Phase I Trial of Inhaled Nitric Oxide to Treat Acute Pulmonary Embolism
Phase I Trial of Inhaled Nitric Oxide to Treat Acute Pulmonary Embolism
This study will test the hypothesis that patients with acute PE and dyspnea can safely inhale
 NO. The secondary hypothesis is that patients who are blinded to the inhaled NO concentration
 will sustain subjective improvement in their perception of dyspnea based upon their reported
 Borg dyspnea score, during inhalation of NO.

 Specific aims

 1. Test if patients with acute PE and shortness of breath of severity ≥ 5 on a 0-10 scale
 called the Borg score can have inhaled nitric oxide administered via nasal cannula or
 face mask in a titration protocol that increases concentration by 5 ppm in 5 min steps
 to a maximum of 25 ppm.

 2. We will measure the number of patients who meet an absolute safety endpoint during
 titration. An absolute safety endpoint requires execution of a rapid weaning protocol (2
 ppm decrease per minute to 0 ppm).

 Absolute safety endpoints: Two consecutive SBP measurements more than one min apart with
 both readings < 80 mm Hg;SaO 2 <80% for more than 15 seconds; Patient deterioration as
 defined by: Clinical decision for need of inotropic or pressor support for any reason,
 seizure, new altered mental status, focal neurological signs suggestive of cerebral
 ischemia, evidence of myocardial ischemia, protracted vomiting.

 3. Test if the patient-reported Borg score decreases with administration of NO. Patients
 will not be told any details about the timing of the titration and will not be made
 aware of their iNO concentration when the Borg score is assessed.
We propose to enroll a total of 25 patients with recently diagnosed pulmonary embolism.
 Inclusion criteria will include moderate to severe shortness of breath as rated by the
 patient on a standard scoring system, a systolic blood pressure of >89 mm Hg unless the
 patient has a known prior history of low blood pressure, and blood oxygen saturation of >80%.
 Exclusion criteria will include: altered mental status, inability to use a nasal cannula, a
 large need for supplemental oxygen, pregnancy, pneumothorax, recent use of nitrate-containing
 medications, recent use of thrombolytic drugs, requirement for inotropic or pressor support,
 or a level of methemoglobin greater than 10%.

 After obtaining informed consent, subjects will have blood drawn and vital signs will be
 obtained. They will subsequently begin to breathe oxygen and NO supplied through a nasal
 cannula delivered from the iNOvent device. The patients will undergo serial measurements of
 their blood pressure, arterial oxygen saturation and will have their serum methemoglobin
 level monitored via a non-invasive probe. Titration of the amount of NO delivered will be
 made periodically based on the patient's vital signs. If an absolute safety endpoint is
 reached, NO will be rapidly weaned. Based on the patient's response to NO as determined by
 their vital signs, a maintenance dose of NO, not to exceed 25 ppm, will be reached. Subjects
 will continue to receive this concentration for up to 2 hours prior to weaning. Patients will
 be asked once more to rate the severity of their shortness of breath and blood will be drawn
 just prior to weaning. Should the patient reach a safety endpoint, the NO will be weaned at
 an earlier timepoint.

 We will determine the percentage of patients able to complete the full protocol without
 reaching a safety endpoint, the percent change in methemoglobin level, the trend in
 patient-reported shortness of breath, percent change in SBP and oxygen saturation and the
 number of patients who withdraw during induction for any reason.
Inclusion Criteria:

 Inclusion Criteria:

 1. Diagnosis of acute PE requires symptoms of PE present <14 days with CT angiography
 interpreted as positive for acute PE. Initial evaluation for PE must be predicated
 upon the investigation of new or unexplained cardiopulmonary or chest-related clinical
 features consistent with PE, including shortness of breath, chest pain, respiratory
 distress, dizziness, unexplained tachypnea, tachycardia, syncope, cough or hemoptysis.
 All patients must have CT chest angiography with <2 mm collimation,(36) with or
 without indirect venography. Pulmonary arterial opacification will be achieved with
 power injection of non-ionic, low osmolar contrast in an antecubital vein with a
 timing run; the pitch, voltage, gantry speed and other technical details appropriate
 for each scanner.(37;38) Images will be interpreted as positive for intrapulmonary
 arterial filling defect consistent with acute PE using our published
 definitions(37;38) by a board-certified radiologist with specialty training in body CT
 or emergency medicine imaging in all cases.

 2. SBP (SBP)> 89 mm Hg at the time of enrollment. We will allow enrollment for a patient
 with an SBP < 90 mm Hg prior to enrollment, or a patient with a SBP>80 mm Hg, if the
 patient has a documented or patient-identified history of low blood pressure and has
 no symptoms of shock, as described by Jones et al.(39)

 3. SaO2% >80% at time of enrollment.

 4. Patients must have a Borg score greater than 4/10.

 Exclusion Criteria:

 1. Altered mental status such that they are unable to provide consent.

 2. Inability to use a nasal cannula or face mask (e.g., anatomic defect)

 3. Supplemental oxygen requirement greater than can be administered via nasal cannula or
 face mask in order to maintain SaO2 >80%.

 4. Pregnancy

 5. Pneumothorax with decompression

 6. A serum mtHb greater than 10%

 7. Concurrent therapies including:

 1. Viagra® (sildenafil) use within the past 24 hours

 2. Levitra® (vardenafil) use within the past 24 hours

 3. Cialis® (tadalafil) use within the past 72 hours

 4. Use nitroprusside or nitroglycerine with in the past 4 hours

 5. Concomitant use of pressor or inotropic agents

 6. Use of fibrinolytic agent with in the past 14 days

 7. Use of nitrates within the past 24 hours