Individualized PEEP titration guided by intratidal compliance profile analysis improves regional ventilation – a randomized controlled trial

Background Application of positive end-expiratory pressure (PEEP) improves lung aeration and reduces mechanical stress during mechanical ventilation. Although numerous approaches for PEEP titration have been proposed, there is no accepted strategy to titrate optimal PEEP. By analyzing the intratidal compliance profiles, PEEP may be titrated patient-individually. Methods After obtaining informed consent, we measured respiratory system mechanics, regional ventilation in 60 consecutive patients undergoing elective surgery, randomly allocated to the control group (PEEP = 5 cmH2O) or the intervention group receiving individually titrated PEEP, guided by intratidal compliance profile analysis. Primary endpoint was the frequencies of nonlinear intratidal compliance (CRS) profiles of the respiratory system (horizontal, increasing, decreasing and mixed). We further investigated respiratory and hemodynamic variables and regional ventilation. Results Frequencies of CRS profiles were comparable between the groups. Besides PEEP control: 5.0 (0.0), intervention: 5.8 (1.1) cmH2O, p<0.001 respiratory and hemodynamic variables were comparable between the two groups. The compliance profile analysis showed no significant differences between the two groups. The loss of ventral and dorsal regional ventilation was higher in the control ventral: 41.0 (16.3) %, dorsal: 25.9 (13.9) % than in the intervention group ventral: 29.3 (17.6) %, dorsal: 16.4 (12.7) %, p (ventral) = 0.039, p (dorsal) = 0.028. Conclusions Individualized PEEP titration according to bedside compliance profile analysis improves regional ventilation without affecting respiratory and hemodynamic variables negatively and may be a promising approach to patient-individual ventilation setting. in consecutive with American physical status I-III, undergoing otorhinolaryngeal surgery The study was performed as a prospective parallel arm, randomized, controlled trial with an allocation ratio of 1:1. Randomization was carried out in blocks of 30 by a computer generated allocation sequence. Participiants were enrolled and assigned to the interventions by a study related anesthetist. Exclusion criteria were ASA physical status > III, age < 18 years, pregnancy, emergency procedure, cardiac pacemaker and other active implants, obesity (BMI ≥ 30 kg·m -2 ) history of pulmonary disease, laparoscopic surgery or refusal of participation.


Abstract
Background Application of positive end-expiratory pressure (PEEP) improves lung aeration and reduces mechanical stress during mechanical ventilation. Although numerous approaches for PEEP titration have been proposed, there is no accepted strategy to titrate optimal PEEP. By analyzing the intratidal compliance profiles, PEEP may be titrated patient-individually. Methods After obtaining informed consent, we measured respiratory system mechanics, regional ventilation in 60 consecutive patients undergoing elective surgery, randomly allocated to the control group (PEEP = 5 cmH2O) or the intervention group receiving individually titrated PEEP, guided by intratidal compliance profile analysis.
Primary endpoint was the frequencies of nonlinear intratidal compliance (CRS) profiles of the respiratory system (horizontal, increasing, decreasing and mixed). We further investigated respiratory and hemodynamic variables and regional ventilation. Results Frequencies of CRS profiles were comparable between the groups. Besides PEEP control: 5.0 (0.0), intervention: 5.8 (1.1) cmH2O, p<0.001 respiratory and hemodynamic variables were comparable between the two groups. The compliance profile analysis showed no significant differences between the two groups. The loss of ventral and dorsal regional ventilation was higher in the control ventral: 41.0 (16.3) %, dorsal: 25.9 (13.9) % than in the intervention group ventral: 29.3 (17.6) %, dorsal: 16.4 (12.7) %, p (ventral) = 0.039, p (dorsal) = 0.028. Conclusions Individualized PEEP titration according to bedside compliance profile analysis improves regional ventilation without affecting respiratory and hemodynamic variables negatively and may be a promising approach to patient-individual ventilation setting.

