Lung-protective properties of expiratory flow-initiated pressure-controlled inverse ratio ventilation: A randomised controlled trial.

BACKGROUND: Expiratory flow-initiated pressure-controlled inverse ratio ventilation (EF-initiated PC-IRV) reduces physiological dead space. We hypothesised that EF-initiated PC-IRV would be lung protective compared with volume-controlled ventilation (VCV).
METHODS: Twenty-eight men undergoing robot-assisted laparoscopic radical prostatectomy were enrolled in this randomised controlled trial. The EF-initiated PC-IRV group (n = 14) used pressure-controlled ventilation with the volume guaranteed mode. The inspiratory to expiratory (I:E) ratio was individually adjusted by observing the expiratory flow-time wave. The VCV group (n = 14) used the volume control mode with a 1:2 I:E ratio. The Mann-Whitney U test was used to compare differences in the serum cytokine levels.
RESULTS: There were no significant differences in serum IL-6 between the EF-initiated PC-IRV (median 34 pg ml-1 (IQR 20.5 to 63.5)) and VCV (31 pg ml-1 (24.5 to 59)) groups (P = 0.84). The physiological dead space rate (physiological dead space/expired tidal volume) was significantly reduced in the EF-initiated PC-IRV group as compared with that in the VCV group (0.31 ± 0.06 vs 0.4 ± 0.07; P<0.001). The physiological dead space rate was negatively correlated with the forced vital capacity (% predicted) in the VCV group (r = -0.85, P<0.001), but not in the EF-initiated PC-IRV group (r = 0.15, P = 0.62). Two patients in the VCV group had permissive hypercapnia with low forced vital capacity (% predicted).
CONCLUSIONS: There were no differences in the lung-protective properties between the two ventilatory strategies. However, EF-initiated PC-IRV reduced physiological dead space rate; thus, it may be useful for reducing the ventilatory volume that is necessary to maintain normocapnia in patients with low forced vital capacity (% predicted) during robot-assisted laparoscopic radical prostatectomy.

RCT Entities:   Population Interventions Outcomes

Introduction

Patients are placed in a steep Trendelenburg position with CO2 pneumoperitoneum during robot-assisted laparoscopic radical prostatectomy. This procedure can decrease lung functional residual capacity and lung-thoracic compliance and increase ventilation-perfusion mismatch [1-3]. Pressure-controlled inverse inspiratory to expiratory ratio ventilation has been used in acute respiratory distress syndrome [4-8]. However, its clinical utility remains controversial [9-12]. Earlier studies used pressure-controlled inverse ratio ventilation (PC-IRV) with an inspiratory to expiratory (I:E) ratio of 2:1 to 4:1 without individual adjustment; this resulted in a very short expiratory phase and increased the risk of lung hyperinflation and circulatory depression. PC-IRV with an IE ratio that is individually adjusted by observing the expiratory flow-time wave can appropriately maintain moderate total positive end-expiratory pressure (total PEEP). We previously reported that expiratory flow (EF)-initiated PC-IRV reduced physiological dead space (VDphys) without lung hyperinflation and circulatory depression in patients undergoing robot-assisted laparoscopic radical prostatectomy [13]. Additionally, we hypothesised that EF-initiated PC-IRV may have lung-protective properties because this method can lower mechanical stress on the lung tissue by reducing VDphys and the ventilatory volume required to maintain the partial pressure of CO2 (PaCO2).

This study primarily aimed to evaluate the lung-protective properties of EF-initiated PC-IRV and to compare the differences in the lung-protective properties between EF-initiated PC-IRV and volume-controlled ventilation (VCV) in patients undergoing robot-assisted laparoscopic radical prostatectomy. The secondary aim was to compare the ventilatory efficacy of these methods.

Materials and methods

Study design and ethics

This study was designed as a prospective, mono-centre, single-blinded, randomized controlled clinical trial. It was approved by the Ethical Committee of Teikyo University School of Medicine, Tokyo, Japan on 12 September 2017 (No. 17–063) and was registered at UMIN Clinical Trials Registry (UMIN000029552). The study was conducted in the Mizonokuchi Hospital Teikyo University School of Medicine, Kanagawa, Japan, between December 2017 and September 2018. The original Japanese study protocol approved by the Ethical Committee of Teikyo University School of Medicine as the S1 File, and English protocol as the S2 File. This study is reported in adherence to the CONSORT guidelines, and the CONSORT checklist is provided in the S1 Checklist.

