Attaining Low Tidal Volume Ventilation During Patient Triggered Ventilation in Sedated Subjects
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* Moe Koide
* Akinori Uchiyama
* Tomonori Yamashita
* Takeshi Yoshida
* Yuji Fujino

## Abstract

**BACKGROUND:** Low tidal volume (VT) ventilation has become the preferred approach in patients in the ICU. Sedation reduces VT by attenuating respiratory drive. Even in deep sedation, some patients exhibit high VT. We aimed to determine factors associated with low VT ventilation in deeply sedated subjects who exhibited an inspiratory effort by examination of the acid/base balance using the Stewart model.

**METHODS:** The medical records of 630 consecutive subjects admitted to the ICU over 1 y were reviewed retrospectively, and daily data sets of patients with a persistent inspiratory effort, PaO2/FIO2 < 300 mm Hg, PEEP > 5 cm H2O, and a Richmond Agitation Sedation Scale score of −4 or −5 who received assisted pressure-regulated ventilation were collected. The data sets were stratified into high VT (≥ 8 mL/kg predicted body weight [PBW]) and low VT (> 8 mL/kg PBW) groups.

**RESULTS:** Among 235 matched data sets from 100 subjects, 101 and 134 data sets were in the low VT and high VT groups, respectively. Set pressure was not different between the groups. PEEP was lower in the low VT group, and opioids were more frequently used in the high VT group. Strong ion difference (SID) was higher in the low VT group. Multivariate analysis revealed that higher SID, lower total nonvolatile weak anion (ATOT), and absence of opioid administration were associated with attaining low VT ventilation. Furthermore, VT/PBW and SID demonstrated a weak inverse correlation, whereas VT/PBW and ATOT exhibited a weak correlation. VT/PBW was lower in the group with higher SID and lower ATOT, indicating a tendency of metabolic alkalosis.

**CONCLUSIONS:** Despite weak effects of high SID and low ATOT, efficient management of the buffering function might be a feasible strategy to achieve low VT ventilation.

*   acid/base balance
*   patient triggered ventilation
*   deep sedation
*   low tidal volume
*   Stewart model

## Introduction

Low tidal volume (VT) ventilation is essential for ensuring lung protection during mechanical ventilation in patients with ARDS.1–4 Low VT ventilation reportedly reduces postoperative pulmonary complications related to general anesthesia5–7 and improves clinical outcomes of patients without ARDS.8 Low VT ventilation is increasingly preferred in mechanically ventilated patients in the ICU, although its efficacy in routine postoperative patients has not been confirmed. Volume controlled ventilation maintains a low VT; however, interactions with a patient's inspiratory effort can cause ventilator asynchrony, leading to lung injury.9,10 Patient triggered, pressure-regulated ventilation modes, such as pressure controlled ventilation and pressure support ventilation, are alternatives that can resolve ventilator asynchrony11; however, maintaining a low VT can be difficult in pressure targeted ventilation in subjects with inspiratory effort.

While several studies reported factors associated with low VT ventilation,12,13 there is limited information on attainment of low VT with assisted pressure-regulated ventilation modes in subjects with an inspiratory effort. Low VT ventilation can be achieved with appropriate sedation, ventilator settings, and the maintenance of arterial blood gases. However, the efficacy of these approaches has not been confirmed in subjects maintaining an inspiratory effort. Due to the depressive effects of sedatives on respiration, sedation is expected to reduce VT by attenuating respiratory drive. Chen et al12 reported that adherence to a low-VT strategy was associated with the depth of sedation. Even in deep sedation, some subjects exhibited a high VT due to a persistent strong inspiratory effort. Patients often exhibit a strong inspiratory effort because of hypercapnia and abnormal lung mechanics. In addition, other factors such as metabolic acidosis, pain, discomfort, anxiety, and excitation can stimulate the respiratory center. Deep sedation is sometimes necessary to improve the circulatory and respiratory status of patients in the ICU, and it is occasionally needed after cardiac surgery.14 This study aimed to determine factors associated with low VT ventilation in deeply sedated subjects on patient triggered pressure-regulated ventilation.

