Impact of Decreasing Respiratory Rate on Lung Injury Biomarkers in ARDS Patients

Impact of Decreasing Respiratory Rate, While Tolerating Moderate Hypercapnia, on Lung Injury Markers in Patients With Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a form of acute lung injury of inflammatory origin, which represents a public health problem worldwide due to its prevalence, and its high mortality rate, close to 40%. Mechanical ventilation is a fundamental therapy to improve gas exchange, however, it can also induce further lung injury, a phenomenon known as ventilator induced lung injury (VILI). The limitation of tidal volume is the strategy that has shown the greatest decrease in mortality and is the cornerstone of protective ventilation. However, the respiratory rate, a fundamental parameter in the programming of the mechanical ventilator, has not been evaluated in most of the main clinical studies to date. Moreover, the natural clinical response to the use of a low tidal volume strategy is the increase in respiratory rate, which may harm the lung as it increases the energy applied to the lung parenchyma. The investigators hypothesize that the use of a lower respiratory rate, tolerating moderate hypercapnia, is associated with less VILI, measured by the release of proinflammatory mediators at the systemic level (biotrauma), compared to a conventional higher respiratory rate strategy in patients with moderate to severe ARDS. This effect is mediated by lower energy applied to the pulmonary parenchyma. To confirm this hypothesis the investigators propose a prospective cross-over clinical trial in 30 adult patients with ARDS in its acute phase, which will be randomized to two sequences of ventilation. Each period will last 12 hours, and respiratory rate (RR) will be set according to PaCO2 goal: 1) Low RR, PaCO2 60-70 mmHg; and 2) High RR, PaCO2 35-40 mmHg.

Protective ventilation will be applied according to ICU standards under continuous sedation and neuromuscular blockade. Invasive systemic arterial pressure and extravascular lung water will be monitored through an arterial catheter (PICCO® system), and airway and esophageal pressures and hemodynamics continuously measured throughout the protocol. The main outcome will be Interleukin-6 in plasma. At baseline and at the end of each period blood samples will be taken for analysis, and electrical impedance tomography (EIT) and transthoracic echocardiography will be registered. After the protocol, patients will continue their management according to ICU standards.

Study Overview

• Status: Completed
• Conditions: Acute Respiratory Distress Syndrome; Ventilator-Induced Lung Injury; Respiration, Artificial
• Intervention / Treatment: Procedure: Respiratory rate modification

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Guillermo Bugedo, MD; Phone Number: 223549024; Email: gbugedo@gmail.com

Study Locations

• Chile
  • Santiago, Chile
    • Hospital Clinico Universidad Catolica

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients intubated and under mechanical ventilation with acute respiratory distress syndrome less than 48 hours

1. Acute onset (less than 1 week)
2. Chest-X-ray: bilateral infiltrates
3. Absence of heart failure or hydrostatic pulmonary edema
4. Oxygenation disorder: PaO2/FiO2 ratio <200, with PEEP ≥5 cmH2O

Exclusion Criteria:

• Age <18 years
• Previous chronic respiratory disease (chronic obstructive lung disease, asthma, intersticial lung disease, pulmonary fibrosis, chronic bronchiectasis)
• Hypercapnic respiratory failure, defined as PaCO2 >60 mmHg or pH<7.25 despite a RR >30.
• Concomitant severe metabolic acidosis: pH<7.20
• Catastrophic respiratory failure, defined as PaO2/FiO2 ratio <80, despite optimization of ventilatory parameters, or need for ECMO.
• Contraindication to hypercapnia, such as intracranial hypertension or acute coronary syndrome
• Use of vasoconstrictor drugs in increasing doses in the last 2 hours (≥0.5 μg/kg/min of noradrenaline) or average blood pressure <65mmHg
• Pneumothorax or subcutaneous emphysema, not drained.
• Pregnancy
• Presence of mental or intellectual disability prior to hospitalization
• Early limitation of therapeutic effort

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Sequence A; Sequence A: Low RR for 12 hours - High RR for 12 hours	Procedure: Respiratory rate modification; During the Low RR and High RR periods, respiratory rate will be set depending on baseline ABG and according a nomogram so as to have an approximate difference of 10 points between groups, while maintining PaCO2 and pH values within safety limits (pH 7.20 to 7.45, and PaCO2 35 to 60 mmHg). Once defined the target respiratory rate, this will be decreased or increased in 4 points each 30 to 45 min, and ABG repeated at 2 hours. At this time, changes will be made to keep PaCO2 and pH values within safety limits, and ABG repeated at 6 and finally 12 hours. During the whole period, inspiratory to expiratory ratio will be maintained constant, and only changed to keep inspiratory time above 0.6 seconds (usually at high resp rate).
Other: Sequence B; Sequence B: High RR for 12 hours - Low RR for 12 hours.	Procedure: Respiratory rate modification; During the Low RR and High RR periods, respiratory rate will be set depending on baseline ABG and according a nomogram so as to have an approximate difference of 10 points between groups, while maintining PaCO2 and pH values within safety limits (pH 7.20 to 7.45, and PaCO2 35 to 60 mmHg). Once defined the target respiratory rate, this will be decreased or increased in 4 points each 30 to 45 min, and ABG repeated at 2 hours. At this time, changes will be made to keep PaCO2 and pH values within safety limits, and ABG repeated at 6 and finally 12 hours. During the whole period, inspiratory to expiratory ratio will be maintained constant, and only changed to keep inspiratory time above 0.6 seconds (usually at high resp rate).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in IL-6	levels of IL-6 in plasma	baseline, 12 and 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in transpulmonary driving pressures		Baseline, 12 and 24 hours
Changes in Auto PEEP		Baseline, 12 and 24 hours
Changes in mean airway pressure		Baseline, 12 and 24 hours
Changes in level of energy applied to the lungs		Baseline, 12 and 24 hours
Changes in arterials blood gases		Baseline, 12 and 24 hours
Changes overtime in distribution of ventilation	Distribution of ventilation as assessed by Electrical impedance tomography	Baseline, 6,12, 24 hours
Changes in cardiac function and pulmonary edema	measured by PICCO®.	Baseline, 12 and 24 hours
Changes pulmonary edema	measured by PICCO®.	Baseline, 12 and 24 hours

Collaborators and Investigators

• Sponsor: Pontificia Universidad Catolica de Chile

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2020
• Primary Completion (Actual): February 1, 2022
• Study Completion (Actual): February 1, 2022

Study Registration Dates

• First Submitted: October 9, 2020
• First Submitted That Met QC Criteria: November 18, 2020
• First Posted (Actual): November 24, 2020

Study Record Updates

• Last Update Posted (Actual): April 5, 2023
• Last Update Submitted That Met QC Criteria: April 3, 2023
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: ARDS; Mechanical ventilation; Respiratory rate; Ventilator induced lung injury
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Infant, Premature, Diseases; Thoracic Injuries; Syndrome; Wounds and Injuries; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Lung Injury; Ventilator-Induced Lung Injury
• Other Study ID Numbers: 180813016; 1191315 (Other Grant/Funding Number: Fondecyt)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No