Arm (Control-acute): Ventilator management will be per usual care until the patient meets weaning criteria and passes the oxygenation test. Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Intervention Arm (REDvent-weaning): Patients will be managed in a pressure support/CPAP mode of ventilation with assessments or changes to the level of pressure support every 4 hours, targeting maintaining effort of breathing (esophageal manometry) in a normal range. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT. Control Arm (Control-weaning): Ventilator management will be per usual care. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT. Analysis Plan and Sample Size Justification: Aim 1: The primary outcome is weaning duration. Sample size has been determined to adequately power 3 separate comparative analyses: (a) REDvent-acute versus Acute Phase control (b) REDvent-weaning phase versus Weaning Phase control (c) REDvent both phases versus control both phases. Power is based on 2 planned methods for analysis: cox proportional hazard ratios for multivariable analysis and univariate analysis with an independent t-test using log transformation (as needed) to account for the expected distribution of weaning duration. For all three of the planned comparisons above, with the proposed sample size the investigators would be adequately powered (>0.8) to detect a difference in weaning duration of ≥ 1 day, or a hazard ratio of ≥ 1.4 between groups. The secondary outcomes are ventilator free days and extubation failure. Directly comparing control only patients to REDvent only patients, with an expected standard deviation for VFDs between 5 to 9 days, the investigators will be able to detect a 2-day change in VFDs between groups with a power between 0.35 and 0.82. Re-intubation rates are expected to be 10%, allowing the investigators to confirm that REDvent is not inferior to usual care in regards to re-intubation with a non-inferiority margin of 0.10 with a power of 0.8 and alpha of 0.05. Aim 2: The primary outcome of this aim is weaning duration. For respiratory muscle strength the investigators will compare the first measured aPiMax (after resolution of the acute phase, before the first SBT), the trajectory and value of the daily aPiMax during the weaning phase prior to extubation, the lowest and highest measured aPiMax, and aPiMax on the day of extubation against weaning duration. For analysis, aPiMax will be dichotomized at 30 cmH2O, and weaning duration will be compared between patients with aPiMax > 30 versus ≤ 30 cmH2O using a t-test with or without log-transformation, or Mann-Whitney U test, depending on the distribution. From preliminary data, it is anticipated at least 35% of patients (n=84) will have aPiMax ≤ 30 cmH2O. Based on a similar power analysis as presented above, this would allow the investigators to determine whether low aPiMax is associated with a ≥ 1-day increase in weaning duration, with an alpha of 0.05 and power of 0.8. The investigators will perform identical analysis for ePiMax. Diaphragm Thickness analysis will compound daily ultrasound measures to detect the relative change in diaphragm thickness from study day 1 until passage of an SBT. The investigators will compare the change in thickness after resolution of the acute phase (on the day of the first SBT) against weaning duration, in a similar manner as proposed above for aPiMax. In addition to weaning duration, the investigators will also examine whether the respiratory measures taken just prior to or during each SBT are associated with the patient passing the SBT. For example with aPiMax and ePiMax, the investigators will examine if there is a dose response relationship between PiMax measured just before the SBT and the rate of passage of the subsequent SBT. Aim 3: The primary outcome of this aim is aPiMax < 30 cmH2O.The analysis will focus on determining whether the degree of patient effort of breathing is independently associated with the development of respiratory muscle weakness. For the acute phase, the investigators will generate a time-weighted average PRP during the acute phase and graph it against aPiMax at the first SBT. They will subsequently dichotomize aPiMax at the first SBT and compare mean time weighted average PRP in the acute phase between aPiMax groups (> 30 vs. ≤ 30 cmH2O). For the weaning phase, the investigators will graph the changes in aPiMax throughout the weaning phase (from first failed SBT until successful SBT) against time-weighted average PRP, with the anticipation that low PRP will be associated with either further reductions in aPiMax, or no improvement, while PRP in the physiologic range of 150-400 will be associated with improvement in aPiMax. The investigators will subsequently dichotomize aPiMax (at 30 cm H2O) at the time of successful passage of an SBT and compare time-weighted average PRP in the weaning phase between aPiMax groups. Subsequently, the investigators will build a multivariable logistic regression model on the outcome of aPiMax ≤ 30 cmH2O to determine if time-weighted PRP in the acute phase, weaning phase or both have an independent association with preserving aPiMax, after controlling for confounding variables.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ventilation Therapy; Complications, Diaphragm Disease, Pediatric Respiratory Diseases

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Randomized Controlled Trial
Masking
Outcomes Assessor
Masking Description
Analysis Blinded
Allocation
Randomized
Enrollment
276 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
REDvent-acute
Arm Type
Experimental
Arm Description
Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Patients will be managed with pressure control plus pressure support ventilation using a computerized decision support tool that will recommend changes to ventilator settings approximately every 4 hr (with or without a new blood gas). If the patient is spontaneously breathing, it will incorporate real-time measures of effort of breathing (esophageal manometry) to keep it in a target range.
