The Association Between Mechanical Power and Mortality in Ventilated Patients with Pneumonia


 Background: Recent studies reported that mechanical power (MP) has been associated with increased mortality in patients with acute respiratory distress syndrome (ARDS). We aimed to investigate the association between 28-day mortality and MP in patients with severe pneumonia. Methods: In total, 313 patients with severe pneumonia were enrolled. Serial MP was recorded daily for either 21 days or until ventilator support was no longer required. The associations between all variables and 28-day mortality were analyzed using binary logistic regression analyses. Results: The ARDS group (106 patients) demonstrated lower age, higher Acute Physiology and Chronic Health Evaluation II score, lower history of diabetes mellitus, high incidences of shock and jaundice, higher MP and driving pressure on Day 1, and higher death within 28 days than the non-ARDS group. Regression analysis revealed that MP was an independent factor associated with 28-day mortality (odds ratio, 1.041; 95% confidence interval, 1.013-1.071). MP persisted high in non-survivors and low in survivors among the ARDS group, the non-ARDS group and all patients.Conclusions: MP was associated with the 28-day mortality in ventilated patients with severe pneumonia both in the ARDS and non-ARDS groups. MP had better predicted value for 28-day mortality than driving pressure.

Amato's study reported that driving pressure was most strongly associated with survival in patients with ARDS who received mechanical ventilation with different combinations of tidal volume and PEEP [5]. In patients with severe ARDS receiving extracorporeal membrane oxygenation (ECMO), higher driving pressure during the rst 3 days of ECMO support was independently associated with increased mortality [6]. In a rat-model of open abdominal surgery, lower driving pressure was associated with reduced lung damage [7]. In patients with severe pneumonia without ARDS, higher driving pressure was associated with 28-day mortality [8]. Thus, driving pressure could be used as a non-invasive method to predict lung injury in patients with and without ARDS.
Recently, a new concept of safe mechanical ventilation using mechanical power (MP) was introduced [9].
The MP enrolled several underlying relevance. First, it imports static compliance inducing VILI [10].
Second, it accounts for the nal effect of PEEP. The PEEP is positively associated with VILI, but PEEP may decrease the lung-dependent VILI by reducing lung inhomogeneity and intratidal alveolar collapsedecollapse. Third, transpulmonary MP increased with the respiratory rate (RR) [11]. Serpa et al. reported that MP of ventilation in the rst 48 h is associated with mortality in critically ill patients in two observational cohorts. In patients with ARDS, initial MP was also associated with mortality [12][13][14]. These four studies all used simpli ed equation proposed by Gattinoni et al. to calculate MP in patients with volume-controlled ventilation [9,15]. Therefore, we used a consecutively sampled observational cohort data of patients with severe pneumonia to identify three questions: (1) the association between MP and 28-day mortality in patients with pressure-controlled ventilation (PCV), (2) the predicted value of 28-day mortality between driving pressure and MP, and (3) the usefulness of the simpli ed equation of MP for PCV.

Subjects
The cohort study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, and the need for a written informed consent was waived (96-0132B, 97-0121C, 98-1682C, 201700804B0).
Patients admitted to the medical intensive care unit (ICU) at Chang Gung Memorial Hospital, Keelung from July 2007 to June 2010 due to severe pneumonia were selected. We screened 493 patients who were admitted to the ICU ( Supplementary Fig. 1). In total, 313 patients were enrolled in this study, and 180 patients were excluded. The exclusion criteria included infections other than pneumonia, absence of invasive ventilator support, an unknown arterial partial pressure of oxygen (PaO 2 )/fraction of inspired oxygen (FiO 2 ) ratio or death on the day of admission. None of the included patients withdrew from this study. A total of 61 ARDS patients and 56 non-ARDS patients died within 28 days of ICU admission during the course of this study.

