Extracorporeal CO2 Removal for Acute Decompensation of COPD (ORION)

Extra-Corporeal Carbon Dioxide Removal for Acute Decompensation of Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial (The ORION Study)

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, resulting in a social and economic burden that is substantial and increasing. Exacerbations affect the prognosis and quality of life of patients with COPD. Hospital mortality of patients admitted for a hypercapnic exacerbation of COPD is approximately 10% and the long-term outcome is poor. In addition, hypercapnic exacerbation of COPD have serious negative impacts on patient quality of life, lung function and costs. Thus, prompt treatment of exacerbations may impact the clinical progression of COPD by ameliorating quality of life and prognosis.

Standard of care for patients with COPD exacerbation that need ICU admission for management of acute hypercapnic respiratory failure and severe respiratory acidosis is non-invasive ventilation (NIV). When NIV fails (arterial pH remains < 7.30), invasive ventilation through endotracheal intubation is initiated to restore adequate gas-exchange. Extracorporeal circuits designed to remove CO2 (ECCO2R) may enhance the efficacy of NIV to remove CO2 and avoid the worsening of respiratory acidosis.

A recent matched cohort study with historical control, showed that: (a) the hazard of being intubated was three times higher in patients treated with "NIV-only" than in patients treated with "NIV-plus-ECCO2R"; (b) hospital mortality was significantly lower in "NIV plus ECCO2R" than in "NIV-only" [8% (95% CI 1.0-26.0%) vs. 33% (95% CI 18.0-57.5%), respectively]. However, ECCO2R-related complications were observed in almost half of the patients.

The consistency of the above discussed data, and the observation of the continuous increase use of ECCO2R despite the lack of solid evidence confirm that the equipoise regarding the use of ECCO2R may justify a randomized clinical trial to evaluate whether patients with respiratory acidosis refractory to NIV should be intubated and take the risks associated with invasive mechanical ventilation, or should be connected to ECCO2R to avoid intubation, but run the risk of the potentially serious ECCO2R-related complication The main objective of this randomized multicenter clinical trial is to test the hypothesis that in patients with acute life-threatening exacerbation of COPD, use of ECCO2R could increase event-free survival as compared to standard of care.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Device: NIV; Device: ECCO2R

Detailed Description

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, resulting in a social and economic burden that is substantial and increasing. Exacerbations affect the prognosis and quality of life of patients with COPD. Hospital mortality of patients admitted for a hypercapnic exacerbation of COPD is approximately 10% and the long-term outcome is poor. In addition, hypercapnic exacerbation of COPD have serious negative impacts on patient quality of life, lung function and costs. Thus, prompt treatment of exacerbations may impact the clinical progression of COPD by ameliorating quality of life and prognosis.

The pathophysiological hallmarks of COPD patients include expiratory flow limitation and small airway closure. Under these circumstances, a prolonged expiratory time is the compensatory mechanism patients adopt to maintain a stable tidal breathing. COPD exacerbations result in higher respiratory rates and reduced expiratory time, leading to dynamic hyperinflation, elevated intrathoracic pressures, and excessive work of breathing. Alteration of the balance between (a) the decreased capacity of the respiratory muscles to generate pressure, and (b) the increased mechanical respiratory load due to expiratory flow limitation and small airway closure leads to CO2 retention. The consequent reduction of alveolar ventilation leads to a further worsening of CO2 retention and increased work of breathing. This vicious circle is the underlying mechanisms responsible of acute respiratory failure requiring admission in the intensive care unit (ICU) for ventilatory support.

Standard of care for patients with COPD exacerbation that need ICU admission for management of acute hypercapnic respiratory failure and severe respiratory acidosis is non-invasive ventilation (NIV). When NIV fails (arterial pH remains < 7.30), invasive ventilation through endotracheal intubation is initiated to restore adequate gas-exchange.

Extracorporeal circuits designed to remove CO2 (ECCO2R) have been used in patients with acute hypercapnic respiratory failure since ECCO2R may enhance the efficacy of NIV to remove CO2 and avoid the worsening of respiratory acidosis. Although available studies are limited to case series, several ECCO2R devices have been developed and proposed for the clinical use in patients with COPD. These systems often represent modifications of renal replacement therapy circuits, and are characterized by:

1. veno-venous by-pass systems
2. extracorporeal blood flow of 0.3-0.5 litres/min
3. 13 Fr bore catheters or a single co-axial catheter
4. very low doses or no heparin
5. minimal volumes for "priming"

This technological implementation of ECCO2-R is therefore closer to device for renal replacement therapy than full ECMO. CO2 is removed through a double-lumen catheter and constantly propelled, by a non-occlusive rotating pump, though an artificial membrane lung (a filter adding oxygen and removing carbon dioxide) connected to a source of 100% O2 (flow 6-8 liters/min). These systems are able to reduce PaCO2 by 20-25%.

