Effects of FiO2 adjustment on hyperoxia biomarkers and postoperative complications using oxygen reserve index during one-lung ventilation

Abstract

Background

One-lung ventilation (OLV) is commonly used in thoracic surgery but increases the risk of intraoperative hypoxemia. To prevent hypoxia, high fractions of inspired oxygen (FiO₂) are frequently administered; however, excessive oxygen exposure may lead to hyperoxia and oxidative tissue injury. The Oxygen Reserve Index (ORi) is a non-invasive monitoring parameter that provides real-time information on moderate hyperoxia. This study aimed to evaluate whether ORi-guided oxygen titration reduces intraoperative FiO₂ exposure and influences oxidative stress biomarkers and postoperative outcomes in patients undergoing OLV.

Methods

In this prospective, randomized controlled trial, 60 patients undergoing elective thoracic surgery requiring OLV were allocated to either an ORi-guided group or a conventional oxygen management group. In the ORi group, FiO₂ was adjusted according to predefined ORi thresholds, whereas in the control group oxygen management was guided solely by pulse oximetry. The primary outcome was the mean intraoperative FiO₂ administered during OLV and throughout the entire surgery. Secondary outcomes included serum and tracheal aspirate levels of interleukin-6 (IL-6), superoxide dismutase (SOD), and malondialdehyde (MDA), postoperative pulmonary complications, and surgical site infections.

Results

Mean intraoperative FiO₂ was significantly lower in the ORi group compared with the control group during OLV and across total surgery duration (p < 0.001). Oxygen saturation and ventilatory parameters were comparable between groups. Biomarker levels showed significant time-dependent changes; however, no significant differences were observed between groups, and no significant group × time interaction was detected. The incidence of postoperative pulmonary complications and surgical site infections did not differ between groups.

Conclusions

ORi-guided oxygen titration during OLV enables safe reduction of intraoperative FiO₂ while maintaining adequate oxygenation. Although this strategy did not translate into measurable differences in oxidative stress biomarkers or postoperative complications, these findings provide important clinical evidence regarding the physiological impact of moderate hyperoxia in thoracic surgery.

Trial registration

ClinicalTrials.gov identifier NCT07359833. First submission date: 17.01.2026 Retrospectively registered on 21.1.2026.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12871-026-04020-6.

Introduction

Thoracic surgical procedures such as thoracotomy and lung resection are commonly employed in the treatment of pulmonary pathologies. In these surgeries, optimal visualization of the operative field is essential to facilitate surgical access and reduce operative difficulty. One-lung ventilation (OLV), achieved via the temporary cessation of ventilation to the operative lung using a double-lumen endotracheal tube (DLT), is a well-established technique for this purpose.

However, OLV and the associated surgical manipulation may compromise oxygenation and contribute to the development of hypoxemia during the intraoperative period. Several strategies are available to mitigate this risk, including increasing the fraction of inspired oxygen (FiO₂) and the application or adjustment of positive end-expiratory pressure (PEEP) [1]. While increasing FiO₂ is an effective method to prevent hypoxia, excessive oxygen administration may lead to hyperoxia, which is associated with the generation of reactive oxygen species (ROS), oxidative stress, and potential damage to pulmonary and systemic tissues. The adverse effects of hyperoxia—such as absorption atelectasis, systemic vasoconstriction, and ROS-mediated tissue injury—have been widely discussed in the literature [2–5].

The clinical decision to administer supplemental oxygen is typically guided by both patient symptoms and objective monitoring tools. Pulse oximetry is the most used non-invasive method for assessing oxygenation, effectively detecting hypoxemia by measuring haemoglobin saturation. However, it fails to reflect oxygen levels beyond full haemoglobin saturation (SpO₂ ≥ 100%). Arterial blood gas (ABG) analysis, in contrast, provides a more accurate assessment of hyperoxia by measuring the partial pressure of dissolved oxygen (PaO₂). However, it is intermittent, invasive, and cost-intensive [6].

The Oxygen Reserve Index (ORi^®; Masimo Corp., Irvine, CA, USA) is a relatively new, non-invasive, and continuous monitoring parameter that reflects moderate hyperoxia by providing a unitless value between 0.00 and 1.00, corresponding to a PaO₂ range of 100–200 mmHg [7]. When used alongside SpO₂, ORi enables real-time estimation of oxygen reserves, allowing for earlier detection of impending hypoxemia and avoidance of hyperoxia [8–10].

In studies involving patients undergoing OLV with ORi monitoring, the primary focus has predominantly been on the assessment of oxygenation and the evaluation of postoperative pulmonary complications [11–14]. However, no studies have been identified that compare hyperoxia-related biomarker levels within this specific patient population. In our study, intraoperative hyperoxia levels were monitored in real time using ORi, and biomarker levels as well as complication rates were compared between the ORi-monitored group and the non-monitored group.

The primary aim of this study is to determine whether ORi-guided oxygen administration during OLV in thoracic surgery allows for effective oxygenation with lower FiO₂ levels compared to conventional monitoring. The primary outcome was the mean intraoperative FiO₂ administered during one-lung ventilation and throughout the entire duration of surgery. FiO₂ was recorded continuously during the intraoperative period and compared between the ORi-guided and conventional oxygen management groups.

Secondary objectives include

Oxidative stress biomarkers

Changes in serum and tracheal aspirate levels of interleukin-6 (IL-6), superoxide dismutase (SOD), and malondialdehyde (MDA), assessed at four predefined time points: anesthesia induction, extubation (tracheal aspirate), postoperative 12 h, and postoperative 24 h. Results were compared between the ORi and Non-ORi groups.

Postoperative pulmonary complications

Incidence of postoperative pulmonary complications, including prolonged drainage, haemothorax, bronchopleural fistula, reintubation, atelectasis, bronchopneumonia, and acute respiratory distress syndrome, assessed during the postoperative hospital stay.

Surgical site infections

Incidence of surgical site infections recorded during the postoperative hospital stay. comparing blood and tracheal aspirate levels of oxidative stress markers as well as evaluating the incidence of postoperative pulmonary complications and surgical site infections (SSI) between groups with and without ORi monitoring.

