Temporary increase in tidal volume to improve the reliability of dynamic preload indices during robot-assisted laparoscopic surgery in the Trendelenburg position with lung-protective ventilation

Background: Pulse pressure variation (PPV) and stroke volume variation (SVV) induced by mechanical ventilation are widely used as predictors of fluid responsiveness. However, the reliability of these dynamic preload indices is controversial under pneumoperitoneum. In addition, the usefulness of these indices is being called into question with the increasing adoption of lung-protective ventilation using low tidal volume (VT) in surgical patients. We investigated whether increasing tidal volume (VT) from 6 to 8 ml/kg can improve the predictive power of PPV and SVV during pneurmoperitoneum. Methods: We performed a prospective observational study in patients undergoing robot-assisted laparoscopic surgery in the Trendelenburg position under lung-protective ventilation. PPV, SVV, and the stroke volume index (SVI) were measured at a VT of 6 mL/kg and 3 minutes after increasing the VT to 8 mL/kg. The VT was reduced to 6 mL/kg, and measurements were performed before and 5 minutes after volume expansion (infusing 6% hydroxyethyl starch 6 ml/kg over 10 minutes). Fluid responsiveness was defined as ≥ 15% increase in the SVI. Results: Twenty-four of the 38 patients enrolled in the study were responders. In the receiver operating characteristic curve analysis, the augmented PPV and SVV associated with a temporary increase in VT from 6 to 8 ml/kg improved the predictability of fluid responsiveness, with area under the curve (AUC) values of 0.85 (95% confidence interval (CI), 0.70–0.95, P < 0.0001) and 0.77 (95% CI 0.61–0.89, P = 0.0003), compared to PPV and SVV values (as measured by VT) of 6 ml/kg. The absolute change in PPV and SVV values obtained by transiently increasing VT also predicted fluid responsiveness, with AUC values of 0.95 (95% CI 0.83– 0.99, P < 0.0001) and 0.76 (95% CI 0.60–0.89, P = 0.0006). Conclusions: Augmented PPV and SVV values, and absolute changes therein obtained by increasing VT from 6 to 8 ml/kg, parameters were compared between responders and non-responders using the Mann–Whitney U-test or t -test, as appropriate. The effects of the temporary increase in V T from 6 to 8 ml/kg and VE on hemodynamic parameters were assessed using the paired t -test or the Wilcoxon signed-rank sum test after the normality test. A Bonferroni-adjusted P -value (normal P -value multiplied by the number of outcomes being tested) was used to control for multiple comparisons.

flow (RBF) and post-operative renal dysfunction [2,3]. As the level of hydration required to maintain RBF under pneumoperitoneum depends on the baseline volume status [4], an adequate assessment of intravascular volume and optimal fluid management are important [5].
Dynamic preload indices such as pulse pressure variation (PPV) and stroke volume variation (SVV), are generally accepted as accurate indicators of fluid responsiveness during surgery and in the intensive care unit [6,7]. To optimize surgical conditions, robot-assisted laparoscopic surgery requires pneumoperitoneum and the Trendelenburg position, which have been shown to significantly alter respiratory mechanics [8]. As dynamic preload indices are generated by cyclic transmission of airway pressure to the pleural and pericardial spaces under positive ventilation, their reliability can be affected under these conditions. Several studies have highlighted the effect of intra-abdominal pressure (IAP) on the accuracy and cut-off values of these indices [9][10][11][12][13]. In addition, as the application of lung-protective ventilation using low tidal volume (V T ) with positive end expiratory pressure (PEEP) is gradually increasing in surgical patients [14][15][16], the usefulness of these indices during robot-assisted laparoscopic surgery has been questioned.
It has been clearly shown that the values of dynamic indices are significantly correlated with the magnitude of V T [17,18]. Min et al. [19] reported that augmentation of PPV and SVV via a temporary increase in V T from 8 to 12 ml/kg improved their predictive power in mechanically ventilated patients during surgery. Another recent study reported that on increasing V T from 6 to 8 ml/kg, augmented PPV and SVV, as well as their absolute changes, predicted fluid responsiveness with high sensitivity and specificity, even in critically ill patients receiving low V T [20]. Therefore, the aim of the current study was to investigate whether increasing V T from 6 to 8 ml/kg would improve the predictive power of PPV and SVV in patients undergoing robot-assisted laparoscopic surgery in the Trendelenburg position under lung-protective ventilation. We also assessed the ability of absolute changes in PPV and SVV values induced by a temporary increase in V T from 6 to 8 ml/kg to predict fluid responsiveness.