Subjects

Patients aged 18 to 85 years with American Society of Anesthesiologists (ASA) physical status I or II and who were scheduled for robot-assisted laparoscopic radical prostatectomy were considered eligible for participation in this study. The exclusion criteria were as follows: ASA physical status 3 to 5, a history of pneumothorax, and previous lung surgery. Written informed consent was obtained from all eligible patients. The participants were recruited between December 2018 and September 2019.

Randomization and blinding

Researchers at the Teikyo Academic Research Centre randomised patients to the VCV or EF-initiated PC-IRV groups with a 1:1 allocation ratio using an envelope method after generating the allocation sequence. Only the patients remained blinded during the whole study procedure.

Anaesthesia protocol

Routine patient monitoring included electrocardiography, pulse oximetry, oesophageal temperature measurement, non-invasive arterial blood pressure measurement, and anaesthetic gas CO2 analysis. Moreover, the Vigileo with the Flo-Trac sensor (Edwards Lifesciences, Irvine, CA, USA) was used to monitor continuous radial arterial pressure, cardiac index (CI), and stroke volume variation (SVV). Mainstream CO2 and flow sensors were attached to the proximal end of the tracheal tube to enable volumetric capnography (Senko Medical Instrument Co., Ltd., Tokyo, Japan). Anaesthesia was induced by the administration of 1–3 mg kg-1 of intravenous propofol and 2–4 μg kg-1 of fentanyl. Tracheal intubation was performed with an 8.0-mm cuffed tube following the administration of 0.6–0.9 mg kg-1 of rocuronium. Anaesthesia was maintained with volatile anaesthetic gas that was composed of 3–4% desflurane and supplemented with continuous intravenous infusions of 0.2–0.3 μg kg-1 min-1 remifentanil and intermittent intravenous injections of 0.1–0.2 mg kg-1 rocuronium and 1–2 μg kg-1 fentanyl when needed.

The same anaesthesia ventilator (Avance Carestation, Datex-Ohmeda, GE Healthcare, Helsinki, Finland) was used for all of the patients. The initial ventilator settings included the volume control (VC) mode, the tidal volume (VT) that was set at 8–10 ml kg-1 of the ideal body weight (IBW) (i.e., 50 + 0.91 × [height in cm—152.4]), a respiratory rate of 12 breaths min-1, a baseline airway pressure (BAP) (used as set PEEP) of 5 cmH2O, 0.5 fraction of inspired oxygen (FiO2), and an I:E ratio of 1:2.

Interventions and ventilatory strategies

Ventilator settings were switched to the EF-initiated PC-IRV or VCV strategy (Table 1) following the establishment of the 25–30° Trendelenburg position and CO2 pneumoperitoneum at 12 mmHg. The EF-initiated PC-IRV strategy included the pressure-controlled ventilation-volume guaranteed (PCV-VG) mode. In this mode, the airway pressure is adjusted to achieve a target tidal volume, and plateau pressures are allowed to reach an upper limit of 30 cmH2O. BAP was set off. The initial respiratory rate was 12 beats min-1, and the I:E ratio was individually adjusted by observing the expiratory flow-time wave [13]. I:E ratios of 2:1, 1.5:1, or 1:1 were selected so that inspiration was initiated at the midpoint between the expiratory flow change point and the return point to the expected baseline. The VCV strategy included the VC mode, and a pause ratio of 20% was used in order to measure plateau pressure. A target tidal volume was set with a plateau pressure upper limit of 30 cmH2O. BAP was set to 5 cmH2O. The I:E ratio was 1:2, and the initial respiratory rate was 12 beats min-1. Both strategies allowed for an increase in the respiratory rate to an upper limit of 18 beats min-1 to achieve a PaCO2 of less than 50 mmHg that was estimated from end-tidal CO2 (ETCO2) changes and differences between ETCO2 and PaCO2 on arterial blood gas analysis. Hypercapnia (> 50 mmHg) was permitted if the respiratory rate increased to 18 beats min-1 with a plateau pressure of 30 cmH2O.

Table 1

Ventilator strategy.

	VCV strategy	EF-initiated PC-IRV strategy
Ventilator mode	volume control with pause ratio of 20%	pressure-controlled ventilation-volume guaranteed
Inspiratory:Expiratory (ratio)	1:2	2:1, 1.5:1, or 1:1 were selected so that inspiration was initiated at the midpoint between the expiratory flow change point and the return point to the expected baseline
Baseline airway pressure (cmH2O)	5	0
Respiratory rate	The initial respiratory rate was 12 beats min-1, allowed for an increase in the respiratory rate to an upper limit of 18 beats min-1 to achieve a PaCO2 of less than 50 mmHg
Target tidal volume	Adjusted to achieve a plateau pressure upper limit of 30 cmH2O

VCV, volume-controlled ventilation; EF-initiated PC-IRV, expiratory flow-initiated pressure-controlled inverse ratio ventilation.