Materials and methods

Patient selection and exclusion criteria

This prospective, randomized clinical study was conducted following the approval of the Başkent University Clinical Research Ethics Committee (IRB number: KA22-169, dated June 10, 2022) and in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to inclusion in the study. This study was conducted and reported in accordance with the CONSORT guidelines. Elective thoracic surgery patients were prospectively enrolled in a planned randomized controlled study starting in August 2022. The target sample size of 60 patients, which was determined by a power analysis, was reached in July 2023. Patients whose FiO₂ was adjusted based on intraoperative ORi monitoring were assigned to the ORi group (study group), while those who did not receive this intervention were assigned to the Non-ORi group (control group).

Inclusion criteria were patients older than 18 years of age who were scheduled for elective thoracic surgery requiring one-lung ventilation with a double-lumen endotracheal tube. Exclusion criteria for our study included heart failure (ejection fraction (EF) < 45%), severe valvular disease, admission as an emergency case, a history of prior lung resection, and the presence of peripheral arterial disease.

During the enrolment period from August 5, 2022, to July 15, 2023, a total of 119 elective cases from the Department of Thoracic Surgery were screened. The surgeries were performed at Başkent University Ankara Hospital. Of these, 41 patients were excluded because they were intubated using single-lumen endotracheal tube. Of the remaining 78 patients, 15 were removed from the study due to an EF below 45%. Additionally, three patients were excluded as they could not be intubated with a DLT to difficult intubation (Fig. 1).

Fig. 1.

Consort flow diagram

Randomization and blinding

Participants were randomly assigned in a 1:1 ratio to either the ORi group or the control group using a computer-generated randomization sequence. Patients were allocated into ORi-monitored and non-ORi groups using a double block randomization method. In accordance with the study design, patients were randomized into ORi-monitored and non-ORi groups using a block randomization method generated by Random Allocation Software (RAS, version 1.0.0; M. Saghaei, Isfahan, Iran). Randomization was performed according to the predefined allocation sequence based on the order of patient enrolment; accordingly, patients were assigned to either the study or control group in the order in which they were included in the study. Therefore, a sealed-envelope method was not used. All patients were followed and managed by the attending anesthesiologist responsible for conducting the study. Due to the nature of the intervention, the anaesthesiologist managing intraoperative oxygen titration could not be blinded. However, laboratory personnel analysing biomarker levels and investigators assessing postoperative outcomes were blinded to group allocation.

Preoperative assessment

In the preoperative period, patients’ file numbers, age, gender, height, weight, and body mass index were recorded on the patient follow-up form. Preoperative laboratory values, including haemoglobin, leukocyte, neutrophil, platelet, ALT, AST, LDH, CRP, BUN, creatinine, sodium, and potassium, were also recorded.

Additionally, preoperative SpO₂, FEV1, FEV1/FVC, and if measured, pulmonary artery pressure and EF, were documented. The presence of comorbidities such as COPD, use of an oxygen concentrator and O₂ support in l/min, use of a non-invasive ventilator, smoking history (pack-years and duration since last smoked in days), and other comorbidities were also recorded on the patient follow-up form.

Anesthesia and monitoring

All patients were kept on an 8-hour preoperative fasting regimen. Upon arrival in the operating room, they received standard monitoring, including 5-lead ECG, pulse oximetry, and non-invasive blood pressure measurement. After venous cannulation, a blood sample was drawn to measure baseline levels of MDA, SOD, and IL-6 before oxygen exposure, as these levels were expected to change due to hyperoxia.

For intraoperative and postoperative analgesia, an Erector Spinae Plane Block was performed at the T5-T6 vertebral level under ultrasound guidance using 40 mL of 0.25% bupivacaine. Patients were sedated with 2 mg of intravenous midazolam and 50 mcg of intravenous fentanyl before the block.

Following the block procedure, patients were placed in a supine position and pre-oxygenated with a face mask using a fresh gas flow (FGF) of 5 l/min with 0.8 FiO₂. Anesthesia induction was performed with 2–3 mg/kg of propofol, 1–2 mg/kg of lidocaine, and 0.6–1.2 mg/kg of rocuronium intravenously. A left-selective DLT was inserted with the aid of a fibreoptic bronchoscope 90 s after rocuronium administration. Anesthesia was maintained with 1 MAC of sevoflurane and 0-0.25 mcg/kg/min of remifentanil. Following induction, a 20G catheter was inserted for radial artery cannulation to monitor invasive blood pressure. If deemed necessary by the attending anaesthesiologist, a central venous catheter was inserted via the internal jugular or subclavian vein on the operative side. After the patient was placed in the lateral decubitus position, the position of the DLT was re-confirmed with a fiberoptic bronchoscope.

Mechanical ventilation strategy

Patients were ventilated using protective mechanical ventilation strategies. For two-lung ventilation (TLV), the tidal volume was set at 6–8 ml/kg, with a PEEP of 5 cmH₂O, and the respiratory rate was adjusted to maintain an ETCO₂ of 30–40 mmHg. During OLV, the tidal volume was reduced to 4–5 ml/kg, PEEP was kept at 5 cmH₂O, and the respiratory rate was adjusted to maintain an ETCO₂ level of 35–45 mmHg. The average values of peak inspiratory pressure, plateau pressure, and positive end-expiratory pressure were recorded every 5 min for both OLV and TLV.

Oxygenation protocol

The ORi group was managed with the following oxygenation protocol based on ORi monitoring:

• * If the ORi value remained above 0.24 for 5 min, FiO2 was decreased by 0.05.

• * If the ORi value was between 0 and 0.24, the FiO₂ was not changed.

• * If the ORi value was 0 and SpO₂ remained between 90 and 100%, the FiO₂ was not changed.

• * If the ORi value was 0 and SpO2 dropped below 90%, FiO2 was increased by 0.05. If a response was not achieved, a recruitment manoeuvre (30 cmH2O pressure for 15 s) and an increase in PEEP were performed in coordination with the surgical team. PEEP changes were recorded at 5-minute intervals.