A recent matched cohort study with historical control, compared "NIV-plus-ECCO2R" and "NIV-only" in patients at risk of NIV failure, and showed that (a) the hazard of being intubated was three times higher in patients treated with "NIV-only" than in patients treated with "NIV-plus-ECCO2R"; (b) hospital mortality was significantly lower in "NIV plus ECCO2R" than in "NIV-only" [8% (95% CI 1.0-26.0%) vs. 33% (95% CI 18.0-57.5%), respectively]. However, ECCO2R-related complications were observed in almost half of the patients. A recent systematic review evaluated the efficacy and safety of ECCO2R in patients with hypercapnic respiratory failure across 12 studies and showed that the majority of patients were either successfully weaned from mechanical ventilation or sustained on NIV, avoiding intubation. However, this high success rates, was associated with a high frequency of potentially severe complications.

The consistency of the above discussed data, and the observation of the continuous increase use of ECCO2R despite the lack of solid evidence confirm that the equipoise regarding the use of ECCO2R may justify a randomized clinical trial to evaluate whether patients with respiratory acidosis refractory to NIV should be intubated and take the risks associated with invasive mechanical ventilation, or should be connected to ECCO2R to avoid intubation, but run the risk of the potentially serious ECCO2R-related complication

Objectives:

The main objective of this randomized multicenter clinical trial is to test the hypothesis that in patients with acute life-threatening exacerbation of COPD, use of ECCO2R could increase event-free survival as compared to standard of care. Event free survival is defined as survival at day 28 free of any of the followings: (a) development of sepsis; (b) occurrence of a second episode of COPD exacerbation requiring or not mechanical ventilation; (c) occurrence of severe hypoxemia; (d) prolonged mechanical ventilation (e) death.

• Study Type: Interventional
• Enrollment (Estimated): 284
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lara Pisani, M.D.; Phone Number: +39-051-2143253; Email: lara.pisani@unibo.it
• Study Contact Backup: Name: Tommaso Tonetti, M.D.; Phone Number: +39-051-2143268; Email: tommaso.tonetti@unibo.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients older than 18 and younger than 90 years
• Documented clinical history of COPD
• ICU admission for exacerbation of COPD requiring non-invasive ventilatory support After two hours of NIV at least two of the following criteria must be fulfilled
• arterial pH ≤ 7.25
• respiratory rate ≥30 breaths/min
• use of accessory muscles or paradoxical abdominal movements

Exclusion Criteria:

• mean arterial pressure <60 mmHg despite infusion of fluids and vasoactive drugs
• ratio of arterial-to-inspired oxygen O2 fraction (PaO2/FiO2) ≤ 150 with FiO2 of less than 0.6 and PEEP of at least 5 cm H2O
• contraindications to anticoagulation (i.e. any of the following: platelet count <50,000/mm3; prothrombin time-international normalized ratio (INR) >1.5; stroke or severe head trauma or intracranial arterio-venous malformation, or cerebral aneurysm, or central nervous system mass lesion within the previous 3 months; epidural catheter in place or expected to be positioned during the study; history of congenital bleeding diatheses; gastrointestinal bleeding within the 6 weeks prior to study entry; esophageal varices, chronic jaundice, cirrhosis, or chronic ascites; trauma);
• heparin-induced thrombocytopenia;
• body weight >120 Kg;
• contraindication to continuation of active treatment;
• failure to obtain consent
• catheter access to femoral vein or jugular vein impossible
• pneumothorax
• inclusion in other trials
• patient moribund
• severe liver insufficiency (Child-Pugh scores > 7) or fulminant hepatic failure
• diagnosed with acute or chronic neuromuscular disease
• required chronic mechanical ventilation prior to hospital admission

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care (NIV); Patients in the control group will be treated with non-invasive ventilation only.	Device: NIV; Non-invasive ventilation
Experimental: Extracorporeal CO2 Removal (NIV+ECCO2R); Patients in the treatment group will be treated with non-invasive ventilation combined with Extracorporeal CO2 Removal.	Device: NIV; Non-invasive ventilation; Device: ECCO2R; Extracorporeal CO2 Removal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Combined 28-day mortality or surrogate events	Incidence of death, prolonged mechanical ventilation, development of septic shock, development of severe hypoxemia, second episode of COPD exacerbation	28 days after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endotracheal intubation	Cumulative incidence of endotracheal intubation	28 days after enrollment
Tracheostomy	Cumulative incidence of tracheostomy	28 days after enrollment
Hospital length-of-stay	Duration of stay in the hospital	Whole hospital stay
ICU length-of-stay	Duration of stay in the intensive care unit	Whole ICU stay
90-day mortality	Incidence of death	90 days after enrollment

Collaborators and Investigators

• Sponsor: University of Bologna
• Collaborators: University of Roma La Sapienza; University of Turin, Italy; University of Milan
• Investigators: Study Chair: V. Marco Ranieri, M.D., University of Bologna; Study Chair: Stefano Nava, M.D., University of Bologna

Publications and helpful links

General Publications

• Tonetti T, Pisani L, Cavalli I, Vega ML, Maietti E, Filippini C, Nava S, Ranieri VM. Extracorporeal carbon dioxide removal for treatment of exacerbated chronic obstructive pulmonary disease (ORION): study protocol for a randomised controlled trial. Trials. 2021 Oct 19;22(1):718. doi: 10.1186/s13063-021-05692-w.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: October 3, 2020
• First Submitted That Met QC Criteria: October 3, 2020
• First Posted (Actual): October 12, 2020

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: COPD; ECCO2R
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Lung Diseases, Obstructive; Chronic Disease; Lung Diseases; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: ORION

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