Inhaled Nitric Oxide ReDuce postoperatIve pulmoNAry complicaTions in patiEnts with recent COVID-19 infection (INORDINATE): protocol for a randomised controlled trial

Abstract

Background

A history of SARS-CoV-2 infection has been reported to be associated with an increased risk of postoperative pulmonary complications (PPCs). Even mild PPCs can elevate the rates of early postoperative mortality, intensive care unit (ICU) admission and prolong the length of ICU and/or hospital stays. Consequently, it is crucial to develop perioperative management strategies that can mitigate these increased risks in surgical patients who have recently been infected with SARS-CoV-2. Accumulating evidence suggests that nitric oxide (NO) inhalation might be effective in treating COVID-19. NO functions in COVID-19 by promoting vasodilation, anticoagulation, anti-inflammatory and antiviral effects. Therefore, our study hypothesises that the perioperative use of NO can effectively reduce PPCs in patients with recent SARS-CoV-2 infection.

Method and analysis

A prospective, double-blind, single-centre, randomised controlled trial is proposed. The trial aims to include participants who are planning to undergo surgery with general anaesthesia and have been recently infected with SARS-CoV-2 (within 7 weeks). Stratified allocation of eligible patients will be performed at a 1:1 ratio based on the predicted risk of PPCs using the Assess Respiratory Risk in Surgical Patients in Catalonia risk index and the time interval between infection and surgery.

The primary outcome of the study will be the presence of PPCs within the first 7 days following surgery, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm and aspiration pneumonitis. The primary outcome will be reported as counts (percentage) and will be compared using a two-proportion χ² test. The common effect across all primary components will be estimated using a multiple generalised linear model.

Ethics and dissemination

The trial is approved by the Institutional Review Board of Xijing Hospital (KY20232058-F1). The findings, including positive, negative and inconclusive results, will be published in scientific journals with peer-review processes.

Trial registration number

NCT05721144.

Correspondence to Professor Chong Lei; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• The pragmatic anaesthetic procedure enhances the external validity of our findings and reflects the real-world variability in perioperative management.

• The study’s capacity to draw definitive conclusions on the impact of inhaled NO on postoperative pulmonary complications is constrained due to the potential influence of diverse anaesthetic managements; as no restrictions were stated in the protocol, individual anaesthesiologists will determine the most appropriate anaesthesia managements for patients.

• Possible misclassification of patients as some with recent SARS-CoV-2 infection may be diagnosed based on clinical symptoms alone.

Introduction

The COVID-19 pandemic has rapidly unfolded over the past 3 years significantly impacting global health and safety. Despite efforts, SARS-CoV-2 is still mutating at a fast and to some extent unknown way, generating more transmissible strains with increased immune evasion capabilities.^{1 2} Consequently, the population with a history is expected to markedly increase. As the epidemic persists, new strategies to perioperative management of infected patients are urged.

It has been reported that a history of SARS-CoV-2 infection is associated with a transiently elevated risk of postoperative complications.^3–5 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 7 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).^6–8 Despite that viral load diminishes after 7 weeks, scholars have reported 55% COVID-19 patients still have at least one COVID-19 sequelae after 6 months, with a fair proportion suffer for over 2 years. In particular, around 24% of patients reported diffuse dysfunctions, and 13% reported abnormal pulmonary function ventilation.⁹ Other different patterns of long-term postacute COVID-19 pulmonary dysfunctions include but not limited to dyspnoea, impaired diffusion capacity, pulmonary muscular deconditioning and cerebral breathing dysregulation.^{10 11} All these conditions suggest that for a long time in the future, the proportion of hospitalised patients and surgical patients who were once infected with COVID-19 and still have pulmonary sequelae and other sequelae will increase greatly. These patients are all at high risk for postoperative pulmonary complications (PPCs). Such perioperative morbidity risks among patients with SARS-CoV-2 infection are influenced by multiple factors. Patient individual factors and surgery procedure factors post additional risk for postoperative morbidities.^{12 13}

PPCs were the most common and frequent complications in patients with a history of COVID-19 infection.^{4 14} Even mild PPCs are associated with increased early postoperative mortality, intensive care unit (ICU) admission and length of ICU and/or hospital stays.¹⁵ Various strategies have been proposed to prevent or mitigate PPCs, such as protective ventilation,¹⁶ selective anticoagulant and anaesthetics,¹⁷ and prophylactic treatment.¹⁸ However, their efficacy remains limited.