The control group followed a different oxygenation protocol:

• * FiO₂ was maintained at 0.5 during TLV and at 0.6 during OLV unless hypoxemia (SpO₂ < 90%) was observed.

• * In the presence of hypoxemia, FiO₂ was increased until the SpO₂ value was greater than 90%. If a response was not achieved, a recruitment manoeuvre and an increase in PEEP were performed in coordination with the surgical team. PEEP changes were also recorded at 5-minute intervals.

In both groups, the average intraoperative FiO₂ was calculated. ABG analysis was performed if deemed necessary by the attending anaesthesiologist, and the measured PaO₂, PaCO₂, pH, and SaO₂ values were recorded.

Extubation and sample collection

Before extubation, a sterile aspiration catheter was used to perform tracheal aspiration after a lavage with 40 mL of sterile saline through the lumen of the DLT leading to the non-collapsed lung. The tracheal aspirate was then analysed for cell count, IL-6, MDA, and SOD levels. Patients were extubated after spontaneous breathing and neuromuscular blockade reversal were achieved, and a level of consciousness sufficient to maintain a patent airway was observed.

Postoperative period

Both patient groups were transferred to the intensive care unit (ICU) for postoperative follow-up. During their stay in the ICU, the oxygen support provided to the patients was recorded. Patients were monitored throughout the hospital stay for the development of postoperative pulmonary complications (e.g., atelectasis, pneumonia, prolonged air leak) and SSI, which were recorded using standardized clinical criteria (Table 1) [15]. Patients were also followed up by the Department of Thoracic Surgery on the ward until their hospital discharge.

Table 1.

Postoperative complication

Complication	Definition
Prolonged drainage	Drainage lasting over 7 days
Haemothorax	Requiring transfusion, over 800 ml or necessitating reoperation for haemostasis
Bronchopleural fistula	Requiring glue application via bronchoscopy or reoperation (direct repair, thoracocentesis, lavage).
Reintubation	Due to respiratory failure
Atelectasis	Lobar collapse observed on chest radiograph, requiring CPAP and/or bronchoscopy
Bronchopneumonia	Fever ≥ 38 °C, leucocytosis (neutrophil predominance), new infiltration on chest radiograph, and positive culture (BALF, sputum)
Acute Respiratory Distress Syndrome	Acute onset of respiratory failure, diffuse pulmonary infiltrates and alveolar oedema, with a PaO2/FiO2 ratio < 200, in the absence of fluid overload and cardiac failure.

Blood samples for biomarker analysis (IL-6, SOD, and MDA) were collected at three time points: before induction of anesthesia, at 12 h postoperative, and at 24 h postoperative. Tracheal aspirate samples were obtained at the end of surgery prior to extubation. All blood and tracheal aspirates samples were analysed with ELISA method.

Statistical analysis

The sample size of the study was calculated to detect a statistically significant 15% difference in FiO₂ measurements, which was the primary outcome variable, between the groups with and without the use of ORi. In this context, the mean FiO₂ value (74.6 ± 16.6) of the normal flow ORi non-user group reported by Saraçoğlu et al. was taken as a reference value from the literature [10]. Based on this reported mean FiO₂ value and assuming a 15% difference (63.4 ± 14.2), the required sample size to detect a statistically significant difference was calculated using the G*Power 3.1.9.6 software. With an alpha level of 0.05 and a minimum power of 80%, a minimum of 60 participants (n₁ = 30, n₂ = 30) was determined using a two-tailed Student’s t-test.

For the comparison of quantitative variables, the “Student’s t-test” and “One-Way ANOVA” were used when parametric test assumptions were met. When these assumptions were not met, the “Mann-Whitney U test” and “Kruskal-Wallis test” were applied. For time-dependent intergroup comparisons, the “Paired t-test” and “Repeated Measures ANOVA” were used if parametric assumptions were satisfied, whereas the “Wilcoxon Signed-Rank Test” and “Friedman Test” were used otherwise. Correlations between variables were examined using the “Pearson correlation test” and the “Spearman correlation test.”

Results

Patient demographics and preoperative characteristics

Both the ORi group and the Non-ORi group consisted of an equal number of patients, with 30 patients in each group. When comparing the demographic characteristics of the two groups, they were similar in terms of age, gender, and body mass index. Preoperative respiratory function test results, including FEV1 and FEV1/FVC values, along with preoperative SpO₂ values and pulmonary artery pressures measured by echocardiography, were also comparable between the groups. However, statistical analysis revealed a significant difference in left ventricular EF between the two groups. Furthermore, the results of preoperative blood samples showed no statistically significant differences between the control and study groups (Table 2).

Table 2.

Patient demographics and preoperative characteristics

	ORi*	Non-ORi†	p value§
Age(year)	58.9 ± 13.3‡	61.1 ± 14.6	0.555
Sex(M/F)	15/15	16/14	0.796
Height(cm)	166.7 ± 9.3	166.4 ± 10.1	0.915
Weight(kg)	75.2 ± 17.3	73.4 ± 13.2	0.658
BMI (kg/cm2)	27.0 ± 5.3	26.7 ± 5.4	0.821
FEV1/FVC	92.5(86–101)	96.5(88–103)	0.271
FEV1 (l)	2.4(2.1–3.1)	2.5(2–3)	0.749
PAP (mmHg)	20(20–20)	20(20–20)	1.000
EF (%)	59.5(58–60)	58.5(56–60)	0.042
Preoperative SpO2 (%)	97(96–98)	96(95.8–98)	0.116
Hb (g/dl)	13.8(12.9–14.7)	14.2(12.8–15.1)	0.267
Creatinine (mg/dl)	0.9(0.8-1)	0.8(0.7-1)	0.243
BUN (mg/dl)	14.5(11–18)	15.5(12–19)	0.199
Leukocyte (103/µl)	6.6(5.8–7.3)	7.3(5.1–9.4)	0.169
Neutrophil (103/µl)	3.9(3.2–4.7)	4(3-5.7)	0.610
Platelet(103/µl)	239(191–290)	254.5(237–307)	0.176
LDH (U/l)	184(168-199.5)	174(153.25-201.25)	0.304
CRP (U/ml)	2(2–5)	3(2–6)	0.375
Na (mEq/l)	140(138–142)	140(139–142)	0.846
K (mEq/l)	4.2(4-4.4)	4.2(4.1–4.7)	0.567
ALT (U/l)	16(12–21)	17(12–22)	0.906
AST (U/l)	17(13–23)	16.5(14–20)	0.614

