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01.12.2016 | Research | Ausgabe 1/2016 Open Access

Annals of Intensive Care 1/2016

End-inspiratory pause prolongation in acute respiratory distress syndrome patients: effects on gas exchange and mechanics

Zeitschrift:
Annals of Intensive Care > Ausgabe 1/2016
Autoren:
Hernan Aguirre-Bermeo, Indalecio Morán, Maurizio Bottiroli, Stefano Italiano, Francisco José Parrilla, Eugenia Plazolles, Ferran Roche-Campo, Jordi Mancebo
Abbreviations
ARDS
acute respiratory distress syndrome
Crs
static compliance of the respiratory system
EIP
end-inspiratory pause
EtCO2
end-tidal carbon dioxide concentration in the mixed expired gas
IE
inspiratory–expiratory ratio
PaCO2
partial pressure of carbon dioxide in arterial blood
PaO2
partial pressure of arterial oxygen
PBW
predicted body weight
PeCO2
partial pressure of carbon dioxide in mixed expired gas
PEEP
positive end-expiratory pressure
PEEPi
intrinsic positive end-expiratory pressure
P plat
plateau airway pressure
P(a-et)CO2
arterial to end-tidal CO2 gradient
Vd/Vt
dead space-to-Vt ratio
Vdphys
physiological dead space
Vt
tidal volume
∆Paw
driving airway pressure

Background

Mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) must combine both low tidal volumes (Vt) and adequate positive end-expiratory pressure (PEEP) [1, 2]. However, in patients with ARDS, respiratory acidosis and high airway plateau pressures (P plat) may limit management of ventilatory adjustments. In particular, the functional consequences of hypercapnia and respiratory acidosis may differ considerably depending on a patient’s condition, and they may involve almost any physiological function [36].
Optimization of mechanical ventilation parameters is associated with a reduction in dead space and is a useful strategy to reduce hypercapnia in ARDS patients [7]. Many other strategies have also been developed to decrease hypercapnia at the bedside, such as increases in respiratory rate [8], use of active humidifiers [9] and the tracheal gas insufflation [10] or aspiration of dead space [11]. At bedside, the dead space could be calculated using the Enghoff modification of the Bohr equation. The use of this equation implies the use of PaCO2 as surrogate for alveolar carbon dioxide. Therefore, this equation measures a global index of efficiency of gas exchange because it takes also shunt effect into account [12].
Some authors have also shown that prolonging the end-inspiratory pause (EIP) is a feasible maneuver to achieve similar targets [13, 14]. In experimental models [15] and in ARDS patients [14, 1618], EIP prolongation has proven effective at enhancing CO2 elimination and decreasing partial pressure of carbon dioxide in arterial blood (PaCO2) and also physiological dead space (Vdphys). Prolonging EIP extends the time available for an enhanced diffusion between inhaled Vt and resident alveolar gas, thus facilitating the transfer of CO2 from alveoli toward the airways [17, 18].
Although several of the physiological studies described above have reported that EIP prolongation improves gas exchange, none have investigated the potential physiological benefits of this approach in terms of Vt reduction or improved respiratory system mechanics when hypercapnia is of no concern. To address this gap, the objective of our study was to ascertain whether EIP prolongation decreases PaCO2 and whether this effect can be used to decrease Vt while keeping PaCO2 constant. We hypothesized that this approach may have beneficial effects on respiratory system mechanics in ARDS patients.

Methods

The study was performed in the Intensive Care Unit at Hospital de la Santa Creu i Sant Pau, Barcelona (Spain). The institutional ethics committee approved the study (Reference: 10/089), and the patients’ relatives gave signed informed consent.

Patients

Fourteen patients who met the criteria for ARDS [19] were included in the study. Exclusion criteria were: age <18 years, pregnancy, hemodynamic or respiratory instability, and variation of more than 0.5 °C in body temperature in the last 12 h before the study was planned [20]. One patient was excluded during the study period (see Results).
All patients were under sedation and analgesia with intravenous perfusion of midazolam and opiates. Neuromuscular blockade was used in all patients to prevent triggering of the ventilator. Careful endotracheal suctioning was performed before the protocol was started. Heated humidifiers (Fisher & Paykel; MR 290 chamber and MR 850 ALU electric heater; Panmure, New Zealand) were used for airway humidification in all patients. These humidifiers were placed in the inspiratory limb of the circuit in accordance with the manufacturer’s recommendations. The respiratory rate, FiO2, inspiratory flow (square pattern) and PEEP were kept constant throughout the study.

