
==== Front
Trials
Trials
Trials
1745-6215
BioMed Central London

8416
10.1186/s13063-024-08416-y
Study Protocol
Effect of perioperative sigh ventilation on postoperative hypoxemia and pulmonary complications after on-pump cardiac surgery (E-SIGHT): study protocol for a randomized controlled trial
Wang Zhichang 1
Cheng Qiyu 1
Huang Shenglun 1
Sun Jie 2
Xu Jingyuan 1
Xie Jianfeng 1
Cao Hailong 13675186233@163.com

3
http://orcid.org/0000-0001-9766-4927
Guo Fengmei fmguo2022@163.com

1
1 https://ror.org/04ct4d772 grid.263826.b 0000 0004 1761 0489 Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009 China
2 https://ror.org/04ct4d772 grid.263826.b 0000 0004 1761 0489 Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009 China
3 https://ror.org/04ct4d772 grid.263826.b 0000 0004 1761 0489 Department of Cardiothoracic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009 China
4 9 2024
4 9 2024
2024
25 58517 5 2024
21 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

Postoperative hypoxemia and pulmonary complications remain a frequent event after on-pump cardiac surgery and mostly characterized by pulmonary atelectasis. Surfactant dysfunction or hyposecretion happens prior to atelectasis formation, and sigh represents the strongest stimulus for surfactant secretion. The role of sigh breaths added to conventional lung protective ventilation in reducing postoperative hypoxemia and pulmonary complications among cardiac surgery is unknown.

Methods

The perioperative sigh ventilation in cardiac surgery (E-SIGHT) trial is a single-center, two-arm, randomized controlled trial. In total, 192 patients scheduled for elective cardiac surgery with cardiopulmonary bypass (CPB) and aortic cross-clamp will be randomized into one of the two treatment arms. In the experimental group, besides conventional lung protective ventilation, sigh volumes producing plateau pressures of 35 cmH2O (or 40 cmH2O for patients with body mass index > 35 kg/m2) delivered once every 6 min from intubation to extubation. In the control group, conventional lung protective ventilation without preplanned recruitment maneuvers is used. Lung protective ventilation (LPV) consists of low tidal volumes (6–8 mL/kg of predicted body weight) and positive end-expiratory pressure (PEEP) setting according to low PEEP/FiO2 table for acute respiratory distress syndrome (ARDS). The primary endpoint is time-weighted average SpO2/FiO2 ratio during the initial post-extubation hour. Main secondary endpoint is the severity of postoperative pulmonary complications (PPCs) computed by postoperative day 7.

Discussion

The E-SIGHT trial will be the first randomized controlled trial to evaluate the impact of perioperative sigh ventilation on the postoperative outcomes after on-pump cardiac surgery. The trial will introduce and assess a novel perioperative ventilation approach to mitigate the risk of postoperative hypoxemia and PPCs in patients undergoing cardiac surgery. Also provide the basis for a future larger trial aiming at verifying the impact of sigh ventilation on postoperative pulmonary complications.

Trial registration

ClinicalTrials.gov NCT06248320. Registered on January 30, 2024. Last updated February 26, 2024.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-024-08416-y.

Keywords

Postoperative hypoxemia
Postoperative pulmonary complications
Cardiac surgery
Cardiopulmonary bypass
Sigh
Mechanical ventilation
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Postoperative pulmonary complications (PPCs) remain a frequent event after on-pump cardiac surgery and mostly characterized by pulmonary atelectasis [1]. Atelectrauma, denoting the cyclic expansion and collapse of atelectatic lung regions, and volutrauma, involving excessive distension of neighboring patent alveoli, are recognized as pivotal contributors to ventilator-induced lung injury (VILI) subsequent to atelectasis [2, 3]. This injurious sequence is associated with hypoxemia, pneumonia, ventilator-induced lung injury, and acute respiratory distress syndrome (ARDS), thereby engendering escalated healthcare resource utilization, delayed patient mobilization, prolonged reliance on supplementary oxygen or mechanical ventilation, and protracted hospitalization [4].

Patients undergoing on-pump cardiac surgery are subject to a convergence of pulmonary insults. The administration of general anesthesia combined with invasive mechanical ventilation initiates a distinctive lung insult recognized as ventilator-induced lung injury [5]. Additionally, cardiac surgery introduces a secondary insult: cardiopulmonary bypass (CPB) elicits a systemic inflammatory response [6], while the application of the aortic cross clamp contributes to pulmonary ischemic injury [7]. Moreover, the frequent necessity for blood transfusions and the experience of postoperative pain significantly contribute to the heightened incidence of postoperative pulmonary complications (PPCs) [8, 9]. Pulmonary atelectasis is very common in this context.

The implementation of targeted perioperative ventilatory strategies aimed at mitigating pulmonary atelectasis and postoperative pulmonary complications (PPCs) represents a well-established approach [10–12]. Numerous investigations have described the concept of lung protective ventilation. Inspired by the results obtained in critical care medicine in patients with acute respiratory distress syndrome (ARDS), the use of low tidal volumes (6–8 mL/kg predicted body weight) has spread to the operation room and there is now an established consensus [13]. However, the use of low tidal volumes may precipitate the constitution of pulmonary atelectasis in the poorly ventilated, dependent regions of the lung [14]. Constant low tidal volume ventilation [15] combined with multiple insults from cardiac surgery may engender significant perturbations in lung surfactant homeostasis.

Surfactant, pivotal for maintaining low surface tension and averting atelectasis, undergoes continuous inactivation and/or depletion, necessitating ongoing secretion for its preservation [15]. Meanwhile, animal studies revealed that the diminishment of large aggregate forms of lung surfactant precedes the abnormalities in lung permeability and gas exchange [16]. Mechanical strain on type II pneumocytes, induced notably by large tidal volumes (VTs), represents the strongest stimulus for surfactant release [17–19]. Pattle’s seminal observations nearly six decades ago underscored the significance of yawning or deep breaths in augmenting surfactant recruitment to the alveolar lining film [20]. He postulated that the prevention of deep breaths could precipitate the collapse of alveolar, proposing periodic maximal inflations during mechanical ventilation to forestall such occurrences.

Short-term administration of sighs improves compliance and gas exchange, reducing ventilation heterogeneity and regional lung strain, reversing and preventing atelectasis, and mitigating the production of inflammatory cytokines [21–23]. Recent studies also suggested that sighs seem to be safe when administered to patients with lung injury or trauma [24, 25]. This single-center, randomized study is going to be conducted in patients undergoing scheduled on-pump cardiac surgery to test whether incorporating sigh to perioperative protective ventilation was safe and the efficacy to reduce postoperative hypoxemia and pulmonary complications.

The primary objective is to assess the efficacy of the perioperative sigh breaths in terms of oxygenation during post-extubation period, assessed by time-weighted average SpO2/FiO2 ratio during the initial post-extubation hour. Key secondary objectives are to assess the severity of respiratory failure by post-extubation day 7 and PPCs by postoperative day 7.