In recent years, there has been growing interest in the use of inhaled nitric oxide (iNO) as a potential prophylactic or therapeutic intervention for PPCs. iNO, a selective pulmonary vasodilator, has demonstrated its ability to improve oxygenation, reduce pulmonary hypertension,¹⁹ and modulate inflammation in various clinical settings, including pulmonary hypertension, acute lung injury and acute respiratory distress syndrome (ARDS).^20–23 Moreover, iNO has been shown to have a favourable safety profile, with few serious adverse events reported.²⁴

Although iNO is not routinely recommended for the treatment of ARDS, many studies have reported potential benefits, including reduced pulmonary artery pressure and improved shunt and oxygenation status.^25–29 In particular, analyses from factorial studies and extended multicentre research have indicated a tendency towards reduced length of mechanical ventilation with 5 parts per million (ppm) iNO and improved long-term pulmonary functions in ARDS survivors.^{30 31} For patients who underwent cardiac surgeries, iNO has been shown to dilate pulmonary blood vessels,³² reduce pulmonary arterial pressure (PAP) and lower pulmonary vascular resistance,^33–38 and significantly improve oxygenation and patients prognosis.^{39 40} Particularly in patients undergoing aortic dissection surgeries, low-dosed iNO was shown to improve oxygenation, thereby reducing the duration of mechanical ventilation and ICU stay.⁴¹ Additional benefits include a reduction in postoperative complications related to inflammatory responses among patients undergoing knee replacement surgery.⁴²

The guidelines pertaining to the management of critically ill adults with COVID-19⁴³ advise against the routine administration of inhaled oxide in mechanically ventilated adult COVID-19 ARDS patients. However, it is recommended as a rescue therapy for COVID-19 patients experiencing refractory hypoxaemia.⁴⁴ Reports indicated that SARS-CoV-2 could directly infect endothelial cells, leading to vasoplegia, vascular thromboses, pulmonary oedema, endothelial sloughing and abnormal regulation of pulmonary perfusion in COVID-19 patients.⁴⁵ Studies have proposed NO inhalation as an effective strategy for COVID-19 treatment,⁴⁶ as SARS-CoV-2 modulates endogenous NO levels and availability on entering host cells. It was demonstrated that NO can reduce SARS-CoV-2 viral load by 95% within 24 hours and over 99% within 72 hours.⁴⁷ It also significantly shortens the conversion time in positive patients (p=0.044) and improves the conversion rate at 7 days after treatment (82.8% vs control 66.7%, p=0.046).⁴⁸ Despite its theoretical plausibility and potential, the clinical evidence supporting the efficacy of NO in treating COVID-19-related pulmonary complications has primarily originated from observational studies^{49 50} or small trials,⁵¹ yielding inconsistent reported results. Recently, a phase II study demonstrated an improvement of PaO₂/fraction of inspired oxygen (FIO₂) with high-dose NO (at 80 ppm) at 48 hours compared with usual care in adults with acute hypoxaemic respiratory failure due to COVID-19.⁵² Although the patient-centred outcomes did not differ, the exploratory results suggested that inhaled NO leads to a steeper reduction in plasma viral load. In addition, at 80 ppm (relatively high dose), iNO was safe and well tolerated.

The rationale for using iNO in treating surgical patients with COVID-19 lies in several key mechanisms: (1) after inhaling NO, pulmonary arterioles in well-ventilated lung units are preferentially vasodilated, thereby decreasing blood flow to poorly ventilated lung units. (2) Consequently, the ventilation/perfusion (V/Q) mismatch is attenuated, leading to improved oxygenation. (3) NO induces bronchodialtion and improves ventilation. (4) NO acts as an anti-inflammatory and (5) possesses antithrombotic properties. (6) Additionally, NO demonstrates antibacterial and antiviral properties.⁴⁷ The improvement in patients oxygenation as well as inhibited reproduction of virus thus should in theory improve the postoperative prognosis of patients, especially in reduced PPCs. There are, however, very limited study exploring whether inhaled NO can improve postoperative lung function, especially in non-cardiac surgeries. Furthermore, no randomised controlled trial (RCT) is available evaluating iNO in surgical patients with a history of recent SARS-CoV-2 infection.⁵³

In this single-centred randomised placebo controlled trial, our hypothesis posits that the intraoperative administration of high concentration NO will reduce the PPCs in surgical patients with recent (within 7 weeks) SARS-CoV-2 infection. As such, we aim to provide evidence to help make clinical decisions and facilitate perioperative management for surgical patients with recent SARS-CoV-2 infections.

Method and analysis

Study design, approval and registration

The planned study is a parallel-group, double-blinded, randomised controlled, single-centred trial with 1:1 allocation ratio. The study has been approved by the institutional review board (IRB) at Xijing Hospital (KY20232058-F1) and has been registered on ClinicalTrials.gov as Inhaled Nitric Oxide ReDuce postoperatIve pulmoNAry complicaTions in patiEnts (INORDINATE) trial with the identifier NCT05721144. The study protocol is reported in accordance with the Standard Protocol Items Recommendations for Interventional Trials checklist.⁵⁴

Study aim

The aim of our study is to investigate and test the hypothesis that intraoperative NO inhalation can reduce PPCs from 30% to 20% in participants planning to undergo surgery with general anaesthesia and who have recently (within 7 weeks) been infected with SARS-CoV-2.

Participants

Our study aims to include a total of 660 participants who have been recently infected with SARS-CoV-2 within a period of 7 weeks. The eligibility criteria for participation in the study include being 18 years of age or older and scheduled for surgery under general anaesthesia. However, participants who meet any of the exclusion criteria listed in table 1 will not be included in the trial.