Immediately after returning the patients to the supine position and relieving CO2 pneumoperitoneum, patients in the EF-initiated PC-IRV or VCV groups were switched back to the initial VCV mode. Haemodynamics were maintained throughout the study with a mean arterial pressure (MAP) >70 mmHg, CI >2 l min-1 m-2, and an SVV <15%. If MAP fell below 70 mmHg, intravenous ephedrine (4–8 mg) was administered. If the SVV exceeded 15%, an additional intravenous fluid challenge was provided with 10 ml kg-1 of Ringer’s acetate solution or hydroxyethyl starch. Pulse oximetry-monitored oxygen saturation was allowed to drop to a lower limit of 93%. When these parameters exceeded the predetermined limits, alveolar recruitment manoeuvres consisting of applying a continuous positive airway pressure of 30 cmH2O for 30 seconds were conducted, and the ventilator setting was changed by increasing the respiratory rate and FiO2 and increasing or decreasing the set tidal volume.

Outcomes

The primary outcome was the change in serum IL-6 levels, which was used as a surrogate marker for both surgical- and ventilator-induced lung injury. The proinflammatory cytokines, IL-8 and IL-1β, were also evaluated [14]. Each cytokine was measured at TBaseline (20 min after the initial setting) and TEnd (end of surgery). The secondary outcome included VDphys, which was calculated as [VDphys = VTE × (PaCO2—PECO2) PaCO2-1]. Expired tidal volume (VTE) and expired CO2 partial pressure (PECO2) were measured with volumetric capnography. Static compliance (Cstat) was modified as [Cstat = VTI/(Pplat—PEEP)] (VTI, inspired tidal volume measured by volumetric capnography; Pplat, plateau airway pressure). Driving pressure was calculated as (Driving pressure = Pplat−PEEP). Each respiratory or haemodynamic parameter was measured at TBaseline and T2h (2 h after intervention). The incidences of permissive hypercapnia (PaCO2 > 50 mmHg) and respiratory complications were also recorded.

Statistical analysis

Based on previous study data [14], the calculated sample size was 14 subjects per group to detect differences in IL-6 concentration between the ventilatory settings with the given one-sided test with a power of 0.8 and a type I error rate of 0.05 based on an estimated difference of 1 of the parameter’s estimated SD.

All parametric data were described using mean (SD) and the non-parametric data using median (first and third quartiles). Parametric data comparisons were performed using Student’s t-test and non-parametric data analyses were conducted using the Mann-Whitney U test. The association between serum cytokines and other parameters was evaluated using Spearman's correlation coefficient, and the association between the other continuous variables was evaluated using linear regression analysis. P-values <0.05 were considered statistically significant. Statistical analyses were performed using EZR provided by the Comprehensive R Archive Network.

Results

A detailed study flow chart is presented in Fig 1. The enrolment of patients started on 6 December 2017. A total of 39 consecutive patients who were undergoing robot-assisted laparoscopic radical prostatectomy were screened; five patients did not meet the inclusion criteria, and six patients refused consent. Written informed consent was obtained from the 28 eligible patients who were randomly divided into the following two groups: 1) the VCV group (n = 14) and 2) the EF-initiated PC-IRV group (n = 14). Thus, 14 patients from each group were analysed.

Fig 1

CONSORT diagram of patient recruitment for the comparisons between volume-controlled ventilation (VCV) and expiratory flow-initiated pressure-controlled inverse ratio ventilation (EF-initiated PC-IRV).

There were no significant differences in patient and surgical characteristics between the two groups (Table 2).

Table 2

Patient and surgery characteristics.