Methods/design

Trial design

This study is an investigator-initiated, prospective, single-center, randomized, controlled, parallel group, clinical trial with a 1:1 allocation. Participants, care providers, and outcomes assessor will be blinded to the group allocation. Two perioperative ventilatory strategies in cardiac surgery with cardiopulmonary bypass are compared: (1) experimental strategy: intermittent sigh breaths plus perioperative lung protective ventilation; (2) control strategy: conventional perioperative lung protective ventilation (Fig. 1). The study will be conducted in adherence to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act (WMO). Ethics approval was obtained before starting enrollment and consent will be obtained for each patient following local regulations. The Institutional Review Board of the Zhongda Hospital approved the protocol on 22 Feb 2024 under reference number 2024ZDSYLL037-P01. The trial was registered at www.clinicaltrials.gov with code NCT06248320 in Jan 2024. First patient was enrolled in 25 Feb 2024. The Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) checklist can be found in Additional file 1 and the SPIRIT figure is included in the main body of the manuscript (Fig. 2).Fig. 1 Consolidated Standards of Reporting Trials (CONSORT) diagram for the E-SIGHT trial. ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; CPAP, continuous positive airway pressure; LPV, lung protective ventilation

Fig. 2 E-SIGHT trial schedule during the study period. HFNC high-flow nasal cannula, ICU intensive care unit, IMV intensive mechanical ventilation, NIV non-invasive ventilation, PaO2 arterial pressure in oxygen, POD postoperative day, SpO2 pulse oximetry, FiO2 inspired oxygen fraction

Study setting

This clinical trial will be conducted at Zhongda Hospital, a tertiary teaching hospital affiliated to Southeast University, situated in Nanjing, China. This high-volume university hospital performs a minimum of 400 cardiac surgical operations involving CPB annually.

Eligible criteria

Inclusion criteria

Patients are eligible if they are 18 years or older, scheduled for elective cardiac surgery with general anesthesia, conventional CPB, and aortic cross clamp. Signed, informed consent provided by the patient or the legally authorized representatives will be obtained precede the study inclusion.

Exclusion criteria

Considering the minimal impact of sigh breaths on individuals with pre-existing hypoxemia resulting from chronic lung diseases, and those with high risk of developing lung dysfunction due to pre-existing severe cardiac impairment or other non-pulmonary risk factors not attributable to perioperative ventilation strategy, these individuals will be excluded from the study.

The exclusion criteria are:Emergent surgery including aortic dissection, cardiac rupture, and active endocarditis surgery

Left ventricular assist device implantation

Patients who are anticipated to require continuously perioperative circulatory support with extracorporeal membrane oxygenation (ECMO) or intra-aortic balloon pump (IABP)

Chronic pulmonary disease requiring long-term home oxygen therapy or continuous positive airway pressure support (CPAP)

Receiving invasive mechanical ventilation within 7 days prior to surgery

Preoperative shock

Obstructive sleep apnea syndrome (OSAS) requiring intermittent non-invasive ventilator support

Preoperative left ventricular ejection fraction (LVEF) < 40%

Pulmonary arterial systolic pressure > 50 mmHg

Redo surgery within the same hospitalization

Intervention

Mechanical ventilation is performed during general anesthesia and intensive care unit (ICU) on volume-controlled mode. All patients are ventilated with low tidal volumes (6–8 mL/kg of predicted body weight) before and after CPB; ventilation is interrupted during CPB. The predicted body weight is calculated with the formula: 50 + 0.91*(Height in cm − 152.4) in men and 45.5 + 0.91*(height in cm − 152.4) in women. The respiratory rate will be adjusted before and after CPB by the anesthesiologist and/or intensivist to maintain end-tidal CO2 partial pressure between 35 and 45 mmHg. The lowest fraction of inspired oxygen (FiO2) will be targeted in both groups to maintain SpO2 ≥ 96%. The inspiratory to expiratory ratio (I:E) is set at 1:2. Positive end-expiratory pressure (PEEP) is set according to low PEEP/FiO2 table for ARDS [26] before and after CPB (Table 1). During sternal sawing, PEEP is temporarily set to 0 cmH2O to prevent pleural injury. No additional recruitment maneuvers are performed in both groups. Table 1 Low PEEP/FiO2 table

FiO2, %	30	40	40	50	50	60	70	70	70	80	90	90	90	100	
PEEP, cmH2O	5	5	8	8	10	10	10	12	14	14	14	16	18	18–24	

The intervention timeframe commences at randomization and concludes at endotracheal extubation, postoperative day 7, or death, whichever occurs first (i.e., during intraoperative and invasive mechanical ventilation in ICU). In the event of reintubation within postoperative day 7, patients will resume the intervention based on their assigned group.

Experimental strategy: intermittent sigh breaths plus lung protective ventilation

Sigh breaths are administered by elevating the positive end-expiratory pressure (PEEP), targeting a plateau pressure (Pplat) of 35 cmH2O (or 40 cmH2O for patients with a body mass index (BMI) > 35 kg/m2, considering chest wall compliance would be reduced in those patients). The appropriate delta level of PEEP necessary to achieve the target Pplat is determined manually prior to the initiation of sigh breaths. These sigh breaths will be administered over a 5-s interval once every 6 min, a methodology informed by the findings of Bendixen [27] and SiVent study [24]. Sigh breaths will be administered manually by an anesthesiologist in the operating room, while through ventilators configured to deliver sigh breaths in the ICU, utilizing equipment such as Mindray SV300 or Mindray SV600 or Mindray SV800 or Drager Evita Infinity V500, depending on availability.

Sigh breaths are administered at predetermined intervals throughout the entire duration of invasive mechanical ventilation:From endotracheal intubation to the surgical opening of the chest cavity

From the surgical closure of the chest cavity to exiting the operating room

From ICU admission to the start of the spontaneous breathing trial

Patient needs not continue to receive sigh breaths during the time out of operating room and ICU (i.e., transported to CT, transported from operation department to ICU. Sigh breaths should be restarted on their return).

Subsequent sigh breaths will be suspended if the systolic arterial pressure drops below 90 mmHg, despite adequate administration of fluids and/or vasoactive drugs. Sigh breaths will resume once the systolic arterial pressure returns to ≥ 95 mmHg and remains stable for at least 5 min. Records of sigh interruption will be documented and analyzed (Table 2). Table 2 Perioperative ventilatory protocol in each of the two treatment arms

	Experimental strategy	Control strategy	
From endotracheal intubation to chest cavity opening	LPV + sigh breaths	Lung protective ventilation (LPV)

• Tidal volume 6–8 mL/kg PBW

• PEEP: ARDS low PEEP-FiO2 table

• RR ETCO2 35–45 mmHg

• FiO2 lowest to maintain SpO2 ≥ 96%

• I:E ratio 1:2

	
Lung recruitment maneuvers	No	No	
During chest cavity opening	Lung protective ventilation	Lung protective ventilation	
During CPB	Ventilation interrupted	Ventilation interrupted	
Ventilation after chest cavity closure (including in ICU)	LPV + sigh breaths	LPV	
LPV lung protective ventilation, ICU intensive care unit, CPB cardiopulmonary bypass, FiO2 inspired oxygen fraction, I:E inspiratory time to expiratory time ratio, PEEP positive end-expiratory pressure, PBW predicted body weight, RR respiratory rate, SpO2 pulse oximetry, ETCO2 end-tidal CO2

Control strategy: lung protective ventilation

Patients are ventilated with low tidal volumes (6–8 mL/kg of predicted body weight) before and after CPB; ventilation is interrupted during CPB. PEEP is set according to low PEEP/FiO2 table for ARDS. Ventilation is interrupted during CPB (Table 2).

Rescue therapy

In both groups, unplanned recruitment maneuvers are permitted as rescue therapy in case of hypoxemia during the intervention period. Hypoxemia is determined as SpO2 ≤ 92% despite FiO2 of 80%.

Standard of care

Surgery

The type of drugs used for the anesthesia, the management of the CPB, and fluid and transfusion strategies are implemented according to local protocol.

