Associations between intraoperative ventilator settings during one-lung ventilation and postoperative pulmonary complications: a prospective observational study.

BACKGROUND: The interest in perioperative lung protective ventilation has been increasing. However, optimal management during one-lung ventilation (OLV) remains undetermined, which not only includes tidal volume (VT) and positive end-expiratory pressure (PEEP) but also inspired oxygen fraction (FIO2). We aimed to investigate current practice of intraoperative ventilation during OLV, and analyze whether the intraoperative ventilator settings are associated with postoperative pulmonary complications (PPCs) after thoracic surgery.
METHODS: We performed a prospective observational two-center study in Japan. Patients scheduled for thoracic surgery with OLV from April to October 2014 were eligible. We recorded ventilator settings (FIO2, VT, driving pressure (ΔP), and PEEP) and calculated the time-weighted average (TWA) of ventilator settings for the first 2 h of OLV. PPCs occurring within 7 days of thoracotomy were investigated. Associations between ventilator settings and the incidence of PPCs were examined by multivariate logistic regression.
RESULTS: We analyzed perioperative information, including preoperative characteristics, ventilator settings, and details of surgery and anesthesia in 197 patients. Pressure control ventilation was utilized in most cases (92%). As an initial setting for OLV, an FIO2 of 1.0 was selected for more than 60% of all patients. Throughout OLV, the median TWA FIO2 of 0.8 (0.65-0.94), VT of 6.1 (5.3-7.0) ml/kg, ΔP of 17 (15-20) cm H2O, and PEEP of 4 (4-5) cm H2O was applied. Incidence rate of PPCs was 25.9%, and FIO2 was independently associated with the occurrence of PPCs in multivariate logistic regression. The adjusted odds ratio per FIO2 increase of 0.1 was 1.30 (95% confidence interval: 1.04-1.65, P = 0.0195).
CONCLUSIONS: High FIO2 was applied to the majority of patients during OLV, whereas low VT and slight degree of PEEP were commonly used in our survey. Our findings suggested that a higher FIO2 during OLV could be associated with increased incidence of PPCs.

Background

Postoperative pulmonary complications (PPCs) affect morbidity, mortality, length of hospital stay [1, 2] and are at least as frequent as cardiovascular complications [2]. Therefore, PPCs are one of the most serious problems during perioperative period [2, 3]. The incidence of PPCs depends on patients’ co-morbidity, surgical procedures and anesthetic factors [1, 3]. Among these, intraoperative ventilator settings are suggested to be one of the most crucial factors [4].

To prevent the occurrence of PPCs, intraoperative lung protective ventilation, mainly comprised of low tidal volume (VT), slight degree of positive end-expiratory pressure (PEEP), and limited airway pressure, has been reviewed [5-8]. According to several studies in open abdominal surgery, this approach improved not only postoperative respiratory function [8] but also clinical outcomes [5, 7]. This lung protective strategy has been steadily filtering into our ventilation strategy as a standard clinical practice.

In one-lung ventilation (OLV), it is indicated that high VT and inspiratory airway pressure are risk factors for acute lung injury after thoracic surgery [9-11], while high ventilator support is sometimes needed during OLV to maintain patient’s oxygenation and eliminate carbon dioxide. However, the evidence for optimal ventilator settings during OLV remains insufficient. Consequently, there are numerous variations of ventilator settings, including inspired oxygen fraction (FIO2) as well as VT and PEEP, due to specific pathophysiology and historical background [12-15], especially for the management of oxygen concentrations [13-16].

In this clinical study, we investigated the current practice of intraoperative ventilation during OLV in adult patients undergoing thoracic surgery. Furthermore, we tested whether the intraoperative ventilator settings were associated with the incidence of PPCs after thoracic surgery.

Methods

Study design, setting, and participants

A two-center prospective observational study was conducted from April 2014 to October 2014 in Japan. Participating hospitals included an academic tertiary care hospital and a community hospital. This study was approved by the institutional ethics review board (IRB) of Okayama University Hospital (No. 1922) and Fukuyama City Hospital (No. 182). The requirement for written informed consent was waived by each IRB. We screened consecutive patients over the age of 20 who were scheduled for a thoracic surgical procedure and required general anesthesia with OLV. We excluded emergency surgery, re-operative surgery, and patients who did not receive OLV. There was no specific protocol for perioperative management at the participating hospitals.