The acid/base balance in blood is one of the vital factors that affect respiratory center function. Umoh et al15 reported that a low serum HCO3– (< 22 mEq/L) was negatively correlated with a low VT. However, serum HCO3– is also affected by ventilation and PaCO2, which hinders the precise elucidation of metabolic and respiratory factors that affect serum acid/base status. The Stewart model considers the following 3 factors as independent variables to determine the acid/base status16–19: PaCO2; strong ion difference (SID), which is the difference between the sums of all strong cations and all strong anions; and total nonvolatile weak anions (ATOT). Accordingly, pH and HCO3– are dependent variables and are altered when one or more of the independent variables change. Thus, the Stewart model facilitates the elucidation of metabolic and respiratory factors separately. Although some studies have utilized the Stewart model to investigate the acid/base status in critically ill subjects,20–24 the correlation between the characteristics of mechanical ventilation and the acid/base status according to the Stewart model has not been examined extensively. In this retrospective study, we examined ventilatory characteristics, including VT, using the Stewart model in a consecutive series of ICU subjects.

### QUICK LOOK

#### Current knowledge

Low tidal volume ventilation has become the preferred approach in patients in the ICU. Sedation reduces tidal volume by attenuating respiratory drive. Even in deep sedation, some patients exhibit high tidal volume. Methods of maintaining a low tidal volume in assisted pressure-regulated ventilation remain unclear in deeply sedated patients with a significant inspiratory effort.

#### What this paper contributes to our knowledge

Management of the buffering function using the Stewart model is a feasible strategy to achieve a lung protective tidal volume ventilation.

## Methods

### Study Population

The medical records of 630 consecutive patients admitted to the medical and surgical ICU of the Osaka University Hospital from January 1, 2014, to December 31, 2014, were reviewed retrospectively. 59.2% of the patients were admitted to the ICU for care after cardiac surgery. Data on arterial blood gases and ventilator and sedation status during the first 14 d after ICU admission were collected from subjects' records. This study was approved by the Institutional Review Board of Osaka University Hospital (No. 15239).

The mechanical ventilation strategy in the ICU was as follows. The attending ICU physicians determined the ventilator mode and setting adjustments according to the status of each subject. Generally, target VT was in the range of 6–8 mL per kg predicted body weight (PBW). However, individual target VT values were determined by the attending physician according to the status of each subject. The default mechanical ventilation settings were volume controlled synchronized intermittent mandatory ventilation (SIMV) with pressure support ventilation. However, pressure controlled ventilation was used in subjects requiring mechanical ventilation for > 12 h. Pressure targeted ventilation was chosen to maintain better synchrony between the subject's inspiratory effort and the ventilator. Arterial blood gases, which were evaluated regularly every 6 h by the attending nurse or physician, were assessed more frequently if needed. The mechanical ventilation settings at the time of arterial blood gas measurements were recorded on the subjects' charts.

The following sedation strategy was utilized in the ICU. Richmond Agitation Sedation Scale (RASS) scores were evaluated and recorded hourly during sedation by the attending nurse. The primary goal of sedation in subjects receiving invasive mechanical ventilation is to attain RASS scores of 0 to −2. In subjects who were deemed to need deep sedation by the attending physician, the target RASS score was set to −4 or −5. In this study, the primary goal with deep sedation was the stabilization of circulatory status because approximately half of the subjects were in the ICU for care after cardiac surgery. The first-line and second-line sedatives were propofol and dexmedetomidine, respectively, and midazolam was added if these 2 drugs were inadequate. For subjects with significantly unstable circulatory status, midazolam was preferred over propofol. If needed, fentanyl or morphine by continuous infusion was used as an analgesic, per the attending physician's evaluation. Bolus opioids were approved and delivered by the attending nurses according to the pain score, which was evaluated every hour based on the critical care pain observation tool.25 The target level of pain relief was defined as < 2. Because most of the subjects in the current study were in postoperative care, the main reason for the narcotics was pain relief of surgical sites.

The strategy for fluid therapy in the ICU was as follows. The basic infusion rate of maintenance fluids was 24 mL/kg body weight daily. The attending ICU physician determined the detailed composition and actual infusion rate of the maintenance solutions, according to the subject's status. Balanced acetate Ringer's solution was used as the regular resuscitation fluid. If needed, 5% human albumin in saline was administered. The regular threshold of blood transfusion was 8 g/dL hemoglobin, and the decision to start a blood transfusion was made by the attending ICU physician.