Extubation protocol

Patients will be excluded from the protocol if one of the following criteria is met:Postoperative continuous drainage exceeding 100 mL per hour for 3 consecutive hours.

Left ventricular ejection fraction less than 30% or signs suggesting persistent deteriorating heart failure.

Presence of escalating pericardial effusion or evident manifestations of obstructive shock.

Perturbations in internal milieu: pH below 7.35 or above 7.45, serum potassium less than 3.0 mmol/L or greater than 5.5 mmol/L; blood lactate concentration ≥ 6 mmol/L.

Hourly urine output less than 0.5 mL/kg/h.

Difficulty in endotracheal intubation during anesthesia.

Persistent hypothermia despite aggressive rewarming measures, with temperatures below 36 °C.

Newly onset arrhythmias: heart rate below 40 beats/min or above 140 beats/min; ventricular rhythm disturbances; atrial fibrillation accompanied by hemodynamic instability.

After excluding the aforementioned conditions, the patient will enter a rapid extubation protocol. The tidal volume will remain unchanged, while adjusting the positive end-expiratory pressure (PEEP) to 5 cmH2O. Sedative medications will be discontinued, and analgesic medication dosages will be adjusted personally. During this period, close monitoring of the patient’s oxygenation, blood pressure, and other vital signs will be conducted. After 1–2 h, depending on the patient’s arousal status, readiness for a spontaneous breathing trial (SBT) will be assessed. Patients meeting the following criteria will undergo an SBT:Pulse oximetry saturation ≥ 92% given inspired oxygen fraction (FiO2) ≤ 40%.

Alertness, able to follow commands, without agitation (Richmond Agitation-Sedation Scale [RASS] score of − 2 to 0).

Hemodynamically stable (norepinephrine dose ≤ 0.1 µg/kg/min or equivalent doses of other vasopressor agents; or gradual tapering of vasopressor medications over the past 4 h).

No potential short-term need for controlled ventilation due to other reasons.

During the 30-min spontaneous breathing trial (SBT) conducted in pressure support ventilation (PSV) mode with PEEP set at 5 cmH2O and PSV between 5 and 10 cmH2O, if any of the following conditions are met at the end of the 30-min period, the patient will fail the SBT:Respiratory rate > 35 breaths per minute or significant accessory muscle involvement.

Oxygen saturation (SpO2) < 92%.

Heart rate > 140 beats per minute or an increase in heart rate > 20%, or newly onset arrhythmias.

Systolic blood pressure > 180 mmHg or < 90 mmHg.

Patient reports significant respiratory distress.

Evidence of active myocardial ischemia (dynamic ST-segment changes on electrocardiogram monitoring).

Significant alteration in consciousness (Glasgow Coma Scale [GCS] score < 13, Richmond Agitation-Sedation Scale [RASS] score <  − 3), weak cough effort, or inadequate airway clearance capability.

Patients who fail the SBT will be reverted to controlled ventilation or pressure support ventilation mode as deemed appropriate. A subsequent SBT screening and assessment will be conducted if the symptoms listed above are effectively relieved, with ventilation continued according to the predefined group allocation.

Post-extubation ventilatory support

After extubation, routine oxygen therapy is typically administered via nasal cannula or face mask. For patients receiving face mask oxygen therapy at a flow rate of ≥ 5 L/min and failing to achieve a pulse oximetry level greater than 92% or respiratory rate ≤ 25 breaths/min will be considered for escalation to high-flow oxygen therapy (HFNO) or non-invasive ventilation (NIV), specific option depends on the clinical judgment of the attending physician, and no priorities will be predefined [28].

High-flow nasal oxygen (HFNO) therapy

Initial parameters for HFNO therapy include a flow rate of 30 L/min and an oxygen concentration of 100%. Subsequently, oxygen concentration will be titrated to maintain pulse oximetry within the range of 92–98%, and adjust the flow rate to the maximum tolerated by the patient, all maneuvers will completed within the first 10 min after HFNO therapy initiation. Subsequent adjustments in oxygen concentration and flow rate are made based on the target pulse oximetry (SpO2 92–98%) and personal tolerance. If the patient meets the criteria of FiO2 less than 40% and respiratory rate < 25 breaths/min after high-flow therapy, an HFNO weaning trial will be conducted.

Maintaining the oxygen concentration and reduce the flow rate to 10 L/min, and maintain for 10 min. If the patient maintains a pulse oximetry between 92 and 98% and a respiratory rate of ≤ 25 breaths/min during the trial, HFNO can be discontinued, and conventional nasal cannula or face mask oxygen therapy can be initiated. If the patient does not pass the HFNO weaning trial, HFNO therapy will continue.

For patients who fail the HFNO weaning trial for the first time, if they subsequently meet the following criteria during HFNO therapy: FiO2 less than 40%, flow rate less than 30 L/min, and respiratory rate < 25 breaths/min, consideration may be given to discontinuing HFNO therapy and switching to regular nasal cannula or face mask oxygen therapy after passing the HFNO weaning trial. If oxygen saturation falls below 92% or respiratory rate exceeds 25 breaths/min during subsequent treatment, HFNO therapy can be resumed.

Non-invasive ventilation (NIV)

Initial parameters for NIV include an inspiratory positive airway pressure (IPAP) of 8 cmH2O, expiratory positive airway pressure (EPAP) of 5 cmH2O, and FiO2 of 100%. Subsequently, IPAP is adjusted within the range of 5–15 cmH2O to achieve a tidal volume of 6–8 mL/kg and a respiratory rate < 25 breaths/min. FiO2 is adjusted within the range of ≤ 60%, and EPAP within the range of 5–10 cmH2O to maintain SpO2 between 92 and 98%. Once oxygenation and respiratory distress symptoms improved, intermittent use of NIV will be considered, and NIV can be discontinued if applied for less than 4 h daily.

Reasons for reintubation

Reintubation indications include emergent anesthesia intubation for postoperative complications such as significant bleeding or cardiac tamponade requiring urgent reoperation, altered consciousness (Glasgow Coma Scale [GCS] score < 12), cardiac arrest or malignant arrhythmias, severe hemodynamic instability (norepinephrine dose > 0.1 µg/kg/min or equivalent doses of other vasopressor agents), and deteriorating respiratory failure (meeting at least two of the following criteria): unresolved hypoxemia (PaO2 < 60 mmHg or pulse oximetry persistently below 90% despite high-flow nasal oxygen [HFNO] at a flow rate exceeding 30 L/min and 100% oxygen concentration), respiratory acidosis (pH < 7.30, PaCO2 > 50 mmHg), respiratory rate > 30 breaths/min, inability to effectively clear airway secretions.

Standard procedures

Screening and inclusions

Patients are screened for inclusion and exclusion criteria during the preoperative visit by anesthesiologist. Patients who meet all inclusion criteria and do not meet any exclusion criteria will be included in the study after providing written, signed informed consent.

Randomization and allocation

The computer-generated randomized lists were drawn up by an independent biostatistics expert before the beginning of the study, using a permuted block design. Biostatistics will employ the SAS 9.4 statistical software PLAN procedure statement on a computer, specifying a seed, to generate randomized treatment assignments for sample subjects. The allocation will be implemented automatically in the electronic case report form (REDCap 10.6.9—© 2024 Vanderbilt University, USA). Allocation concealment will be ensured, as the anesthesiologist will assign the patient to the study group only upon the patient’s arrival in the operating room, ensuring that withdrawal of informed consent has not occurred, and after all baseline measurements will be completed.