Data source and collection

We investigated perioperative information, including preoperative characteristics, details of surgery and anesthesia, and postoperative course. Demographics and clinical data were extracted from electronic medical records. The preoperative data included sex, age, Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score [17], preoperative respiratory function, and preoperative percutaneous oxygen saturation (SpO2). We collected anesthetic and surgical information, such as surgical procedures, types of general anesthesia, use of epidural anesthesia, and airway management as well as duration of procedure, anesthesia, and OLV. Total blood loss and volume of infusion were also collected. Minimum SpO2 throughout the course of anesthesia was recorded.

During OLV (0, 30, 60, and 120 min after the start of OLV and at the end of OLV), the following variables were recorded: ventilator mode, FIO2, VT corrected for predicted body weight (PBW), driving pressure (ΔP) (peak inspiratory pressure minus PEEP on both pressure control and volume control ventilation), and PEEP. These data were collected by attending anesthesiologists. PBW was calculated as follows: for men, 50 + 0.91 (height (cm) - 152.4); and for women, 45.5 + 0.91 (height (cm) - 152.4) [18].

Quantitative variables and bias

To avoid surveillance bias, time weighted average (TWA) of ventilation parameters was calculated for the first 2 h of OLV. TWA was determined by summing the mean value between consecutive time points (0, 30, 60, and 120 min after the start of OLV) multiplied by the period of time between consecutive time points and then divided by the total time. We calculated and assessed TWA of FIO2, VT, ΔP, and PEEP during OLV.

Outcome measures

The primary outcome was the incidence of PPCs occurring within 7 days of thoracotomy. PPCs included pneumonia, pleural effusion, atelectasis, prolonged air leakage, pulmonary embolism and respiratory failure diagnosed according to the definitions (Table 1), which referred to previous studies [17, 19, 20]. In each center, a predetermined researcher evaluated all patients in accordance with the definitions of PPCs. To investigate the length of hospital stay (LOS) and mortality, patients were followed-up until hospital discharge or death (whichever occurred first).

Table 1

The definition of PPCs

PPCs	Definition
Pneumonia [19]	1. Presence of new or progressive infiltrates on chest radiograph2. Fever (> 38 °C) or leukocyte count (< 4000, ≥12,000 WBC/mm3)3. New or changed sputum, tachypnea, impaired gas exchange
Pleural effusion [17]	Chest radiograph demonstrating blunting of the costophrenic angle or loss of the sharp silhouette of the hemidiaphragm on the nonoperative side
Atelectasis [17]	Opacities evidenced on chest radiograph with a shift of the mediastinum, hilum, or hemidiaphragm toward the affected area
Prolonged air leakage [20]	Air leak requiring insertion of new chest tube or ≥7 days of postoperative chest tube drainage
Pulmonary embolism [20]	Pulmonary arteriogram or ventilation/perfusion radioisotope scan documenting thrombus
Respiratory failure [20]	Postoperative ventilator dependence ≥24 h or Need of reintubation or noninvasive ventilation

PPCs postoperative pulmonary complications

Statistical analysis

Variables were assessed for normality. Categorical data were compared using chi-square tests or Fisher exact tests and reported as n (%). Continuous normally distributed variables were compared using Student t tests and reported as means (standard deviation), while non-normally distributed data were compared using Wilcoxon rank-sum tests and reported as medians (interquartile range). Univariate analysis was performed to compare perioperative characteristics between patients with and without PPCs. A multivariate logistic regression analysis was performed to estimate the associations between intraoperative ventilator settings and PPCs, adjusting for ARISCAT score and all univariate relevant factors that discriminate between the two groups. To explore subgroup differences in associations between the ventilator settings and PPCs, the same multivariate analyses were performed for subgroups classified according to the ARISCAT score, preoperative SpO2 and surgical procedures, respectively. All analyses were performed using JMP version 8.0.2 (SAS Institute, Cary, NC, USA). P < 0.05 was considered statistically significant. This manuscript adheres to the applicable Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Results

Participants characteristics

Overall, 212 cases underwent thoracic surgery with OLV during the study period. Two patients were younger than 20 years old, and 13 cases underwent thoracic surgeries twice during the study period. Thus, 197 patients met the eligibility criteria (Fig. 1).

Fig. 1

Study flow diagram. OLV one-lung ventilation

Baseline characteristics and intraoperative procedures of all patients are noted in Additional file 1. Most patients (n = 190, 96.4%) had an intermediate or high risk of having PPCs according to the ARISCAT score. More than 80% of patients underwent lung resections; however, there was no patient who underwent pneumonectomy.