Study design and patient population
This prospective observational study was approved by the institutional review board of Hallym University Kangnam Sacred Heart Hospital (approval number: 2017-09-003). From March to June 2018, adult patients undergoing robot-assisted laparoscopic surgery with pneumoperitoneum in the Trendelenburg position were enrolled after obtaining their written informed consent. The trial was registered prior to patient enrollment at ClinicalTrials.gov (NCT03467711). Reporting of data was done in accordance with the STROBE guideline for observational trials [21]. Exclusion criteria were body mass index (BMI) > 30 or < 15 kg/m 2 , preoperative arrhythmia, moderate to severe valvular heart disease, preoperative left ventricular ejection fraction < 40%, right ventricular dysfunction, intracardiac shunt, 1-second forced expiratory volume < 60% of predicted value, moderate to severe renal or liver disease, new-onset arrhythmia after anesthesia induction, and contraindications for oesophageal Doppler monitor (ODM) probe insertion (i.e., oesophageal stent, carcinoma of the esophagus or pharynx, previous oesophageal surgery, oesophageal stricture, oesophageal varices, pharyngeal pouch, and severe coagulopathy). During surgery, all patients were placed in the 25°T rendelenburg position, and pneumoperitoneum was achieved by continuous carbon dioxide insufflation maintaining an IAP of 15 mmHg.

Anesthetic technique
After the patients arrived at the operating room, pulse oximetry, three-lead electrocardiography (ECG), and non-invasive arterial pressure monitoring were applied. Anesthesia was induced with propofol (1.5-2.5 mg/kg) and remifentanil (0.05-0.15 μg/kg/min), and tracheal intubation was facilitated with rocuronium (0.8 mg/kg). The patient's lungs were mechanically ventilated with a mixture of oxygen in air, with an inspired oxygen fraction of 0.5 using the volume-controlled mode. V T was adjusted to 6 ml/kg predicted body weight (PBW, determined as x + 0.91[height (in cm) − 152.4], where x = 50 for males and x = 45.5 for females) [22]. The PEEP of 5 cm H 2 O was applied without inspiratory pause. Respiratory rate was adjusted to maintain an end-tidal carbon dioxide tension between 35 and 40 mmHg. The inspiratory to expiratory ratio was set to 1:2. Peak inspiratory airway pressure (PIP) and compliance of the respiratory system (Crs) were recorded from the anesthesia machine (Datex-Ohmeda Avance CS 2 Anesthesia Machine; GE Healthcare, Helsinki, Finland).

Hemodynamic monitoring
After induction of anesthesia, a radial arterial catheter and ODM probe (CardioQ; Deltex Medical, Chichester, UK) were inserted. Both were connected to the CardioQ-ODM+ (Deltex Medical Ltd.) monitor.
The ODM probe was positioned to obtain the optimum signal for descending aorta blood velocity.
Stroke volume index (SVI), and peak velocity (PV) were measured continuously and displayed, and their mean values were calculated over 10 s.
After zeroing the arterial transducer, a flush test was performed to ensure that the arterial pressure measurement system was critically damped. The arterial pulse pressure wave was simultaneously monitored through the patient monitor (CARESCAPE Monitor B850; GE Healthcare) and CardioQ-ODM+ monitor using a serial cable. The patient monitor displayed the automatically calculated PPV in real time using the algorithms described previously [23].

PPV (%) = [(PP max -PP min ) / PP mean ] × 100
where PP max and PP min represent the maximum and minimum arterial pulse pressure (PP), and PP mean is the mean arterial PP.
The CardioQ-ODM+ monitor combines ODM with pulse pressure wave analysis to measure SVI. It uses ODM-derived SVI for initial and periodic calibrations, and then continuously calculates pulse pressure wave analysis-derived SVI using the Liljestrand-Zander formula [24]. By continuous beat detection and analysis, the SV, SVI, and SVV were displayed continuously in a separate pressure-based data window as a column of values. SVV were obtained as described previously, regardless of the respiratory cycle [25]. SVV (%) = [(SV max -SV min )/SV mean ] × 100 where SV min and SV max are the minimum and maximum SV values over one respiratory cycle, respectively.
All values were averages of at least three consecutive measurements acquired over 30 s. An independent investigator who was trained in maneuvering the ODM probe but was not involved in the present study assessed ODM and all other variables during the study. ODM is routinely used to monitor surgical patients in our center and shows good inter-observer reliability [12]. Fig. 1. shows a schematic representation of the protocol, which was initiated at least 1 hour after increasing IAP to 15 mmHg, and after stabilization of hemodynamic parameters, defined as changes in mean arterial pressure (MAP) < 10% during 5 minutes. In addition, to minimize acute changes in IAP and sympathetic tone due to ongoing surgery [26,27], which could confound the effects of fluid challenge, the study protocol was performed with little or no surgical stimulation (absence of cautery and instrumentation of intra-abdominal structures).