Background
During mechanical ventilation, it is widely accepted that the application of low tidal volume and low driving pressure [i.e. the difference between plateau pressure (P Plat ) and (positive) end-expiratory pressure (PEEP)] protect the lung from destructive effects of alveolar overdistension [1][2][3][4].
In combination with low tidal volumes, application of adequate PEEP and the performance of recruitment maneuvers was shown to improve postoperative pulmonary function, arterial oxygenation and to reduce health care utilization [2,5]. However, there are conflicting data regarding the setting of adequate PEEP during general anesthesia [6].
With regard to the conflicting clinical data, many techniques were developed to determine adequate PEEP [7][8][9][10]. One of these techniques, first described in 1979 for patients with severe lung injury [11], is based on setting the PEEP slightly above the lower inflection point of the inspiratory limb of the static pressure-volume (PV) curve [7,12,13]. Other techniques focus on the respiratory system compliance (C RS ). For example, PEEP can be titrated to reach the maximum quasi-static compliance, calculated by dividing V T by the driving pressure [10,14,15]. However, a single value compliance cannot reflect the nonlinearity of intratidal respiratory system mechanics during the breathing cycle [16,17] and therefore always a maneuver is required to identify the PEEP for maximal compliance.
To cope with the non-linearity of the intratidal C RS under the dynamic conditions of mechanical ventilation, the gliding-SLICE method [18,19] was introduced, enhancing the classical SLICE method [20,21]. In brief, the pressure-volume curve is subdivided in several volume steps and the volume dependent compliance is calculated on the base of data points within a certain volume range ('slice') around the current step via multiple linear regression analysis (Fig. 1). The resulting compliance-volume curve can then be classified as follows: An increasing compliance profile is interpreted to indicate intratidal recruitment, suggesting an increase of PEEP. A decreasing compliance profile indicates overdistension, suggesting a decrease of PEEP. A horizontal compliance profile is assumed preferable as it does not indicate either of both unwished conditions. According to these three basic compliance profiles, combinations may be observed [19] (Fig. 1). A previously described Decision Support System with a Graphical User Interface (GUI) implements the gliding-SLICE method into a user-friendly tool to recommend a bedside patient-individual PEEP titration during mandatory ventilation [22]. Using exemplary data from patients ventilated in the volume-and pressure-controlled mode, a theoretical study demonstrated that the Decision Support System allows to estimate the intratidal compliance-profiles and that the recommended PEEP adjustments directed to ventilation with horizontal compliance profiles [22].
The primary hypothesis of this randomized controlled clinical trial is that individualized PEEP titration based on the analysis of the intratidal compliance profile improves respiratory system mechanics and regional ventilation during perioperative mandatory ventilation, compared to a non-personalized PEEP ventilation technique. Therefore we determined frequencies of nonlinear intratidal compliance (C RS ) profiles, regional ventilation, and respiratory and hemodynamic variables in 60 mandatory ventilated consecutive patients undergoing otorhinolaryngeal surgery.

Ethics, consent and permission
The study was approved by the Ethics Committee of the University Medical Centre of Freiburg (vote # 268/15) on 29 th June 2015 and registered at the German Register for Clinical Trials (DRKS00008924). This study adheres to CONSORT guidelines.

Study design and patient population
After obtaining written informed consent from all individual participants included in the study, we studied respiratory mechanics, hemodynamic variables and regional ventilation in 60 consecutive patients with American Society of Anesthesiologists (ASA) physical status I-III, undergoing otorhinolaryngeal surgery at the Medical Center of the University of Freiburg, Germany. The study was performed as a prospective parallel arm, randomized, controlled trial with an allocation ratio of 1:1. Randomization was carried out in blocks of 30 by a computer generated allocation sequence. Participiants were enrolled and assigned to the interventions by a study related anesthetist. Exclusion criteria were ASA physical status > III, age < 18 years, pregnancy, emergency procedure, cardiac pacemaker and other active implants, obesity (BMI ≥ 30 kg·m -2 ) history of pulmonary disease, laparoscopic surgery or refusal of participation.

Procedure
After primary recruitment and preoperative evaluation, the patients received routine Ventilation frequency was set to maintain an end-tidal carbon dioxide partial pressure between 35 and 40 mmHg. The initial PEEP was set to 5 cmH 2 O, according to our local standard. Following baseline measurements, the randomization was disclosed. In the control group, this PEEP was maintained for the whole procedure, in the intervention group, the PEEP was adjusted dynamically according to the recommendations resulting from the intratidal compliance profile analysis (see below).