Protocol

All patients were in steady state in the 60-min preceding data recording, and all of them were in a semirecumbent position. The study was performed in three consecutive 30-min phases. Measurements in the first phase (baseline phase) were taken under the mechanical ventilation parameters set by the patient’s attending physician. In the second phase (EIP prolongation phase), the EIP was prolonged until one of the following parameters was reached: (1) EIP of 0.7 s; (2) intrinsic positive end-expiratory pressure (PEEPi) ≥1 cmH2O; or (3) inspiratory–expiratory ratio (I/E) of 1:1. We chose the EIP prolongation time (0.7 s) based on findings from a previous study by Devaquet et al. [18] in which a 20 % prolongation of the inspiratory time induced a significant decrease in PaCO2 and dead space. In the third phase (Vt reduction phase), the Vt was diminished in steps of 30 mL every 30 min until PaCO2 reached baseline levels.
The following data were collected at inclusion: demographic variables (age, sex, height), simplified acute physiology score II, ARDS etiology and days of mechanical ventilation.
During the last minute of each phase, we collected the following respiratory variables: peak airway pressure, Pplat, mean airway pressure, PEEPi, PEEP, driving airway pressure (∆Paw), Vt, dead space-to-Vt ratio (Vd/Vt), static compliance of the respiratory system (Crs) and airway resistance. At the same time, we recorded the following gas exchange variables: pH, partial pressure of arterial oxygen (PaO2), PaCO2 and end-tidal carbon dioxide concentration in the mixed expired gas (EtCO2). PEEPi was measured with a prolonged end-expiratory pause of 4 s, performed using the ventilator expiratory hold button. EtCO2 was measured continuously with a CO2 mainstream sensor (General Electric Capnostat, Milwaukee, WI, USA). The mean value of the last 10 recorded EtCO2 values in each phase of the study was used for analysis.
Ventilatory settings and airway pressures were recorded directly from the ventilator monitoring system. Plateau pressure was measured during an end-inspiratory pause. Dead space was calculated using the Enghoff modification of the Bohr equation [21]: Vd/Vt = (PaCO2 − PeCO2)/PaCO2, being PeCO2 the partial pressure of carbon dioxide in mixed expired gas. Expired gas was measured by collecting gas for 3 min with a Douglas bag (P-341–60; Warren E. Collins Inc., Boston, MA, USA) attached directly to the expiratory port of the ventilator. An automated analyzer (ABL 520; Radiometer A/S, Copenhagen, Denmark) was used to measure expired and arterial gases. Dead space data were expressed as physiological dead space (Vdphys in mL), defined as the sum of instrumental, anatomic and alveolar dead space [22]. Driving pressure (cmH2O) was calculated as Pplat-PEEP. Crs (mL/cmH2O) was calculated as Vt/[Pplat-(PEEP + PEEPi)], and airway resistance (cmH2O/L/s) was calculated as (peak airway pressure − plateau pressure)/Flow. Predicted body weight (PBW) was calculated as follows: 50 + 0.91(height in cm-152.4) for men and 45.5 + 0.91(height in cm-152.4) for women [8]. Arterial to end-tidal CO2 gradient (P(a-et)CO2) was calculated in each study phase. We used Puritan Bennett™ 840 (Covidien, Galway, Ireland) and Dräger Evita XL (Dräger Medical, Lübeck, Germany) ventilators. All the ventilators used have a compressible volume compensation system.

Statistical analysis

Data are expressed as mean ± standard deviation. The results were analyzed using one-way analysis of variance for repeated measures (ANOVA) with the Greenhouse–Geisser correction. We performed the Kolmogorov–Smirnov test to confirm normal data distribution. Since the distribution of the data was normal, we used the Student’s t test and the Pearson linear correlation to compare data and correlations between phases and variables, respectively. A two-tailed p value less than 0.05 was considered statistically significant. The SPSS® Statistics (version 20.0, Chicago, IL, USA) statistical software was used for statistical analysis.