Study protocol
We first measured the hemodynamic response to a temporary increase in V T from 6 to 8 ml/kg, and then performed volume expansion (VE) to assess the subsequent changes in SVI. The first set of measurements, including (HR), MAP, SVI, PV, PIP, C rs , PPV with 6 ml/kg PBW V T ventilation (PPV 6 ), and SVV with 6 ml/kg PBW V T ventilation (SVV 6 ), were recorded at baseline (T1, base 1). After the baseline measurement, V T was increased from 6 to 8 ml/kg PBW for 3 minutes. During the last minute of high V T ventilation, measurements of the above-mentioned hemodynamic and respiratory variables, including PPV with 8 ml/kg PBW V T ventilation (PPV 8 ) and SVV with 8 ml/kg PBW V T ventilation (SVV 8 ), were again recorded (T2). The changes in PPV and SVV values induced by a temporary increase in V T from 6 to 8 ml/kg (ΔPPV 6-8 and ΔSVV 6-8 ) were calculated as follows: After the V T was returned to 6 ml/kg PBW and all of the hemodynamic variables had returned to baseline values (variations < 10%), VE was performed for 10 minutes using an infusion of 6% hydroxyethyl starch (HES 130/0.4, Volulyte; Fresenius Kabi, Stans, Switzerland) 6 ml/kg PBW. Two sets of measurements (HR, MAP, SVI, PV, PIP, Crs, PPV, and SVV) were performed before (T3, base 2) and 5 minutes after VE (T4) [28,29]. Percentage differences in ODM-derived SVIs before and after VE were used as principal indicators of fluid responsiveness. Patients were classified as responders to VE if they showed an increase in SVI ≥ 15% and as non-responders if they showed an increase < 15% [30,31]. The changes in SVV and PPV values after VE (ΔPPV VE and ΔSVV VE ) were calculated as follows: With the expectation of a 10% dropout rate, 42 patients were enrolled in the study.
The normality of the continuous data was tested with the Shapiro-Wilk test. Data are presented as the mean (SD), median [interquartile range (IQR)], or number of patients (%).Student's t-test or the Mann-Whitney U test for continuous variables, and the chi-square test for categorical data, were used to compare patient characteristics between responders and non-responders. The hemodynamic parameters were compared between responders and non-responders using the Mann-Whitney U-test or t-test, as appropriate. The effects of the temporary increase in V T from 6 to 8 ml/kg and VE on hemodynamic parameters were assessed using the paired t-test or the Wilcoxon signed-rank sum test after the normality test. A Bonferroni-adjusted P-value (normal P-value multiplied by the number of outcomes being tested) was used to control for multiple comparisons.
The relations between percentage changes in SVI after VE and hemodynamic parameters before VE (PPV 6 , PPV 8 , ΔPPV 6-8 , SVV 6 , SVV 8 , and ΔSVV [6][7][8] were assessed using Spearman's rank correlation. The relationship between the percentage changes in SVI after and the changes in PPV and SVV after VE (ΔPPV VE and ΔSVV VE ) were also assessed using Spearman's rank correlation analysis. The intraclass correlation between the SVI, PPV, and SVV measurements at the two baseline steps (T1 and T3) was measured using random-effects models [32].
To test the abilities of dynamic preload indices to predict fluid responsiveness, the AUCs of receiver operating characteristic (ROC) curves were calculated and compared using the DeLong method.
Briefly, the general interpretations of a test according to the value of the AUC of the ROC were as follows: AUC = 0.5, no better than chance, a useless test with no prediction possible; AUC = 0.6-0.69, a test with a poor predictive capability; AUC = 0.7-0.79, a fair test; AUC = 0.8-0.89, a test with good predictive capability; AUC = 0.9-0.99, an excellent test; AUC = 1.0, a perfect test with the best possible prediction. An optimal threshold value was determined for each variable to maximize the Youden index (sensitivity + specificity -1). Statistical analyses were performed using MedCalc (ver. 15.6.1) and SPSS software (ver. 24.0; IBM Corp., Armonk, NY, USA). In all analyses, P < 0.05 was taken to indicate statistical significance.