		VCV group (n = 14)	EF-initiated PC-IRV group (n = 14)	aP-value
Patient characteristics (all men)
	Age (years)	67.8 ± 5.9	69.3 ± 4.4	0.49
	Height (cm)	168 ± 4.4	166 ± 5.4	0.33
	Weight (kg)	70.9 ± 10.6	71.2 ± 11.5	0.8
	Body mass index (kg m-2)	25.1 ± 3.3	25.6 ± 3.6	0.71
	FVC % predicted (%)	106 ± 14	108 ± 13	0.82
	FEV1% predicted (%)	78.1 ± 8.1	80.5 ± 6.4	0.43
	ASA physical status; 1/2/3 (n)	4/10/0	2/12/0	0.65
Surgery characteristics
	Duration of surgery (min)	228 ± 64	204 ± 36	0.24
	Duration of the Trendelenburg position and pneumoperitoneum (min)	191 ± 55	175 ± 43	0.41
	Perioperative blood loss (ml)	260 ± 195	180 ± 139	0.45

Values are presented as the mean ± SD or numbers.

aP-values are from Fisher’s exact test (qualitative data) or Mann-Whitney U test (quantitative data), respectively. VCV, volume-controlled ventilation; EF-initiated PC-IRV, expiratory flow-initiated pressure-controlled inverse ratio ventilation; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second.

The I:E ratio in the EF-initiated PC-IRV group was 1.8 ± 0.2 (10 patients at 2:1 ratio and 4 patients at 1.5:1 ratio), and the I:E ratio in the VCV group was 0.5 (14 patients at 1:2 ratio). Although there were significant differences in VDphys/VTE and SVV between the EF-initiated PC-IRV group and the VCV group, there were no significant differences in any of the other respiratory or haemodynamic parameters between the two groups (Table 3).

Table 3

Ventilator settings and respiratory and haemodynamic variables.

Variable	Time period	VCV group	EF-initiated PC-IRV group		95% CI of the difference	aP-value
		VCV strategy	VCV strategy	PC-IRV strategy
Respiratory rate (beats min-1)	TBaseline	12	12
	T2h	13.4 ± 1.7		13.2 ± 1.5	-1.6 to 1	0.62
Expired tidal volume (ml)	TBaseline	522 ± 34	527 ± 32		-21.7 to 32.3	0.69
	T2h	453 ± 62†		471 ± 66†	-35.1 to 70	0.5
Plateau pressure (cmH2O)	TBaseline	13.8 ± 1.5	14.4 ± 1.9		-8.3 to 2	0.41
	T2h	24.3 ± 2.9†		23.4 ± 2.9†	-3.3 to 1.4	0.42
Driving pressure (cmH2O)	TBaseline	8.9 ± 1.5	9.4 ± 2		-0.83 to 1.97	0.41
	T2h	19.4 ± 2.9†		18.9 ± 2.5†	-2.95 to 1.95	0.68
PaCO2 (mmHg)	TBaseline	36.6 ± 4	36.6 ± 2.9		-3.1 to 2.6	0.84
	T2h	46.3 ± 5.5†		43.8 ± 4.6†	-1.3 to 1.6	0.22
ETCO2 (mmHg)	TBaseline	33.3 ± 2.5	32.4 ± 2.9		-3.1 to 1.2	0.39
	T2h	39.3 ± 3.3†		38.7 ± 3.6†	-3.3 to 2.2	0.67
PaO2/FIO2 (ratio)	TBaseline	409 ± 86	381 ± 93		-99.5 to 44.7	0.44
	T2h	374 ± 97		365 ± 84	-82.8 to 63.7	0.79
Static compliance (ml cmH2O-1)	TBaseline	63.5 ± 9.8	61 ± 11.3		-11 to 6.1	0.56
	T2h	25.2 ± 6.6†		26.2 ± 7.9†	-4.8 to 6.9	0.73
VDphys/VTE (ratio)	TBaseline	0.38 ± 0.05	0.37 ± 0.03		-0.04 to 0.03	0.67
	T2h	0.4 ± 0.07		0.31 ± 0.06†	-0.15 to -0.04	<0.001
Cardiac index (l min-1 kg-1)	TBaseline	2.3 ± 0.2	2.4 ± 0.5		-0.2 to 0.4	0.5
	T2h	2.4 ± 0.5		2.3 ± 0.4	-0.54 to 0.25	0.46
Stroke volume variation (%)	TBaseline	7 ± 3.2	8.3 ± 2.3		-0.95 to 3.5	0.25
	T2h	8.3 ± 2.9		11.6 ± 2.8†	0.92 to 5.5	0.008

Values are presented as the mean ± SD.

aP-values are from Student’s t-test.

†P<0.05 compared with TBaseline (paired t-test). VCV, volume-controlled ventilation; EF-initiated PC-IRV, expiratory flow-initiated pressure-controlled inverse ratio ventilation; TBaseline, 20 min after the initial setting; T2h, 2 h after randomisation; PaO2/FiO2, partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen; VDphys/VTE, physiological dead space/expired tidal volume.