Table 1

Eligibility criteria of participants

Eligibility criteria
Inclusion	Patients who are ≥18 years. Patients who are diagnosed COVID-19 via RT-PCR, rapid antigen or clinical symptoms verified by trained professionals. Surgery should have taken place within 7 weeks of diagnostics of COVID-19. Patients should have understood and signed the informed consent.
Exclusion	The healthcare professionals, including surgeons, anaesthesiologists and other personnel responsible for the patient’s treatment, or the investigators, have chosen to abstain from participating in the study. Their decision is grounded in the belief that the patient may not derive significant benefits from inhaled nitric oxide ASA≥4 or life expectancy <24 hours. Females during pregnancy pr lactation. Patients with severe liver diseases (defined as Child Pugh score ≥12). Patients with severe respiratory failure, requiring mechanical ventilation or ECMO support before surgery. Patients with severe kidney dysfunction (eGFR ≤30 mL/min/1.73 m2) or requiring any of ordinary renal replacement therapy, haemodialysis or peritoneal dialysis. Patients who have been participating in a different clinical trial within a month.

ASA, American Society of Anesthesiologists physical status classification; COVID-19, Coronavirus Disease 2019; ECMO, Extracorporeal Membrane Oxygenation; eGRF, estimated glomerular filtration rate; RT-PCR, reverse transcription- polyrase chain reaction.

Randomisation, allocation and concealment, and blinding

Eligible participants will be randomly allocated at 1:1 ratio using a web-based randomisation service (Research Electronic Data Capture, REDCap, developed by Vanderbilt University). The randomisation process will use permuted-block randomisation, with stratification based on the predicted risks of PPCs using the Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) index (<45 (low and medium risk), ≥45 (high risk); as specified in table 2), as well as the time interval from infection to surgery(≤10 days, 11–28 days and 29–49 days). Random blocks of 4 or 6 will be used for randomisation.

Table 2

The Assess Respiratory Risk in Surgical Patients in Catalonia risk index (ARISCAT)

Factors in consideration		Risk score
Age	≤50	0
	51–80	3
	>80	16
Preoperative SpO2	≥96%	0
	91%–95%	8
	≤90%	24
Preoperative anaemia (Hgb, g/L)	>100	0
	≤100	11
Respiratory tract infections in the past month	No	0
	Yes	17
The incision position	Periphery	0
	Upper abdominal	15
	Intrathoracic	24
Operation duration	<2 hours	0
	2–3 hours	16
	>3 hours	23
Whether emergency surgery	No	0
	Yes	8
Risk	ARISCAT scores
Low	<26 (1.6%)
Medium	26–44 (13.3%)
High	≥45 (42.1%)

Hgb, haemoglobin.

The allocation of participants into groups will be carried out in a manner that ensured blinding. This means that the participants, caregivers and investigators responsible for analysing data and assessing outcomes were unaware of the group assignments. Only one investigator will be unblinded and tasked with preparing the appropriate test gas. Subsequently, the test gases are to be then covered and kept blinded to the other individuals involved in the study. Both NO and placebo gas (air and O2) will be delivered to the breathing circuit through an NO delivery system. The entire device would be covered with a surgical drape. The unblinded investigator, who has no involvement in any aspect of the surgery, anaesthesia, data recording, outcome assessment or data analysis, would adjust the concentration and gas flow as necessary.

Interventions

Participants will be randomised to receive either NO or placebo gas during general anaesthesia (figure 1).

Figure 1. Study flow chart. ARISCAT, Assess Respiratory Risk in Surgical Patients in Catalonia; ICU, intensive care unit; NO, nitric oxide; DVT, deep venous thrombosis

The NO group will receive NO inhalation at a concentration of 80 ppm through the respiratory circuit of a mechanical ventilator. The intervention will commence immediately after tracheal intubation and will persist until either extubation or the patient exits the operation room, whichever happens first.^48–50 The treatment gas will be delivered to the breathing circuit through an NO delivery system (iNO will portable NO therapy device, Nanjing Novlead Biotechnology, China; or SLE 3600 INOSYS iNO System, SLE, UK). The concentration of NO delivered to each participant will be closely monitored by the unblinded investigator. NO and the nitrogen dioxide (NO₂) levels will be monitored through in-line NO/NO₂ sensors incorporated in the NO delivery system. Met haemoglobin levels will be monitored via blood gas or periopheral pulse oximeter (Masimo Rainbow Pulse CO-Oximetry, Masimo, California, USA).

To ensure safety, the NO₂ levels will be monitored and maintained below 5 ppm. Previous tests have demonstrated that our delivery circuits do not exceed 1.5 ppm of NO₂ when delivering 80 ppm of NO gas at 90% FiO₂.⁵⁵ Methaemoglobin levels will be monitored and kept below 5%. If the safety threshold is exceeded, the concentration of NO delivered will be halved from 80 ppm to 40 ppm and closely monitored until a reduction is observed. If the levels of NO2 or methaemoglobin persist above 5 ppm or 5%, respectively, the NO concentration will be progressively halved until reaching a safe level. The reason and frequency of adjustments made to the delivery of NO will be carefully documented and recorded. Any modifications or changes to the NO delivery, such as concentration adjustments or reductions, will be noted in the study records. The reasons for these adjustments, such as safety concerns or specific participant requirements, will also be documented. The frequency of these adjustments, including how often and when they occur, will be recorded as well. This detailed documentation will help ensure accurate monitoring and assessment of the NO delivery throughout the study.