Gliding-SLICE
To calculate nonlinear intratidal C RS profiles of via the gliding-SLICE method, we chose a number of 21 equidistant slices as a tradeoff between calculation effort and reasonable resolution. The resulting intratidal compliance curves were classified into six different compliance profiles, as described earlier [21,24,25]. In brief, a second order polynomial was fit into the compliance-volume curve, and the resulting segment of a parabola was assumed to represent the compliance-volume curve in a filtered form. If the segment showed an increase of more than 20% of the compliance maximum, the profile was classified as containing an increasing part. A segment decreasing by more than 20% of the compliance maximum was classified as containing a decreasing part. A segment containing the angular point of the parabola was classified as containing the horizontal part. A compliance profile with less than 20% change was classified as horizontal ( Fig. 1) [22]. The Decision Support Systems suggested a PEEP increase of 2 cmH 2

Electrical impedance tomography
Regional ventilation was measured via electrical impedance tomography (EIT, PulmoVista 500, Dräger Medical) every 10 minutes for a duration of 2 minutes. EIT recordings were offline evaluated using software developed in Matlab (MATLAB R2014a, The Mathworks Inc., Natick, MA, USA). As a first step, the relevant lung areas were determined for each patient by applying the lung area estimation method [26,27] to the raw EIT data.
Therefore, functional region of interest was selected by deleting all pixels with impedance change smaller than 20% of maximum tidal impedance change. After mirroring the deleted pixels, cardiac area was removed. The obtained lung area was then applied to all recorded raw EIT images. After this preprocessing, functional impedance images were generated. This was done by subtracting the frames corresponding to the start of inspiration from the frames corresponding to the end of inspiration. Thus, these functional images (f-EIT) represent the distribution of the tidal volume for each breath. To assess potential changes in regional ventilation, tidal variation as well as a gain and loss calculation was performed. Gain and loss calculation is based on subtracting functional impedance images of baseline measurements from the functional impedance images of the recording under investigation. Subsequently, the resulting differential images were split into ventral and dorsal parts and the number of positive ('gain') and negative ('loss') pixels were calculated for each such region. Considering the difference between the calculated gain and loss (net impedance difference) ultimately provides a measure for changes in regional ventilation. If this difference was positive, we assumed an increase in regional ventilation in the respective lung area whereas a negative difference indicates a decrease in regional ventilation [28].

End points and data collection
Frequencies of nonlinear intratidal C RS profiles (measured using the gliding-SLICE method) was the primary endpoint of this study. Secondary endpoints were regional ventilation (ventral and dorsal ventilation distribution, ventral and dorsal gain and loss), the respiratory system variables [peak inspiratory pressure (PIP), P Plat , mean tracheal pressure (P m ean ), PEEP] and hemodynamic variables [systolic blood pressure (BP sys ), diastolic blood pressure (BP dias ), heart rate and mean arterial pressure (MAP)].

Sample size calculation and statistical evaluation
There are no data available concerning the variance of frequencies of compliance profiles. Therefore, we based our sample size calculation on estimation of a general standardized effect size e, being the quotient of differences in means and SD. With regard to our approach, adapting PEEP according to the measured compliance profile, we assumed a large effect size and therefore chose e = 0.8 [29]. In regard to the trial design (unpaired test conditions) and an assumed e of 0.8, 50 patients were required to reach a test power of 0.8 with a desired level of significance of 0.05.
To compensate for potential incomplete data sets, a total of 60 patients were recruited.
Data are presented as mean (SD). Differences between the two groups were assessed with unpaired Students t-test, respectively. Statistical significance was considered for p < 0.05. Preceding, Shapiro-Wilk tests were used to confirm that the assumed normal distribution cannot be rejected. For not normally distributed data, differences between the two groups were assessed with Mann-Whitney U tests.

Results
Patients were recruited from November, 5 th 2015 to January, 29 th 2016. In total, 60 patients were included. 12 patients had to be excluded due to incomplete data sets (Fig.   2). During the study protocol, no adverse or serious events occurred. Age, gender, ASA physical status, PBW, actual body weight (ABW) and BMI were comparable between the two groups (Table 1).