Disease de nitions
The following diseases were de ned at the time of admission to the ICU. Pneumonia was de ned as a new abnormal in ltration on chest radiograph with respiratory symptoms or fever. Severe pneumonia was de ned as pneumonia complicated by acute respiratory failure requiring intubation and mechanical ventilation with or without septic shock [16]. Sepsis and septic shock were de ned according to Sepsis-3 guidelines [17]. Sepsis was de ned as a suspected or documented infection with acute increase (≥2) in the Sequential Organ Failure Assessment points. Septic shock was de ned as sepsis with blood lactate level >18 mg/dL and hypotension that was unresponsive to uid resuscitation, requiring vasopressors to maintain mean arterial pressure ≥65 mm Hg during the rst 3 days following ICU admission. Acute renal failure was diagnosed by a rapidly increasing serum creatinine level ³ 0.5 mg/dL over the baseline value [18]. Disease severity was assessed with the Acute Physiology and Chronic Health Evaluation (APACHE) II score [19]. ARDS was de ned according to the Berlin de nition [20]. ARDS was evaluated via chest radiographs obtained after intubation with ventilator support. Patients who were initially diagnosed as non-ARDS and developed ARDS within 1 week were classi ed as ARDS. Patients who were initially diagnosed as non-ARDS and developed ARDS after 1 week were still classi ed as non-ARDS. Patients who survived for at least 28 days since ICU admission were considered as survivors.

Treatment
Standard therapies, including uid resuscitation, broad-spectrum antibiotic administration, infected uid drainage, blood transfusion, sedation/paralysis, blood glucose control, hemodialysis, stress ulcer prophylaxis, and basic support were provided to all patients according to the recommended guidelines [21,22]. The initial broad-spectrum antibiotics were selected based on either the Taiwan Guidelines for Pneumonia Management (2007 version) or the Guidelines of the American Thoracic Society [16,23].

Ventilator settings
In our hospital, volume-controlled ventilation (VCV) was not used to prevent VILI due to rapid change of peak pressure. Following intubation, all patients were routinely administered by PCV with a separate target tidal volume of approximately 6 and 10 mL/kg PBW for patients with ARDS and non-ARDS, respectively. The goal was to maintain an inspiratory plateau pressure (Pplat) of less than 30 cm H 2 O.
The PEEP level and FiO 2 were adjusted to maintain PaO 2 greater than 60 mmHg or oxygen saturation by pulse oximetry (SpO 2 ) greater than 90%. Ventilator settings were adjusted after 2 h of the rst setting.
Ventilator weaning and adjustment were performed at regular intervals (every 8 h) and as necessary, based on the general weaning guidelines and clinical practice of our respiratory therapy department [24]. Data records ICU admission date was considered as Day 0. The next date of ICU admission was de ned as Day 1. The following patient data were recorded within 24 h after admission: age, sex, medical history, and APACHE II score. Adverse events were recorded within the rst 3 days following admission. Arterial blood gases demonstrating the lowest PaO 2 /FiO 2 ratio were used within 24 h after intubation with ventilator support.
Driving pressure (∆P) was de ned as the difference between Pplat and PEEP [25]. MP for PCV was calculated according to the simpli ed equation [15,26], using RR, tidal volume size (L) (V T ), ∆P insp and PEEP: where ∆P insp is the change in airway pressure during inspiration. Driving pressures and MP were recorded every 8 h per day. Serial mean data of ∆P insp , RR, V T and PEEP were recorded daily for either 21 days or until the ventilator support was no longer required.

Statistical analyses
Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 17.0 for Windows (SPSS, Inc., Illinois, USA). Differences in the continuous variables between the two groups were analyzed using Student's t-test. Differences in categorical variables between the ARDS and non-ARDS groups were compared using the Pearson chi-squared test or Fisher's exact test. Univariate binary logistic regression model analyses were performed to study the association between the 28-day mortality and all variables. Statistically signi cant variables were entered into a multivariate binary logistic regression model to assess their independent contribution to the outcome. The cut-off value of driving pressure and MP on Day 1 to predict 28-day mortality was identi ed according to the receiver operating characteristic (ROC) curve ( Fig. 1) Table 1 demonstrates the baseline clinical characteristics of patients with pneumonia between ARDS and non-ARDS. Some patients with the PaO 2 /FiO 2 ratio less than 300 mm Hg were classi ed as non-ARDS due to the absence of bilateral opacities on chest radiography. The ARDS group had lower age and higher APACHE II score, MP, and driving pressure than the non-ARDS group. The incidences of shock, jaundice and death were higher and mean age was lower in the ARDS group than those in the non-ARDS group. In total, pathogens were identi ed in 88.2% of patients (Supplementary Table 1). The most frequently isolated pathogens, in decreasing order, were Pseudomonas aeruginosa, Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. Abbreviations: ARDS = acute respiratory distress syndrome; APACHE = Acute Physiology and Chronic Health Evaluation; COPD = chronic obstructive pulmonary disease; CHF = congestive heart failure; PaO 2 = arterial partial pressure of oxygen; FiO 2 = fraction of inspired oxygen; GI = gastrointestinal Table 2 Binary logistic regression to analyze the independent factors for 28-day mortality Abbreviations: OR = odds ratio; CI = con dence interval; APACHE = Acute Physiology and Chronic Health Evaluation; COPD = chronic obstructive pulmonary disease; ARDS = acute respiratory distress syndrome