After the intervention, the weaning and discontinuation of NO will be conducted while closely monitoring the participant’s haemodynamics. Abrupt discontinuation of inhaled NO can potentially lead to a rebound of PAP, resulting in worsened oxygenation, hypoxaemia, systemic hypotension, bradycardia and right ventricular failure.⁵⁶

Therefore, the weaning process for NO at our institution involves gradually decreasing the concentration. If any of the following adverse events occurs during the NO weaning process and is considered to be related to the discontinuation, after ruling out other potential causes, the concentration of NO will be reset to the lowest level at which the participant stabilises. This occurrence will be documented as a failed attempt at NO weaning

• Steeply worsening hypotension: This is defined as a decrease in mean arterial pressure by more than 20 mm Hg. In such cases, intravenous vasopressors will be initiated. For patients who were already receiving vasopressors before the weaning process, a greater than 50% increase in the vasopressor dose will be required to maintain haemodynamics.

• Sharp deterioration of hypoxaemia: If there is a significant worsening of hypoxaemia, characterised by the need for an increase in the FiO2 by more than 20%, or an elevation of positive end-expiratory pressure by more than 5 cm H2O, the intervention will be adjusted accordingly.

By carefully monitoring and adjusting the weaning process, we aim to minimise any potential adverse effects associated with the discontinuation of NO.

The control group will receive a mixture of air and O₂ inhalation through the respiratory circuit of a mechanical ventilator, with the settings identical to those in the NO.

Participants will be allowed to discontinue the study at any time, either voluntarily or based on the clinician’s or investigator’s judgement for safety reasons. These reasons may include but are not limited to, adverse reactions to the intervention, worsening health conditions or any other factors that could jeopardise the participant’s well-being.

• Sudden onset of hypotension attributed to ventricular (left and/or) dysfunction, characterised by a drop in MAP exceeding 20 mm Hg, not attributable to hypovolaemia, haemorrhage or vasoplegia.

• Severe hypoxia defined as decrease in oxygen saturation (SpO₂) to below 88% (equivalent to a PaO₂ level below 54 mm Hg) while on 100% oxygen, not attributable to pulmonary oedema, ARDS or pulmonary embolism.

• Elevated NO₂ levels exceeding 5 ppm and methaemoglobin levels exceeding 5%, which prove irreversible even after reducing NO delivery to below 5 ppm.

All participants will receive perioperative management based on our institutional standard practice, which includes various components such as preoperative evaluation and preparation, general anaesthesia with or without neuraxial anaesthesia and/or nerve blocks, mechanical ventilation, inotropic drugs and vasopressors, postoperative sedation and analgesia, diuretics, intravenous fluids, antibiotics and invasive monitoring. This management regimen will encompass a range of interventions and monitorings, including but not limited to non-invasive or invasive arterial pressure, ECG, central venous pressure, cardiac output, pulse oximetry, temperature, urine output, arterial blood gases, coagulation monitoring and frequent routine laboratory examinations. No additional interventions or laboratory tests beyond the standard perioperative management will be conducted on participants.

Data collection and management

Data will be collected prospectively at various time points throughout the study. The baseline evaluation will capture information about patients’ characteristics, including demographics, comorbidies, medications, preoperative lab tests, symptoms, vaccination and treatment history of SARS-CoV-2 infection. During the surgical procedure, data will be collected on the administration of anaesthesia, including dosage, timing, mode of administration of all drugs, as well as the mode and parameters for mechanical ventilation. Surgical procedure-related characteristics, such as the incision position, duration of procedure and any intraoperative adverse events, will also be recorded. Postoperative management, including analgesia regimen, transfer location from the operation room (postoperative anaesthesia care unit, ICU or ward) and any complications, will be documented.

Regarding the intervention treatment, specific data will be collected concerning its implementation. This will encompass whether the intervention adhered to the randomisation results, the dosage range of NO inhalation, maximum levels of NO2 and methaemoglobin, any adjustments in NO concentration, the intervention’s duration and any unsuccessful attempts to discontinue NO. These intervention-related characteristics will be collected and recorded by the unblinded investigator and will remain inaccessible to other study stakeholders during the implementation period. Follow-up data will be gathered 30 days postsurgery, focusing on adverse pulmonary events, hospital readmissions and survival.

All data collected for the trial will be entered into the REDCap application,⁵⁷ a secure data management system. Access to the data will be restricted and granted by the principal investigator (PI) to authorised investigators within the study team. The PI will assign specific privileges for data import and export to study investigators. To ensure the quality and integrity of collected data, various measures are implemented. Software properties, such as logic checks and validation of data fields (eg, reference range, valid or invalid values), are used to optimise data quality. Additionally, study investigators will conduct weekly checks to ensure data consistency. If any errors related to data collection or entry are identified, the study team will correct them by referring to the original data source. These corrections will be summarised in data quality reports to maintain accuracy and reliability.