### Data Collection

Data on body weight, height, age, sex, and reason for the ICU admission were collected from the subjects' medical records. Data on pH, PaCO2, PaO2, HCO3–, lactate, Na+, K+, and Ca2+ were derived from the arterial blood gas measurements using an ABL800 Flex blood gas analyzer (Radiometer, Copenhagen, Denmark). Serum albumin, Cl–, and inorganic phosphate (P) were measured more than once a day at the laboratory of the study hospital; thus, albumin, Cl–, and *P* values at times that were closest to the times of arterial blood gas measurements were used. The anion gap was calculated according to the following equation16: anion gap = Na+ − Cl– − HCO3–.

Data sets including mechanical ventilation mode, ventilator setting, ventilator status, blood biochemistry, use of opioids, and body temperature at the time of arterial blood gas measurements were reviewed, and data sets that fulfilled the following inclusion criteria were included in the analyses: PaO2/FIO2 < 300 mm Hg with PEEP ≥ 5 cm H2O; ventilation modes of continuous mandatory ventilation, SIMV, or CPAP with patient triggered pressure-regulated ventilation modes, including pressure controlled ventilation and pressure support ventilation; the presence of spontaneous inspiratory effort confirmed by the difference between the mandatory ventilator rate setting and the actual breathing frequency (if the difference was ≥ 2, subjects were considered to have a maintained inspiratory effort); and a RASS score ≤ −4. The exclusion criteria were as follows: presence of a neurological complication affecting respiratory center function; absence of an arterial cannula for continuous pressure monitoring and blood sampling; no usage of invasive mechanical ventilation; age < 18 y; support provided by a membrane oxygenation device; and cyanosis due to right–left cardiac shunting. One data set per day was included for each subject; however, if more than one data set fulfilled the study criteria, the data set recorded closest to 12 pm was included in the analyses. Mean VT was calculated by dividing minute volume by breathing frequency. Pressure target was based on the pressure support ventilation and pressure controlled ventilation settings. In subjects receiving SIMV, mean pressure target was calculated from the ratio of mandatory ventilation rate and the breathing frequency.

### The Stewart Model

According to the Stewart model, independent variables to determine the acid/base status are PaCO2, SID, and ATOT. In our study, the following formulae were used to determine the acid/base status26: 

*   SID = Na+ + K+ + Ca2+ + Mg2+ – Cl– − lactate–

*   ATOT = albumin (g/L) × (0.123 × pH − 0.631) + P (mmol/L) × (0.309 × pH − 0.469)

*   strong ion gap = SID − ATOT − HCO3–

Although Mg2+ measurements were not included in the routine chemistry profile at the study institution, changes in Mg2+ are typically very small and can be neglected, so a constant Mg2+ value can be assumed in these formulas. In this study, a constant Mg2+ value of 1.7 mEq/L was used, as described previously.20

All data sets were described based on the VT/PBW ratio into low VT (< 8 mL/kg) and high VT (≥ 8 mL/kg) groups to determine factors associated with low VT/PBW. In addition, all collected data were categorized by 2 independent variables, SID and ATOT, according to the Stewart model to evaluate non-respiratory (metabolic) acid/base status. Of note, lower SID and higher ATOT levels are causative factors of metabolic acidosis. Accordingly, the data sets were further divided into 4 groups to examine the achievement of a low VT/PBW under the Stewart model: high SID with low ATOT, high SID with high ATOT, low SID with low ATOT, and low SID with high ATOT. Median SID and ATOT values were used as cutoff values to categorize the high and low groups for both parameters.

### Statistical Analysis

Continuous variables were compared using the Mann-Whitney *U* test or the Kruskal-Wallis test. Categorical variables were expressed as numbers with percentages, and values were compared using the chi-square test. In addition, post hoc analysis was performed as needed per the Steel-Dwass method. Univariate analyses of data set characteristics were conducted to determine factors associated with the risk of not adhering to the low VT ventilation policy. Predictive factors with a *P* < .2 in univariate analyses were included in a multivariate logistic regression model. In addition, linear regression analysis was performed to elucidate the correlation of SID, ATOT, and VT/PBW with the low VT ventilation policy. For all analyses, *P* < .05 was considered as statistically significant. All data were analyzed with the JMP statistical software version 12.2 (SAS Institute, Cary, North Carolina).

## Results

During the study period, 630 patients were admitted to the ICU; of these, 100 subjects who fulfilled the inclusion criteria provided 235 individual data sets of clinical and ventilator parameters (Fig. 1). Table 1 summarizes the characteristics of the matched data sets included in this study. Of these 235 VT/PBW data sets, 101 and 134 data sets were in the low and high VT groups, respectively. In addition, the VT/actual body weight and PEEP values were lower in the low VT group than in the high VT group. Furthermore, the breathing frequency, PaCO2, HCO3–, and SID were higher in the low VT group than in the high VT group, whereas, opioids were used more frequently in the high VT group than in the low VT group.