Results

One of the 14 patients enrolled in the study was excluded from the analysis due to fever, tachypnea and unstable EtCO2 during the second phase of the study. The study was performed 5 ± 4 days after starting mechanical ventilation. Table 1 shows demographic data at admission, ARDS etiology and baseline characteristics at study day.
Table 1
Demographic data at admission and baseline characteristics of patients on the study day
Admission
Study day
Patient
Age (years)
Gender
SAPS II
PBW (kg)
Measured weight (kg)
ARDS etiology
Days of MV before study
PaO2/FiO2 (mmHg)
FiO2a
PEEP (cmH2O)a
Flow (L/min)a
RR (bpm)a
1
75
M
59
67.7
58.5
Pneumonia
8
112
0.7
10
70
22
2
52
M
42
68.7
78
Aspiration
13
185
0.65
12
57
20
3
46
F
30
52.4
61
Multiple Trauma
7
118
0.7
12
60
25
4
62
F
69
47.9
55
Pneumonia
5
131
0.6
10
60
25
5
56
F
23
52.4
61.5
Pneumonia
3
100
0.8
12
60
22
6
66
M
40
63.2
72.5
Pneumonia
1
184
0.5
10
60
20
7
57
M
62
69.6
83
Pneumonia
1
147
0.5
8
60
17
8
36
M
24
61.4
90
Pneumonia
4
242
0.5
14
75
23
9
55
M
49
66.8
72
Pneumonia
2
219
0.6
14
70
21
10
51
F
60
43.3
64
Sepsis
12
269
0.4
8
50
21
11
74
F
61
47.9
62.5
Sepsis
1
266
0.5
10
60
21
12
43
M
61
59.6
80.5
Sepsis
3
194
0.7
10
60
22
13
63
M
30
83.1
106
Pneumonia
6
283
0.35
8
60
30
Mean ± SD
57 ± 11
 
47 ± 16
60.3 ± 11.2
72.6 ± 14.6
 
5 ± 4
188 ± 64
0.58 ± 0.13
11 ± 2
61 ± 7
22 ± 3
ARDS acute respiratory distress syndrome, FiO 2 fraction of inspired oxygen, MV mechanical ventilation, PaO 2 /FiO 2 partial pressure of arterial oxygen over fraction of inspired oxygen, PBW predicted body weight, PEEP positive end-expiratory pressure, RR respiratory rate, SAPS II simplified acute physiology score II
aThese settings were kept constant throughout the study
Baseline EIP was 0.12 ± 0.04 s, and it was increased to 0.7 ± 0 s in all patients (p < 0.001). This EIP change was performed maintaining PEEPi <1 cmH2O (0.2 ± 0.2 to 0.5 ± 0.4 cmH2O, p = 0.06) and without the I/E inverse ratio ventilation (1:4.7 ± 0:1.3 to 1:1.7 ± 0:0.4, p = <0.001). EIP prolongation decreased Vdphys and PaCO2 significantly with respect to basal conditions (267 ± 71 to 244 ± 65 mL and 54 ± 9 to 50 ± 8 mmHg, respectively; p < 0.001 for both comparisons). The decrease in PaCO2 levels due to EIP prolongation was correlated with the drop in Vdphys (r = 0.871; p < 0.001). Individual changes in PaCO2 and in Vdphys are shown in Figs. 1 and 2, respectively.
Between the first and second phase, significant decreases were observed in both the Vd/Vt ratio (0.70 ± 0.07 to 0.64 ± 0.08; p < 0.001) and EtCO2 (41 ± 6 to 39 ± 6 mmHg; p = 0.006). Basal Vdphys and P(a-et)CO2 had a close correlation (r = 0.75; p = 0.003). The change in Vdphys and the change in P(a-et)CO2 between the first and second phase also showed a close correlation (r = 0.68; p = 0.001).
In the third phase (EIP prolongation and Vt reduction), the Vt was significantly reduced as compared to previous phases (6.3 ± 0.8 to 5.6 ± 0.8 mL/Kg PBW; p < 0.001). In the third phase, as per protocol design, the PaCO2 and pH values were statistically identical to those at baseline (54 ± 9 vs. 54 ± 10 mmHg; p = 0.90 and 7.31 ± 0.07 vs. 7.31 ± 0.08; p = 0.90, respectively).
The Vdphys decreased progressively and significantly during all phases of the study (267 ± 71 to 244 ± 65 to 216 ± 58 mL; p < 0.001). The Vdphys and Vt at baseline were strongly correlated (r = 0.946; p < 0.001). Additionally, the Vt reduction was tightly correlated with the decrease in Vdphys (r = 0.894; p < 0.001). Respiratory system mechanics, gas exchange, hemodynamics, and temperature data throughout the study are also given in Table 2.
Table 2
Respiratory system mechanics, gas exchange and hemodynamic data during the study
 