*ORi group: patients managed with Oxygen Reserve Index–guided FiO₂ titration during one-lung ventilation

†Non-ORi group: patients managed with conventional FiO₂ management without ORi monitoring, control group ‡Values are presented as mean ± SD or median (Q1, Q3)

The number of patients and the percentage are shown as n(%)

§Between-group comparisons were performed using Student’s t-test or Mann–Whitney U test, as appropriate

Within-group comparisons across time points were analysed using repeated-measures ANOVA or Friedman test with Bonferroni correction for multiple comparisons. Categorical variables were analysed using the Chi-square test or Fisher’s exact test. A p-value < 0.05 was considered statistically significant

When comparing ASA scores, the groups exhibited similar characteristics. While there were no ASA I patients in the ORi group, one patient in the Non-ORi group was classified as ASA I. The number of patients with ASA II and ASA III scores was comparable between the groups (Table 3).

Table 3.

ASA scores

ASA scores	ORi	Non-ORi	p value
I	0	1	0.718
II	12	12
III	18	17

No statistically significant difference was observed when comparing the pre-induction SpO2 values of the two patient groups (p = 0.148). In the ORi group, the median and interquartile range (IQR) for SpO2 were 96% and 96–97%, respectively, while in the Non-ORi group, these values were found to be 96% and 95–97%.

Patient comorbidities and smoking status

The most frequent comorbidity among the patients included in the study is hypertension, affecting 27 patients in total. Of these, 15 are in the ORi group and 12 are in the Non-ORi group. Additionally, 11 patients have a diagnosis of non-pulmonary malignancy, with 5 in the ORi group and 6 in the Non-ORi group. A comprehensive list of patient comorbidities is provided (Table 4).

Table 4.

Patient comorbidities

Comorbidities	ORi	Non-ORi	p value
DM	3(10)	2(6.7)	1.000
Previous PTE	3(10)	0(0)	0.237
Hypothyroidism	1(3.3)	3(1)	0.612
Hyperlipidaemia	3(10)	1(3.33)	0.612
Hypertension	15(50)	12(40)	0.406
CAD	4(13.3)	2(6.7)	0.671
CHF	1(3.3)	1(3.33)	1.000
COPD	2(6.7)	4(13)	0.671
Pulmonary Hypertension	1(3.3)	3(10)	0.612
Non-pulmoner Malignancy	5(16.7)	6(20)	0.741

There was no statistically significant difference between the groups regarding smoking status in terms of pack-years (p = 0.132). Fifteen patients in the ORi group and 10 patients in the Non-ORi group had never smoked. The median and interquartile range (IQR) for smoking in pack-years were 1 and 0–25 in the ORi group, and 20 and 0–30 in the Non-ORi group. The number of days since last smoking before surgery was also similar between the two groups (p = 0.515). In the Ori group, the median and IQR for smoke-free days were 720 and 5-5400, respectively, whereas in the Non-ORi group, these values were 3600 and 150–6480.

Surgical procedures

The most frequently performed surgical procedure among patients in the study was lobectomy, which was carried out on 15 patients in both the ORi group and the Non-ORi group. While pleurodesis and biopsy procedures were exclusively performed in the ORi group, sympathectomy and thorax wall resection surgeries were only conducted in the Non-ORi group. A detailed breakdown of all surgical procedures performed is presented (Table 5).

Table 5.

Surgical procedures

Surgical Procedures	ORi	Non-ORi	p values
Wedge Resection	3(10)	1(3.3)	0,835
Segmentectomy	3(10)	3(10)
Lobectomy	15(50)	15(50)
Pneumonectomy	4(13.3)	3(10)
Pleurodesis	1(3,3)	0(0)
Extrapulmonary mass excision	2(6.7)	5(17)
Biopsy	1(3.3)	0(0)
BI lobectomy	1(3.3)	1(3.3)
Sympathectomy	0(0)	1(3.3)
Thoracic wall reconstruction	0(0)	1(3.3)

Intraoperative features

Comparing the OLV duration, there are no significant differences between ORi and Non-ORi group. We compared the mechanical ventilator pressure parameters during the intraoperative period for both patient groups. Pressure values were assessed separately for the entire surgery duration, OLV, and during TLV. The ventilator parameters analysed included peak inspiratory pressure (PIP), plateau pressure (Pplateau), driving pressure (Pdrive), and positive end-expiratory pressure (PEEP). These parameters were found to be similar between the groups overall (Table 6).

Table 6.

Intraoperative durations, mechanical vent parameters, SpO₂ levels

Duration Total Surgery (min)	ORi	Non-ORi	p values
	195(155–245)	177.5(150–240)	0.745
Duration OLV (min)	82.5(50–115)	70(50–95)	0.657
PIP Total Surgery (cmH2O)	20.3(18-21.5)	19.2(16.1–22)	0.549
PIP OLV (cmH2O)	22.1(20.3–24.9)	21.4(18.2–26.1)	0.460
PIP TLV (cmH2O)	17.5(16.2–19.9)	18.1(15.5–19.7)	0.947
Pplateu Total Surgery (cmH2O)	16.8(15.3–18.3)	15.9(13.3–18.2)	0.324
Pplateu OLV (cmH2O)	19.1(16.4–20.8)	17.3(13.8–21.5)	0.294
Pplateu TLV (cmH2O)	15.1(13.7–16.6)	14.9(12.6–17.1)	0.756
PEEP Total Surgery (cmH2O)	5(4.8–5.3)	5(4.9-5)	0.522
PEEP OLV (cmH2O)	5(4.9–5.89)	5(4.8-5)	0.350
PEEP TLV (cmH2O)	5(5–5)	5(5–5)	0.778
Pdrive Total Surgery (cmH2O)	14.8(13.2–16.4)	14.3(11.3–16.9)	0.642
Pdrive OLV (cmH2O)	14(11.4–15.5)	12.3(9.1–16.5)	0.433
Pdrive TLV (cmH2O)	9.9(8.4–11.7)	9.5(7.6–11.2)	0.626
SpO2 OLV (%)	94.9(93.9–96.3)	95.9(93.7–97.4)	0.442
SpO2 TLV (%)	98.4(97.9–98.6)	98.9(97.7–99.2)	0.246
SpO2 Total Surgery (%)	96.8(96.2–97.6)	97.5(96.5–98.4)	0.132