Masking

Trial participants will be blinded to group assignment. Assessments regarding study outcomes will be conducted by an assessor blind to treatment allocation, ensured by concealment of group allocation in the REDCap system to outcome assessor. The assessor will go through a profound assessment training program. Due to the necessity of data collection during intervention, investigators occupied for data collection could not be blinded to allocation, but are strongly inculcated not to disclose the allocation status of the participant at the follow-up assessments. Data analysts can analyze data only after study completion without having access to information about the allocation.

Unblinding to study participants will happen only after the study completion and at participants’ request.

End of follow-up

Patients enrolled will be followed up until postoperative day 28, hospital discharge, or death, whichever comes first.

Study endpoints

Given the high sensitivity and specificity of SpO2/FiO2 in diagnosing acute lung injury without the need for repeated blood sampling [29], we consider it to be a suitable alternative to PaO2/FiO2. The primary endpoint is time-weighted average SpO2/FiO2 ratio during the initial post-extubation hour. We first calculated the SpO2/FiO2 ratio every 15 min during the initial post-extubation hour, and then averaged all SpO2/FiO2 ratios weighted by measurement interval. Adequate waveform and proper oximeter placement will be confirmed during the initial post-extubation hour. Oxygen flow will be adjusted to maintain pulse oximetry between 92 and 97% during the initial post-extubation hour and ensuring stability for at least 5 min before measurement at each time point. The relationship between oxygen flow and estimated inspired oxygen concentration through different oxygen delivery devices is listed in the Additional file 2.

The secondary endpoints include:Respiratory failure by post-extubation day 7 No respiratory failure: SpO2 ≥ 90% after breathing ambient air for 10 min (excluding hypoventilation)

Mild respiratory failure: SpO2 < 90% or PaO2 < 60 mmHg after breathing ambient air for 10 min (excluding hypoventilation) and corrected with 1–3 L/min with a nasal cannula

Moderate respiratory failure: SpO2 < 90% or PaO2 < 60 mmHg despite a 3 L/min oxygen supply with a nasal cannula (excluding hypoventilation) and corrected with an oxygen supply from 4 to 10 L/min with a face mask

Severe respiratory failure: SpO2 < 90% or PaO2 < 60 mmHg despite a 10 L/min oxygen supply with a face mask (excluding hypoventilation) and corrected with an oxygen supply > 10 L/min with a high-flow face mask or with non-invasive ventilation or with high-flow nasal oxygen therapy or with invasive mechanical ventilation

Severity of postoperative pulmonary complications by postoperative day 7, scored on an ordinal scale ranging from 0 to 5, using a modified definition of pulmonary complications [10] Grade 0: No symptoms or signals

Grade 1: One of the following: dry cough, abnormal lung findings and temperature 37.5 °C or higher with normal chest radiograph, or dyspnea without other documented cause

Grade 2: Two of the following: productive cough, bronchospasm, hypoxemia (SpO2 90%) at room air, atelectasis with gross radiological confirmation (concordance of 2 independent experts) plus either temperature higher than 37.5 °C, or abnormal lung findings, hypercarbia (PaCO2 > 50 mmHg) requiring treatment

Grade 3: One of the following: pleural effusion resulting in thoracentesis, pneumonia, pneumothorax, extended noninvasive ventilation or high-flow nasal cannula, or reintubation lasting less than 48 h

Grade 4: Reintubation or invasive mechanical ventilation for 48 h or more

Grade 5: Death before hospital discharge

Invasive mechanical ventilation (IMV) days in ICU by postoperative day 7

Duration of invasive mechanical ventilation by postoperative day 7, initiated from ICU

admission.

Use of high-flow nasal cannula or non-invasive ventilation by postoperative day 7.

Use of new invasive mechanical ventilation by postoperative day 7.

No ventilatory support days by postoperative day 7.

No ventilatory support days are defined as days without invasive mechanical ventilation,

high-flow nasal cannula, and non-invasive ventilation.

In-hospital mortality

Death occurred during hospital stay, time frame from the day of surgery up to hospital

discharge or death, maximum censoring at day 28 after surgery.

ICU length of stay

Days since surgery until ICU discharge. The censoring will be performed at day 28 after

surgery. Patients dying before leaving the ICU were censored as not discharged from ICU at

day 28 after surgery.

Length of hospital stay

Days since surgery until hospital discharge. The censoring was performed at 28 days. Patients

dying before leaving the hospital were censored as not discharged from hospital at day 28.

Adverse events by postoperative day 7: Use of high-dose vasopressors (> 1 µg/kg/min of norepinephrine)

Postoperative barotrauma

Defined as the presence of radiological evidence suggesting pneumothorax, mediastinal emphysema, new-onset pulmonary emphysema, or subcutaneous emphysema. Reoperation before the 12th postoperative hour

Data collection

Study data are managed with a password-protected electronic case report form (REDCap 10.6.9—Copyright 2024 Vanderbilt University, USA). Patient data will be anonymous and coded according to a number. The eCRF includes tools to promote data quality, such as range checks for data values. Data monitoring will be performed by means of queries on the database done by statisticians and analyzed to identify abnormalities and inconsistencies.

All participants will be informed that they will be followed up until postoperative day 28, hospital discharge, or death, whichever occurs first, to ensure the completion of surveys upon consent. Participants choosing to withdraw consent to the study will be encouraged to continue with the follow-up of the trial for the evaluation of efficacy and safety. The reasons and circumstances for discontinuing the study will be recorded.

Baseline data

The following baseline data are collected after the patient’s inclusion: gender, age, height, weight, BMI, smoking status, history of COPD or asthma with chronic inhalation therapy, American Society of Anesthesiologists (ASA) score, Euroscore II, lower respiratory tract infection in the past 3 months, abnormal preoperative chest imaging, cardiovascular status (diabetes mellitus, arterial hypertension, dyslipidemia, liver disease, previous acute myocardial infarction, history of cardiac surgery, left ventricular ejection fraction, echocardiographic right ventricular distention defined by a right ventricle/left ventricle ratio > 1, brain natriuretic peptide level, cardiac troponin I level), and status of preoperative creatininemia > 3 mg/dL.

Intraoperative variables

During the surgery, the anesthesiologist in charge of the patient will record the following variables: type of surgery (coronary artery bypass graft, valve surgery, aortic surgery, mixed surgery, none of the above), site of vascular graft harvesting (great saphenous vein, mammary artery, radial artery), number of vessels for coronary arterial bypass, CPB duration, aortic cross clamp duration, surgical duration, intraoperative fluid volume (crystalloid and colloid), fluid balance during surgery, use of blood transfusions (include red cell, platelets, or plasma), use of inotropic agents and vasopressors, use of rescue therapy. Gas exchange parameters (arterial blood partial pressure of carbon dioxide, arterial blood partial pressure of oxygen, PaO2/FiO2), mechanical ventilation parameters (tidal volume, respiratory rate, positive end-expiratory pressure, inspired oxygen fraction, minute ventilation), and respiratory mechanics (peak airway pressure, plateau pressure, driving pressure, respiratory system compliance) will be recorded within 10 min after endotracheal intubation and within 10 min after the conclusion of the surgery.

For patients allocated to the experimental strategy, further details of the experimental intervention will be documented as follows: the total duration of sigh breaths during the intraoperative period. Hemodynamic variables, including heart rate, systolic arterial pressure, diastolic arterial pressure, and mean arterial pressure, will be assessed during the first and second intraoperative sigh breath. Any interruptions in sigh breaths during the intraoperative period will also be documented.