Phase 1 (baseline)
Phase 2 (EIP prolongation)
Phase 3 (Vt reduction)
Overall p value
Intergroup differences
EIP (s)
0.12 ± 0.04
0.7 ± 0
0.7 ± 0
<0.001
a, b
Ppeak (cmH2O)
38 ± 6
38 ± 6
35 ± 5
<0.001
b, c
Pmean (cmH2O)
15 ± 3
18 ± 2
17 ± 2
<0.001
a, b, c
Pplat (cmH2O)
24 ± 3
24 ± 3
22 ± 3
<0.001
b, c
PEEPi (cmH2O)
0.2 ± 0.2
0.5 ± 0.4
0.5 ± 0.4
0.06
 
Vt (mL)
378 ± 73
378 ± 73
336 ± 61
<0.001
b, c
Vt (PBW; mL/Kg)
6.3 ± 0.8
6.3 ± 0.8
5.6 ± 0.8
<0.001
b, c
Vdphys (mL)
267 ± 71
244 ± 65
216 ± 58
<0.001
a, b, c
Vd/Vt
0.70 ± 0.07
0.64 ± 0.08
0.64 ± 0.08
<0.001
a, b
Crs (mL/cmH2O)
29 ± 9
29 ± 9
32 ± 11
0.001
b, c
∆ Paw (cmH2O)
13.6 ± 3.6
13.4 ± 3.6
10.9 ± 3.1
<0.001
a, b, c
Raw (cmH2O/L/s)
14 ± 5
13 ± 5
13 ± 4
0.28
 
pH
7.31 ± 0.07
7.34 ± 0.09
7.31 ± 0.08
<0.001
a, c
PaO2 (mmHg)
102 ± 23
98 ± 23
105 ± 29
0.35
 
PaCO2 (mmHg)
54 ± 9
50 ± 8
54 ± 10
<0.001
a, c
EtCO2 (mmHg)
41 ± 6
39 ± 6
43 ± 7
0.002
a, c
P(a-et)CO2 (mmHg)
13 ± 6
12 ± 8
12 ± 9
0.27
 
MAP (mmHg)
80 ± 12
76 ± 9
77 ± 12
0.08
 
HR (beats/min)
87 ± 19
83 ± 20
86 ± 21
0.14
 
Temperature (°C)
36.7 ± 0.9
36.7 ± 0.9
36.6 ± 0.8
0.61
 
Data are presented as number (%) or mean ± SD
Intergroup differences (p < 0.05): a, phase 1 versus phase 2; b, phase 1 versus phase 3; c, phase 2 versus phase 3
Crs static compliance of the respiratory system, EIP end-inspiratory pause, EtCO 2 end-tidal carbon dioxide concentration in the expired air, FiO 2 fraction of inspired oxygen, HR heart rate, MAP mean arterial pressure, PaO 2 partial pressure of oxygen in arterial blood, PaCO 2 partial pressure of carbon dioxide in arterial blood, PBW predicted body weight, PEEPi intrinsic positive end-expiratory pressure, Pmean mean airway pressure, Ppeak peak airway pressure, Pplat plateau airway pressure, P(a-et)CO2 arterial to end-tidal CO2 gradient, Raw airway resistance, Vd phys physiological dead space, Vd/Vt dead space-to-Vt ratio, Vt tidal volume, ∆Paw driving airway pressure