OLV one-lung ventilation, TLV Two lung ventilation, PIP Peak Inspiratory pressure, PEEP Positive end expiratory pressure, Pdrive Driving pressure

However, when intraoperative pressure trends were displayed graphically, a significant difference in PIP values was observed between the two groups. Specifically, between 50 and 65 min after anesthesia induction, patients in the ORi group exhibited significantly lower PIP values compared to the Non-ORi group (Fig. 2). No significant differences were found between the groups for other pressure parameters during sub-time evaluations. Intraoperative SpO₂ values were separately evaluated for both patient groups throughout the entire surgery duration, during OLV and during TLV (Table 6). Graphical analysis also revealed no statistically significant differences between the two groups for any of these SpO₂ measurements.

Fig. 2.

Intraoperative PIP trending

During the intraoperative period, both patient groups exhibited similar characteristics regarding the FGF administered. Across the total surgery duration, OLV and TLV phases, an average FGF of 2 l/min was utilized in both groups.

In light of these findings, no intraoperative hypoxemia was observed in either patient group, or their SpO₂ trends were similar. Both groups were exposed to comparable pressures from mechanical ventilation and received similar amounts of FGF. However, when comparing the FiO₂ administered to patients, the ORi group was found to be ventilated with statistically significantly lower oxygen concentrations compared to the Non-ORi group (Table 7; Figs. 3 and 4).

Table 7.

Intraoperative FiO₂ levels

FiO2 levels	ORi	Non-ORi	p value
FiO2 OLV	0.5(0.4–0.6)	0.6(0.6–0.6)	< 0.001
FiO2 TLV	0.4(0.4–0.5)	0.5(0.5–0.6)	< 0.001
FiO2 Total Surgery	0.4(0.4–0.4)	0.5(0.5–0.5)	< 0.001

FiO₂: fraction of inspired oxygen

Fig. 3.

Distributions of FiO2 ratios between ORi and Non-ORi groups

Fig. 4.

Intraoperative first 120 min FiO₂ trending

Intraoperative monitoring of ORi values in the ORi group demonstrated adherence to the predefined follow-up rules established in the research methodology (Fig. 5).

Fig. 5.

Intraoperative ORi trending

Postoperative outcomes

Analysis of IL-6, SOD, and MDA levels in both blood and tracheal aspirate samples revealed similar findings between the two groups. In the model constructed to evaluate biomarker levels across four time points in the ORi and Non-ORi groups, a significant main effect of time was observed (p1), indicating a statistically significant change over time. Post hoc analysis demonstrated that the increase observed at the second time point was significantly different from all other time points. There was no significant difference between the ORi and Non-ORi groups (p2). The most important parameter in these analyses was the group × time interaction, which was not statistically significant (p3), indicating that the temporal patterns of change were similar between the two groups (Table 8). In both groups, biomarker levels in tracheal aspirates were found to be significantly higher compared to those in blood samples collected at different time points. Statistical analysis revealed that, although the sample types differed, the increase in biomarker levels observed in tracheal aspirates was significantly different for all three biomarkers when evaluated in terms of their temporal changes. The graphical representations of IL-6, SOD, and MDA levels are presented below (Fig. 6).

Table 8.

Biomarker analysis

BiomarkersII	ORi	Non-ORi	p1	p2	p3
Induction IL6 (ng/L)	103.2 ± 47.8	100 ± 71.2	< 0.001	0.565	0.374
Tracheal aspirate IL6(ng/L)	165 ± 31.9	166.1 ± 38.3
Post-op 12. Hour IL6(ng/L)	98.7 ± 53.2	96 ± 45.3
Post-op 24. Hour IL6(ng/L)	102.1 ± 51	95.5 ± 49.8
Induction SOD (ng/ml)	33.9 ± 16.4	34.1 ± 28.2	< 0.001	0.711	0.333
Tracheal aspirate SOD (ng/ml)	40.8 ± 8.5	42.4 ± 11.8
Post-op 12. Hour SOD (ng/ml)	33.1 ± 17.2	32.5 ± 16.7
Post-op 12. Hour SOD (ng/ml)	34.1 ± 16.3	33.9 ± 23.4
Induction MDA (mmol/ml)	19.9 ± 2.8	20.2 ± 6	< 0.001	0.701	0.618
Tracheal aspirate MDA (mmol/ml)	14.1 ± 7.4	13.4 ± 8.4
Post-op 12. Hour MDA (mmol/ml)	13.5 ± 7.19	13.5 ± 6.8
Post-op 24. Hour MDA (mmol/ml)	14 ± 6.4	14.3 ± 10.5

II IL-6 interleukin-6, SOD superoxide dismutase, MDA malondialdehyde

Fig. 6.

IL-6, SOD and MDA values through anesthesia induction to post operative 24^th hour

When comparing the two groups based on lymphocyte count, neutrophil count, and total nucleated cell count obtained from tracheal aspirate samples, no statistically significant differences were observed between them (Table 9).

Table 9.

