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

May 9, 2024 updated by: Chong Lei, MD & phD, Xijing Hospital

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

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

660

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Shaanxi
      • Xi'an, Shaanxi, China, 710032
        • Xijing Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. ≥ 18 years old
  2. Planned for surgery under general anesthesia
  3. With a history of COVID-19 infection within 7 weeks prior to surgery.

Exclusion Criteria:

  1. 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
  2. ASA ≥ IV, life expectancy< 24 h.
  3. Pregnant or lactating women.
  4. Severe liver disease (Child-Pugh score ≥ 12).
  5. Patients with severe respiratory failure need mechanical ventilation support or ECMO life support before the operation.
  6. Severe renal dysfunction (eGFRC≤30 ml/min/1.73m2) or receiving continuous renal replacement therapy, hemodialysis, and peritoneal dialysis.
  7. Having received or participated in other clinical trials within the previous month.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
postoperative pulmonary complications
Time Frame: within 7 days after operation
It is composite outcome including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis
within 7 days after operation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
mortality within 30 days postoperatively
Time Frame: within 30 days after operation
All-cause mortality
within 30 days after operation
Classification of pulmonary complications (Clavien-Dindo)
Time Frame: 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).
within 7 days after operation
the rate of unplanned ICU admission
Time Frame: within 7 days after operation
Percentage of patients admitted into ICU after surgery, which is not expected before surgery
within 7 days after operation
postoperative length of hospital stay
Time Frame: 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
From the date of surgery until the date patient discharge from hospital, assessed up to 30 days
Incidence of thrombotic events
Time Frame: From the date of surgery until the date patient discharge from hospital, assessed up to 30 days
including DVT and pulmonary embolism
From the date of surgery until the date patient discharge from hospital, assessed up to 30 days
incidence of nonpulmonary complications
Time Frame: 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
From the date of surgery until the date patient discharge from hospital, assessed up to 30 days
postoperative comprehensive complication index (CCI)
Time Frame: within 7 days after operation
Ranging from 0 (no complication) to 100 (death) was computed based on the Clavien-Dindo classification
within 7 days after operation

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of hypotension
Time Frame: 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
From anesthesia induction until leave operation room, assessed up to 12 hrs
Incidence of hypertension
Time Frame: 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
During surgery, from anesthesia induction to end of anesthesia
Occurrence of arrhythmia
Time Frame: 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
From anesthesia induction until leave operation room, assessed up to 12 hrs
Incidence of airway hyperresponsiveness
Time Frame: From anesthesia induction until leave operation room, assessed up to 12 hrs
airway peak pressure > 40 cm water
From anesthesia induction until leave operation room, assessed up to 12 hrs
Number that the concentration of NO was adjusted
Time Frame: 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
During NO inhalation, from anesthesia induction until leave operation room, assessed up to 12 hrs
massive bleeding
Time Frame: From anesthesia induction until leave operation room, assessed up to 12 hrs
bleeding exceed 1000 ml
From anesthesia induction until leave operation room, assessed up to 12 hrs

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Xijing Hospital

Investigators

  • Principal Investigator: Chong Lei, MD&phD, Xijing Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 17, 2023

Primary Completion (Actual)

April 14, 2024

Study Completion (Actual)

May 7, 2024

Study Registration Dates

First Submitted

February 7, 2023

First Submitted That Met QC Criteria

February 7, 2023

First Posted (Actual)

February 9, 2023

Study Record Updates

Last Update Posted (Actual)

May 10, 2024

Last Update Submitted That Met QC Criteria

May 9, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KY-20230079

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underline the results reported in this article, after deidentification.

IPD Sharing Time Frame

beginning 12 months

IPD Sharing Access Criteria

Investigators who provide a methodologically sound proposal and whose proposed use of data has been approved by the steering of INORDINATE identified for individual participant data meta-analysis. Proposals should be directed to corresponding author of the publication. To gain access, data requestors will need to sign a data access agreement.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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