Clinical trial NCT05721144: Inhaled NO in Surgical Patients With Recent COVID-19 Infection
Official title: Inhaled NO ReDuce postoperatIve pulmoNAry complicATions in patiEnts With Recent COVID-19 Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nitric Oxide
COVID-19
Surgery
Postoperative Complications
Keywords: Nitric Oxide Inhalation
Postoperative Pulmonary Complications
Surgery
COVID-19
Lead sponsor: Xijing Hospital
Sponsor class: OTHER
First posted: 2023-02-09
Enrollment: 660
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: postoperative pulmonary complications
timeFrame: within 7 days after operation
Secondary outcomes:
measure: mortality within 30 days postoperatively
timeFrame: within 30 days after operation
measure: Classification of pulmonary complications (Clavien-Dindo)
timeFrame: within 7 days after operation
measure: the rate of unplanned ICU admission
timeFrame: within 7 days after operation
measure: postoperative length of hospital stay
timeFrame: From the date of surgery until the date patient discharge from hospital, assessed up to 30 days
measure: Incidence of thrombotic events
timeFrame: From the date of surgery until the date patient discharge from hospital, assessed up to 30 days
measure: incidence of nonpulmonary complications
timeFrame: From the date of surgery until the date patient discharge from hospital, assessed up to 30 days
measure: postoperative comprehensive complication index (CCI)
timeFrame: within 7 days after operation
Other outcomes:
measure: Incidence of hypotension
timeFrame: From anesthesia induction until leave operation room, assessed up to 12 hrs
measure: Incidence of hypertension
timeFrame: During surgery, from anesthesia induction to end of anesthesia
measure: Occurrence of arrhythmia
timeFrame: From anesthesia induction until leave operation room, assessed up to 12 hrs
measure: Incidence of airway hyperresponsiveness
timeFrame: From anesthesia induction until leave operation room, assessed up to 12 hrs
measure: Number that the concentration of NO was adjusted
timeFrame: During NO inhalation, from anesthesia induction until leave operation room, assessed up to 12 hrs
measure: massive bleeding
timeFrame: From anesthesia induction until leave operation room, assessed up to 12 hrs
Locations:
city: Xi'an
country: China
facility: Xijing Hospital
state: Shaanxi
Study officials:
affiliation: Xijing Hospital
name: Chong Lei, MD&phD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585.
citation: Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. Epub 2020 Jan 24.
citation: Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr;8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X. Epub 2020 Feb 18. No abstract available.
citation: Chen L, Liu P, Gao H, Sun B, Chao D, Wang F, Zhu Y, Hedenstierna G, Wang CG. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin Infect Dis. 2004 Nov 15;39(10):1531-5. doi: 10.1086/425357. Epub 2004 Oct 22.
citation: Keyaerts E, Vijgen L, Chen L, Maes P, Hedenstierna G, Van Ranst M. Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound. Int J Infect Dis. 2004 Jul;8(4):223-6. doi: 10.1016/j.ijid.2004.04.012.
citation: Valsecchi C, Winterton D, Safaee Fakhr B, Collier AY, Nozari A, Ortoleva J, Mukerji S, Gibson LE, Carroll RW, Shaefi S, Pinciroli R, La Vita C, Ackman JB, Hohmann E, Arora P, Barth WH Jr, Kaimal A, Ichinose F, Berra L; DELiverly oF iNO (DELFiNO) Network Collaborators. High-Dose Inhaled Nitric Oxide for the Treatment of Spontaneously Breathing Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19) Pneumonia. Obstet Gynecol. 2022 Aug 1;140(2):195-203. doi: 10.1097/AOG.0000000000004847. Epub 2022 Jul 6.
citation: Fang W, Jiang J, Su L, Shu T, Liu H, Lai S, Ghiladi RA, Wang J. The role of NO in COVID-19 and potential therapeutic strategies. Free Radic Biol Med. 2021 Feb 1;163:153-162. doi: 10.1016/j.freeradbiomed.2020.12.008. Epub 2020 Dec 22.
citation: Al Sulaiman K, Korayem GB, Altebainawi AF, Al Harbi S, Alissa A, Alharthi A, Kensara R, Alfahed A, Vishwakarma R, Al Haji H, Almohaimid N, Al Zumai O, Alrubayan F, Asiri A, Alkahtani N, Alolayan A, Alsohimi S, Melibari N, Almagthali A, Aljahdali S, Alenazi AA, Alsaeedi AS, Al Ghamdi G, Al Faris O, Alqahtani J, Al Qahtani J, Alshammari KA, Alshammari KI, Aljuhani O. Evaluation of inhaled nitric oxide (iNO) treatment for moderate-to-severe ARDS in critically ill patients with COVID-19: a multicenter cohort study. Crit Care. 2022 Oct 3;26(1):304. doi: 10.1186/s13054-022-04158-y.