Tracheal aspirate samples cell counts

	ORi	Non-ORi	p value
Lymphocyte	0.5(0.2-1)	0.3(0-0.8)	0.157
Total Cell	0(0–0)	0(0-0.1)	0.862
Neutrophile	0.1(0-0.5)	0.1(0-0.6)	0.948

Patients were monitored in the postoperative ICU for the need for invasive mechanical ventilation or non-invasive mechanical ventilation. All patients, except for one in the Non-ORi group, were extubated in the operating room at the end of surgery and transferred to the ICU. The single patient from the Non-ORi group who remained intubated after a thoracotomy for abdominal malignancy with thoracic wall reconstruction was extubated on postoperative day 1. Another patient in the Non-ORi group required non-invasive mechanical ventilation due to the development of atelectasis and respiratory distress during ICU follow-up. No other patients required positive pressure ventilation support. There was no statistically significant difference in the need for positive pressure mechanical ventilation support between the groups (p = 1.000). Similarly, no statistically significant difference was observed between the two groups regarding non-positive pressure oxygen support therapies (p = 0.272). The median and IQR for oxygen administered to patients in the ORi group were 5 and 5–5 l, respectively, while for the Non-ORi group, these values were 5 and 5-6.3 l.

Postoperative pulmonary complications were also examined. ARDS, bleeding requiring surgery, and prolonged drainage lasting more than 7 days were not observed in either group. The most frequently observed complication overall was bleeding requiring transfusion. Analysis of pulmonary complications showed that both groups were similar (Table 10).

Table 10.

Postoperative complications

	ORi	Non-ORi	p value
Bronchopneumonia	0	2	0.150
Bronchoalveolar fistula	0	1	0.313
ARDS(P/F < 200)	0	0	-
Hemorrhage (require transfusion)	1	3	0.301
Hemorrhage (require surgical repair)	0	0	-
Prolonged drainage (> 7days)	0	0	-
Atelectasis	0	1	0.313
Air Leak (require invasive procedure)	1	1	1.000
Re-intubation	0	0	-

No SSI were observed in any of the 60 patients included in the study up to their discharge.

Patients were also assessed for their length of stay in the ICU and inpatient ward. No statistically significant differences were found between the groups regarding either ICU stay duration or inpatient ward stay duration.

Discussion

ORi monitoring offers continuous, non-invasive data flow related to hyperoxia. When used in conjunction with SpO₂ monitoring, it can provide sufficient oxygenation data. In our study, the goal was to titrate FiO₂ in elective thoracic surgery patients OLV using ORi monitoring to prevent hyperoxia. Our findings demonstrate that compared to the group without ORi monitoring, lower FiO₂ levels could be utilized while still avoiding hypoxemia. Furthermore, both groups were similar regarding hyperoxia biomarker levels in blood and tracheal aspirates, the incidence of postoperative pulmonary complications, and the development of SSI. To the best of our knowledge, this is the first study to simultaneously evaluate intraoperative ORi use, oxygen exposure, and biomarker dynamics in this patient population.

Baseline demographic and preoperative characteristics were comparable between the groups, except for left ventricular EF. Although this difference reached statistical significance, receiver operating characteristic (ROC) curve analysis demonstrated that EF had poor discriminatory ability between groups (AUC = 0.378), suggesting that this difference is unlikely to be clinically meaningful.

A 2018 retrospective analysis conducted in the United Kingdom revealed that anesthesiologists nationwide generally maintained intraoperative FiO₂ levels around 0.5, though there was variability in individual preferences [16]. The same study also noted mild hyperoxia in patients’ ABG analyses. Similar results were found in another study [17]. This study showed that, higher oxygen exposure observed especially older patients, OLV and emergency surgeries.

In a prospective study by Applegate et al., which compared ORi measurements with ABG results in 106 patients, it was demonstrated that when the ORi value was above 0.24 and SpO₂ was measured at 98%, the PaO₂ value was above 100 mmHg [18]. The same study also showed that when the ORi value was greater than 0.55, PaO₂ was above 150 mmHg. In our study, in accordance with the data obtained by Applegate et al., an ORi value of 0.24 was accepted as the upper limit, and the FiO₂ level was accordingly reduced. We demonstrated that with ORi monitoring, lower FiO₂ could be applied in our patients without observing hypoxemia. Similarly, Saraçoğlu et al. stated that ORi monitoring in elective thoracic surgery patients undergoing OLV significantly reduced the FiO2 levels administered to patients [10].

In our study, when examining the intraoperative FiO₂ trends of our patients, the Non-ORi group’s FiO₂ trajectory began at 0.50, consistent with the study methodology. When the surgical team requested the initiation of OLV, FiO₂ increased to 0.60. Further increases in FiO₂ were made if there was a tendency toward hypoxemia at the start of OLV. It’s likely that ventilation-perfusion mismatch decreased over time due to factors such as clamping of the pulmonary artery in the surgically treated lung, the occurrence of hypoxic pulmonary vasoconstriction, or the completion of resection. This reduction in ventilation-perfusion mismatch is thought to have lessened the tendency for hypoxemia, allowing the anesthesiologist to decrease the FiO₂ level. Another study mentioned ventilation/perfusion mismatch due to OLV, lateral decubit position [14]. When pulmonary artery ligation was performed, possibly ventilation/perfusion mismatch reduce and ORi values begun rise.

Conversely, in the ORi group, the FiO₂ level was reduced from immediately after induction until the start of OLV. While FiO₂ was increased with the onset of a hypoxemic tendency during OLV, there was no need to use FiO₂ levels as high as those in the Non-ORi group during similar periods.

Analysing the graph of the ORi group’s trajectory reveals that ORi values were consistently above 0.24 during the first 20 min following anesthesia induction. This observation can be attributed to the pre-oxygenation strategy, which involved 90 s of mask ventilation with 0.8 FiO2. In some instances of difficult intubation, repeated attempts and changes in technique necessitated ventilating patients with 0.8-1.0 FiO₂ to prevent hypoxemia. During this period, an increase in ORi values was considered normal, provided effective ventilation was maintained.

Similarly, during the confirmation of the DLT position with a bronchoscope, effective ventilation was compromised due to deflation of the DLT cuffs and the insertion of the bronchoscope through the tube. This period was managed as apnoeic oxygenation, with patients receiving 0.8 FiO₂ via FGF. Once the airway was secured, FiO₂ levels were adjusted every 5 min by decreasing 0.05, based on ORi values, as outlined in the methodology. These practices explain the presence of ORi values above 0.24 in the initial 20 min of the graph. Given that this duration was relatively short and applied to both groups, it was anticipated that there would be no significant differences between the groups regarding laboratory findings or FiO₂ monitoring.