Discussion

The main finding of our study was that the end-inspiratory pause prolongation allowed to decrease tidal volume while maintaining similar PaCO2 levels. Indeed, the decrease in tidal volume led to a significant decrease in Pplat and ∆Paw, and it also improved the respiratory system compliance.
Several studies have shown that prolongation of EIP enhances CO2 elimination and decreases dead space and PaCO2 levels [1418]. Diffusion of CO2 is time dependent, and EIP prolongation increases the time available for alveolar gas exchange [14, 23, 24]. Devaquet et al. [18] extended inspiratory time from 0.7 ± 0.2 to 1.4 ± 0.3 s by increasing the inspiratory pause time from 0 to 20 % of the total breathing cycle. They observed that this modification significantly decreased both Vd/Vt (around 10 %) and PaCO2 (around 11 %). Despite these beneficial effects of prolonged EIP and the direct relationship between inspiratory time and enhanced CO2 elimination [16, 18], EIP prolongation may lead to potentially adverse effects such as PEEPi production and inversion of the I/E ratio together with increases in mean airway pressure. These effects might also provoke hyperinflation, thus altering cardiac performance [25, 26]. Nevertheless, Devaquet and colleagues [18] showed that EIP could be prolonged without significantly increasing PEEPi (I/E ratio 1:1.5). Not surprisingly, and in spite of a significant increase in EIP, we did not induce any significant increase in PEEPi since the expiratory time was long enough to avoid air trapping at the end of a passive expiration (average expiratory time 1.7 ± 0.3 s). Actually (see Table 2), the average product of three time constants (the time needed to passively exhale 96 % of inhaled tidal volume) was in our patients about 1.1 s. (0.373 × 3 = 1.1 s), well below to the average expiratory time.
Prolongation of EIP in our patients caused a significant decrease in dead space and PaCO2 levels that was similar to previously reported [1418]. When comparing phase 1 (baseline) and phase 2 (isolated EIP prolongation), we found that the decrease in the Vd/Vt correlated well with the drop in PaCO2 (r = 0.810; p < 0.001). These changes observed in our patients may be explained by the increase on the time available for distribution and diffusion of inspired tidal gas within resident alveolar gas during EIP prolongation [14]. Indeed, total PEEP levels, airflow, respiratory rate, tidal volume and respiratory mechanics were totally unchanged in this phase of our study [14, 27, 28].
Comparing the second (isolated EIP prolongation) and third (EIP prolongation and Vt reduction) phases, our data showed that the Vd/Vt ratio remained unchanged. However, the Vdphys, expressed in mL, decreased significantly between phases 2 and 3. This is explained by the significant reduction in Vt (that also provoked a decrease in Vdphys) during the third phase as compared to the previous phases, and thus Vd/Vt ratio did not change. The fact that the reduction in Vt in the third phase was accompanied by a significant decrease in Vdphys and ΔPaw (with a significant increase in compliance) suggests that some degree of overdistension might be present at baseline.
As previously described, low tidal volume ventilation in ARDS may induce hypercapnia and, secondarily, induce pulmonary artery hypertension that may impair right ventricular function [29] and eventually cause acute cor pulmonale [30]. To reduce hypercapnia in ARDS ventilated patients, active heated humidifiers are often used. These devices significantly decrease dead space, PaCO2 and ventilator mechanical load [9] without increasing airflow resistance [31]. Although active humidification is recommended over heat and moisture exchangers in ARDS patients [32], two studies focussing on the effects of EIP prolongation on gas exchange [16, 17] did not describe the type of humidification used in their patients. A third study used passive or active humidification (10 and 5 patients, respectively) [18]. However, the effects on PaCO2 in all these studies [1618] were consistently the same, thus suggesting that humidification type per se does not influence the effects of EIP on PaCO2.
Another technique used to decrease hypercapnia is to increase the respiratory rate. However, in ARDS patients, several studies have shown that a high respiratory rate led to gas trapping and induced PEEPi [33, 34]. In addition, experimental models suggested that higher respiratory rates may contribute to the development of ventilator-induced lung injury [35, 36]. Vieillard-Baron et al. [25] compared two respiratory rate strategies, 30 versus 15 breaths/min. They found that the high respiratory rate did not reduce PaCO2 levels but produced dynamic hyperinflation and reduced the cardiac index. In our patients, EIP prolongation was achieved with a relatively high inspiratory flow rate (1 L/s), thus avoiding inverse I/E ratio. This was a safe strategy to decrease PaCO2 levels, while keeping respiratory rate constant (22 breaths/min) and not generating PEEPi.
In our study, the reduction in Vt to maintain isocapnia was modest. Should major reductions in Vt were required, then the use of invasive extracorporeal carbon dioxide removal devices had to be considered in order to avoid acute hypercapnia [37].