Further, there were no significant differences in serum IL-6 and IL-8 levels between the VCV and EF-initiated PC-IRV groups (Table 4).

Table 4

Changes in serum cytokine levels.

	Time period	VCV group	EF-initiated PC-IRV group	aP-value
IL-6 (pg ml-1)	TBaseline	8 [8–8]	8 [8–8]	-
	TEnd	31 [24.5–59]	34 [20.5–63.5]	0.84
IL-8 (pg ml-1)	TBaseline	8 [8–8]	8 [8–8]	-
	TEnd	8 [8–9]	8 [8–9.75]	0.62

Values are presented as the median [first and third quartiles].

aP-values are from The Mann–Whitney U test. VCV, volume-controlled ventilation; EF-initiated PC-IRV, expiratory flow-initiated pressure-controlled inverse ratio ventilation; TBaseline, 20 min after the initial setting; TEnd, end of surgery.

Measurements of IL-1β were discontinued after 10 patients because no increases were detected. There was a significant positive correlation between serum IL-6 at TEnd and the duration of surgery in both the EF-initiated PC-IRV group (r = 0.82, P<0.001) and the VCV group (r = 0.85, P<0.001) (Fig 2), and the duration of the Trendelenburg position and pneumoperitoneum in both the EF-initiated PC-IRV group (r = 0.83, P<0.001) and the VCV group (r = 0.88, P<0.001).

Fig 2

Correlation between serum IL-6 at TEnd and the duration of surgery in the volume-controlled ventilation (a) and expiratory flow-initiated pressure-controlled inverse ratio ventilation groups (b).

The VDphys/VTE ratio in the EF-initiated PC-IRV group was significantly smaller than that in the VCV group at T2h (Table 2). The VDphys/VTE ratio at T2h was also negatively correlated with preoperative FVC (% predicted) (r = -0.85; 95% CI -0.95 to -0.56; P<0.001) and Cstat (r = -0.63; 95% CI -0.88 to -0.12; P = 0.02) in the VCV group; however, the VDphys/VTE ratio was not correlated with either parameter in the EF-initiated PC-IRV group FVC (% predicted)(r = 0.15; 95% CI -0.42 to 0.6; P = 0.62) and Cstat (r = 0.17; 95% CI -0.39 to 0.65; P = 0.55) (Fig 3).

Fig 3

Correlation between forced vital capacity (% predicted) and physiological dead space/expired tidal volume at T2h in the volume-controlled ventilation (a) and expiratory flow-initiated pressure-controlled inverse ratio ventilation groups (b). *VDphys/VTE, physiological dead space/expired tidal volume; †FVC (% predicted), forced vital capacity (% predicted).

Two patients became difficult to ventilate and required permissive hypercapnia in the VCV group, PaCO2 over 50 mmHg with plateau pressure of 30 cmH2O, respiratory rate of 18 bpm. One patient with a low FVC (% predicted) of 79% required permissive hypercapnia (PaCO2 = 60.7 mmHg) during the entire Trendelenburg position and CO2 pneumoperitoneum period. This patient had a VDphys/VTE of 59%, Cstat of 13 ml cm H2O-1, driving pressure of 24 cm H2O-1, respiratory rate of 18 bpm, and VTE/IBW of 4.9 ml kg-1 at T2h. Another VCV patient with an FVC (% predicted) of 92% had a VDphys/VTE of 45%, Cstat of 22 ml cm H2O-1, driving pressure of 20 cm H2O-1, respiratory rate of 14 bpm, VTE/IBW of 6.4 ml kg-1, and PaCO2 of 49.3 mmHg at T2h. However, this patient required permissive hypercapnia (PaCO2 = 52.7 mmHg) four hours after the Trendelenburg position and CO2 pneumoperitoneum period. Permissive hypercapnia was not observed in any of the patients in the EF-initiated PC-IRV group. Despite the low FVC (% predicted) value of 80% and low Cstat of 16 ml cm H2O-1, it was easy to ventilate with a VDphys/VTE of 22%, VTE/IBW of 6.2 ml kg-1, and PaCO2 of 41 mmHg.

No instances of respiratory complications were recorded.