A study by Yang et al. used a methodology similar to ours, aiming to reduce oxygen exposure in OLV cases by titrating FiO₂ with ORi monitoring [14]. However, they did not observe a difference in total oxygen exposure between the groups and suggested that targeting ORi levels lower than 0.21 might be more effective. In a separate study, Choi et al. found that using low and high FiO₂ levels did not result in a statistically significant difference in SpO2 [19].

Studies suggest that hyperoxia can increase biomarkers of organ damage in septic patients. For instance, a preclinical animal study by Garcia-Laorden et al. investigating the effects of hyperoxia in an intra-abdominal sepsis model demonstrated that high oxygen concentrations exacerbated inflammatory organ damage [20]. However, the same study could not establish a link between ROS release and the degree of organ damage when comparing biomarker levels in blood samples from rats across groups. It’s important to note that our study did not include patients with sepsis or septic shock. Among our patients, two with elevated CRP levels underwent pneumonectomy and extrapulmonary mass resection due to malignancy. One patient who underwent pleurodesis had pleural thickening due to previous empyema but showed no signs of active inflammation or infection.

In a prospective study by Williams et al., which investigated pneumonectomies and lobectomies, a decrease in blood thiol and carbonyl levels was observed as an indicator of oxidative stress, yet no significant change in myeloperoxidase levels was detected [21]. Ottolenghi et al., in a prospective clinical study involving 20 patients, compared blood levels of MDA, hydro peroxidases, and glutathionylated haemoglobin in patients oxygenated with FiO₂ 0.4 and 0.8 [22]. They demonstrated that MDA levels were statistically significantly higher in the high FiO₂ group at 24-hour postoperative measurements. Conversely, Fisher et al. could not show a statistically significant difference in inflammatory biomarker levels in the blood of pigs subjected to OLV with FiO₂ 0.5 and 1.0 in their animal study [23].

In our present study, we anticipated changes in blood and tracheal aspirate IL-6, SOD, and MDA levels due to hyperoxia and inflammation. However, we found no significant differences in these levels, neither between the groups nor in the time-dependent changes within each group.

Most studies investigating oxidative damage indicators in tracheal aspirate and bronchoalveolar lavage fluid (BALF) samples are animal studies. For instance, Garcia-Laorden et al.‘s research in rats indicated that in BALF and pulmonary tissue samples, inflammatory markers and tissue damage increased with rising FiO₂ [20]. However, a 2017 study by Helmerhorst et al. noted that while mechanical ventilation led to an increase in neutrophil and protein content in bronchoalveolar lavage, they couldn’t demonstrate a statistically significant increase in protein content with elevated FiO₂ [24]. They did, however, find a significant difference in neutrophil counts. In contrast, our study found no statistically significant differences in cell counts within tracheal aspirates between the groups.

Reference values for IL-6, MDA, and SOD in BALF in healthy adults are not clearly established in the literature. The majority of data comes from diseased populations or animal studies. When interpreting the results of the biomarkers IL-6, MDA, and SOD, one should take into consideration the possibility of differences between their levels in BALF and blood. Local pulmonary inflammation tends to result in greater IL-6 levels in BALF than in plasma since alveolar macrophages, epithelial cells, and endothelial cells secrete this cytokine directly into the alveolar space [25]. By comparison, with systemic inflammatory processes like sepsis, plasma levels of IL-6 can equal or even surpass those in BALF. Similar to IL-6, BALF levels of SOD and MDA may also differ from plasma levels [26, 27]. Therefore, biomarker interpretation in our study should be viewed in a comparative context between the study groups, rather than against absolute reference ranges, as normative values for these markers in BALF are not well established in healthy individuals.

It’s important to consider that even in Non-ORi group, relatively acceptable oxygen concentrations were used. The average duration of intraoperative oxygen exposure was approximately 3–4 h. Studies on hyperoxia often use FiO2 of 1.0 as high oxygen and involve significantly longer oxygen exposure durations compared to our study. This difference in methodology might explain why we couldn’t demonstrate the oxidative damage results reported in those studies within our own.

Lung injury due to hyperoxia is a widely studied topic in literature. A review on the subject discussed mechanisms of apoptosis and necrosis development in alveolar epithelium via various cellular signaling pathways triggered by hyperoxia [28]. Furthermore, mice exposed to 1.0 FiO₂ for 24 h developed laboratory and clinical signs of lung injury in the subsequent days [29]. Kallet and Matthay provided a comprehensive review of the pathophysiology and clinical aspects of hyperoxic lung injury [5]. A study by Douville et al. found that using lower FiO2 in patients undergoing OLV did not reduce postoperative pulmonary complications [11]. In their research, high FiO2 was defined as values above 0.8. Both the study group and the control group in our own research had median FiO2 levels that would be classified as low oxygen according to their standards. Conversely, Lee et al. investigated the effect of adjusting FiO2 during pre-oxygenation with ORi monitoring on postoperative pulmonary complications [13]. They observed that the use of ORi was associated with a reduction in the incidence of these complications. Similarly, Choi et al. compared the effects of low versus high FiO2 (with 0.8 as the threshold) in patients undergoing OLV [19]. Their findings indicated that higher FiO2 levels were associated with a greater incidence of postoperative oxygenation impairment. Okahara et al. found that higher FIO2 during OLV could be associated with increased incidence of postoperative pulmonary complications [30].

In our study, however, we found no difference in postoperative pulmonary complications between patients ventilated with different FiO₂ levels during OLV. Notably, no patient in either group developed ARDS. While atelectasis was observed in one patient in the Non-ORi group, it was not seen in the ORi group. The atelectasis in the affected patient was on the operative side, which could be explained by insufficient intraoperative recruitment after resection or the patient’s inability to perform adequate postoperative respiratory exercises. No clinically or radiologically significant atelectasis was observed in the non-operative lung field in either patient group. Two patients in the Non-ORi group were diagnosed with pneumonia, both clinically and radiologically. Bleeding, bronchoalveolar fistula, and minimal air leak were considered minor surgical complications, with no statistically significant differences observed between the groups.

