Inhaled Nitric Oxide After Out-of-Hospital Cardiac Arrest
Condition: Heart Arrest, Out-Of-Hospital
MeSH terms: Heart Arrest; Out-of-Hospital Cardiac Arrest
Intervention: Nitric Oxide; Nitrogen
Intervention description: An endogenous gaseous signaling molecule which stimulates soluble guanylate cyclase and may act via S-nitrosation, nitrite/nitrate or nitrated fatty acid formation.; Nitrogen is the carrier gas (vehicle) for iNO. Subjects receiving placebo will receive equivalent doses of nitrogen.
Intervention MeSH terms: Nitric Oxide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will be randomized 1:1 to either placebo or active study drug (iNO). This will be stratified within blocks of 8 subjects at each center.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Gas canisters will be marked with a bar code which will be recorded by the study coordinator and available to the study team. Only the respiratory therapy directors will be aware of the canister content (placebo vs. active drug). Treatment assignment will be revealed upon opening a sealed opaque envelope after enrollment has been confirmed.
Enrollment: 57.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Phase II double blind (participants and investigator) placebo controlled randomized (1:1)
      clinical trial of inhaled nitric oxide (iNO) 20 ppm administered over 12h beginning as soon
      as possible but within 4 h of return of spontaneous circulation (ROSC) from out-of-hospital
      cardiac arrest (OHCA). Planned enrollment is 180 subjects over 48 months at University of
      Pittsburgh Medical Center (UPMC) Hospitals with randomization stratified in blocks of 8.
      Recruitment will be performed under exception from informed consent (EFIC) to facilitate
      early enrollment and treatment. The study will have a pre-specified safety analysis at the
      mid-point (after 1 year or 60 patients whichever occurs first). Subjects will be screened by
      members of the University of Pittsburgh post-cardiac arrest service (PCAS), all of whom will
      serve as the study co-investigators, and the Research Coordinators. Notification of inclusion
      under EFIC will be performed as soon as possible by a member of the study team generally to a
      surrogate as the subjects will be comatose after OHCA.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Intubated and comatose adult (>18 yo) resuscitated from out-of-hospital cardiac arrest
             (OHCA)*

             *Cardiac arrest within an emergency department or outpatient medical center will be
             included). OHCA includes Emergency Medical Service (EMS) witnessed cardiac arrest.

          -  Return of spontaneous circulation (ROSC) within 40 min of CPR initiation

          -  Full Outline of Unresponsiveness (FOUR) Brainstem score ≥ 2 (i.e. patient must have
             pupil OR corneal reflex at the time of ED presentation or within 1h if
             sedation/neuromuscular blockade clouds the picture)

        Exclusion Criteria:

          -  Traumatic etiology of OHCA

          -  Prisoner

          -  Known pregnancy (beta-human chorionic gonadotropin screening is NOT REQUIRED for
             enrollment in women of appropriate age)

          -  Hemodynamic instability defined as >1 recurrent arrest prior to enrollment OR
             inability to maintain mean arterial blood pressure (MAP) > 65 using vasopressors and
             inotropes (ie actively up titrating medications or giving fluid bolus)

          -  Head CT grey-white ratio < 1.2; Head CT is NOT REQUIRED prior to enrollment

          -  Fixed and dilated pupils without another explanation

          -  Known intracranial hemorrhage or acute cerebral infarction; Head CT is NOT REQUIRED
             prior to enrollment

          -  Malignant EEG upon presentation defined as: myoclonic status epilepticus,
             non-convulsive status epilepticus, generalized periodic epileptiform discharges. EEG
             screening is NOT REQUIRED prior to enrollment

          -  ROSC >3h from time of ED arrival (treatment allocation must be within 4h so anything
             that will prevent this is reason for exclusion)

          -  Alert and interactive patient with minimal evidence of neurologic injury

          -  Plan to extubate within 12 hours

          -  Post-cardiac arrest service (PCAS) physician opinion that patient will die with >95%
             likelihood. This may be based on:

               -  Multiple medical comorbidities

               -  Late discovery of don not resuscitate (DNR) or advanced directive

               -  Terminal diagnosis (other than OHCA; may have caused OHCA)

               -  Clinical judgement based on current exam and data

          -  Patient is known to be taking phosphodiesterase type 5 (PDE5) inhibitors, soluble
             guanylyl cyclase (sGC) stimulator, or has a known diagnosis of Chronic thromboembolic
             pulmonary hypertension (CTEPH), pulmonary hypertension (PAH), or erectile dysfunction

          -  Known enrollment in another acute interventional study.