Respiratory and hemodynamic variables
In 12 patients in the intervention group (48%) the PEEP was adjusted according to the intratidal compliance profile analysis. In 7 of these patients (28%) the PEEP was thenceforward held constant. In 3 of the patients in the intervention group (12%) the PEEP was adjusted twice. In 2 patients (8%), the PEEP was adjusted three times. In 11 patients (44%), the PEEP was increased as the corresponding compliance profile analysis. PEEP was higher in the intervention group compared to the control group [control: 5.0 (0.2) cmH 2 O, intervention: 5.8 (1.1) cmH 2 O, p < 0.001; range control: 5.0-5.0 cmH 2 O, range intervention: 3.9-8.5 cmH 2 O]. In total, a PEEP adaption was performed in 12 patients in the intervention group (48%). These individualized PEEP adaptations had no significant effect on the other measured respiratory system or hemodynamic variables ( Table 2). The frequencies of nonlinear intratidal C RS profiles showed no significant difference between the two groups ( Table 3).

EIT measurements
Regional impedance distribution showed no significant difference in ventilation distribution between the two groups (Fig. 3). Gain and loss calculations showed a significant decrease in loss of ventral regional ventilation between the two groups [loss of  Table 4).
TV v and TV d showed no significant difference between the two groups (Table 4).

Discussion
In this study, we compared the effects of an individualized PEEP titration according to bedside analysis of the frequencies nonlinear intratidal C RS profiles (measured using the gliding-SLICE method). The main findings are that only small PEEP adaptations are required to transfer increasing to horizontal compliance profiles and that the individualized PEEP titration improved regional ventilation without affecting impedance distribution and respiratory or hemodynamic variables negatively.

Respiratory and hemodynamic variables
Besides PEEP, none of the respiratory and hemodynamic variables differed between the two investigated patient groups. PEEP is generally associated with recruitment and one might expect that C RS increases with increasing PEEP. However, in agreement with earlier studies [16,30] C RS remained unchanged besides PEEP related changes in regional ventilation. Compared to lungs with severe lung-injury and impaired respiratory system mechanics, healthy lungs are in a well recruited state, thus compliance may barely depend on lung volume. In particular, in our study, patients showed respiratory system mechanics that were mostly characterized by a horizontal compliance profile and consequently PEEP adaptations were performed less frequent than we had expected. It follows that the observed improvement in regional ventilation may have increased C RS , if the studied patient collective would have included more patients with impaired respiratory system mechanics and/or surgical procedures associated with an increased risk for alterations of respiratory functions (e.g. laparoscopic surgery, patient positioning, obesity). Since this is the first study in which we applied individualized PEEP titration according to the compliance profile analysis, we did not include patients at risk for impaired respiratory system performance. One might speculate further that the comparably high alveolar recruitment in the studied patients was the reason that we did not find significant differences in C RS . This hypothesis can be supported by two clinical trials to provide preliminary investigations of the gliding-SLICE method [16,30]. In both studies, lower levels of PEEP (such as 5 and 7 cmH 2 O) did not prevent from C RS profiles indicating recruitment/derecruitment. In both studies, intratidal compliance profile analysis was used as a bedside measurement for predefined PEEP settings. In the present study, this analysis was used to guide PEEP titration individually. One might speculate that the higher duration of surgical procedure [mean duration of surgery of 120 min [30] and 184 min [16] vs. 83.2 min (control group) and 87.5 min (intervention group) in the present study] leaded to a more pronounced impairment of respiratory system mechanics and thus of intratidal C RS profiles. Further, in the present study, obesity was an exclusion criterion. In one of the previous studies [16], obese patients were included. Since obesity is associated with a low respiratory system compliance, early expiratory alveolar collapse, consecutive atelectasis and increased airway resistance [31], it seems obvious that the results from intratidal compliance profile analysis differs from them in the present study.
It follows that further are needed to provide more detailed information about the impact of an individualized PEEP titration strategy based on the gliding-SLICE method on respiratory function in patients with impaired respiratory system mechanics.
By increasing the intrathoracic pressure, PEEP was shown to affect the cardiac performance by altering the left ventricular preload, afterload and cardiac contractility [32]. Previous studies found that in case of increasing intratidal compliance profiles, a small increase in PEEP directed to ventilation with horizontal compliance [16,30]. Since the overall increase of PEEP in our intervention group was comparably low, it is not surprising that our individualized PEEP titration had no effect on the measured hemodynamic variables. With regard to the unaffected respiratory and hemodynamic variables, it is even more remarkable that our ventilation strategy improved regional ventilation, anyway.
Further, it should be noticed that our PEEP titration strategy is based on analyses of the intratidal compliance profiles utilizing only data which are available from standard monitoring. In contrast, previously described techniques for titrating PEEP (decremental PEEP trial [33], dead space fraction [34], indices of regional ventilation [35][36][37], esophageal pressure [38] or other imaging techniques [39]) require additional equipment, involve additional burden for the patient or may per se not be available at the bedside.
The techniques based on the determination of best PEEP from static respiratory system variables, such as the static PV curve, did not contribute to the dynamic intratidal changes in respiratory system mechanics [40], required sedation and often muscle relaxation [7].
Moreover, they required a prolonged maneuver during which the patient is not sufficiently ventilated. During a decremental PEEP trial, adequate ventilation is warranted however, to identify the PEEP for maximum C RS , the optimal PEEP must necessarily be exceeded during the maneuver. Thus, both PEEP titration methods bear the risk for overdistension and cannot be applied continuously. By contrast, PEEP titration based on the intratidal compliance profile does not require a maneuver, may be applied on a breath-by-breath analysis and is applicable for consecutive PEEP adjustment.