![Fig. 1.](http://rc.rcjournal.com/http://rc.rcjournal.com/content/respcare/64/8/890/F1.medium.gif)

[Fig. 1.](http://rc.rcjournal.com/content/64/8/890/F1)

Fig. 1. 
Flow chart. ECMO = extracorporeal membrane oxygenation.

View this table:
[Table 1.](http://rc.rcjournal.com/content/64/8/890/T1)

Table 1. 
Characteristics of Data Sets

The subjects providing these 235 data sets included 34 subjects in the low VT group, 49 subjects in the high VT group, and 17 subjects who overlapped both the low and high VT groups. The actual body weights of subjects in the high VT group were higher than those of subjects in the low VT group; however, the differences in other characteristics among the 3 groups were not significant (Table 2).

View this table:
[Table 2.](http://rc.rcjournal.com/content/64/8/890/T2)

Table 2. 
Characteristics of Subjects Whose Data Sets Were Classified as High VT, Low VT, and Overlapping VT Groups

Table 3 shows the results of the univariate logistic analysis. PEEP, SID, and absence of opioid administration were associated with the attainment of a low VT. The multivariate logistic analysis included 7 parameters based on the results of the univariate logistic analysis. The number of mechanical ventilation days represented the disease stage, SOFA score represented the severity of the clinical condition, PEEP represented the mechanical ventilation settings, PaO2/FIO2 indicated lung function, SID represented the acid/base balance of a strong ion, ATOT represented the acid/base balance of a weak ion, and the use of opioids represented the drug treatment. Table 4 shows the results of the multivariate logistic analysis. SID, ATOT, and the use of opioids were associated with VT/PBW. The median (interquartile range) VT/PBW in subjects who were administered intravenous opioids was significantly higher than the median VT/PBW in subjects who did not receive intravenous opioids (8.36 [7.41–9.50] vs 7.67 [6.57–9.13] mL/kg PBW, *P* = .01). Regression analysis revealed that VT/PBW and SID exhibited a weak inverse correlation and that VT/PBW and ATOT had a weak correlation (Fig. 2).

View this table:
[Table 3.](http://rc.rcjournal.com/content/64/8/890/T3)

Table 3. 
Univariate Analysis of Variables Associated With Attainment of Low VT Ventilation

View this table:
[Table 4.](http://rc.rcjournal.com/content/64/8/890/T4)

Table 4. 
Multivariate Analysis of Variables Associated With the Attainment of Low VT Ventilation

![Fig. 2.](http://rc.rcjournal.com/http://rc.rcjournal.com/content/respcare/64/8/890/F2.medium.gif)

[Fig. 2.](http://rc.rcjournal.com/content/64/8/890/F2)

Fig. 2. 
Regression analysis between strong ion difference (SID) (A), and total nonvolatile weak anion (ATOT) (B) and ratio of tidal volume (VT) to predicted body weight (VT/PBW). VT/PBW exhibits a weak inverse correlation with SID. VT/PBW and ATOT exhibit a weak correlation.

Figure 3 shows the distribution of all collected data on the ATOT-SID plane. In this study, the distribution of the data sets was as follows: high SID with low ATOT (no. = 46), high SID with high ATOT (no. = 71), low SID with low ATOT (no. = 72), and low SID with high ATOT (no. = 46). The cutoff values for SID and ATOT were median values derived from the data sets of the entire study (41.8 mEq/L for SID and 10.4 mEq/L for ATOT). Importantly, the VT/PBW in the group with high SID and low ATOT was significantly lower than those in the other 3 groups (Fig. 4).

![Fig. 3.](http://rc.rcjournal.com/http://rc.rcjournal.com/content/respcare/64/8/890/F3.medium.gif)

[Fig. 3.](http://rc.rcjournal.com/content/64/8/890/F3)

Fig. 3. 
Distribution of all collected data on the total nonvolatile weak anion (ATOT) and strong ion difference (SID) plane. SID and ATOT exhibit a weak correlation. The data are divided into 4 groups: high SID with low ATOT, high SID with high ATOT, low SID with low ATOT, and low SID with high ATOT. The high and low cutoff values for SID and ATOT are based on median values (41.8 mEq/L SID; 10.4 mEq/L ATOT).