Outcomes

The primary endpoint is a composite measure of PPCs occurring within the first 7 days after surgery. The definitions of these complications are based on the European Perioperative Clinical Outcome definitions⁵⁸ as well as other recognised definitions from relevant literature.⁵⁹ The specific components of the composite PPCs include respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, aspiration pneumonitis and pneumonia. Detailed definitions for each of these components can be found in table 3. Outcomes will be measured daily until postoperative day 7 or hospital discharge by blinded investigators. Chest X-rays and routine laboratory tests will be assessed when any pulmonary complications are suspected.

Table 3

Definition of postoperative pulmonary complication components

Terms	Definitions
Respiratory infection	Antibiotics for a suspected respiratory infection and at least one of: new or changed sputum, new or changed lung opacities, fever, leucocyte count >12x10∧9/L .
Respiratory failure	Postoperative PaO2<60 mm Hg on room air, a PaO2 : FIO2 ratio <300 mm Hg or arterial oxyhaemoglobin saturation measured with pulse oximetry <90% and requiring oxygen therapy.
Pleural effusion	Chest X-ray demonstrating blunting of the costophrenic angle, loss of the sharp silhouette of the ipsilateral hemidiaphragm when upright, displacement of adjacent anatomical structures or a hazy opacity in one hemithorax with preserved vascular shadows when supine.
Atelectasis	Lung opacification with mediastinal shift, hilum or hemidiaphragm shift towards the affected area, with compensatory hyperinflation in adjacent non-atelectatic lung.
Pneumothorax	Air in the pleural space with no vascular bed surrounding the visceral pleura.
Bronchospasm	Newly detected expiratory wheeze treated with bronchodilators.
Aspiration pneumonitis	Acute lung injury after the inhalation of regurgitated gastric contents.
Pneumonia	Chest X-ray with at least one of the following: infiltrate, consolidation, cavitation; plus at least one of the following: fever >38oC with no other cause, white cell count <4×109/L or >12×109/L, >70 years of age with altered mental status with no other cause; plus at least two of the following: new purulent/changed sputum, increased secretions/suctioning, new/worse cough/dyspnoea/tachypnoea, rales/bronchial breath sounds, worsening gas exchange

FIO₂, fraction of inspired oxygen.

Secondary endpoints will include postoperative 30-day all-cause mortality; severity of PPCs scaled by Clavien-Dindo classification⁶⁰ (online supplemental file etable 1); unplanned ICU admission; postoperative length of hospital stay; thrombotic events (including deep venous thrombosis and pulmonary embolism) and postoperative Comprehensive Complication Index. Other measurements recorded include non-pulmonary complications including stroke, cardiac infarction, ventricular dysfunction, delirium, acute kidney injury, surgical revision for bleeding, hypotension/hypertension, arrhythmia, hyper-responsiveness. We also recorded the number of times that the concentration of NO was adjusted. To perform 30-day follow-up, telephone contact (patient and/or relatives) will be used. In case loss to follow-up by telephone, the following methods will be used: contacting the patient’s general practitioner or other relatives (during enrolment at least three contact information from close relatives will be collected).

Safety outcomes include hypotension, defined as SBP<90 mm Hg or a drop ≥30% of baseline lasting for 5 min; hypertension, defined as SBP>180 mm Hg or a rise ≥30% of baseline lasting for 5 min; arrhythmia consisting of bradycardia (heart rate (HR) <40 beats per minute (bpm)), tachycardia (HR>100 bpm), or new onset of arrhythmia requiring antiarrhythmic drugs; airway hyper-responsiveness, defined as an airway peak pressure >40 cm H2O; the number of NO concentration adjustments; and massive bleeding (haemorrhage exceeding 1000 mL).

Sample size estimates and statistical analysis

An epidemiologist with extensive experience in designing, conducting and analysing clinical trials, not involved in patient management and blinded to the assigned intervention will be responsible for the statistical analyses.

Data will be stored electronically via a web-based CRF, and analysis will be conducted using the R program (R Core Team, 2016, Vienna, Austria⁶¹). We will not apply any imputation for missing primary outcomes, while other important missing covariates will be imputed appropriately. All analyses will be performed on the cohort of randomised patients according to their assigned randomisation groups, except for those whose planned surgeries are delayed or cancelled after randomisation.

The incidence of PPCs is reported to be approximately 20% among all surgical populations,^{15 62} and this rate can increase to as high as 39.5% after COVID-19 infections.⁵ We hypothesise a PPC incidence of 30% in the control group. Based on recent studies demonstrating the efficacy of inhaled NO in improving oxygenation during COVID-19,^{47 50} we anticipate a reduction in PPC incidence from 30% to 20% (a 30% relative reduction). The sample size calculation is performed using Pearson’s χ² test with a two-sided significance level of 0.05 and 80% power. To account for a 10% drop-out rate with continuity correction, a sample size of 330 per group is needed.

Demographic and baseline disease characteristics will be summarised with the use of descriptive statistics. Categorical variables will be reported as absolute numbers and percentages. Unadjusted univariate analyses, to compare the two treatment groups, will be based on χ² or Fisher’s exact test. Relative risks and 95% CIs will be calculated by means of the two-by-two table method with the use of log-normal approximation. Continuous variables will be reported as mean±SD or median and IQR. Normality will be evaluated using visual histogram evaluation and a Q-Q plot. Between-group differences will be evaluated using the t-test or Wilcoxon signed rank test, in accordance with normality of the distribution. The full analysis R code will be uploaded on GitHub before completion of enrolment.