It’s been suggested that administering high concentrations of oxygen to patients during the perioperative period can influence the development of SSI. The premise is that increased oxygen delivery to tissues during wound healing positively affects neutrophil activity, thereby reducing the risk of infection. In 2016, the World Health Organization (WHO) even recommended inducing hyperoxia in intubated patients during the intraoperative period to potentially lower the risk of SSIs [31]. However, beyond colorectal surgery, there’s limited evidence to consistently support this recommendation [32, 33]. In our study, no SSI were observed in either group. It’s important to note that in both our ORi-monitored and non-ORi-monitored patient groups, oxygen concentrations used were lower than those mentioned in the studies cited above.

When evaluating the limitations of our study, we acknowledge that while there were no differences in demographic characteristics and surgical procedures between the ORi and Non-ORi groups, both groups exhibited heterogeneity in their perioperative characteristics. For future studies employing a similar methodology, focusing on a single type of surgical procedure could offer more definitive insights into postoperative complications. Our current study included a variety of surgical indications, such as malignant and non-malignant masses, neurovascular decompression, and isolated pleural excisions. Among surgeries performed for malignant masses, the pathological diagnoses were diverse. The absence of ABG monitoring at predetermined times or intervals, particularly for the control group, can be considered a limitation, as it prevents us from accurately demonstrating their hyperoxia levels. Therefore, although ORi-guided oxygen titration reduced administered FiO₂, physiological interpretations regarding hyperoxia-related effects should be made cautiously Regarding biomarker tracking, a cohort of patients undergoing surgery for an isolated, specific pathology might yield more conclusive results. The use of a single tracheal aspirate sample also represents a limitation of our study. Comparing biomarker and cell counts from multiple tracheal aspirate samples collected at different time points would not only allow for a more robust comparison of oxygen exposure between groups but also enable the evaluation of disease progression within the same patient group. It should be noted that the present study was powered to detect a difference in intraoperative FiO₂ levels, which was defined as the primary outcome. Therefore, the study was not adequately powered to detect differences in secondary clinical outcomes such as postoperative pulmonary complications and surgical site infections. Accordingly, the absence of statistically significant differences in these outcomes should be interpreted with caution and evidence of equivalence between the groups should not be considered. It should be acknowledged that the lower FiO₂ observed in the ORi group is partly attributable to the study design, as active titration was applied only in this group; therefore, these findings should be interpreted as reflecting the feasibility of an ORi-guided oxygen titration strategy rather than an independent effect of ORi monitoring itself.

Considering our study’s findings, ORi monitoring safely enabled the use of lower oxygen concentrations during the intraoperative period for thoracic surgery patients undergoing OLV. However, this reduction in oxygen administration did not translate to lower levels of hyperoxia-related biomarkers in blood and tracheal aspirate samples. Furthermore, there was no significant difference in pulmonary complications or SSI between the groups. Our study shows that titration of FiO₂ guided by ORi in patients undergoing OLV resulted in lower intraoperative oxygen administration; however, it did not confer any additional clinical benefit in terms of reduction of complications or mortality.

In conclusion, although ORi-guided titration enabled a safe reduction in intraoperative oxygen administration during OLV, this strategy did not translate into measurable biochemical or clinical benefits, suggesting that routine ORi-guided oxygen titration may not provide additional advantage beyond conventional SpO₂-guided management. From this perspective, maintaining intraoperative patient monitoring with an SpO₂ target above 90% appears to be a safe approach. For future similar studies, focusing on longer durations of oxygen exposure, more homogeneous patient cohorts, or more frequent and earlier assessment of biomarker levels would be beneficial in demonstrating the potential harms of hyperoxia.

Abbreviations

OLV

One-Lung Ventilation

DLT

Double-lumen Endotracheal Tube

ORi

Oxygen Reserve Index

TLV

Two-Lung Ventilation

ROS

Reactive Oxygen Species

MDA

Malondialdehyde

IL-6

Interleukin-6

SOD

Superoxide dismutase

SpO₂

Haemoglobin Saturation

FiO₂

Fraction of inspired oxygen

PaO₂

Arterial oxygen partial pressure

ABG

Arterial Blood Gas

BALF

Bronchoalveolar lavage fluid

EF

Ejection Fraction

FEV

Forced expiration volume

FRC

Functional residual capacity

FGF

Fresh gas flow

PEEP

Positive End Expiratory Pressure

PIP

Peak inspiratory pressure

Pdrive

Driving pressure

Pplateu

Plateu pressure

SSI

Surgical site infection

ICU

Intensive care unit

Authors’ contributions

Buğra Aykenar (BA), Mehmet Dalokay Kılıç (MDK) and Pınar Zeyneloğlu (PZ) jointly contributed to the conceptualization and design of the manuscript. BA collected the data. BA, Asude Ayhan (AA), Sinan Issı (SI) made significant contributions to the analysis and interpretation of the data. BA, SI, and MDK evaluated the patients in terms of postoperative pulmonary complications and surgical site infections. All authors have participated to drafting the manuscript, author BA revised it critically. All authors read and approved the final version of the manuscript.

Funding

This study was approved by Baskent University Institutional Review Board and Ethics Committee (Project no: KA22-169) and supported by Baskent University Research Fund. No external funding was received.

Data availability

De-identified individual participant data, the data dictionary, and the SPSS statistical code used in this study will not be made publicly available. However, they may be provided by the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Approved by Başkent University Clinical Research Ethics Committee. Written informed consent was obtained from all participants. IRB number: KA22-169, dated 10.06.2022. The study was carried out according to the Declaration of Helsinki and Good Clinical Practice guidelines. All participants provided informed consent to participate in the study. Written informed consent was obtained from all participants prior to their inclusion in the study.

Consent for publication

Not applicable. Our study complies with CONSORT guidelines.

Competing interests

The authors declare no competing interests.