![Fig. 4.](http://rc.rcjournal.com/http://rc.rcjournal.com/content/respcare/64/8/890/F4.medium.gif)

[Fig. 4.](http://rc.rcjournal.com/content/64/8/890/F4)

Fig. 4. 
Tidal volume (VT)/predicted body weight (VT/PBW) in the 4 groups divided according to strong ion difference (SID) and total nonvolatile weak anion (ATOT) values. The data are expressed as a medians with interquartile ranges. VT/PBW in the group with high SID and low ATOT is significantly lower than those in the other 3 groups.

## Discussion

In this retrospective study, SID, ATOT, and the use of opioids were associated with the attainment of low VT in deeply sedated subjects with preserved inspiratory effort. VT/PBW was significantly lower in in the presence of high SID with low ATOT, indicating a tendency of metabolic alkalosis.

The inspiratory drive of the respiratory center is affected by the pH of the cerebrospinal fluid in the medulla as well as the serum pH level detected by the peripheral chemoreceptor.27 The inspiratory drive can be controlled by the management of the buffering function of the serum. Our multivariate logistic analysis suggested that SID and ATOT were associated with adherence to low VT ventilation. In the context of the acid/base balance, higher SID and lower ATOT might reduce VT/PBW in deeply sedated patients with persistent inspiratory effort. The current findings suggested that VT/PBW correlated with SID and ATOT. Despite the weak effects of a higher SID and a lower ATOT, efficient management of the buffering function of the serum might be a feasible strategy to achieve low VT ventilation. For example, SID can be increased by the administration of sodium bicarbonate, whereas a low serum albumin level can attain a low ATOT.

It is difficult to determine the normal ranges of SID and ATOT because their definitions differ among studies. In our study, the cutoff values of SID and ATOT were 41.8 and 10.4 mEq/L, respectively. In a study by Dubin et al,21 the mean SID and ATOT of normal volunteers were 40.8 and 15.0 mEq/L, respectively, whereas those of the ICU subjects (*n* = 935) were 39.7 and 11.0 mEq/L, respectively. In addition, Boniatti et al22 reported that the mean SID and ATOT of survivors were 35.5 and 10.5 mEq/L, respectively, and those of non-survivors were 32.9 and 8.6 mEq/L, respectively, among a cohort of 175 ICU subjects; they also defined the normal ranges of SID as 40–44 mEq/L. Kaplan and Kellum23 demonstrated that the mean SID of survivors and non-survivors were 37.5 and 31.4 mEq/L, respectively, among a cohort of trauma subjects requiring vascular repair. The cutoff values in our study, therefore, were within previously reported normal ranges for ICU patients. In addition, SID demonstrated a weak positive correlation with ATOT, which was described previously.24 Metabolic alkalosis due to a low ATOT, such as that induced by hypoalbuminemia, might have been compensated by a decrease in SID.

The normal target VT range is 6–8 mL/kg PBW in the ICU. Targeted VT for lung protection differs among published studies, with the strictest threshold reported as < 6 mL/kg PBW in subjects with ARDS.28 Fuiter et al5 reported that the use of 6–8 mL/kg PBW as target VT during general anesthesia for major abdominal surgery was associated with improved clinical outcomes and reduced health care utilization. In a meta-analysis, Neto et al8 reported that a mean VT of 6.45 mL/kg ideal body weight was associated with improved outcomes in subjects without ARDS. In our study, we selected < 8 mL/kg PBW as the low VT ventilation threshold, which was similar to that selected by Cooke et al.29 Although < 8 mL/kg PBW is a lenient definition of low VT ventilation, it is within the upper 95% CI boundary of the low VT ventilation arm of the ARDSNet ARMA study.2

Reducing VT in critically ill patients on mechanical ventilation is not easy. Bellani et al30 reported a VT of > 8 mL/kg PBW in more than one third of all subjects with ARDS. In a systematic review of 93 studies in subjects with ARDS, conducted after the ARMA study, Jaswal et al28 concluded that achieving a VT of ≤ 6 mL/kg PBW might not be easy because the mean VT was > 6 mL/kg PBW. Neto et al8 reported that low VT ventilation was achieved in 50.2% of subjects without ARDS in their meta-analysis. In our study, 43.0% of the matched VT/PBW data sets were classified as low VT. Despite the lenient low VT criterion in the current study, the rate of low VT ventilation attainment was lower than that reported in previous studies.