Discussion

There were no significant differences in serum cytokines change between the two ventilation strategies. The expired tidal volume fell to about ≤6 ml kg-1 (IBW) at a plateau pressure of 30 cmH2O in patients with a low FVC (% predicted), and this led to permissive hypercapnia, which may have been lung-protective. Both VCV and EF-initiated PC-IRV strategies were conducted with a plateau pressure upper limit of 30 cmH2O, and there were no significant differences in expired tidal volume, plateau pressure, and driving pressure between the groups. Thus, the mechanical stress to alveoli is comparable, leading to an equivalent lung-protective property. Although PC-IRV prolongs the plateau time, it does not seem to affect mechanical stress when the tidal volume, plateau pressure, and driving pressure are the same condition. Moreover, IL-6 was correlated with the duration of surgery, and we observed small increases in IL-6, IL-8, and IL-1β in several cases when the duration of surgery was ≤200 min. Michelet P et al also evaluated serum IL-6 and IL-8 to compare the lung-protective strategy with conventional ventilation in patients undergoing esophagectomy. Mean duration of surgery was 300 min, longer than our study, serum IL-6 and IL-8 increased more than our study, resulted in significant differences [14]. Serum IL-6 and IL-8 would not increase in short duration of anaesthesia, surgery and CO2 pneumoperitoneum. Further, in normal static compliance and FVC % predicted cases, there is no difficulty in the respiratory management with both VCV and EF initiated PC-IRV strategies. Therefore, evaluating serum cytokines in patients with healthy lungs who are undergoing surgery under general anaesthesia may require longer ventilation.

The EF-initiated PC-IRV strategy reduced VDphys, but there were no other significant advantages with respect to the respiratory or haemodynamic parameters as compared with the VCV strategy. Tweed and Tan also studied the efficiency of PC-IRV for general anaesthesia during lower abdominal surgery and found minimal improvements in gas exchange [15]. In our study, most patients who underwent the VCV strategy had healthy lungs, normal peak inspiratory and plateau pressures, normal PaCO2 and PaO2, and no need to increase the respiratory rate despite the increased VDphys. In the cases of normal respiratory compliance, a sufficient tidal volume compensated for increased VDphys and led to no differences between the VCV and PCV groups. However, difficulties in ventilation were encountered during the VCV strategy in patients with low respiratory compliance, Cstat, and FVC (% predicted) due to the increase in VDphys/VTE. These patients required permissive hypercapnia to avoid lung injury because of high peak inspiratory and plateau pressures and an increased respiratory rate. Although Cstat and FVC (% predicted) showed a negative correlation with the VDphys/VTE ratio during the Trendelenburg position and CO2 pneumoperitoneum period in the VCV strategy, this correlation was not observed in patients who underwent the EF-initiated PC-IRV strategy. Thus, the VCV strategy considerably increased VDphys in patients with low respiratory compliance; therefore, EF-initiated PC-IRV may be especially effective in maintaining ventilation in patients with low respiratory compliance during robot-assisted laparoscopic radical prostatectomy.

PCV has been used to reduce lung injury associated with increases in peak inspiratory pressure by VCV in patients with acute respiratory distress syndrome and low respiratory compliance [16]. However, the peak inspiratory pressure was lower in the PCV group than that in the VCV group in patients with healthy lungs who were undergoing laparoscopic surgery and robot-assisted laparoscopic radical prostatectomy under general anaesthesia. Still, there were no advantages in maintaining respiratory mechanics or haemodynamics [17-20]. Moreover, Cadi and colleagues reported that lung oxygenation was improved in patients who underwent PCV as compared with that in patients who underwent VCV owing to better alveolar recruitment in patients with obesity during laparoscopic surgery; however, PCV did not reduce VDphys [21]. A respiratory rate of 18 beats min-1 and an I:E ratio of 1:2 were employed, and this led to a short plateau duration and potentially lower improvement of dead space with PCV. Our findings indicate that PCV is more effective than VCV in patients with low respiratory compliance; however, PCV requires a sufficient plateau time to reduce the dead space. A prolonged inspiratory plateau time enhances gas diffusion from the alveoli into the airway, and this ultimately improves extra alveolar-derived pulmonary ventilation/perfusion (V/Q) mismatch = ∞ [13, 22, 23]. It also sufficiently expands the slow opening alveoli and enhances gas diffusion from the pulmonary artery into alveoli, which leads to improvements in inspiratory time-dependent V/Q mismatch <1 [13]. The short expiratory time in conventional PC-IRV may present a risk of lung hyperinflation and circulatory depression [9]. EF-initiated PC-IRV maintains a moderate total PEEP level with a lower risk of dynamic pulmonary hyperinflation. Moderate total PEEP prevents atelectasis and improves V/Q mismatch = 0 [13]. Therefore, EF-initiated PC-IRV provides an adequate expiratory time, a moderately sufficient inspiratory time, improves V/Q mismatch, effectively reduces VDphys, and decreases the risk of dynamic pulmonary hyperinflation.