Postoperative variables

Gas exchange parameters, mechanical ventilation parameters, and respiratory mechanics will be recorded within 10 min, 2 h, and 4 h after ICU admission. Use of rescue therapy will also be recorded during invasive mechanical ventilation in postoperative days. For patients allocated to the experimental strategy, total duration of sigh breaths during the postoperative period, hemodynamic variables, and any interruption of sigh breaths will be documented.

For outcome assessments, SpO2/FiO2 will be assessed during the initial post-extubation hour, measured every 15 min. Then, patients are visited, twice a day, every postoperative day until postoperative day 7, in order to assess the presence of PPCs or other secondary endpoints. Hospital mortality, length of hospital stay, and length of ICU stay will be assessed upon hospital discharge, death, or postoperative day 28, whichever occurred first. The need for supplemental oxygen will be evaluated at each visit by measuring SpO2 and/or PaO2 after 10 min of breathing room air. Lung auscultation and daily symptoms of cough and expectoration will also be assessed at each visit. A daily chest X-ray will be prescribed during ICU stay. In the surgical ward, a chest X-ray will be prescribed at the discretion of the attending physician. A chest CT scan will be conducted between the third and fifth postoperative day.

Sample size and power

The study determined a sample size of 192 patients (96 per group) with a 5% dropout rate and a P value of 0.05 to achieve 90% power in detecting a 10% increase in time-weighted average SpO2/FiO2 during the initial post-extubation hour in the experiment strategy group, compared to the control group. The control group’s mean time-weighted average SpO2/FiO2 was estimated to be 294 with a standard deviation of 60, based on previous research [30], and the 10% difference between groups was determined from previous work showing that a decrease of 10% from baseline in PaO2/FiO2 was clinically meaningful in lung injury induced by ventilatory strategies [31–33]. A dropout rate of 5% was deemed acceptable for informed consent withdrawals post-enrollment.

Statistical analysis

The data will be analyzed using R (version 4.3.3). The primary analysis will be carried out according to the intention-to-treat principle. The full analysis population (including all subjects who will be randomized and will be at least evaluated at baseline) will be used in the primary analysis. No interim analysis is planned. In case of missing data, the reason and mechanism for missing data will be explored. For missing data greater than 20%, multiple imputation may be considered as a sensitivity analysis to evaluate the treatment effect and associated standard error as appropriate.

Categorical variables are reported as number and percentage. Normally distributed variables are reported as mean and SD, non-normally distributed as median and IQR. Normal distribution of data will be assessed with the Kolmogorov–Smirnov test or the Shapiro–Wilk test. To compare continuous variables between experimental strategy and control strategy groups, Student’s t-test or Mann–Whitney U test will be used, as appropriate. Categorical variables will be compared using the Fisher exact test or likelihood ratio tests. The baseline and intraoperative parameters will be described per group (“experimental strategy” and “control strategy”) in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.

The time-weighted average SpO2/FiO2 ratio will be compared as continuous variable. And treatment effects of primary outcome will also be analyzed according to the following subgroups: (1) age; (2) duration of cardiopulmonary bypass; (3) preoperative pathological chest image; (4) red cell transfusion during surgery. For secondary outcomes, the scores of pulmonary complications and severity of respiratory failure will be analyzed through Mann–Whitney U tests and multivariable ordinal logistic regression by estimating the common odds ratio for a shift in the direction of a better outcome on the modified scale. The proportion of other secondary endpoints (use of high-flow nasal cannula or non-invasive ventilation, use of new invasive mechanical ventilation, in-hospital mortality, adverse events) will be compared between the groups. Non-ventilatory support days and invasive mechanical ventilation days by postoperative day 7 will be compared between groups as continuous variables. Multiple comparison corrections will be performed for non-independent outcomes. The duration of ICU and hospital stay was compared using Kaplan–Meier curves and log-rank tests. The censoring was performed at postoperative day 28, and the time to event was the time from surgery end to ICU and hospital discharge. Patients who died before leaving the ICU or hospital were censored as nondischarged at day 28. A 2-sided P value < 0.05 was considered statistically significant.

Oversight and monitoring

No data monitoring committee (DMC) will be established in this trial as our investigator team could closely monitor participants’ safety and data integrity. Trial steering committee comprises two professors of intensive care medicine (JYX and JFX), a professor of cardiac surgery (HLC), a professor of anesthesiology (JS), and two independent statisticians. The trial steering committee convenes quarterly throughout the trial period to review trial conduct. This committee will validate the protocol, oversee the study, and have the authority to make decisions regarding its smooth running and publication strategy. And the Ethics Committee of Zhongda Hospital meets semi-annually or as needed to evaluate trial’s ethical conduct and the ethics committee has the authority to recommend modifications to the trial or its termination if significant concerns arise.

Any unforeseen medical events occurring in participants during the intervention period will be categorized as adverse events (AEs). Serious adverse events (SAEs) are defined as adverse events, including death, life-threatening situations, permanent or severe disability or loss of function, and the need for prolonged hospitalization, that occur following the trial treatment. All AEs will be meticulously recorded in the case report form (CRF), and SAEs will be promptly reported to the principal investigators. Upon identification of an AE, investigators will thoroughly assess the association between the intervention and the AE and determine whether to discontinue the intervention. All serious, unexpected, and study-related adverse events will be reported to the Ethics Committee of Zhongda Hospital within 15 calendar days. Patients who discontinue the intervention due to an AE will continue to be followed up. All patients in this study will be hospitalized in Zhongda Hospital. Accordingly, emergency care will be readily available at all times. The cost of treatment for all study-related adverse events will be covered by the trial initiator. The ancillary and post-trial care will be provided by a medical team, consist of cardiac surgeons, nurses, rehabilitation therapists, and intensivists, after the trial is completed.

Any modifications to the study protocol will necessitate synchronous protocol amendments, which will be promptly submitted for approval to the Ethics Committee/Institutional Review Board. These changes will only be implemented after approval by the ethical committee. Once approved, ClinicalTrials.gov will be promptly updated regarding any significant changes. If required, protocol training for the amendments will be provided by the study team.

Discussion

The E-SIGHT trial is the first single-center, randomized controlled trial designed to evaluate the potential benefits of augmenting lung protective ventilation (LPV) with sigh breaths during the perioperative period in patients scheduled for cardiac surgery. This study aims to ascertain the feasibility and preliminary efficacy of this intervention in comparison to the conventional LPV approach. Should the feasibility be established, the E-SIGHT trial will lay the groundwork for a subsequent, more extensive clinical trial to definitively determine the efficacy of the sigh + LPV strategy in reducing postoperative pulmonary complications (PPCs). Furthermore, this research endeavors to introduce and assess a novel perioperative ventilation approach to mitigate the risk of postoperative hypoxemia and PPCs in patients undergoing cardiac surgery, ultimately enhancing their recovery in the postoperative period.

In the experimental arm, we have chosen a multimodal approach, from intubation to extubation, in order to reflect the prophylactic use nature of sighs, counteract with the risk of atelectasis which persists during the entire mechanical ventilation period. Sigh will not be administered during the opening of chest cavity giving the potential impact on the surgical procedure. The plateau change resulting from increasing PEEP producing a Pplat of 35 or 40 cmH2O was selected for two reasons. First, it produces an end-inspiratory lung volume that approximates total lung capacity in patients with normal chest wall and lung compliances, thereby facilitating secretion of surfactant. Second, a Pplat of 40 cmH2O has been utilized in numerous short-term studies of recruitment maneuvers in patients with ARDS without any evidence that it caused barotrauma or volutrauma [24]. In those patients with BMIs exceeding 35, the volume of the sigh breath will be determined on the basis of a Pplat of 40 cmH2O given the decrease in chest wall compliance that will be present. We did not choose an individualized PEEP titration protocol because of the absence of a validated reference titration protocol and because of the high risk of hemodynamic intolerance and barotrauma [34]. In both groups, PEEP level is selected according to low FiO2-PEEP table adopted from ARDS studies, its pragmatic design limited burden on daily activities and is moderate in comparison with previous studies in cardiac surgery [26]. During CPB, apnea was performed as no firm evidences of benefits of ventilation maintenance during CPB until nowadays [12, 35].

