INORDINATE: Inhaled NO in Surgical Patients With Recent COVID-19 Infection

Sponsor

Xijing Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05721144

Collaborator

(none)

660

Enrollment

Arms

11.7

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The aim of this study is to evaluate the effect of perioperative inhalation of NO on reducing the incidence of postoperative pulmonary complications in patients with recent COVID-19 infection, and to evaluate whether inhaled NO can improve the prognosis of patients.

The investigators will enroll 660 surgical patients who was infected with SARS-CoV-2 within 42days (7 weeks ) prior to planed surgery under general anesthesia. Patients will be randomized to receive either inhaled nitric oxide (per protocol) or a placebo. Perioperative standards of care will be the institution's own protocols (such as ventilation strategies and use and dose of anesthetics, analgesia and fluid management, etc).

Condition or Disease	Intervention/Treatment	Phase
Nitric Oxide COVID-19 Surgery Postoperative Complications	Drug: Nitric Oxide Gas	Phase 2

Detailed Description

The outbreak of COVID-19 and its global pandemic has posed a threat to public health. On December 7, 2022, the National Health Commission (NHC) of China issued an announcement on further optimization of public health control measures. Since then, the rapid spread and breakthrough of SARS-CoV-2 infections have been observed in the majority of China, caused by the more infectious and less virulent Omicron variant of SARS-Cov-2. Consequently, the proportion of surgical patients with current or previous SARS-CoV-2 infections will inevitably increase within a relatively narrow time window.

It has been reported that a history of SARS-CoV-2 infection is associated with a transiently elevated risk of postoperative complications. The longer the time interval between infection and surgery, the lower the risk of postoperative complications. An updated recommendation suggested postponing surgery for at least seven weeks following SARS-CoV-2 infection, thereby reducing the risk of postoperative complications and 30-day mortality to baseline levels (similar to those without a history of SARS-CoV-2 infection).

COVID-19 infection significantly affects respiratory functions by massively disrupting pulmonary oxygenation and activating the synthesis of proinflammatory cytokines, inducing severe oxidative stress, enhanced vascular permeability, and endothelial dysfunction which has rendered researchers and clinicians to depend on prophylactic treatment due to the unavailability of proper disease management approaches. Inhaled nitric oxide gas (NO) has shown antiviral activity against Coronavirus during the 2003 SARS outbreak. Previous studies have indicated that nitric oxide (NO) application appears to be significant concerning the antiviral activities, antioxidant, and anti-inflammatory properties in relieving disease-related symptoms. Inhaled nitric oxide had been widely used during the Covid-19 pandemic. In the scoping and systemic reviews, it was demonstrated that nitric oxide inhalation was effective in improving oxygenation, cardiopulmonary function, and fastening virus clearance. The investigators designed this study to assess whether inhaled NO reduces postoperative pulmonary complications in patients with a COVID-19 infection history 7 weeks prior to surgery.

Here, the investigators propose a randomized clinical trial aimed to improve postoperative outcomes in patients with an increased risk of postoperative pulmonary complications after COVID-19 infection.

Control group: the institutional standard of care will be delivered. Treatment group: In addition to standard therapy, the subjects will receive inhalation of NO. Inspired NO/N2 will be delivered at 80 parts per million (ppm) after anesthesia induction and intubation and last until the end of surgery and leave the operating room. The physician will follow their own institutional weaning protocols. In the absence of institutional protocols, NO will be reduced in a step-wise fashion starting from 40 ppm to 20, 10, 5, 3, 2, and 1 ppm. If hypoxemia (SpO2 < 93%) or acute hypotension (systolic blood pressure < 90 mmHg) occurs during weaning, NO should be increased to a prior higher concentration.