Main results

Pressure control ventilation (PCV) was utilized in most cases (n = 181, 92%). At the start of OLV, median FIO2 was 1.0 (0.8-1.0). Specifically, an FIO2 of 1.0 was applied as an initial setting for more than 60% of all patients. In other initial settings, median VT was 6.1 (5.2-7.3) ml/kg, and median ΔP was 16 (14-20) cm H2O. PEEP was applied in 171 patients (87%) at a median level of 4 (4-5) cm H2O. The distributions of ventilator settings throughout OLV are shown as TWA values in Fig. 2. Median TWA FIO2 was 0.8 (0.65-0.94), and 83% of patients received TWA FIO2 ≥ 0.6. Other median TWA values, such as VT, ΔP, and PEEP, were at almost similar levels as the initial settings (VT, 6.1 (5.3-7.0) ml/kg; ΔP, 17 (15-20) cm H2O; and PEEP, 4 (4-5) cm H2O). As a rescue therapy, oxygen therapy to the non-ventilated lung was adopted in only five cases.

Fig. 2

Distribution of ventilator settings during one-lung ventilation. Each graph represents the distributions of TWA values during one-lung ventilation: (a) FIO2, (b) VT, (c) ΔP, and (d) PEEP. TWA time weighted average, FO inspiratory oxygen fraction, V tidal volume, ΔP driving pressure, PEEP positive end-expiratory pressure

PPCs occurred in 51 of 197 cases (25.9%). Atelectasis developed in 35 patients (17.8%), prolonged air leakage in 10 (5.1%), pneumonia in 3 (1.5%), pleural effusion in 3 (1.5%), and respiratory failure in 2 (1.0%). Two cases with respiratory failure occurred with atelectasis or pleural effusion. None of the patients were diagnosed with pulmonary embolism in this period. Only one patient died during hospital stay, and overall mortality was 0.5%. Baseline characteristics and intraoperative procedures in patients with and without PPCs were shown in Table 2. There were no significant differences in preoperative baseline characteristics, surgical procedures, and intraoperative management regarding anesthesia.

Table 2

Baseline characteristics and intraoperative information of patients with and without PPCs

	Patients with PPCs (N = 51)	Patients without PPCs (N = 146)	P value
Preoperative baseline
Age - years	67.4 ± 12.9	63.7 ± 13.2	0.094
Sex (male) - no. (%)	33 (64.7)	88 (60.3)	0.57
ARISCAT score	50 (43-50)	50 (27-50)	0.44
Preoperative SpO2 - %	97 (96-98)	98 (96.25-99)	0.055
%VC - %	101 ± 18	104 ± 18	0.31
FEV1.0% - %	75 ± 13	75 ± 10	0.72
Anesthesia & Operation
Lung resection (+) - no. (%)	45 (88.2)	123 (84.2)	0.64
TIVA - no. (%)	31 (60.8)	78 (53.8)	0.39
Epidural anesthesia - no. (%)	37 (72.6)	109 (74.7)	0.77
Oxygen therapy to the non-ventilated lung - no. (%)	3 (5.9)	2 (1.4)	0.08
Duration of anesthesia - min	285 (185-362)	263 (162-333)	0.17
Duration of operation - min	205 (118-276)	194 (102-258)	0.15
Duration of OLV - min	173 (96-240)	167 (77-224)	0.33
Total volume of infusion - ml	1660 (1250-2190)	1550 (958-2100)	0.14
Total blood loss - ml	40 (10-100)	15 (10-93)	0.37
Minimum SpO2 - %	94 (91-96)	95.5 (93-97)	0.0053

Baseline and procedural characteristics are shown as n (%), means ± standard deviation or medians (interquartile range)

PPCs postoperative pulmonary complications, ARISCAT Assess Respiratory Risk in Surgical Patients in Catalonia, %VC % vital capacity, FEV1.0% forced expiratory volume in one second %, TIVA total intravenous anesthesia, OLV one-lung ventilation

Among ventilator settings, only TWA FIO2 in patients with PPCs was significantly higher than that in patients without PPCs (0.85 (0.73-1.0) vs. 0.77 (0.63-0.89); P = 0.0032) (Table 3). There was no significant difference in TWA VT, TWA ΔP, and TWA PEEP between the two groups. Throughout the anesthesia, minimum SpO2 in patients with PPCs was significantly lower than that in patients without PPCs (94 (91-96) % vs. 95.5 (93-97) %; P = 0.0053). Finally, the postoperative LOS was longer in patients with PPCs (13 (8-16) days vs. 8 (7-11) days; P < 0.001).