For the primary analysis, the χ² test will be employed for an unadjusted analysis, and risk ratios with 95% CIs will be estimated using Wald’s likelihood ratio approximation test. The effect size of the intervention will be expressed as risk differences along with their corresponding 95% CIs. The number needed to treat will be calculated as the reciprocal of the risk difference, and the result will be rounded to the nearest whole number. The outcome will be further analysed as a binary variable through generalised linear models (GLM) with a binomial distribution family and a logit link function. This analysis will include adjustments for stratification variables (ARISCAT index and time interval from infection to surgery) as fixed effects.

Several prespecified secondary analyses were conducted. First, for preplanned secondary outcome measures, GLM regression analyses were employed for binary outcomes, with distribution choices capable of handling right-tailed positive data (eg, truncated Poisson, gamma distribution or inverse Gaussian). Cox proportional hazard models were used for length-of-stay outcomes, incorporating a shared frailty model. The proportionality assumption was visually inspected using Kaplan-Meier plots, log-log plots and Schoenfield residuals, with no clear evidence of divergence. Non-parametric comparisons were made using Kaplan-Meier curves and between-group log-rank tests. For continuous outcomes, linear or quartile regression was chosen based on the skewness of the distribution. Models were adjusted for the ARISCAT index and the time interval from infection to surgery as per randomisation strata, treated as fixed effects. Between-group risk differences were estimated and reported with 95% CIs. Adverse reactions were documented and analysed, with differences in incidence tested using Fisher’s exact tests. No type I error corrections were conducted for multiple tests in this context.

Prespecified subgroup analyses of the primary outcomes will be performed using logistic regression models for subgroups defined by age (<65 or ≥65), sex (male or female), types of surgery (cardiac or non-cardiac), body mass index (≤35, >35 kg/m²), surgical complexity grades (minor, intermediate and major), duration of anaesthesia (<2 hours, 2–3 hours or ≥3 hours), a history of smoking, one-lung ventilation, ARISCAT (<26, 26–44 or ≥45), and time intervals between infection and surgery (≤10, 11–28, 29–49 days). The effect modifications or interactions will be assessed through the inclusion of interaction terms between the stratification variable and randomisation group in the logistic regression model.

In a prespecified sensitivity analysis, the effect of the intervention on the primary outcome will be re-estimated with GLM using a binomial distribution. Additional adjustment will be made for the aforementioned subgroups and any variables showing substantial imbalance across treatment arms at baseline. To achieve this, a logistic regression model with stepwise selection will be employed to estimate the treatment effect and predictors of PPCs. Prerandomisation clinical data will be included in the model if their univariable p<0.1, and there is no correlation between them. Collinearity and overfitting will be assessed using a stepwise regression model and the Pearson correlation test. The treatment group (NO or control) will be forced into the multivariate model. If the outcome event proves to be rare, a Poisson regression model will be used. Classic logistic regression will be performed with a consistent number of events, and the number of covariates in the model will be decided based on the number of outcomes. The ARISCAT score and operation duration score used as one randomisation stratification will be treated as continuous variables, exploring their continuous impacts on the outcome. Time until pulmonary complications within seven postoperative days was assessed using Kaplan-Meier survival curves and log-rank test. Per-protocol and as-treated analyses of PPCs will be performed as sensitivity analyses. We anticipate a low missing rate of the primary outcome. If more than 5% data are missing for the primary outcome, multiple imputations will be carried out as a sensitivity analysis.

Since the primary outcome of the present study is a composite one, the choice of the statistical method is an important part of design because various methods provide different power, depending on the situation. In addition to the standard analysis described above, the following analyses will be performed to test the robustness of the trial findings: (1) the number of positive component events (ie, ‘count’) across the composite will be assessed. The groups will be compared on the count using a Wilcoxon rank-sum test, and the OR with the 95% CI will be assessed with a proportional odds logistic regression model; (2) the effect of the intervention in each component will be analysed using a GLM using a Bonferroni correction for multiple comparisons. The 99.37% Bonferroni-corrected CIs will be reported (1–0.05/8=0.9937); (3) a multivariate (ie, multiple outcomes per subject) generalised estimating equations (GEE) model will be used to estimate a common effect OR across the components; (4) the average relative effect test will be assessed by averaging the component-specific treatment effect from the distinct effects model, and testing whether the average is equal to 0. In the GEE distinct effect model, a distinct treatment effect is estimated for each component; (5) heterogeneity of treatment effect across components will be assessed by a treatment-by-component interaction test in the distinct effects GEE model and (6) patients in the treatment and control groups will be formed into matched pairs based on their risk profiles. The win ratio will be calculated and reported to address the inherent limitation of composite outcomes.⁶³

To enhance the interpretability of the results and provide valuable information for decision-making, the INORDINATE trial will employ Acceptability Curve Estimation using Probability above Threshold (ACCEPT) analysis.⁶⁴ This analysis method involves calculating and plotting the probabilities of the true difference between treatments being above various acceptability thresholds, based on the data obtained from the trial. By using this approach, the limitations of traditional binary trial conclusions, which categorise results as either positive (meeting the trial aim) or negative (not meeting the trial aim), can be overcome. ACCEPT analysis provides a more nuanced understanding of the data and allows for a range of possible threshold values to be considered, thereby facilitating more informed decision-making.

