This is a single-center proof-of-concept clinical trial designed to establish the feasibility of transvenous phrenic-nerve stimulation (PNS) to maintain diaphragm activation over the first 24 hours and for up to seven days of mechanical ventilation in patients who are likely to require more than 48 hours of invasive mechanical ventilation.

The diaphragm is the main muscle of breathing and for most of us therefore is continuously being used (and hence exercised) when in health. When people are unwell with severe breathing difficulties to the degree that their lungs are needing a lot of support from a breathing machine (ventilator) in the intensive care unit (ICU), or are recovering from major lung/chest surgery on a ventilator in ICU, the diaphragm can quickly start to weaken from its inactivity. This means that even when starting to recover from the underlying medical problem, or from the surgery itself, the diaphragm may be unable perform well enough to take over the work of breathing once again. This can lead to not only longer times on the ventilator (time to gradually rebuild diaphragm strength by rehabilitation and physiotherapy) but also therefore longer times in ICU and in hospital with the risk of complications that can be associated with this.

Stimulating the diaphragm by use of a pacemaker (electrical stimulation) is an established treatment for a number of patients with certain types of long-term breathing problems. These pacemakers are permanent and are inserted by invasive surgical methods. More recently however, there have also been a number of studies looking to see if it is possible to safely, temporarily and less invasively stimulate the diaphragm of patients who only have temporary diaphragm inactivity. This has been done either during surgery or during their intensive care stay. A number of methods of temporarily stimulating the diaphragm have been looked at, but the simplest has been to integrate the function of stimulating the nerves (that ultimately control the diaphragm) with a catheter that is frequently placed into a vein in the neck to enable delivery of medications during surgery and in ICU.

Group 1: Acute hypoxemic respiratory failure (AHRF)

Inclusion Criteria:

• Age ≥18 years old, and,
• Invasive mechanical ventilation for ≤ 7 days, and,
• Have hypoxemia as defined by one of:
• A PaO2:FiO2 ratio < 300 and PEEP ≥ 5 cm H2O, or
• SpO2:FiO2 < 315% on PEEP ≥ 5 cm H2O in absence of an available arterial blood gas, and in the presence of a reliable Sp)2 trace and a SpO2 < 97%, or
• Are receiving inhaled nitric oxide for acute hypoxemia, or
• Require extracorporeal membrane oxygenation, and,
• Are on controlled mechanical ventilation with no patient-triggered ventilator-delivered breaths with no imminent plan to transition to assisted ventilation within 6 hours, and,
• Are not expected to be liberated from mechanical ventilation within the next 48 hours (from time of enrollment)

Group 2: Pulmonary endarterectomy

Inclusion Criteria:

• Age 18 to 65 years old
• Are listed for pulmonary thromboendarterectomy
• Have pulmonary vascular resistance < 1000 dynes.sec.cm-5

Group 3: Lung transplant

Inclusion Criteria:

• Age 18 years or older
• Are listed for bilateral lung transplant for a primary indication of idiopathic pulmonary fibrosis with no plan for concomitant transplant of other solid organs

All groups

Exclusion Criteria:

• Pregnant or lactating
• Previously diagnosed neuromuscular disorder or known phrenic nerve injury
• BMI >70kg/m2
• Implanted electronic cardiac or neurostimulation device in situ
• Contraindications to left internal jugular or subclavian vein catheterization (e.g., infection over the site, known central venous stenosis, septic thrombophlebitis, left internal jugular ECMO cannula in situ) and/or subclavian vein catheterization (to include poor target vessel)
• Contraindications to esophageal balloon or EMG catheter placement (e.g. active bleeding or high-grade esophageal varices with recent bleeding or banding in previous 14 days, recent esophageal surgery or esophageal rupture)
• Patient transitioning fully to palliative care
• Treating clinician deem enrollment not clinically appropriate for other reason
• Currently being treated in another clinical trial studying an experimental treatment that could affect the study primary outcome