The use of ventilator parameters in the prediction of development and outcome of acute respiratory distress syndrome in postoperative patients

: Background : To investigate the usefulness of ventilator parameters in the prediction of development and outcome of acute respiratory distress syndrome (ARDS) in postoperative patients with esophageal or lung cancer on admission to the surgical intensive care unit (SICU). Methods : A total of 32 post-operative patients with lung or esophageal cancer from SICU in a tertiary medical center were retrospectively analyzed. The study patients was divided into ARDS group (n = 21) and non-ARDS group (n = 11). ARDS group were the post-operative patients who developed ARDS after lung or esophageal cancer surgery. The ventilator variables were analyzed in this study. Principal component analysis (PCA) was performed to reduce the correlated ventilator variables to a small set of variables. By using the PCA selection method, top three ventilator variables with large coefficients can be considered as sensitive variables and were included in the analysis model based on the rule of 10 events per variable. Firth logistic regression with selective stepwise elimination procedure was performed to identify the most important predictors of morbidity and mortality in patients with ARDS. The ventilator parameters including rapid shallow breath index during mechanical ventilation (RSBIv), rate pressure product of ventilation (RPPv), rate pressure volume index (RPVI), mechanical work (MW), and inspiration to expiration time ratio (IER) were analyzed in this study Result s : The newly defined parameter MW/IER was the most important predictors for the development of ARDS, and both RPPv and RPVI were the significant predictors of mortality in patients with ARDS. Conclusion : Some ventilator parameters can be derived from ventilator readings and be used to predict the development and outcome of ARDS in mechanically ventilated patients on admission to the SICU, such as RPPv, RPVI and MW/IER defined in this study.


Background
Acute respiratory distress syndrome (ARDS), a life threatening inflammatory lung disease that affects both medical and surgical patients, was first reported by Ashbaugh and colleagues in 1967 in a case series of 12 ICU patients. 1 The clinical, radiological, biochemical and pathological features of ARDS was defined in 1994 by the American-European Consensus Conference (AECC). 2 The current definition of ARDS is the "Berlin definition" devised by a panel of experts based on the timing of clinical insult, radiographic pattern, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) and positive end-expiratory pressure (PEEP) in 2013. 3 ARDS is associated with an extremely high mortality rate in patients with lung resection or esophagectomy. [4][5][6][7][8] ARDS is a diffuse, progressive inflammatory lung disease with hypoxemia, reduced lung compliance, bilateral opacities on chest x-ray image. Although mechanical ventilation provides essential life support, it can also induce and worsen the lung injury. [9][10] However, the mechanical ventilation strategies till now remain the mainstay of respiratory support for patients with ARDS.
Due to the progress of modern digital technology, advanced new-generation ventilators allow extensive and integrated monitoring of patients' respiratory mechanics. Data regarding the control variables, phase variables, breath type, respiration rates, tidal volumes and so on, can be easily read and recorded constantly from the ventilator. 6 In this study we investigated the usefulness of ventilator parameters derived from the ventilator readings in the prediction of development and outcome of ARDS in postoperative patients with lung or esophageal cancer on admission to the surgical ICU (SICU).

Study Cohort and Design
This was a prospective, single-centric, case-controlled study with retrospective data analysis. The study protocol has been approved by Institute Review Board of National Taiwan University Hospital (NTUH200808065R) and Taipei Veterans General Hospital (VGHIRB97-01-02A).
Retrospective analysis of the data to find the key ventilator parameters for the prediction of development and outcome of ARDS in postoperative patients with esophageal or lung cancer has been approved by the Institute Review Board of Changhua Christian Hospital (CCH IRB 190521).
This study was conducted in the SICU of the National Taiwan University Hospital. All patients were over 18 years old, and had received thoracic surgery for lung or esophageal cancer.
They were transferred to the SICU for post-operative care. Patients without post-operative ARDS were included as the control group, while patients complicated with ARDS were included as the ARDS group. The ARDS of the patients was diagnosed according to the Berlin Definition. Patients who had severe coronary artery disease, persistent arrhythmia, cardiac pacing, diabetes mellitus, 7 cerebral vascular accident, or major diseases of kidney or autoimmune system were excluded from the study. Patient selection criteria in this study have been presented in our previous article. [11] Eleven patients in the non-ARDS group and 21 patients in the ARDS group were analyzed in this study.
All patients were intubated and mechanically ventilated using pressure control mode.
Fentanyl was given to all patients as an analgesic. The demographic data, vital signs, medications, ventilator readings, and relevant clinical data were recorded within 4 hours of admission to the SICU.