Our study had several limitations. First, both VCV and EF-initiated PC-IRV strategies were conducted with a plateau pressure upper limit of 30 cmH2O, which led to a comparable alveolar response to mechanical stress. However, EF-initiated PC-IRV reduced VDphys, which may lead to a reduction in tidal volume, plateau pressure, and driving pressure. Second, this study included patients with normal respiratory compliance for a short duration of surgery; therefore, there were small differences between the VCV and EF initiated PC-IRV strategies. Further studies that include patients with low respiratory compliance under long-term general anaesthesia and ventilatory strategies that are targeted with PaCO2 and PaO2 but not tidal volume nor plateau pressure are warranted to determine the utility and lung-protective properties of EF-initiated PC-IRV.

Conclusions

There were no differences in the lung-protective properties between the VCV and EF-initiated PC-IRV strategies with a plateau pressure upper limit of 30 cmH2O. However, VCV increased VDphys and sometimes required permissive hypercapnia to prevent high plateau pressure in patients with a low FVC (% predicted). EF-initiated PC-IRV reduced VDphys and facilitated effective CO2 elimination; thus, it may be useful for reducing the ventilatory volume that is necessary to maintain normocapnia in low respiratory compliance situations, such as the Trendelenburg position and CO2 pneumoperitoneum, in patients with a low FVC (% predicted).

CONSORT checklist.

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Japanese protocol submitted to IRB.

(DOCX)

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English protocol.

(DOCX)

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Dataset.

(XLSX)

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1 Aug 2020

PONE-D-20-10447

Lung-protective properties of expiratory flow-initiatedpressure-controlled inverse ratio ventilation:  A randomised controlled trial

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4. In your Methods section, please provide additional information about the participant recruitment method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as: a) the recruitment date range (month and year).

5. Please provide a sample size and power calculation in the Methods, or discuss the reasons for not performing one before study initiation.

6.Thank you for stating the following financial disclosure:

[The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.].

At this time, please address the following queries:

Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

If any authors received a salary from any of your funders, please state which authors and which funders.

If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: It is thought that the results of previous studies suggesting that the serum cytokines selected in this study could was used as a surrogate marker for lung injury should be included in the introduction or discussion. In addition, I think it is necessary to consider why there were no differences of cytokines between the two groups although EF-initiated PC-IRV reduce dead space. The primary endpoint of this study was not change of respiratory mechanics but the change of serum cytokines.

Page 4, 91-93. Has the same surgeon performed surgery on all enrolled patients?

Page 6, 158-160. Please add references about the cytokines selected in this study.

Page 6, 172-175. Was there data regarding serum cytokine obtained from previous studies or preliminary study for calculating the sample size? Please describe the sample size calculation in more detail.

Page 6, 175-178. What are the criteria for using non-parametric and parametric methods differently depending on the type of variable? Did you perform a normality test?

Page 9, 231-233. In this study, correlation analysis was performed between IL-6 and the duration of surgery. Did your group conduct correlation analysis between cytokine and duration of the Trendelenburg position?

Page 10, 270-272. The meaning of the sentence regarding permissive hypercapnia is not clear. Can permissive hypercapnia in two patients observed only in VCV give special significance compared to PC-IRV?

Page 11, 280-282. Isn't the duration of the Trendelenburg position and pneumoperitoneum more meaningful than simply duration of surgery?

Page 11, 303-308. The meaning of this paragraph is unclear. It was noted that the peak inspiratory pressure was lower in the PCV group than that in the VCV in patients with laparoscopy and robot surgery. Why were there advantages in maintaining respiratory mechanics?

Reviewer #2: It is well written and well designed study

These are my suggestions

It would be better to give the ventilator strategy as a scheme in to the method part

It would be better to add VDshunt/VTE , ETCO2 , PaCO2-PetCO2 in results and table 2

Is PVC statement in line 306 actually PCV ?

Reviewer #3: A prospective two-arm randomized clinical trial was conducted to compare differences in serum cytokine levels in men undergoing robot-assisted laparoscopic radical prostatectomy. No significant differences in IL-6 levels at the end of surgery were observed between the two arms.

Minor revisions:

1- Line 91: Provide specific details on how the randomization list was generated. If randomized blocks were used, indicate the block size.

2- Line 172: Provide more complete details for the statistical power calculation. The power calculation should include: sample size, alpha level (indicating one or two-sided), minimal detectable difference and statistical testing method.