Statistical significance for the primary outcome will be indicated by a p value of 0.05 with use of a two-sided hypothesis test. No correction for multiple comparisons was applied in the evaluation of secondary or other outcomes. Thus, such results are exploratory and are reported as point estimates with 95% CIs.

Monitoring of the study

Independent auditors will be responsible for ensuring compliance with the clinical trial protocol and verifying the accuracy of data collection in accordance with the Good Clinical Practice (GCP) guidelines. The study will be monitored and followed up according to the protocols established during the initial set-up, and all reporting will adhere to current national and international requirements. This rigorous monitoring and adherence to guidelines aim to maintain the integrity and quality of the study.

Ethical considerations

The administration of NO is deemed clinically safe in this trial and will be conducted by a skilled professional with experience in respiratory therapy. To mitigate the potential inflammatory response in the respiratory tract or lung tissue injuries resulting from the generation of NO₂, the entire process will be continuously monitored to ensure concentrations remain below 5 ppm. Although there is a recognised risk of harm to healthy individuals when methaemoglobin (metHb) content exceeds 15%–20%,⁶⁵ adverse effects of inhaling NO are rarely reported in the literature. Furthermore, it is noteworthy that the binding of NO to haemoglobin is reversible, with a half-life of 15–20 min after stopping NO administration.⁶⁶

This protocol strictly follows the principles of the ‘Declaration of Helsinki’ in full. The study will be governed by the implementation of current International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Good Clinical Practice (ICH-GCP) and China National Drug Administration (NMPA) related regulations. The study data planned to be collected are essential for assessing the efficacy, safety, quality and application of drugs. The collection and utilisation of this data ensure confidentiality and compliance with relevant laws and regulations, thereby protecting subject privacy. Written informed consent (online supplemental file 2) will be obtained in accordance with the Declaration of Helsinki,⁶⁷ laws and regulations for conducting clinical trials, the General Data Protection Regulation, the data protection directive and other rules applying to the protection of personal data. Patients are allowed to decline consent at any point during the study; in such cases, all relevant information shall be removed. All private information will be kept confidential and removed before data analyses.

Patient and public involvement

No patients or members of the public were involved in the design and development of the protocol. Furthermore, they will not participate in the analysis or presentation phases of the study on its completion.

Ethics and dissemination

Ethical approval has been obtained on 2 February 2023 from the Xijing Hospital Ethical Committee (KY20232058-F-1, protocol version: 1.0, date: 2 February 2023). The study is registered on ClinicalTrials.gov (NCT05721144) and available online (https://clinicaltrials.gov/ct2/show/NCT05721144?term=NCT05721144&draw=2&rank=1). Any protocol changes will be approved by relevant ethical review boards. Final results will be submitted to a peer-reviewed journal and presented at relevant academic conferences.

Study initiation, timing and source of funding

The study commenced after receiving approval from the institutional ethical committee and subsequent registration on clinicaltrials.gov. Enrolment includes consecutive participants who have provided written informed consent. The first patient was enrolled on 17 February 2023, and the first 60 participants were randomised by 8 June 2023. The study team is exclusively responsible for designing, conducting the trial, as well as analysing, drafting and editing the final reports.

Funding for the trial is provided by the National Natural Science Foundation of China (81970448), the university and the hospital foundation for patient outcome improvement (2021LC2202 and XJZT21L17).

Discussion

The significance of this RCT lies in its potential to offer anaesthesiologists valuable evidence on perioperative management strategies that could improve clinical outcomes for surgical patients who have recently been infected with SARS-CoV-2. Given the likelihood of living with this virus and its variants for an extended period, the findings from this study can help guide healthcare professionals in making informed decisions about patient care. By identifying effective perioperative management approaches, this research has the potential to enhance the overall quality of care and patient outcomes in the context of ongoing COVID-19 challenges.

The administration of NO is a straightforward and relatively safe technique that can be implemented in patients under the supervision of experienced respiratory therapists or anaesthesiologists who have received comprehensive training in respiratory management during surgical anaesthesia. The advancements in NO delivery and generation systems have made this intervention treatment easily accessible. If the hypothesis is confirmed and the incidence of PPCs is reduced, it would lead to a substantial improvement in the postoperative prognosis of this particular surgical population.