Safety: prolonged treatment with inhaled NO can lead to increased methemoglobin levels. Blood levels of methemoglobin will be monitored via a non-invasive CO-oximeter or MetHb levels in the blood. If methemoglobin levels rise above 5% at any point in the study, inhaled NO concentration will be halved.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

660 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Inhaled NO ReDuce postoperatIve pulmoNAry complicATions in patiEnts With Recent COVID-19 Infection

Anticipated Study Start Date :

Feb 10, 2023

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Jan 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental: Treatment Group Inspired NO/N2 will be delivered at 80 parts per million (ppm) after anesthesia induction and intubation and lasted until the end of surgery and leave the operating room. The physician will follow their own institutional weaning protocols.	Drug: Nitric Oxide Gas Inspired NO/N2 will be delivered at 80 parts per million (ppm) after anesthesia induction and intubation and lasted until the end of surgery and leave the operating room. Other Names: Nitric Oxide inhalation
No Intervention: Sham Comparator: Control Group The delivery system will be set up anyway without studying gas administration

Arm

Intervention/Treatment

Experimental: Experimental: Treatment Group

Inspired NO/N2 will be delivered at 80 parts per million (ppm) after anesthesia induction and intubation and lasted until the end of surgery and leave the operating room. The physician will follow their own institutional weaning protocols.

Drug: Nitric Oxide Gas

Inspired NO/N2 will be delivered at 80 parts per million (ppm) after anesthesia induction and intubation and lasted until the end of surgery and leave the operating room.

Other Names:

Nitric Oxide inhalation

No Intervention: Sham Comparator: Control Group

The delivery system will be set up anyway without studying gas administration

Outcome Measures

Primary Outcome Measures

postoperative pulmonary complications [within 7 days after operation]
It is composite outcome including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis

Secondary Outcome Measures

mortality within 30 days postoperatively [within 30 days after operation]
All-cause mortality
Classification of pulmonary complications (Clavien-Dindo) [within 7 days after operation]
Evaluation of the severity of pulmonary complications according to Clavien-Dindo classification. It consists of 7 grades (I, II, IIIa, IIIb, IVa, IVb and V).
the rate of unplanned ICU admission [within 7 days after operation]
Percentage of patients admitted into ICU after surgery, which is not expected before surgery
postoperative length of hospital stay [From the date of surgery until the date patient discharge from hospital, assessed up to 30 days]
duration between end of surgery and discharge from hospital
Incidence of thrombotic events [From the date of surgery until the date patient discharge from hospital, assessed up to 30 days]
including DVT and pulmonary embolism
incidence of nonpulmonary complications [From the date of surgery until the date patient discharge from hospital, assessed up to 30 days]
including acute kidney injury, Stroke and myocardial infarction
postoperative comprehensive complication index (CCI) [within 7 days after operation]
Ranging from 0 (no complication) to 100 (death) was computed based on the Clavien-Dindo classification

Other Outcome Measures

Incidence of hypotension [From anesthesia induction until leave operation room, assessed up to 12 hrs]
It is diagnosed as SBP < 90mmHg or drop ≥ 30% of baseline lasted for 5 min
Incidence of hypertension [During surgery, from anesthesia induction to end of anesthesia]
It is diagnosed as SBP > 180 mmHg or rise ≥ 30% of baseline lasted for 5 min
Occurrence of arrhythmia [From anesthesia induction until leave operation room, assessed up to 12 hrs]
consisted of bradycardia (HR < 40bpm) or tachycardia (HR> 100 bpm) or new onset of arrhythmia that require Anti-arrhythmic drugs
Incidence of airway hyperresponsiveness [From anesthesia induction until leave operation room, assessed up to 12 hrs]
airway peak pressure > 40 cm water
Number that the concentration of NO was adjusted [During NO inhalation, from anesthesia induction until leave operation room, assessed up to 12 hrs]
For safety, if the N2O or metHb level exceed safety threshold, the NO concentration needs to be adjusted. The number of adjustment is recorded
massive bleeding [From anesthesia induction until leave operation room, assessed up to 12 hrs]
bleeding exceed 1000 ml

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

≥ 18 years old
Planned for surgery under general anesthesia
With a history of COVID-19 infection within 7 weeks prior to surgery.

Exclusion Criteria:

Physician makes a decision that trial involvement is not in the patient's best interest or any condition that does not allow the protocol to be followed safely
ASA ≥ IV, life expectancy< 24 h.
Pregnant or lactating women.
Severe liver disease (Child-Pugh score ≥ 12).
Patients with severe respiratory failure need mechanical ventilation support or ECMO life support before the operation.
Severe renal dysfunction (eGFRC≤30 ml/min/1.73m2) or receiving continuous renal replacement therapy, hemodialysis, and peritoneal dialysis.
Having received or participated in other clinical trials within the previous month.