Inhaled Nitric Oxide for High Amplitude Pulmonary Edema (HAPE)

This study utilized the inaugural nitric oxide therapeutic device sanctioned by the State Drug Administration, which possesses independent intellectual property rights (INOwill N300, Nanjing Novlead Biotechnology Co., LTD.). The device is compact and generates nitric oxide gas upon activation, eliminating the need for cylinders for the storage and transport of nitric oxide. It employs an electrochemical catalytic reduction method to produce nitric oxide gas in real-time and automatically administers the gas to the respiratory circuit at a predetermined concentration, based on flow monitoring. The phase change sensor sampling technology enables real-time monitoring of the concentrations of nitric oxide, nitrogen dioxide, and oxygen at the patient end of the respiratory circuit, thereby ensuring the safety of clinical interventions.

The primary aim of this investigation was to assess the efficacy of inhaled nitric oxide (iNO) in the management of mild to moderate high altitude pulmonary edema (HAPE) in comparison to a control group. Key parameters evaluated included the onset time of changes in oxygenation, the duration until symptom resolution (as measured by the Lake Louise Acute Mountain Sickness score), the time required for improvement in imaging indicators, and the proportions of patients categorized as cured, effective, ineffective, or experiencing severe HAPE by days 3 to 7 of treatment. Additionally, the length of hospital admission or stay was recorded for patients receiving iNO therapy for high altitude pulmonary edema. This study aimed to elucidate the impact of iNO on enhancing oxygenation and pulmonary circulation in patients with high altitude pulmonary edema relative to the control group.

• Nitric Oxide Generation and Delivery System (Device): The Nitric Oxide Generation and Delivery System is used to deliver nitric oxide for inhalation therapy into the inspiratory limb of the patient breathing circuit in a way that provides a constant concentration of nitric oxide (NO), as set by the user, to the patient throughout the inspired breath.

Primary outcomes

• Change of Oxygen Index [Through study completion, an average of 5 days]: The change of oxygenation index (PaO2 or SpO2/FiO2) from baseline, and the time required for oxygenation index to improve by ≥20%

Secondary outcomes

• Progression of HAPE [Through study completion, an average of 5 days]: The proportion and time of HAPE cured, markedly effective, ineffective, or severe
• Symptoms Improvement [Through study completion, an average of 5 days]: Change of symptom improvement (Lake Louise AMS score, vital signs, imagings)
• Hospital Stays [Through study completion, an average of 5 days]: The length of hospital stay compared between groups

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. Individuals aged between 18 and 65 years.
2. A score on the Lake Louise Acute Mountain Sickness Scale ranging from 3 to 9 points, as outlined in Annex 2, recorded in 2018.
3. Chest X-ray findings that demonstrate either thickening of the lung texture bilaterally or the presence of nodular opacities in the lower regions of both lungs.
4. Capacity to provide informed consent in accordance with local regulatory requirements.

Exclusion Criteria:

1. Confirmed contraindications for the use of nitric oxide include the following (refer to "5.3.4 NO Contraindications"):

   * Severe hypoplasia of the left heart or duct-dependent congenital heart disease;
   * Life-threatening congenital anomalies and congestive heart failure;
   * Congenital methemoglobinemia;
   * Severe hemorrhagic conditions, including intracranial hemorrhage, intraventricular hemorrhage, and pulmonary hemorrhage.
2. Severe left ventricular dysfunction, characterized by a left ventricular ejection fraction (LVEF) of less than 40%.
3. Pulmonary edema resulting from other cardiac, pulmonary, thoracic, or systemic disorders.
4. Coexistence with high altitude cerebral edema.
5. A history of lung malignancy, lung resection, or lung transplantation.
6. Barotrauma, which may include pneumothorax, subcutaneous and mediastinal emphysema, or the presence of a closed drainage tube in the thoracic cavity.
7. Clinically significant or persistent thrombocytopenia, defined as a platelet count of less than 50×10\^9/L.
8. Administration of pulmonary hypertension medications, such as sildenafil, bosentan, or prostacyclins, within the preceding 30 days.
9. Noncompliance with study protocols and unwillingness to provide informed consent.
10. Any other conditions that the clinician deems render the subject unsuitable for participation in the study.

• Jingxin Cao, Principal investigator, Tibet Fokind Hospital