It has been demonstrated that low doses of inhaled NO facilitate pulmonary vasodilation and improve oxygenation by enhancing ventilation-perfusion (V/Q) matching.⁶⁸ In addition to its effects on pulmonary function, the inhalation of NO also exhibits antiviral and anti-inflammatory properties, including the inhibition of neutrophil adhesion and the release of proinflammatory cytokines.⁶⁹ Although the concentrations of inhaled NO required for antimicrobial effects remain unknown, previous studies have shown that up to 300 ppm of inhaled NO is safe and well tolerated in patients with viral pneumonia, such as COVID-19^{51 52} and respiratory syncytial virus pneumonia.⁷⁰

As a result, a relatively higher dose may be appropriate for achieving the anti-inflammatory and antimicrobial effects of inhaled NO. While the most commonly used doses of inhaled NO range from 20 to 40 ppm, these studies have primarily focused on improving oxygenation. Higher doses have been suggested to be necessary for organ protection and for improving patient-centred outcomes.⁷¹ Previous studies have demonstrated the safety and effectiveness of inhaled NO at 80 ppm in preventing the depletion of plasma NO by circulating plasma haemoglobin.⁷² Furthermore, a previous study conducted in our centre demonstrated that the inhalation of 80 ppm NO was well tolerated and effective in reducing the incidence of acute kidney injury associated with cardiovascular surgery.⁵⁵ Additionally, it has been suggested to increase the concentration of inhaled NO (eg, to 80 ppm) during cardiovascular pulmonary bypass, when there is a maximum level of haemolysis and ischaemia-reperfusion injury, to reduce extrapulmonary complications involving the myocardium and kidneys. Following this, a subsequent decrease in the concentration of inhaled NO to 10–40 ppm after weaning off cardiopulmonary bypass and switching to mechanical ventilation is recommended to ensure ‘lung protective’ and ‘right ventricular protective’ ventilation.⁷³ Hence, in this study, as the primary endpoint is PPCs, the administration of NO at 80 ppm was selected to seek improvement in pulmonary function.

The design of the trial leans towards being pragmatic rather than strictly controlled. It aims to minimise disruptions and deviations from routine clinical practice at the institution, allowing for variations in the choice of anaesthetic drugs, anaesthesia technologies and modes of respiratory management. Any differences between these techniques will be further investigated through subgroup analysis or adjusted for in sensitivity analysis if significant between-group differences are detected. Similarly, no restrictions on surgery types allow wider generalisability of this study. It is generally accepted that patients undergoing cardiac surgery are particularly vulnerable for developing PPCs.⁷⁴ The ARISCAT score (table 2) accounting for the incision position where intrathoracic is assigned the highest score (24) comparing to upper abdominal (15) and periphery (0) suggests that the cardiac/chest surgery patients are likely to face elevated respiratory risks. At the same time, the incidence of PPCs among patients who underwent cardiac or chest surgeries was generally reported to be 39%–60%^75–77 comparing to 5%–20% in all surgery types;^{15 62 75 78} some small cohort studies even showed up to 90% incidence⁷⁹ for cardiac surgeries. In addition, most evidence on the benefits of iNO was suggested in cardiac surgeries.^{80 81} We, therefore, anticipate potential interaction between cardiac and non-cardiac surgeries in this study and predefined subgroup analysis for further investigation. The pragmatic design allows for a conservative estimation of the incidence of PPCs and ensures the study is adequately powered. Moreover, the outcome of the trial holds great relevance for anaesthesiologists.

Limitations

One potential limitation, which we consider as a strength of our study, is the absence of a strict anaesthetic protocol governing specific opioids, induction agents, intraoperative fluid management and mechanical ventilation settings. Instead, each patient received treatment based on the best available practices at our centre. This approach boosts the external validity of our findings, mirroring real-world variability in perioperative management. However, it is important to acknowledge that this variability might introduce confounding factors, limiting our ability to draw definitive conclusions about the effects of particular interventions. Nevertheless, it offers valuable insights into the practical application of different approaches in a clinical setting.

Another limitation involves the process of patient screening, as SARS-CoV-2 testing is not mandatory for surgical patients. Consequently, some patients with recent SARS-CoV-2 infection might be diagnosed based solely on clinical symptoms, potentially leading to misclassification. In other words, asymptomatic infections could be overlooked, and infections caused by other viruses might be included, introducing potential selection bias. Nevertheless, this aspect of our study reflects the real clinical scenario, enhancing the generalisability of our findings by examining the intervention’s effectiveness in a broader population, including those not identified through mandatory testing protocols.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Contributors CL, ZZ and LW drafted the manuscript and were responsible for trial design, preparing the protocol and revisions, preparing investigators brochure(IB) and case report forms (CRFs), managing clinical trial office, publishing study reports. CL, HD and HN formed the steering committee which provided thoughts, evaluated and discussed the study rationale, and approved the final protocol. They were also engaged in the reviewing processes. SW, QF and HZ were responsible for rationalising, finalising and conducting the patient screening and selection procedures. BG and XY were responsible for drafting the patient consent form and obtaining written consent forms. Data management team (ZZ, GL, BG, BZ and XW) is responsible for development and maintenance of trial electronic data collection (EDC) system and data entry, data verification. XY was responsible for patients’ follow-up strategies. Endpoint adjudication committee (CL, LW, XY and HN) is responsible for determining if the participant’s experienced the event that meets the protocol’s predefined criteria. All investigators approved the study rationale and reviewed the manuscript. Trial management committee (all investigators, administrator, Anesthesia Clinical Research Center) is responsible for planning study, organising steering committee meetings, providing annual report and serious unexpected suspected adverse events (SUSAR) reports to institutional IRB, audit the trial, data verification.

Funding The trial is funded by the National Natural Science Foundation of China (81970448), the university and hospital foundation for patient outcome improvement (2021LC2202 and XJZT21L17).

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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