citation: Garfield B, McFadyen C, Briar C, Bleakley C, Vlachou A, Baldwin M, Lees N, Price S, Ledot S, McCabe C, Wort SJ, Patel BV, Price LC. Potential for personalised application of inhaled nitric oxide in COVID-19 pneumonia. Br J Anaesth. 2021 Feb;126(2):e72-e75. doi: 10.1016/j.bja.2020.11.006. Epub 2020 Nov 14. No abstract available.
citation: Ghosh A, Joseph B, Anil S. Nitric Oxide in the Management of Respiratory Consequences in COVID-19: A Scoping Review of a Different Treatment Approach. Cureus. 2022 Apr 5;14(4):e23852. doi: 10.7759/cureus.23852. eCollection 2022 Apr.
citation: Bunch CM, Moore EE, Moore HB, Neal MD, Thomas AV, Zackariya N, Zhao J, Zackariya S, Brenner TJ, Berquist M, Buckner H, Wiarda G, Fulkerson D, Huff W, Kwaan HC, Lankowicz G, Laubscher GJ, Lourens PJ, Pretorius E, Kotze MJ, Moolla MS, Sithole S, Maponga TG, Kell DB, Fox MD, Gillespie L, Khan RZ, Mamczak CN, March R, Macias R, Bull BS, Walsh MM. Immuno-Thrombotic Complications of COVID-19: Implications for Timing of Surgery and Anticoagulation. Front Surg. 2022 May 4;9:889999. doi: 10.3389/fsurg.2022.889999. eCollection 2022.
citation: COVIDSurg Collaborative; GlobalSurg Collaborative. SARS-CoV-2 infection and venous thromboembolism after surgery: an international prospective cohort study. Anaesthesia. 2022 Jan;77(1):28-39. doi: 10.1111/anae.15563. Epub 2021 Aug 24.
citation: COVIDSurg Collaborative. Outcomes and Their State-level Variation in Patients Undergoing Surgery With Perioperative SARS-CoV-2 Infection in the USA: A Prospective Multicenter Study. Ann Surg. 2022 Feb 1;275(2):247-251. doi: 10.1097/SLA.0000000000005310.
citation: Abbott TEF, Fowler AJ, Dobbs TD, Gibson J, Shahid T, Dias P, Akbari A, Whitaker IS, Pearse RM. Mortality after surgery with SARS-CoV-2 infection in England: a population-wide epidemiological study. Br J Anaesth. 2021 Aug;127(2):205-214. doi: 10.1016/j.bja.2021.05.018. Epub 2021 Jun 11.
citation: COVIDSurg Collaborative; GlobalSurg Collaborative. Timing of surgery following SARS-CoV-2 infection: an international prospective cohort study. Anaesthesia. 2021 Jun;76(6):748-758. doi: 10.1111/anae.15458. Epub 2021 Mar 9.
citation: El-Boghdadly K, Cook TM, Goodacre T, Kua J, Denmark S, McNally S, Mercer N, Moonesinghe SR, Summerton DJ. Timing of elective surgery and risk assessment after SARS-CoV-2 infection: an update: A multidisciplinary consensus statement on behalf of the Association of Anaesthetists, Centre for Perioperative Care, Federation of Surgical Specialty Associations, Royal College of Anaesthetists, Royal College of Surgeons of England. Anaesthesia. 2022 May;77(5):580-587. doi: 10.1111/anae.15699. Epub 2022 Feb 22.
citation: Mavrothalassitis O, Pirracchio R, Fong N, Lazzareschi D, Sharma A, Vaughn MT, Mathis M, Legrand M. Outcome of surgical patients during the first wave of the COVID-19 pandemic in US hospitals. Br J Anaesth. 2022 Jan;128(1):e35-e37. doi: 10.1016/j.bja.2021.09.023. Epub 2021 Oct 1. No abstract available.
citation: Wijeysundera DN, Khadaroo RG. Surgery after a previous SARS-CoV-2 infection: data, answers and questions. Anaesthesia. 2021 Jun;76(6):731-735. doi: 10.1111/anae.15490. Epub 2021 Apr 17. No abstract available.
citation: Lieberman N, Racine A, Nair S, Semczuk P, Azimaraghi O, Freda J, Eikermann M, Wongtangman K. Should asymptomatic patients testing positive for SARS-CoV-2 wait for elective surgical procedures? Br J Anaesth. 2022 May;128(5):e311-e314. doi: 10.1016/j.bja.2022.02.005. Epub 2022 Feb 16. No abstract available.
citation: Dobbs TD, Gibson JAG, Fowler AJ, Abbott TE, Shahid T, Torabi F, Griffiths R, Lyons RA, Pearse RM, Whitaker IS. Surgical activity in England and Wales during the COVID-19 pandemic: a nationwide observational cohort study. Br J Anaesth. 2021 Aug;127(2):196-204. doi: 10.1016/j.bja.2021.05.001. Epub 2021 Jun 18.