The most popular approach to attain low VT ventilation is a reduction in the pressure target. Neto et al8 reported that the mean pressure target was lower in subjects with low VT (10.2 cm H2O) than those with high VT (17.9 cm H2O). In our study, the mean pressure target of the low and high VT groups did not differ and were comparable to that of subjects with low VT levels in the study by Neto et al.8 One difference between our study and previous reports is the presence of a spontaneous breathing effort, which was not explicitly reported in a majority of previous studies. In our study, VT would have decreased if the pressure target had been set lower by the attending physicians. However, an increasing inspiratory drive might preserve VT. Restricting the pressure target levels might have a limited effect on reducing the VT in patients with persisting inspiratory efforts. Chen et al12 reported that the adherence to a low VT strategy was related to the use of muscle relaxants that suppressed inspiratory muscle activity.

### Limitations

The subjects in our study were selected based on the PaO2/FIO2 ratio according to the Berlin ARDS definition for lung oxygenation. We used the Berlin ARDS definition because subjects with deteriorated lung oxygenation are considered to be affected more by low VT ventilation. Low VT ventilation might be associated with improved outcomes in ICU patients receiving ventilatory support for other reasons. Further investigation is thus needed to examine the attainment of low VT ventilation in subjects without impaired lung oxygenation.

Most of the subjects in our study were admitted to the ICU after cardiac surgery and put under deep sedation for circulatory stabilization. However, the cause could not be determined in all subjects. The study subjects differed from other critically ill populations, especially those intubated for primary respiratory failure. Therefore, it remains unclear whether the results would be different in subjects with respiratory issues as the primary cause of deep sedation.

Our results suggest that the absence of opioid administration was associated with the attainment of low VT ventilation. This finding does not conflict with known respiratory center depression by opioids, which is mainly evident as a decrease in the breathing frequency. The administration of opioids can also affect the depth of sedation. The nurses in the ICU evaluated the subjects using the RASS scale and pain score every hour, and opioids and sedatives were administered accordingly. To date, no methods can precisely evaluate the depth of sedation and analgesia in ICU patients. In this study, we used RASS scores to evaluate the depth of sedation, which is challenging in patients in the ICU, and the actual depth of sedation might not have been comparable between the groups. It is very difficult to evaluate pain relief in deeply sedated patients, and the difficulty of separating the effects of sedatives from those of opioids is a limitation of this study. Further study is needed to examine the sole effect of opioids on VT in ICU subjects on mechanical ventilation.

The presence of an inspiratory effort was confirmed by a difference between the total and set breathing frequency and the ventilation frequency settings, as described previously.29,30 However, it is challenging to assess the level of inspiratory effort precisely. Hence, the presence of an inspiratory effort in entire synchrony with ventilator support remains a possibility. In this study, there is a possibility that not all data sets of the existing inspiratory efforts were collected. Because monitoring esophageal pressure or diaphragmatic electromyography is necessary for precise detection of the inspiratory effort, further studies are warranted to assess the effects of inspiratory effort on low VT ventilation.

Rapid changes in their status, as well as baseline characteristics of the subjects, affected VT. Therefore, although subject and ventilation data were collected daily in this study, the volume of data collected differed among the subjects. A previous study demonstrated that adherence to a low VT strategy was associated with the severity of lung injury,12 thus the results regarding adherence to low VT ventilation might have been significantly affected by the subject characteristics in this study. Therefore, due to the inherent limitations of a retrospective single-center study, a prospective study is warranted to investigate the effects of baseline subject characteristics and instantaneous changes in subject status on the attainment of low VT ventilation in critically ill subjects.

## Conclusion

Despite the weak effects of SID and ATOT, efficient management of the buffering function of the serum might be a feasible strategy to achieve low VT ventilation. Absence of opioid administration was also associated with the attainment of low VT ventilation in subjects with persisting inspiratory effort.

## Footnotes

*   Correspondence: Akinori Uchiyama MD PhD, Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Yamadaoka 2-15, Suita, Osaka Prefecture, 565-0871, Japan. E-mail: auchiyama{at}hp-icu.med.osaka-u.ac.jp.
*   The authors have disclosed no conflicts of interest.

*   See the Related Editorial on Page [1021](http://rc.rcjournal.com/lookup/doi/10.4187/respcare.07198)

*   Copyright © 2019 by Daedalus Enterprises

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