3- Line 175 states, “The Mann–Whitney U test was used to compare differences in the serum

cytokine levels between the two groups.” To clarify, was the Mann-Whitney U test used to compare differences only at the end of surgery?

4- Line 187: Clarify that the patients were randomized rather than simply divided.

5- Table 1: In the statistical analysis section, state the statistical methods used to compare patient and surgery characteristics shown in Table 1. If data is normally distributed, summarize the results using mean and standard deviation. If the data is not normally distributed provide the median, first and third quartiles. Use nonparametric tests (Mann-Whitney U-test) to compare groups when the distribution of the data is not normally distributed. Use parametric tests (t-tests) to compare groups with normally distributed data.

6- Table 2: Tests of the interaction of arm by time is more appropriate than repeatedly applying t-tests when comparing the data shown in Table 2.

7- Line 232: Clarify the rs notation. There appears to be a typographical error “rs=0,082”.

8- The p-value associated with a correlation is a test of the null hypothesis: correlation equal to zero; however, the absolute magnitude of the coefficient indicates the strength of the linear relationship between two variables. In general, the strength or correlation coefficient is the more important statistic to reflect upon.

Below is a table for interpreting correlation coefficients:

Coefficient (absolute value) Interpretation

0.90 - 1.0 Very Strong

0.70 - 0.89 Strong

0.40 - 0.69 Moderate

0.10 - 0.39 Weak

less than 0.10 Negligible correlation

9- Indicate if adverse events were collected according to a standardized method.

10- Add the correlation coefficients to Figures 2 and 3.

11- Indicate the funding source(s), and the role of the funder(s)?

12- All acronyms and abbreviations must be spelled out in first use.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: revision suggestions.docx

Click here for additional data file.

26 Aug 2020

Thank you very much for your letter dated August 1. On behalf of all of the authors, I would like to re-submit our revised manuscript titled “Lung-protective properties of expiratory flow-initiated pressure-controlled inverse ratio ventilation: A randomised controlled trial” (manuscript ID: PONE-D-20-10447) for publication in PLOS One.

We would like to thank you and the reviewers for the helpful comments, which we feel have helped us improve our manuscript.

Submitted filename: revision_suggestions8.26.docx

Click here for additional data file.

19 Oct 2020

PONE-D-20-10447R1

Lung-protective properties of expiratory flow-initiated pressure-controlled inverse ratio ventilation:  A randomised controlled trial

PLOS ONE

Dear Dr. Hirabayashi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Dec 03 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Steven Eric Wolf, MD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Editor - Thank you for resubmitting your paper. As promised, I sent it back to the original referees who are now almost completely satisfied save a few minor issues. Please carefully consider the comments below and reply directly to each in a cover letter with appropriate marked and linked changes to the manuscript. I look forward to receiving the next version which I will handle personally for timeliness.

If data is normally distributed, summarize using mean (SD) and compare using parametric methods, possibly t-tests. However, if data is non-parametic summarize using median (first and third quartiles) and compare using non-parametic method such as Mann Whitney U tests.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: N/A

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: If data is normally distributed, summarize using mean (SD) and compare using parametric methods, possibly t-tests. However, if data is nonparametic summarize using median (first and third quartiles) and compare using nonparametic method such as Mann Whitney U tests.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

31 Oct 2020

We thank you and the reviewers for your thoughtful suggestions and insights. The manuscript has benefited from this valuable feedback. We have reviewed our manuscript and made necessary changes in accordance with the reviewers’ suggestions. We have also prepared point-by-point responses to all comments and have attached them herewith. All revisions are marked using Tracked Changes in the revised manuscript and although we have also not listed all minor changes made to the manuscript in the rebuttal letter, none of those changes has modified the content, conclusions, or framework of the paper.

We look forward to working with you and the reviewers to move this manuscript closer to publication in PLOS One.

Submitted filename: revision_suggestions_10_26.docx

Click here for additional data file.

2 Dec 2020

Lung-protective properties of expiratory flow-initiated pressure-controlled inverse ratio ventilation:  A randomised controlled trial

PONE-D-20-10447R2

Dear Dr. Hirabayashi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Steven Eric Wolf, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

9 Dec 2020

PONE-D-20-10447R2

Lung-protective properties of expiratory flow-initiated pressure-controlled inverse ratio ventilation: A randomised controlled trial

Dear Dr. Hirabayashi:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Steven Eric Wolf

Academic Editor

PLOS ONE