Arm Title
Control-acute
Arm Type
Placebo Comparator
Arm Description
Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Ventilator management will be per usual care until the patient meets weaning criteria and passes the oxygenation test.
Arm Title
REDvent-weaning
Arm Type
Experimental
Arm Description
Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Patients will be managed in a pressure support/CPAP mode of ventilation with assessments or changes to the level of pressure support every 4 hours, targeting maintaining effort of breathing (esophageal manometry) in a normal range. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT.
Arm Title
Control-weaning
Arm Type
Placebo Comparator
Arm Description
Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Ventilator management will be per usual care. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT.
Intervention Type
Other
Intervention Name(s)
Computerized Ventilator Protocol
Intervention Description
Computerized Decision Support System which recommends changes to ventilator settings to promote physiologic levels of patient effort of breathing.
Intervention Type
Diagnostic Test
Intervention Name(s)
Esophageal Manometry
Intervention Description
Esophageal Manometry Catheter to measure effort of breathing an transpulmonary pressure
Intervention Type
Diagnostic Test
Intervention Name(s)
Respiratory Inductance Plethysmography (RIP)
Intervention Description
RIP bands to measure thoraco-abdominal synchrony during spontaneous breathing trials
Intervention Type
Diagnostic Test
Intervention Name(s)
Diaphragm Ultrasound
Intervention Description
Daily measurement of diaphragm thickness and diaphragm contractile activity
Intervention Type
Diagnostic Test
Intervention Name(s)
Maximal Inspiratory Pressure
Intervention Description
Prior to Spontaneous breathing trials, measurement of airway and esophageal maximal inspiratory pressure during airway occlusion
Primary Outcome Measure Information:
Title
Median Duration of Weaning
Description
Time from first attempted SBT until SBT passage or extubation [whichever comes first]
Time Frame
First 28 days of Mechanical Ventilation
Secondary Outcome Measure Information:
Title
Median Ventilator Free Days
Description
Days alive and not on mechanical ventilation
Time Frame
28 and 60 days
Title
Number of Participants with Extubation Failure
Description
re-intubation or use of non invasive ventilation
Time Frame
7 days after extubation
Title
Number of Participants with Mortality
Description
Death
Time Frame
Through study completion up to maximum of 90 Days
Title
Median Maximal Inspiratory Airway Pressure During Airway Occlusion (aPiMax)
Description
Measured during standardized airway occlusion maneuvers
Time Frame
Each day after passing oxygenation test through extubation up to a maximum of 28 days
Title
Median Maximal Inspiratory Esophageal Pressure During Airway Occlusion (ePiMax)
Description
Measured during standardized airway occlusion maneuvers
Time Frame
Each day after passing oxygenation test through extubation up to a maximum of 28 days
Title
Median Change in diaphragm thickness on Exhalation (Dte) from baseline
Description
From daily ultrasound measurement
Time Frame
Each day from study initiation until extubation up to a maximum of 28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Days