Regional ventilation
Even in patients without impaired respiratory function, induction of general anesthesia and consecutive mechanical ventilation bear the risk for atelectrauma [41]. Studies that focus on perioperative lung-protective ventilation strategies in patients without severe lung-injury showed that the rate of postoperative pulmonary complications was lower when the ventilation strategy included low tidal volume, high PEEP and repetitive recruitment maneuvers [2,5]. The application of low PEEP levels was shown to promote tidal small airway closure and consecutive atelectasis [42]. As a non-invasive, radiationfree method, EIT can be used to monitor regional ventilation and the formation of atelectasis [43]. Further, EIT can be used to evaluate differences between the measured PV curve from the respirator and regional ventilation [44]. This recently introduced technique to asses these differences may help to understand the heterogeneity of the respiratory system mechanics, especially in patients with impaired respiratory function. In contrast to other studies that showed that the EIT can be used to titrate PEEP individually [36,37], we used the EIT as an external measurement and could demonstrate that an individualized PEEP titration guided by the intratidal compliance profile analysis improved regional ventilation. As should be expected by the increased PEEP in the intervention group, we found an improvement in regional ventilation (assessed by gain and loss calculations). These results demonstrated that EIT can be used to validate changes in regional ventilation when PEEP titration was guided by the gliding-SLICE method. With regard to the comparable respiratory system mechanics and comparable frequencies of compliance profiles between the two groups, it is not surprising that the ventilation distribution and tidal variation was comparable between patients in the control and intervention group.

Limitations
We did not perform invasive blood pressure measurement to evaluate hemodynamic performances with a higher temporal resolution and arterial blood gas analyses. Placing an arterial line is not part of our standard treatment in the patients conducted in the present study. We felt that the risks of an arterial line placement would not outweigh the potential benefits of such measurement. Since the intention of our study was to investigate the impact of comparable new patient-individual PEEP titration strategy in non-injured respiratory system, we did not include patients at high risk to the formation of atelectasis. Thus, further studies are required to investigate the potential impact of PEEP titration based on bedside analysis of non-linear intratidal compliance on the respiratory system mechanics in patients prone to an impaired respiratory function.

Conclusions
This is the first study to investigate regional ventilation during PEEP titration guided by intratidal compliance profile analysis in patients. In lung-healthy patients undergoing short surgical procedures associated with a low risk of pulmonary impairment, bedside analysis of non-linear intratidal mechanics of the respiratory system using the gliding-SLICE method did not improve respiratory system mechanics and compliance profiles distribution. According to the improved gain and loss measurements, we might say that individualized PEEP titration based on the gliding-SLICE method might be of limited importance in patients without impaired respiratory system mechanics.

Availability of data and material
The datasets used and analyzed during the current study are available from the corresponding author on request. Please note that EIT data files require large memory. A separate data transfer service will be used to transfer EIT data files.

Competing interests
J.W., J.G., J.S., S. L.-Z., S. B. and S.W declare no conflicts of interest. S.S. has a consulting contract with Gründler GmbH, Freudenstadt (no relationship to this study).

Funding
This project has not received any funding. The article processing charge was funded by   Differences between the two groups were assessed with Mann-Whitney U tests.
Frequencies were adapted to the duration of mechanical ventilation.    Impedance distribution (ventral and dorsal) for the control and intervention group. There was no significant difference in impedance distribution between the two groups.

Supplementary Files
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