Table 3

Ventilator setting during OLV of patients with and without PPCs

	Patients with PPCs (N = 51)	Patients without PPCs (N = 146)	P value
Ventilator setting during OLV
Mode (PCV) - no. (%)	46 (90.2)	135 (92.5)	0.62
TWA FIO2	0.85 (0.73-1.0)	0.77 (0.63-0.89)	0.0032
TWA VT - ml/kg	6.2 (5.2-7.4)	6.1 (5.4-7.0)	0.8495
TWA ΔP - cmH2O	18 (15-21)	16 (15-18)	0.0717
TWA PEEP - cmH2O	4 (4-5)	4 (4-5)	0.1504

Ventilator settings are shown as n (%) or medians (interquartile range)

OLV one-lung ventilation, PPCs postoperative pulmonary complications, PCV pressure control ventilation, TWA time weighted average, FO inspiratory oxygen fraction, V tidal volume, ΔP driving pressure, PEEP positive end-expiratory pressure

In multivariate logistic regression model (Table 4), which was adjusted for ventilator settings (TWA FIO2, TWA ΔP, and TWA PEEP), ARISCAT score, and minimum SpO2, only TWA FIO2 during OLV was independently associated with the occurrence of PPCs. Odds ratio (OR) per TWA FIO2 increase of 0.1 was 1.30 (95% confidence interval (CI): 1.04-1.65, P = 0.0195). Other variables (TWA ΔP, TWA PEEP, ARISCAT score, and minimum SpO2) were not related to the occurrence of PPCs in this model.

Table 4

Multivariate Analysis of risk factor for PPCs

	Odds Ratio	P value
ARISCAT score (per 1 point)	1.02 (95% CI: 0.99-1.05)	0.3038
Minimum SpO2 (per 1%)	0.89 (95% CI: 0.79-1.00)	0.0544
TWA FIO2 (per 0.1)	1.30 (95% CI: 1.04-1.65)	0.0195
TWA ΔP (per 1 cmH2O)	1.03 (95% CI: 0.91-1.16)	0.6436
TWA PEEP (per 1 cmH2O)	1.09 (95% CI: 0.86-1.40)	0.4994

PPCs postoperative pulmonary complications, ARISCAT Assess Respiratory Risk in Surgical Patients in Catalonia, CI confidence interval, TWA time weighted average, FO inspiratory oxygen fraction, ΔP driving pressure, PEEP positive end-expiratory pressure

Subgroup analyses

There were significant associations between FIO2 and PPCs in patients with low or intermediate risk of having PPCs according to the ARISCAT score (OR, 1.48; 95% CI, 1.00-2.40; P = 0.0496), or undergoing lung resection (OR, 1.31; 95% CI, 1.03-1.70; P = 0.0278) (Additional file 2). Other subgroups including patients with high risk for PPCs and high or low preoperative SpO2, also indicated that higher FIO2 tended to be associated with higher incidence of PPCs.

Discussion

Key results

We conducted a prospective observational study to investigate the current practice of intraoperative ventilation and to evaluate the associations between ventilator settings during OLV and PPCs in patients undergoing thoracic surgery. We found that FIO2 of ≥0.8, VT of approximately 6 ml/kg, and PEEP of approximately 4 cm H2O were common. Patients with PPCs received higher FIO2 during OLV, while they had lower minimum SpO2 than those without PPCs. However, in multivariate logistic regression analysis adjusting for ventilator settings, ARISCAT score, and minimum SpO2, only TWA FIO2 was associated with the occurrence of PPCs, and the adjusted OR per FIO2 increase of 0.1 was 1.30. Therefore, an increase in oxygen concentration of 10% was associated with approximately 30% increase in the risk of PPCs.