Results
The MP persisted high in non-survivors and low in survivors among the ARDS group, the non-ARDS group, and all patients (Fig. 2). In all patients, MP in non-survivors was higher than in survivors during the 21 days recorded except Day 18. In the ARDS group, MP in non-survivors was higher than in survivors on Days 1-11, 16, and 20. In the non-ARDS group, MP in non-survivors was higher than in survivors on Days 1-14, and 17. The Kaplan-Meier curves showed the possibility of survival until 28 days after ICU admission for MP on Day 1 above and below 27 J/min among the ARDS group, the non-ARDS group, and all patients (Fig. 3). Patients with MP < 27 J/min on Day 1 demonstrated signi cantly higher survival rates than those with MP ≥ 27 J/min in all patients and the non-ARDS group (p<0.001). In the ARDS group, patients with MP < 27 J/min did not show higher survival rate than those with MP ≥ 27 J/min (p=0.067).

Discussion
According to multivariate regression analysis, MP on Day 1 and ARDS were independent factors associated with 28-day mortality. Patients with lower MP on Day 1 had better chances to survive compared to those with higher MP on Day 1. In initial univariate regression analysis, driving pressure on Day 1 was a factor associated with 28-day mortality. However, the signi cant association was not observed in multivariate regression analysis. In ROC curves of the ARDS group, driving pressure did not discriminate survivors from non-survivors, but driving pressure could discriminate between survivors and non-survivors in all patients and the non-ARDS group. It suggests that ARDS confounds the association between driving pressure and 28-day mortality.
Our study rst found that ventilated patients with pneumonia with or without ARDS demonstrated higher serial MP in non-survivors than in survivors from Day 1 to Day 11 of ICU admission. The MP between survivors and non-survivors was similar only on Day 18 of ICU admission in all patients statistically. Our study not only con rmed that baseline MP was associated with mortality [11][12][13][14], but also found that the association persisted for 11 days. In the Kaplan-Meier curves of the ARDS group, the two curves were similar within the rst 10 days and separated later evidently. This implied that the bene t of lower MP required a period of time to develop in patients with more severe pneumonia. Furthermore, deep sedation signi cantly reduced MP in patients with moderate to severe ARDS, thereby reducing the occurrence of VILI [14]. All the above suggested that MP might be the cause of VILI, resulting in increased mortality rate.
Certainly, it is reasonable since all mechanical factors in ventilation-tidal volume, driving pressure, ow, resistances, RR, and PEEP-are different components of a unique physical variable, which is the energy delivered into the lung. Up to now, there is no study reporting the results of mortality using MP as a guide of ventilator settings to manage critically ill patients. Further studies are required to elucidate whether MP is a predictor or cause.
In our study, driving pressure was not an independent factor associated with 28-day mortality in ventilated patients with severe pneumonia, but MP was an independent factor. In experimental mild ARDS of rats, even at low V T , high MP promoted VILI [27]. In a computational study, MP showed a strong correlation with the relative risk of death across all ranges of driving pressures and PEEP [28]. Moreover, the areas under the ROC of MP were higher than those of driving pressure among the ARDS group, the non-ARDS group, and all patients in our study. This implied that MP might be a better predictor of 28-day mortality than V T or driving pressure in patients with severe pneumonia with or without ARDS. The positive and negative predictive values of MP using the cutoff value ≥ 27 J/min for 28-day mortality were 50.1% and 75.4%, respectively. This suggests that approximately 75% of ventilated patients with severe pneumonia and low MP would survive for 28 days. Discrimination ability of MP and MP normalized to PBW in predicting 28-day mortality was nearly similar in this study. This result was similar to that of Zhang's study, which found 0.747 and 0.751 of areas under ROC curve for MP and MP normalized to PBW, respectively [12]. For easy use in routine clinical practice, calculation of MP instead of MP normalized to PBW might be su cient.