The primary outcome was the time-weighted average SpO2/FiO2 ratio during the initial post-extubation hour. Given the high sensitivity and specificity of SpO2/FiO2 in diagnosing acute lung injury without the need for repeated blood sampling [29], we consider it to be a suitable alternative to PaO2/FiO2. This is a very pragmatic endpoint, and previous performance in postoperative patients has proved good external validity [36]. To complementary for the primary endpoint, we evaluated long-term respiratory failure and postoperative pulmonary complications in the secondary outcomes, and the specific definitions allow for comparisons with previous studies [10, 12]. The need for non-invasive ventilation or high-flow nasal oxygen therapy has also been included in the secondary outcomes and standard procedures of postoperative ventilatory support were provided in the protocol. Finally, we will evaluate the invasive mechanical ventilation days during ICU stay, non-ventilatory support days, and endotracheal reintubation rate in postoperative day 7. Evaluating different outcomes with tight relationship with postoperative pulmonary function recovery will give a relatively comprehensive point of view on the impact of sigh approach.

One important limitation of the E-SIGHT trial is that double-blinding is not possible due to the nature of intervention. However, the outcome assessor will be blinded to the randomization arms, ensured the reliability of the study results. Second, in the absence of conclusive data on sigh “minimum effective dose,” we chose a rate of 5 s per 6 min because this frequency is considered to be close to the physiological state of a normal person [27]. Finally, we did not plan any biomolecular analysis to verify the impact of addition of sigh on lung protection for budget reasons; in any case, we will collect a huge amount of physiological data during the whole study period that will allow reconstruction on mechanistic effects underlying the clinical benefits.

In conclusion, E-SIGHT is a single-center randomized controlled trial to test the feasibility of long-term addition of sigh to lung protective ventilation. Its results could provide a ready-to-use treatment enhancing perioperative lung protection. Moreover, E-SIGHT will be the basis for planning a future larger trial investigating the use of sigh as a strategy to improve hard clinical outcomes in patients undergoing cardiac surgery through enhanced lung protection.

Trial status

The E-SIGHT trial is currently recruiting patients. The protocol was approved by the Institutional Review Board on 22 February 2024. Current protocol version number was version 2, 10th Feb 2024. The first patient was enrolled on 25 February 2024. Recruitment is expected to be completed in October 2024.

Supplementary Information

Additional file 1: SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents.

Additional file 2: eTable 1 Estimation of inspired oxygen fraction through different oxygen devices.

Abbreviations

CPB Cardiopulmonary bypass

LPV Lung protective ventilation

PEEP Positive end-expiratory pressure

ARDS Acute respiratory distress syndrome

PPCs Postoperative pulmonary complications

ECMO Extracorporeal membrane oxygenation

IABP Intra-aortic balloon pump

BMI Body mass index

VTs Tidal volumes

SpO2 Pulse arterial oxygen saturation

FiO2 Fraction of inspiration oxygen

I:E Inspiratory to expiratory ratio

Pplat Plateau pressure

IPAP Inspiratory positive airway pressure

EPAP Expiratory positive airway pressure

VILI Ventilator-induced lung injury

HFNO High-flow nasal oxygen

CPAP Continuous positive airway pressure

NIV Non-invasive ventilation

SBT Spontaneous breathing trial

OSAS Obstructive sleep apnea syndrome

LVEF Left ventricular ejection fraction

RASS Richmond Agitation-Sedation Scale

GCS Glasgow Coma Scale

CONSORT Consolidated Standards of Reporting Trials

SPIRIT Standard Protocol Items: Recommendation for Interventional Trials

Acknowledgements

Not applicable.

Authors’ contributions

FMG is the principal investigator; ZCW, FMG, JYX, HLC, and JS designed the study protocol; ZCW wrote the manuscript; all authors contributed to manuscript revisions. The authors read and approved the final manuscript.

Funding

This research is supported by the National Key R&D Program of China (No. 2022YFC2504500) and Jiangsu Provincial Key Laboratory of Critical Care Medicine (No. BM2020004). The funders played no role in the study design and will play no role in the data collection, analysis, interpretation, and writing the manuscript.

Availability of data and materials

Any data collected in this study can be obtained from the corresponding author with a reasonable request.

Declarations

Ethics approval and consent to participate

The trial has been approved by the Ethics Committee of the Zhongda Hospital (2024ZDSYLL037-P01). Written, informed consent to participate will be obtained from all participants or his/her next of kin.