Patient characteristics
Of the 49 patients included in the initial screen, 42 fulfilled the inclusion criteria and were enrolled in the study. Four patients were excluded; one developed intraoperative subcutaneous emphysema and required a ventilator mode change, one had severe hypotension during VE and required vasopressor support, one developed paroxysmal atrial fibrillation during surgery, and the remaining patient's arterial pressure measurement system was critically damped. Among the 38 patients included in the final analysis, 24 patients (63%) were responders and 14 (37%) were non-responders (Fig. 2). There were no significant differences in age, PBW, or BMI between responders and non-responders, whereas the surgery type and sex distribution differed between the two groups ( Table 1). The intraclass correlation between the SVI, PPV, and SVV measurements at the two baseline steps (T1 and T3) were 0.98 [95% confidence interval (CI), 0.96-0.99], 0.96 (95% CI, 0.92-0.98), and 0.81 (95% CI, 0.64-0.90), respectively.

Effects of increased V T and VE on hemodynamic and respiratory variables
At baseline, with 6 ml/kg PBW V T ventilation, no significant differences were found in any hemodynamic variables, including PPV 6 and SVV 6 , between responders and non-responders. After increasing V T to 8 ml/kg PBW, MAP decreased and PPV and SVV increased significantly only in responders, resulting in significant differences in MAP, PPV (PPV 8 ), and SVV (SVV 8 ) between responders and non-responders. Baseline PIP and Crs were comparable between the two groups and increased significantly after the temporary increase in V T from 6 to 8 ml/kg in responders and nonresponders ( Table 2).
Significant changes in PIP, Crs, SVI, and PPV were induced in responders and non-responders after VE, while significant decreases in HR and SVV were induced only in responders. (Table 2).
Relationships between changes in PPV and SVV induced by VE and percentage changes in SVI induced by VE PPV VE and ΔSVV VE were significantly correlated with VE-induced percentage changes in SVI (r = -0.61 [95% CI -0.78 to -0.36], P < 0.001; r = -0.44 [95% CI -0.67 to -0.14], P = 0.006, respectively) (Fig. 3), indicating the ability of these variables to track changes in SVI induced by VE during pneumoperitoneum.