The MP was rst determined with the simpli ed formula suggested by Gattinoni et al. for VCV: [9]. As the equation for calculation of MP is based on the assumption of VCV with a linear increase of airway pressure during inspiration, it is not suitable for calculating MP during PCV [29]. For PCV, two accurate equations have been proposed, but both require using some parameters (resistances, respiratory system compliance) that are not usually continuously quanti ed and displayed in the ventilator [26,30]. Finally, we used the simpli ed formula for PCV proposed by Becher et al. [26] since this equation had acceptable accuracy and routine record by our respiratory therapeutist. Our study demonstrated that this simpli ed formula was easy to use, and the MP calculated had acceptable discrimination for 28-day mortality in ventilated patients with severe pneumonia.
The most important current recommendation to provide lung protective ventilation in ventilated patients with pneumonia is low tidal volumes [3]. However, despite the use of lung protective ventilation proposed by ARDSnet protocol, overall ICU and hospital mortality of ARDS patients is still higher than 40% [31]. Low tidal volume ventilation did not show estimated bene t in patients with ARDS. It seems that only low tidal volume ventilation is insu cient to protect the lung. Since 2015, Amato et al. reported the results of a retrospective analysis and concluded that driving pressure was better associated with 60-day mortality in patients with ARDS than tidal volume [5]. Following this, Guerin et al. demonstrated this viewpoint [32], and a meta-analysis from Neto et al. showed that an increase of driving pressure was associated with more postoperative pulmonary complications [33]. Our previous study further found that higher driving pressure was associated with 28-day mortality in patients with severe pneumonia without ARDS [8]. In this study, results showed that MP on Day 1 was independently positively associated with 28-day mortality and had better predicted value than driving pressure either in patients with ARDS or without ARDS. Our results support the hypothesis that a marker with several important indices is better than that with one index. The predicted value of MP, which included tidal volume, inspiratory pressure, RR, and PEEP, was better than driving pressure alone.
This study has an important strength. We presented serial data over the course of 21 days with consistent results during the rst 11 days in patients with or without ARDS. This study also has three limitations.
First, this study was a single-center trial without thousands of case number. More studies are required to con rm our results. Second, there were signi cantly few patients who developed ARDS after a period of 1 week. Third, chest radiograph ndings might have been misinterpreted considering the presence of unilateral in ltrates or opacities due to the limitations of traditional chest radiography. Computed tomography may be a preferred technique to detect lung injury. Considering the similar results between the ARDS and non-ARDS groups, it did not signi cantly in uence the nal conclusion.

Conclusions
Our ndings imply that MP may be an important factor associated with the 28-day mortality in ventilated patients with severe pneumonia both in the ARDS and non-ARDS groups. The MP, which included tidal volume, inspiratory pressure, RR, and PEEP, had better predicted value for 28-day mortality than driving pressure. The simpli ed formula for PCV to calculate MP was useful in patients ventilated with PCV mode.

Consent for publication
Not applicable.

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

Competing interests
The authors declare that they do not have any nancial or personal relationships that might inappropriately in uence their actions and create a con ict of interest relative to the content of this manuscript.

Figure 2
Error bars of serial mechanical powers (J/min, mean ± 1 standard error mean) from Day 1 to Day 21 between non-survivors and survivors. Asterisks represent signi cant differences between non-survivors and survivors using Mann-Whitney U test. Hollow circle bars represent non-survivors, and solid triangle bars represent survivors. Serial mechanical powers were higher in non-survivors than in survivors during