Consent for publication

Not applicable. No identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. Informed consent materials are available from the corresponding author on request.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Tanner TG Colvin MO Pulmonary complications of cardiac surgery Lung 2020 198 889 896 10.1007/s00408-020-00405-7 33175990
Tanner TG, Colvin MO. Pulmonary complications of cardiac surgery. Lung. 2020;198:889–96.33175990 10.1007/s00408-020-00405-7
2. Mead J Takishima T Leith D Stress distribution in lungs: a model of pulmonary elasticity J Appl Physiol 1970 28 596 608 10.1152/jappl.1970.28.5.596 5442255
Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol. 1970;28:596–608.5442255 10.1152/jappl.1970.28.5.596
3. Slutsky AS Ranieri VM Ventilator-induced lung injury N Engl J Med 2013 369 2126 2136 10.1056/NEJMra1208707 24283226
Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369:2126–36.24283226 10.1056/NEJMra1208707
4. García-Delgado M Navarrete-Sánchez I Colmenero M Preventing and managing perioperative pulmonary complications following cardiac surgery Curr Opin Anaesthesiol 2014 27 146 152 10.1097/ACO.0000000000000059 24514031
García-Delgado M, Navarrete-Sánchez I, Colmenero M. Preventing and managing perioperative pulmonary complications following cardiac surgery. Curr Opin Anaesthesiol. 2014;27:146–52.24514031 10.1097/ACO.0000000000000059
5. O’Gara B Talmor D Perioperative lung protective ventilation BMJ 2018 362 k3030 10.1136/bmj.k3030 30201797
O’Gara B, Talmor D. Perioperative lung protective ventilation. BMJ. 2018;362:k3030.30201797 10.1136/bmj.k3030
6. Laffey JG Boylan JF Cheng DCH The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist Anesthesiology 2002 97 215 252 10.1097/00000542-200207000-00030 12131125
Laffey JG, Boylan JF, Cheng DCH. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology. 2002;97:215–52.12131125 10.1097/00000542-200207000-00030
7. Schlensak C Doenst T Preusser S Wunderlich M Kleinschmidt M Beyersdorf F Bronchial artery perfusion during cardiopulmonary bypass does not prevent ischemia of the lung in piglets: assessment of bronchial artery blood flow with fluorescent microspheres Eur J Cardiothorac Surg 2001 19 326 331 10.1016/S1010-7940(01)00581-4 11251274
Schlensak C, Doenst T, Preusser S, Wunderlich M, Kleinschmidt M, Beyersdorf F. Bronchial artery perfusion during cardiopulmonary bypass does not prevent ischemia of the lung in piglets: assessment of bronchial artery blood flow with fluorescent microspheres. Eur J Cardiothorac Surg. 2001;19:326–31. disciussion 331-332.11251274 10.1016/S1010-7940(01)00581-4
8. Huffmyer JL Groves DS Pulmonary complications of cardiopulmonary bypass Best Pract Res Clin Anaesthesiol 2015 29 163 175 10.1016/j.bpa.2015.04.002 26060028
Huffmyer JL, Groves DS. Pulmonary complications of cardiopulmonary bypass. Best Pract Res Clin Anaesthesiol. 2015;29:163–75.26060028 10.1016/j.bpa.2015.04.002
9. Apostolakis E Filos KS Koletsis E Dougenis D Lung dysfunction following cardiopulmonary bypass J Card Surg 2010 25 47 55 10.1111/j.1540-8191.2009.00823.x 19549041
Apostolakis E, Filos KS, Koletsis E, Dougenis D. Lung dysfunction following cardiopulmonary bypass. J Card Surg. 2010;25:47–55.19549041 10.1111/j.1540-8191.2009.00823.x
10. Costa Leme A Hajjar LA Volpe MS Fukushima JT De Santis Santiago RR Osawa EA Effect of intensive vs moderate alveolar recruitment strategies added to lung-protective ventilation on postoperative pulmonary complications: a randomized clinical trial JAMA 2017 317 1422 1432 10.1001/jama.2017.2297 28322416
Costa Leme A, Hajjar LA, Volpe MS, Fukushima JT, De Santis Santiago RR, Osawa EA, et al. Effect of intensive vs moderate alveolar recruitment strategies added to lung-protective ventilation on postoperative pulmonary complications: a randomized clinical trial. JAMA. 2017;317:1422–32.28322416 10.1001/jama.2017.2297
11. Karalapillai D Weinberg L Peyton P Ellard L Hu R Pearce B Effect of intraoperative low tidal volume vs conventional tidal volume on postoperative pulmonary complications in patients undergoing major surgery: a randomized clinical trial JAMA 2020 324 848 858 10.1001/jama.2020.12866 32870298
Karalapillai D, Weinberg L, Peyton P, Ellard L, Hu R, Pearce B, et al. Effect of intraoperative low tidal volume vs conventional tidal volume on postoperative pulmonary complications in patients undergoing major surgery: a randomized clinical trial. JAMA. 2020;324:848–58.32870298 10.1001/jama.2020.12866
12. Lagier D Fischer F Fornier W Huynh TM Cholley B Guinard B Effect of open-lung vs conventional perioperative ventilation strategies on postoperative pulmonary complications after on-pump cardiac surgery: the PROVECS randomized clinical trial Intensive Care Med 2019 45 1401 1412 10.1007/s00134-019-05741-8 31576435
Lagier D, Fischer F, Fornier W, Huynh TM, Cholley B, Guinard B, et al. Effect of open-lung vs conventional perioperative ventilation strategies on postoperative pulmonary complications after on-pump cardiac surgery: the PROVECS randomized clinical trial. Intensive Care Med. 2019;45:1401–12.31576435 10.1007/s00134-019-05741-8
13. Serpa Neto A Hemmes SNT Barbas CSV Beiderlinden M Biehl M Binnekade JM Protective versus conventional ventilation for surgery: a systematic review and individual patient data meta-analysis Anesthesiology 2015 123 66 78 10.1097/ALN.0000000000000706 25978326
Serpa Neto A, Hemmes SNT, Barbas CSV, Beiderlinden M, Biehl M, Binnekade JM, et al. Protective versus conventional ventilation for surgery: a systematic review and individual patient data meta-analysis. Anesthesiology. 2015;123:66–78.25978326 10.1097/ALN.0000000000000706
14. Bendixen HH Hedley-Whyte J Laver MB Impaired oxygenation in surgical patients during general anesthesia with controlled ventilation. A concept of atelectasis N Engl J Med 1963 269 991 996 10.1056/NEJM196311072691901 14059732
Bendixen HH, Hedley-Whyte J, Laver MB. Impaired oxygenation in surgical patients during general anesthesia with controlled ventilation. A concept of atelectasis. N Engl J Med. 1963;269:991–6.14059732 10.1056/NEJM196311072691901
15. Albert RK Constant Vt ventilation and surfactant dysfunction: an overlooked cause of ventilator-induced lung injury Am J Respir Crit Care Med 2022 205 152 160 10.1164/rccm.202107-1690CP 34699343
Albert RK. Constant Vt ventilation and surfactant dysfunction: an overlooked cause of ventilator-induced lung injury. Am J Respir Crit Care Med. 2022;205:152–60.34699343 10.1164/rccm.202107-1690CP
16. Lewis JF Ikegami M Jobe AH Altered surfactant function and metabolism in rabbits with acute lung injury J Appl Physiol 1985 1990 69 2303 2310
Lewis JF, Ikegami M, Jobe AH. Altered surfactant function and metabolism in rabbits with acute lung injury. J Appl Physiol. 1985;1990(69):2303–10.
17. Wirtz HR Dobbs LG Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells Science 1990 250 1266 1269 10.1126/science.2173861 2173861
Wirtz HR, Dobbs LG. Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science. 1990;250:1266–9.2173861 10.1126/science.2173861
18. Faridy EE Effect of distension on release of surfactant in excised dogs’ lungs Respir Physiol 1976 27 99 114 10.1016/0034-5687(76)90021-9 989608
Faridy EE. Effect of distension on release of surfactant in excised dogs’ lungs. Respir Physiol. 1976;27:99–114.989608 10.1016/0034-5687(76)90021-9
19. Hildebran JN Goerke J Clements JA Surfactant release in excised rat lung is stimulated by air inflation J Appl Physiol Respir Environ Exerc Physiol 1981 51 905 910 6895369
Hildebran JN, Goerke J, Clements JA. Surfactant release in excised rat lung is stimulated by air inflation. J Appl Physiol Respir Environ Exerc Physiol. 1981;51:905–10.6895369
20. Pattle RE Surface lining of lung alveoli Physiol Rev 1965 45 48 79 10.1152/physrev.1965.45.1.48 14257161