Studies analyzing the EIP prolongation did not describe changes in PaO2 [14, 18], except one study by Mercat et al. [16]. This latter study found a slight, but not statistically significant, increase in PaO2 levels during EIP prolongation. This finding was not confirmed in our study. We speculate that the length of time that patients are maintained with EIP prolongation and the mean airway pressure achieved during extended EIP may have contributed to this finding. Indeed, in Mercat’s study [16], EIP prolongation was continued for 1 h with a mean airway pressure of 21 cmH2O and an I/E ratio 1.1. In contrast, in Devaquet’s study [18] and in our own study, EIP prolongation was shorter (30 min in both), mean airway pressure was lower (15 and 17 cmH2O, respectively), and the I/E ratios achieved were 1:1.5 in Devaquet’s study and 1:1.7 in ours.
The main novelty of our study is that prolonging EIP allowed to reduce Vt by 11 % (from 6.3 ± 0.8 to 5.6 ± 0.8 mL/kg of PBW; p < 0.001), maintaining PaCO2 levels equal to baseline. These sequential ventilatory changes were accompanied by a reduction in Vdphys. Also, when PaCO2 returned to baseline due to a reduction in Vt, we found a significant decrease in Pplat and an increase in Crs. In addition, these changes in ventilatory mechanics were accompanied by a significant decrease in ∆Paw. All those findings could be explained by a degree of baseline overinflation even though our initial Vt was low [38]. We further support our contention by the tight correlation between Vt and Vdphys at the onset of the study and the tight correlation between the decrease in Vt and Vdphys at the end of the study. Our patients were basally ventilated with parameters similar to those used in previous studies [1618] in terms of Vt and PEEP, and Vd/Vt was also similar. Moreover, in our patients, Crs was lower (29 mL/cmH2O) than in Mercat and Devaquet studies (37 and 50 mL/cmH2O, respectively). Our findings thus suggest that if PaCO2 is clinically tolerable, EIP prolongation in ARDS provides physiological benefits including a small and consistent decrease in Vt which may help decrease dynamic strain [39].
In our study, a slight but not statistically significant decrease in mean arterial pressure was observed. Such trend could have been the result of complex interactions of PaCO2 and mean airway pressure in cardiovascular system.
We think that EIP prolongation is a feasible maneuver to optimize the consequences of mechanical ventilation in ARDS patients. Physicians may consider using an EIP prolongation in the early phase of ARDS when patients often require sedation and neuromuscular blocking agents. In our study, we have effectively implemented this strategy by using active humidification, relatively high inspiratory flow rates and close monitoring of PEEPi. This bundle decreases PaCO2, which in turn will allow to further decrease Vt and the consequent lung strain when isocapnic conditions are met.
One of the limitations of our study is the relatively small number of patients, the majority with pneumonia, and the fact that the study is short term. Studies with patients with different ARDS etiologies and larger numbers are warranted to confirm our data. Also, we did not measure other parameters such as inflammatory mediators or lung volumes. The calculation of dead space using the Enghoff modification of Bohr equation in patients with large shunt fractions (>20–30 %) could underestimate dead space fraction [12]. In our study, we did not measure intrapulmonary shunt. However, according to the gas exchange values that we obtained, shunt fractions above 30 % are unlikely. Additionally, the EIP prolongation increases the mechanical inflation time and it could extend into neural expiration. Asynchronies may thus develop and cause an inadequate patient–ventilator interaction when the patients are not paralyzed [3941]. Our results could be dependent on our routine management of mechanical ventilation in ARDS patients, but our findings have been consistent in all patients and we consider they could be extrapolated to other ARDS patients. Finally, the absolute decrease in tidal volume, although statistically significant, is moderate.

Conclusions

In conclusion, our data indicate that EIP prolongation is a simple and feasible strategy to decrease dead space and PaCO2 levels. In addition, when PaCO2 levels are of no clinical concern, EIP prolongation allows us to further decrease tidal volume. This, in turn, decreases plateau airway pressure, driving airway pressure and improves respiratory system compliance, suggesting less overdistension and less risk of dynamic strain and lung injury. Therefore, the use of this simple ventilator maneuver during mechanical ventilation in sedated and paralyzed ARDS patients merits consideration.

Authors’ contributions

All authors participated in the study design, data collection and analysis, manuscript writing and final approval. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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