Subjects will be identified upon emergency department (ED) arrival or upon transfer from an outside facility and screened for enrollment by a PCAS physician as soon as possible. Eligible patients will have receive any required resuscitation (including central venous and arterial line placement, endotracheal intubation and hemodynamic resuscitation as needed) prior to having baseline labs and studies performed. Subjects will then be started on study drug delivered via the mechanical ventilator with a concealed canister (subject, providers and outcome assessors blind to treatment assignment). Randomization will be performed 1:1 in blocks of 8 using a random number generator. A randomization list will be prepared in advance by the director of respiratory therapy (RT) at each site and verified by a company representative. These individuals (who are not part of the study team) will be unblinded and assure that allocation to placebo and intervention is accurate. The allocation list will assign study drug canisters (by barcode) to each subject in order of study ID. Treatment assignment will be revealed after opening a sealed opaque envelope once enrollment is confirmed by a physician investigator. Study drug will then be administered by RT based on allocation. During study drug administration hourly vital signs will be obtained and methemoglobin levels for safety. Study drug will be weaned off after 12h over the course of 1h (10, 5, 4, 3, 2, 1 ppm each for 10 min) prior to discontinuation. Subjects will then receive standard post-resuscitation care with outcomes assessed by a blinded study team member (see below for outcomes).
Additional clinical variables to be collected Demographics and baseline function. Age, sex, race, maximum education level, employment status, marital status, Barthel activities of daily living (ADL) index prior to OHCA.
Arrest data. Location of OHCA, witnessed, bystander cardiopulmonary resuscitation (CPR), estimated no flow and low flow times, presenting rhythm, doses of epinephrine administered, shocks administered, recurrent arrest, date and time of ROSC.
Medical comorbidities. Diabetes, hypertension, active smoking, hyperlipidemia, chronic obstructive pulmonary disease (COPD), hypertension, drug abuse, prior myocardial infarction, prior coronary artery bypass grafting (CABG), prior coronary angiography with angioplasty or stent, congestive heart failure (EF on last echocardiogram \[ECHO\] prior to OHCA), obstructive sleep apnea, pulmonary hypertension, calculated Charlson comorbidity index (CCI).
Home medications. Statins, nitrates, anticoagulation, antiplatelet agents Hospital Interventions. Coronary angiography, percutaneous coronary intervention, CABG, mechanical ventilation hours and fraction of inspired oxygen (FiO2) from 0-24h after therapy start In-hospital medications. Alteplase, anti-epileptic medication use (valproate, phenytoin, lacosamide, levetiracetam), neurostimulants (methylphenidate, bromocriptine, modafinil, amantadine), cumulative dose of fentanyl, propofol, midazolam, cis-atracurium and vecuronium in at 24 (+/- 12 hours), 48 (+/- 12 hours), and 72 (+/- 12 hours) hours after therapy initiation
Data Storage Subjects will be assigned a study identifier (ID) upon entry and all data/samples stored using that ID. Linkage to patient identifiers will be maintained in a secure spreadsheet and will include name, date of birth and medical record number. Clinical data will be entered on case report forms (source documentation) which will be stored in a locked filing cabinet within a locked office assigned to the study team. Deidentified clinical and lab data will all be subsequently entered from the case report forms into a web based database (REDCap) to be maintained by Dr. Dezfulian's research assistant who has prior experience from other studies.
Statistical Analysis Plan Continuous data will be compared using t-tests and repeated measures ANOVA to compare between iNO and placebo groups at multiple times. Dichotomous outcomes including the primary endpoint will be compared by chi squared test. Time to awakening and 90d survival will be compared by log rank test of Kaplan-Meier survival plots. All tests will be two tailed with unadjusted p\<0.05 considered significant. In the event of a differential distribution of baseline variables strongly associated with outcome (univariate OR \>2), dichotomous outcomes will be adjusted for these baseline variables.