Pattle RE. Surface lining of lung alveoli. Physiol Rev. 1965;45:48–79.14257161 10.1152/physrev.1965.45.1.48
21. Mauri T Eronia N Abbruzzese C Marcolin R Coppadoro A Spadaro S Effects of sigh on regional lung strain and ventilation heterogeneity in acute respiratory failure patients undergoing assisted mechanical ventilation Crit Care Med 2015 43 1823 1831 10.1097/CCM.0000000000001083 25985386
Mauri T, Eronia N, Abbruzzese C, Marcolin R, Coppadoro A, Spadaro S, et al. Effects of sigh on regional lung strain and ventilation heterogeneity in acute respiratory failure patients undergoing assisted mechanical ventilation. Crit Care Med. 2015;43:1823–31.25985386 10.1097/CCM.0000000000001083
22. Foti G Cereda M Sparacino ME De Marchi L Villa F Pesenti A Effects of periodic lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically ventilated acute respiratory distress syndrome (ARDS) patients Intensive Care Med 2000 26 501 507 10.1007/s001340051196 10923722
Foti G, Cereda M, Sparacino ME, De Marchi L, Villa F, Pesenti A. Effects of periodic lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically ventilated acute respiratory distress syndrome (ARDS) patients. Intensive Care Med. 2000;26:501–7.10923722 10.1007/s001340051196
23. Nacoti M Spagnolli E Bonanomi E Barbanti C Cereda M Fumagalli R Sigh improves gas exchange and respiratory mechanics in children undergoing pressure support after major surgery Minerva Anestesiol 2012 78 920 929 22531559
Nacoti M, Spagnolli E, Bonanomi E, Barbanti C, Cereda M, Fumagalli R. Sigh improves gas exchange and respiratory mechanics in children undergoing pressure support after major surgery. Minerva Anestesiol. 2012;78:920–9.22531559
24. Albert RK Jurkovich GJ Connett J Helgeson ES Keniston A Voelker H Sigh ventilation in patients with trauma: the SiVent randomized clinical trial JAMA 2023 330 1982 1990 10.1001/jama.2023.21739 37877609
Albert RK, Jurkovich GJ, Connett J, Helgeson ES, Keniston A, Voelker H, et al. Sigh ventilation in patients with trauma: the SiVent randomized clinical trial. JAMA. 2023;330:1982–90.37877609 10.1001/jama.2023.21739
25. Mauri T Foti G Fornari C Grasselli G Pinciroli R Lovisari F Sigh in patients with acute hypoxemic respiratory failure and ARDS: the PROTECTION pilot randomized clinical trial Chest 2021 159 1426 1436 10.1016/j.chest.2020.10.079 33197403
Mauri T, Foti G, Fornari C, Grasselli G, Pinciroli R, Lovisari F, et al. Sigh in patients with acute hypoxemic respiratory failure and ARDS: the PROTECTION pilot randomized clinical trial. Chest. 2021;159:1426–36.33197403 10.1016/j.chest.2020.10.079
26. Acute Respiratory Distress Syndrome NetworkBrower RG Matthay MA Morris A Schoenfeld D Thompson BT Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome N Engl J Med 2000 342 1301 1308 10.1056/NEJM200005043421801 10793162
Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–8.10793162 10.1056/NEJM200005043421801
27. Bendixen HH Smith GM Mead J Pattern of ventilation in young adults J Appl Physiol 1964 19 195 198 10.1152/jappl.1964.19.2.195 14155280
Bendixen HH, Smith GM, Mead J. Pattern of ventilation in young adults. J Appl Physiol. 1964;19:195–8.14155280 10.1152/jappl.1964.19.2.195
28. Stéphan F Barrucand B Petit P Rézaiguia-Delclaux S Médard A Delannoy B High-flow nasal oxygen vs noninvasive positive airway pressure in hypoxemic patients after cardiothoracic surgery: a randomized clinical trial JAMA 2015 313 2331 2339 10.1001/jama.2015.5213 25980660
Stéphan F, Barrucand B, Petit P, Rézaiguia-Delclaux S, Médard A, Delannoy B, et al. High-flow nasal oxygen vs noninvasive positive airway pressure in hypoxemic patients after cardiothoracic surgery: a randomized clinical trial. JAMA. 2015;313:2331–9.25980660 10.1001/jama.2015.5213
29. Matthay MA Arabi Y Arroliga AC Bernard G Bersten AD Brochard LJ A new global definition of acute respiratory distress syndrome Am J Respir Crit Care Med. 2024 209 37 47 10.1164/rccm.202303-0558WS 37487152
Matthay MA, Arabi Y, Arroliga AC, Bernard G, Bersten AD, Brochard LJ, et al. A new global definition of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2024;209:37–47.37487152 10.1164/rccm.202303-0558WS
30. Parke R McGuinness S Dixon R Jull A Open-label, phase II study of routine high-flow nasal oxygen therapy in cardiac surgical patients Br J Anaesth 2013 111 925 931 10.1093/bja/aet262 23921199
Parke R, McGuinness S, Dixon R, Jull A. Open-label, phase II study of routine high-flow nasal oxygen therapy in cardiac surgical patients. Br J Anaesth. 2013;111:925–31.23921199 10.1093/bja/aet262
31. Villar J Blanco J del Campo R Andaluz-Ojeda D Díaz-Domínguez FJ Muriel A Assessment of PaO₂/FiO₂ for stratification of patients with moderate and severe acute respiratory distress syndrome BMJ Open 2015 5 e006812 10.1136/bmjopen-2014-006812 25818272
Villar J, Blanco J, del Campo R, Andaluz-Ojeda D, Díaz-Domínguez FJ, Muriel A, et al. Assessment of PaO₂/FiO₂ for stratification of patients with moderate and severe acute respiratory distress syndrome. BMJ Open. 2015;5:e006812.25818272 10.1136/bmjopen-2014-006812
32. Douville NJ Jewell ES Duggal N Blank R Kheterpal S Engoren MC Association of intraoperative ventilator management with postoperative oxygenation, pulmonary complications, and mortality Anesth Analg 2020 130 165 175 10.1213/ANE.0000000000004191 31107262
Douville NJ, Jewell ES, Duggal N, Blank R, Kheterpal S, Engoren MC, et al. Association of intraoperative ventilator management with postoperative oxygenation, pulmonary complications, and mortality. Anesth Analg. 2020;130:165–75.31107262 10.1213/ANE.0000000000004191
33. Hovaguimian F Lysakowski C Elia N Tramèr MR Effect of intraoperative high inspired oxygen fraction on surgical site infection, postoperative nausea and vomiting, and pulmonary function: systematic review and meta-analysis of randomized controlled trials Anesthesiology 2013 119 303 316 10.1097/ALN.0b013e31829aaff4 23719611
Hovaguimian F, Lysakowski C, Elia N, Tramèr MR. Effect of intraoperative high inspired oxygen fraction on surgical site infection, postoperative nausea and vomiting, and pulmonary function: systematic review and meta-analysis of randomized controlled trials. Anesthesiology. 2013;119:303–16.23719611 10.1097/ALN.0b013e31829aaff4
34. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) InvestigatorsCavalcanti AB Suzumura ÉA Laranjeira LN Paisani DdM Damiani LP Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial JAMA 2017 318 1335 1345 10.1001/jama.2017.14171 28973363
Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura ÉA, Laranjeira LN, Paisani DdM, Damiani LP, et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2017;318:1335–45.28973363 10.1001/jama.2017.14171
35. Zhang M-Q Liao Y-Q Yu H Li X-F Shi W Jing W-W Effect of ventilation strategy during cardiopulmonary bypass on postoperative pulmonary complications after cardiac surgery: a randomized clinical trial J Cardiothorac Surg 2021 16 319 10.1186/s13019-021-01699-1 34717700
Zhang M-Q, Liao Y-Q, Yu H, Li X-F, Shi W, Jing W-W, et al. Effect of ventilation strategy during cardiopulmonary bypass on postoperative pulmonary complications after cardiac surgery: a randomized clinical trial. J Cardiothorac Surg. 2021;16:319.34717700 10.1186/s13019-021-01699-1
36. Turan A Esa WAS Rivas E Wang J Bakal O Stamper S Tidal volume and positive end-expiratory pressure and postoperative hypoxemia during general anesthesia: a single-center multiple crossover factorial cluster trial Anesthesiology 2022 137 406 417 10.1097/ALN.0000000000004342 35939350
Turan A, Esa WAS, Rivas E, Wang J, Bakal O, Stamper S, et al. Tidal volume and positive end-expiratory pressure and postoperative hypoxemia during general anesthesia: a single-center multiple crossover factorial cluster trial. Anesthesiology. 2022;137:406–17.35939350 10.1097/ALN.0000000000004342