Ventilator Parameters
Flow rate (V̇) during mechanical ventilation is given by the following equation: where VT is the tidal volume and Ti is the inspiration time. Pressure control mode of ventilation typically has decelerating pattern and VT/Ti will provide average flow rate which depends on both resistance and compliance. The flow resistance (R) of air during mechanical ventilation is given by the ratio of peak inspiratory pressure above PEEP (PIP) to the flow rate V̇ R = PIP V̇. (2) The dynamic compliance (Cdyn) represents the pulmonary compliance during inspiration, and is given by the ratio of tidal volume to the PIP during inspiration The rapid shallow breathing index (RSBI) is thought to be a stress response reflecting the balance between respiratory neuromuscular reserve and respiratory demands, and has been widely used in daily clinical practice such as the prediction of successful weaning from ventilator. [12][13][14][15] When the patient is on the ventilator using pressure control or pressure support mode of ventilation, the RSBI during mechanical ventilation (RSBIv) can also be defined as the ratio of respiration rate (RR) to the tidal volume The subscript 'v' in RSBIv indicates that this RSBIv is measured when the patient is still on the ventilator, which is different from the RSBI measured when the patient is temporarily discontinued from mechanical ventilation.
The product of heart rate (HR) and systolic blood pressure (SBP), or the rate-pressure product (RPP), is a very reliable indicator of myocardial oxygen demand, and has been widely used clinically, especially in cardiology, anesthesiology and rehabilitation. [16][17][18] By analogy with the RPP in cardiology, the rate pressure product of ventilation (RPPv) can be defined as the product of RR and PIP in ventilated patients to measure the stress imposed on the respiratory muscle in ventilated patients: 9 Combining RSBIv and RPPv, we can devise the rate pressure volume index (RPVI) as Though RR appears in both RSBIv and RPPv, it is included in the definition of RPVI only once rather than twice so as not to overemphasize its role in the new index of RPVI.
The respiratory interval (RI) is the averaged time of ventilation that can be obtained from the RR using the following equation The expiration time (Te) is the difference between RI and Ti The inspiration to expiration time ratio (IER) is then When the gas flows across a constant cross section, the mechanical work (MW) done by the ventilator can be defined as

Statistical Analysis
Data are presented as a percentage, median (interquartile range) or mean ± standard deviation.
Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test, and were compared between the two groups of patients using Mann-Whitney U test for non-normally distributed data, or independent samples t-test for normally distributed data. Chi-square test or Fisher's exact test, when appropriate, was used for the comparisons of categorical data.
Firth logistic regression with selective stepwise elimination procedure was performed to identify the most important predictors of morbidity and mortality of ARDS. This method used the penalty likelihood approach to reduce the parameter estimation bias due to small sample size.
However, only three variables can be included in the multivariable analysis based on the rule of 10 events per variable (EPV-10), as in our previous study. 11 The candidate of mechanical ventilation measurements, included in the multivariable analysis, were the significant variables in the univariate analysis of differences between the two groups. Since these mechanical ventilation measurements were highly correlated with one another, principal component analysis (PCA) was performed to reduce the correlated variables to a small set of variables. By using the PCA selection method, variables with large coefficients in each component can be considered as sensitive variables because those variables contain most information from the dataset. In this study, the top three variables were selected as the sensitive variables. Furthermore, receiver-operating 11 characteristic (ROC) curves were constructed to assess the predictive performance of important measurements. All statistical analyses were performed using R software (version i386 3.3.2, https://www.r-project.org/) and the contributed R package logistic for Firth's penalized-likelihood logistic regression. A two-tailed p < 0.05 was considered statistically significant. Table 1 shows that the ARDS patients had significantly longer SICU stay, greater RR, R, RSBIv, RPPv, RPVI, PEEP, and IER, and significantly smaller RI, Te, V̇, VT, Cdyn, MW and MW/IER than the control patients. Table 2 shows that the non-survivors had significantly greater PIP, RSBIv, RPPv, and RPVI than the survivors of ARDS.

Results
Two components were extracted after PCA procedure and the coefficients of variables in each component were summarized in Table 3. The variables in the same column of shaded area in Table   3 indicate that they are included in the same component.  12 were shown to be the significant predictors for the development of ARDS (Table 4). Model 3a adjusted for MW/IER and VT, and showed that the MW/IER was the most important predictor for the development of ARDS (Table 4). As depicted in Figure 1A, The PIP, RSBIv, RPPv, and RPVI were the significant variables responsible for the differences between the survivors and non-survivors of ARDS (Table 2). Since the RSBIv, RPPv, and RPVI are highly correlated with one another, we used three separate model to assess the predictors of mortality of ARDS. Model 1b adjusted for PIP and RSBIv, and indicated that none of the parameters in model 1b could significantly affect the mortality of ARDS (p > 0.10). Model 2b and model 3b adjusted for RPPv and RPVI, respectively. The results of RPPv and RPVI could marginally significantly affect the mortality of ARDS (p < 0.10) ( Table 4). As depicted in Figure   1B The RSBI is thought to be a stress response reflecting the balance between respiratory neuromuscular reserve and respiratory demands. It is a clinical parameter often used in the prediction of successful weaning from ventilators in ventilated patients. [12][13][14][15] The RSBI is obtained 14 by measuring the respiratory rate and tidal volume of the patient without ventilatory support, while the RSBIv defined in this study was measured when the patient was still on the ventilator. Thus, the RSBIv is different from the RSBI used clinically to predict weaning outcome of the patients, though the equations used to calculate the RSBI and RSBIv are the same. Since the lungs of the ARDS patients were more rigid than the controls, their tidal volumes were smaller and their respiratory rates was greater, resulting in a greater RSBIv in ARDS patients, as compared to the control patients. That the RSBIv of non-survived ARDS patients was greater than that of survived ARDS patients can also be accounted for by the more rigid lung in the non-survived ARDS patients.
Although the mean value of RSBIv was significantly higher in ARDS patients as well as in non-

Ethics approval and consent to participate
The study protocol has been approved by the Institutional Review Boards of National Taiwan University Hospital (NTUH200808065R) and Taipei Veterans General Hospital (VGHIRB97-01-02A), and written informed consent was obtained from the next of kin of the patients before their enrollment in the study.

Consent for publication
All included patients or their family members signed the informed consent form to report individual patient data. All authors have confirmed the manuscript and approved the publication of the manuscript.

Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on request.