Interpretation

We found that VT was around 6 ml/kg, and PEEP was set around 4 cm H2O in most patients. These findings were consistent with recent studies or textbook oriented lung protective strategy [15, 21, 22]. We also found that high FIO2 was frequently used during OLV. These findings, however, were inconsistent with recent recommended management [22]. An FIO2 of 1.0 was classically a routine component of OLV [15, 23]. However, the incidence of hypoxemia during OLV has been decreasing [15, 22], and the harmful effects of high FIO2, including absorption atelectasis [24-27], production of reactive oxygen species, and increased lung injury [28, 29], have been reported. Therefore, this classic practice has been questioned and avoidance of excessive FIO2 has been proposed [15]. The latest textbook suggests that FIO2 should be titrated to maintain a stable saturation level above 92-94% during OLV [22]. However, some reports revealed that relatively high FIO2 was still applied as a common practice during both two-lung ventilation [30, 31] and OLV [13-16]. In our survey, intraoperative minimum SpO2 was ≥95% in 111 patients (56%), with 83% of them receiving TWA FIO2 of ≥0.6 (Additional file 3). These findings indicated that almost half of the patients may have received excessive oxygen regardless of their SpO2. There was low compliance with recommended standards to maintain a SpO2 above 92-94% during OLV.

According to our results, high FIO2 during OLV was independently associated with the increasing incidence of PPCs, and patients with PPCs had a longer LOS in the hospital. Worse clinical outcomes due to high FIO2 were previously reported in critically ill adults, including patients with chronic obstructive pulmonary disease, myocardial infarction, cardiac arrest, stroke, and traumatic brain injury [32-35]. Given the above concern, a conservative oxygenation strategy has been shown to be feasible, safe, and effective for mechanically ventilated patients in recent decades [36, 37]. Notably, conservative oxygen therapy could be associated with decreased evidence of atelectasis as well as earlier weaning from mandatory ventilation in the ICU [38]. Additionally, a recent randomized control trial of conservative oxygen therapy in ICU showed lower mortality [39].

Only a few studies investigated the effect of intraoperative FIO2 on clinical outcomes in thoracic surgery with OLV. Yang et al. reported a lower incidence of postoperative lung dysfunction and satisfactory gas exchange was provided by the lung protective strategy using FIO2 of 0.5 compared to the conventional strategy using FIO2 of 1.0 during OLV [40]. However, FIO2 was one of components in this lung protective strategy, because VT, PEEP, and mode of mechanical ventilation were also different between the groups. Thus, it remains uncertain whether a conservative approach to oxygen therapy during OLV is beneficial or not. To our knowledge, this is the first study to demonstrate an association between high FIO2 during OLV and the occurrence of PPCs. To confirm and dissect these findings, additional studies should be performed in different settings. Moreover, our findings support the need for randomized control trials to evaluate the safety and feasibility of conservative oxygen therapy during OLV.

Limitations

There were several limitations in this study. First, because this was an observational study, causality was not determined. It should be noted that higher FIO2 might be confounded by the incidence of hypoxemia, which could cause PPCs. Thus, the role of FIO2 is difficult to differentiate between “unnecessary use” and “need for higher support.” However, after adjusting by ARISCAT score, minimum SpO2, ΔP, and PEEP to reduce potential confounding, only higher FIO2 remained statistically significant as an independent risk factor for PPCs. In subgroup analyses, FIO2 has been associated with the incidence of PPCs even in patients with comparatively lower risk for PPCs. Additionally, the present study indicated that patients might receive excessive oxygen during OLV. Therefore, we believe that intraoperative FIO2 could be titrated safely even during OLV.

Second, the incidence of PPCs could have heavily depended on our definition. There are various definitions of PPCs. For instance, pneumonia was diagnosed based on radiologic images, symptoms, laboratory findings, or antimicrobial treatment used. The diagnosis of atelectasis was based on images or bronchoscopy. In our study, we used definitions of PPCs from previous studies [17, 20] and CDC guidelines [19] as shown in Fig. 1. As a result, the incidence of PPCs in our study (25.9%) was similar to that of previous works [17, 20].

Conclusions

In conclusion, liberal oxygen therapy as well as lung protective ventilation comprising low VT and slight PEEP were common for patients undergoing thoracic surgery with OLV in our cohort. Our findings indicated that high FIO2 during OLV was associated with an increased incidence of PPCs, which is related to prolonged LOS in the hospital. These results suggested that current practices of oxygen therapy during OLV may be suboptimal and warrant further investigation.

Baseline characteristics and intraoperative procedures of all patients. (DOCX 21 kb)

Adjusted odds ratio of TWA FIO2 during OLV for the incidence of PPCs in subgroup analyses. (PPTX 79 kb)

The correlation between TWA FIO2 and minimum SpO2. (PPTX 84 kb)