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Children > 1 month (>44 weeks CGA) and ≤ 18 years of age AND Supported on mechanical ventilation with pulmonary parenchymal disease (i.e., pneumonia, bronchiolitis, Pediatric Acute Respiratory Distress Syndrome (PARDS)) with Oxygen Saturation Index (OSI) ≥ 5 or Oxygenation Index (OI) ≥) AND Who are within 48 hours of initiation of invasive mechanical ventilation (allow for up to 72 hours for those transferred from another institution) Exclusion Criteria: Contraindications to use of an esophageal catheter (i.e. severe mucosal bleeding, nasal encephalocele, transphenoidal surgery) OR Contraindications to use of RIP bands (i.e. omphalocele, chest immobilizer or cast) OR Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall defects, pregnancy) OR Conditions on enrollment that preclude conventional methods of weaning (i.e., status asthmaticus, severe lower airway obstruction, critical airway, intracranial hypertension, Extra Corporeal Life Support (ECLS), intubation for UAO, DNR, severe chronic respiratory failure, spinal cord injury above lumbar region, cyanotic heart disease (unrepaired or palliated)) OR Primary Attending physician refuses (will be cleared with primary attending before approaching the patient).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Robinder G Khemani, MD,MsCI
Phone
3233612557
Email
rkhemani@chla.usc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robinder G Khemani, MD, MsCI
Organizational Affiliation
Children's Hospital Los Angeles
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
De-Identified IPD will be made available as per NIH guidelines.
IPD Sharing Time Frame
Within 5 years of publication of primary manuscript
IPD Sharing Access Criteria
Will be made available through biolinc
IPD Sharing URL
https://biolincc.nhlbi.nih.gov/home/
Citations:
PubMed Identifier
36037984
Citation
Knox KE, Hotz JC, Newth CJL, Khoo MCK, Khemani RG. A 30-Minute Spontaneous Breathing Trial Misses Many Children Who Go On to Fail a 120-Minute Spontaneous Breathing Trial. Chest. 2023 Jan;163(1):115-127. doi: 10.1016/j.chest.2022.08.2212. Epub 2022 Aug 28.
Results Reference
derived
PubMed Identifier
35830707
Citation
van Dijk J, Blokpoel RGT, Abu-Sultaneh S, Newth CJL, Khemani RG, Kneyber MCJ. Clinical Challenges in Pediatric Ventilation Liberation: A Meta-Narrative Review. Pediatr Crit Care Med. 2022 Dec 1;23(12):999-1008. doi: 10.1097/PCC.0000000000003025. Epub 2022 Jul 14.
Results Reference
derived
PubMed Identifier
33326335
Citation
Shimatani T, Yoon B, Kyogoku M, Kyo M, Ohshimo S, Newth CJL, Hotz JC, Shime N, Khemani RG. Frequency and Risk Factors for Reverse Triggering in Pediatric Acute Respiratory Distress Syndrome during Synchronized Intermittent Mandatory Ventilation. Ann Am Thorac Soc. 2021 May;18(5):820-829. doi: 10.1513/AnnalsATS.202008-1072OC.
Results Reference
derived
PubMed Identifier
31740425
Citation
Khemani RG, Hotz JC, Klein MJ, Kwok J, Park C, Lane C, Smith E, Kohler K, Suresh A, Bornstein D, Elkunovich M, Ross PA, Deakers T, Beltramo F, Nelson L, Shah S, Bhalla A, Curley MAQ, Newth CJL. A Phase II randomized controlled trial for lung and diaphragm protective ventilation (Real-time Effort Driven VENTilator management). Contemp Clin Trials. 2020 Jan;88:105893. doi: 10.1016/j.cct.2019.105893. Epub 2019 Nov 16.
Results Reference
derived

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Real-time Effort Driven VENTilator Management

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