Discussion
In this study on patients undergoing robot-assisted laparoscopic surgery in the Trendelenburg position under lung-protective ventilation, we demonstrated that augmentation of PPV and SVV via a temporary increase in V T , from 6 to 8 ml/kg, improved the predictability of fluid responsiveness compared to PPV and SVV measured with a V T of 6 ml/kg. The optimal thresholds of augmented PPV and SVV were > 7% and 5%, respectively. This study also showed that the absolute change in PPV and SVV values obtained by transiently increasing V T (ΔPPV 6-8 andΔSVV 6-8 ) can predict fluid responsiveness in these populations. The optimal thresholds of ΔPPV 6-8 and ΔSVV 6-8 were > 1% and > 2%, respectively.
Several studies have demonstrated that a temporary increase in V T directly augments the values of these dynamic indices and their capacity to predict fluid responsiveness [19,33]. Our study also demonstrated that a temporary increase in V T from 6 to 8 ml/kg improved the predictive power of PPV and SVV values, even in patients with elevated IAP. Because PPV and SVV values are augmented in fluid responders, but not in non-responders, the absolute changes in the PPV and SVV values induced by increased V T could also be used to predict fluid responsiveness with high sensitivity and specificity, which is consistent with a study by Myatra et al. [20]. Moreover, changes in PPV values induced by VE were significantly correlated with percentage changes in SVI induced by VE (Fig. 3), showing the ability of this variable to track changes in SV induced by VE during pneumoperitoneum. Thus, observing changes in PPV values during an increase in V T and VE can help predict and confirm fluid responsiveness when continuous cardiac output monitoring is unavailable.
Our study showed discordant results versus those of previous studies regarding the capacity of dynamic preload indices to predict fluid responsiveness during increased IAP [9][10][11][12][13]. In our study, PPV and SVV predicted fluid responsiveness at a V T value of 8 ml/kg. Hoiseth et al. demonstrated that PPV and SVV values at a V T of 8 ml/kg had a relatively poor capacity to predict fluid responsiveness during laparoscopy [12]. This discrepancy can be explained by those researchers not controlling clinical factors, such as blood loss, use of vasopressors, or changes in ventilator settings, which may have altered PPV values independent of the preload condition, whereas we performed VE under controlled clinical conditions with little or no surgical stimulation. Unlike our study, Renner et al. reported that increasing IAP abolished the ability of SVV values, but not PPV values, to predict fluid responsiveness [10]. Increased IAP leads to increased systemic vascular resistance (SVR) by activation of antidiuretic hormones and the sympathetic and renin-angiotensin-aldosterone systems [34]. However, the validity of the SV monitor used in Renner et al.'s study was influenced by SVR [35,36], whereas the CardioQ-ODM+ monitor used in our study calculates pulse pressure wave analysis-derived SV based on the Liljestrand-Zander formula, which has been reported to estimate SV accurately even during arterial load changes [24,37].
Higher PPV and SVV cut-off values for determining fluid responsiveness might be expected in our study population, because pneumoperitoneum decreases chest wall compliance, which increases the variation in pleural pressure associated with an increase in dynamic indices [38]. However, the PPV and SVV cutoff values in our study were not as high as in previous studies [9,10]. These results can be explained by two main factors: the application of small to moderate increases in IAP (10-15 mmHg) and a steep Trendelenburg position. The cardiopulmonary interactions that are altered during pneumoperitoneum depend on the level of IAP [21]. Indeed, previous animal studies have reported that IAP elevations > 20 mm Hg progressively increase the values of dynamic preload indices independent of volume status [10,11], while a lower IAP (10-15 mmHg) in the surgical setting does not modify the cut-off values [9,12,13]. Because the extent of the increase in SV during head-down tilt was unchanged by pneumoperitoneum [12], adding a steep Trendelenburg position to pneumoperitoneum may induce an increase in SV and could have contributed to a lower cutoff value than under pneumoperitoneum alone.
The optimal thresholds of ΔPPV 6-8 and ΔSVV 6-8 for discriminating fluid responsiveness were lower than those reported by Myatra et al. (>3.5% and 2.5%, respectively) [20]. There are several possible explanations for this discrepancy. Pneumoperitoneum and the Trendelenburg position significantly worsen respiratory mechanics by shifting the diaphragm cranially and facilitating transmission of abdominal weight to the lung parenchyma [8]. The extent to which Crs was increased by the temporary increase in V T from 6 to 8 ml/kg was lower in our study than in that by Myatra et al. (1 vs. 7 ml/cmH 2 O). As the extent of airway pressure transmission to the pleural space is decreased according to the degree of Crs [39], it can be assumed that pneumoperitoneum and the Trendelenburg position restricted the increase in Crs, and the increased V T induced a smaller variation in pleural pressure, resulting in smaller absolute changes in PPV and SVV values. In addition, the hemodynamic characteristics of the patients differed between the two studies; Myatra et al.
studied critically ill patients with acute circulatory failure who were tachycardic (mean HR > 130), whereas our study population consisted of patients with no clinical signs of shock who had a normal HR. As a decrease in HR can decrease the PPV [40,41], the higher baseline preload reserve in our patients would also have contributed to the less profound changes in PPV and SVV values.
This study had several limitations. First, the study population consisted of only a small number of highly selected patients receiving robot-assisted laparoscopic surgery in the Trendelenburg position.
As the IAP was maintained at 15 mmHg, our results cannot be extrapolated to different IAP values.
Our results require validation in a larger and more heterogeneous population. Second, ODM was used to track changes in SVI and measure the effects of preload changes. When IAP is increased, blood flow may be redistributed from the descending aorta to vessels leaving the aortic arch. [42] This may contribute to falsely reduced SVI, as ODM measures blood flow in the descending aorta. However, the trending ability of ODM to monitor changes in SVI during patient management is well established. [43,44] Therefore, we assumed that the trending ability of ODM was unaffected by pneumoperitoneum once established. Third, there were sex differences between the responders and non-responders, which may have been due to differences in types of surgery based on sex, resulting in different hemodynamic status at the start of the study protocol. However, we considered it unlikely that this

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Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available due to the regulation of Institutional Review Board, but are available from the corresponding author after getting permission from IRB for sharing the dataset on reasonable request. Values are mean ± SD, median (IQR) or number (%). comparisons of values before (T1) and after the tidal volume challenge (T2); P2-values are for intragroup comparisons of values before (T3) and after volume expansion (T4); P-values were adjusted using the Bonferroni correction    Comparison of receive -operating characteristic curves of PPV6, PPV8, SVV6, and SVV8 to predict fluid responsiveness during robot-assisted laparoscopic surgery in the Trendelenburg position under lung-protective ventilation. PPV6, pulse pressure variation during tidal volume at 6 ml/kg predicted body weight (PBW); PPV8, pulse pressure variation during tidal volume at 8 ml/kg PBW; SVV6, stroke volume variation during tidal volume at 6 ml/kg predicted body weight (PBW); SVV8, stroke volume variation during tidal volume at 8 ml/kg PBW; area under the ROC curve appears in cartouche with 95% confidence interval.

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