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Running title: VD/VT titrated optimal PEEP
1. The optimal PEEP in this study was 13.25 ± 1.36 cm H2O.
2. A significant change of Cdyn and Qs/Qt was induced by PEEP titration.
3. Hemodynamic parameters did not change significantly during PEEP titration.
Objecctive: This study was aimed to apply the dead space fraction [ratio of dead space to tidal volume (VD/VT)] to titrate optimal positive end-expiratory pressure (PEEP) in ARDS swine model.
Methods: Twelve swine models of ARDS were constructed. Then lung recruitment maneuver was conducted and PEEP was set at 20 cm H2O. The PEEP was reduced by 2 cm H2O every 10 min until to 0 cm H2O and VD/VT was measured after each decrement step. The optimal PEEP was identified by the lowest VD/VT method. The respiration parameters and hemodynamic parameters were recorded during the periods of pre-injury, injury, Po – 4, Po – 2, Po, Po + 2, Po + 4 (Po represented optimal PEEP).
Results: The optimal PEEP in this study was 13.25 ± 1.36 cm H2O. During the Po period, VD/VT decreased to a lower value (44.33 ± 7.96%) than during the injury period (67.67 ± 9.78%) (P < 0.05), while intrapulmonary shunt fraction reached to the lowest values. In addition, a significant change of dynamic tidal respiratory compliance and oxygenation indices was induced by PEEP titration.
Conclusion: The minimal VD/VT can be used to assess PEEP titration in ARDS.
Key words: acute respiratory distress syndrome; dead space fraction; positive end-expiratory pressure; recruitment maneuver
Acute respiratory distress syndrome (ARDS), a severe and life-threatening medical condition, is common in critically ill patients with high mortality . It is a main reason of acute respiratory failure, characterized by widespread inflammation in the lungs [1, 2]. ARDS can induce pathophysiologic mechanisms of alveolar collapse, hyoxemia, vascular dysfunction and elevated dead space fraction (the ratio of dead space volume to tidal volume [VD/VT]) [3, 4].
Currently, the lung-protection strategy makes use of high levels of positive end-expiratory pressure (PEEP) combined with the low tidal volumes to prevent the end expiratory alveolar collapse, increase functional residual capacity and effective alveolar ventilation volume, reduce VD/VT and improve the hypoxemia [5, 6]. However, the application of higher level of PEEP may be not necessarily benefical, since it will increase the inflation of lung regions which are already open. Additionally, it will also increase the risk of hemodynamic abnormalities as well as the lung injury induced by ventilator [7, 8].
Many studies have intended to define the optimal PEEP level based on a lot of methods during a recruitment maneuver (RM) with decremental PEEP. The detection parameters include lung maximum dynamic tidal respiratory compliance (Cdyn), maximum alveolar partial pressure of O2 (PaO2), maximum PaO2 + PaCO2, as well as the inflation lower Pflex and deflation upper Pflex on the pressure-volume curve . However, there is still controversy over the best approach to set PEEP.
In recent years, numerous studies have applied the VD/VT method to assess the effects of lung recruitment and PEEP titration in patients with severe ARDS [10-12]. VD/VT is a more specific value compared to O2, because it is based on CO2’s relatively high diffusability across tissue membranes , and the exchange of CO2 depends strictly on alveolar ventilation volume . In addition, measuring VD/VT may be superior to oxygenation indices PaO2/fraction of inspiration O2 (FiO2) (P/F) in assessing lung recruitment . However, several studies can not find similar effect on VD/VT during PEEP titration. For instance, through the investigation of how physiological, airway and alveolar VD varying with the PEEP changes, Beydon et al.  found that alveolar VD did not vary systematically with PEEP. Furthermore, Blanc et al.  also came to similar conclusions with Beydon et al..Taken together, the application of lowest VD/VT method to titrate optimal PEEP in patients with ARDS seems still to be recognized.
In the present study, a recruitment maneuver was conducted and PEEP was set at 20 cm H2O in ARDS swine model. Then the PEEP was reduced step by step until to 0 cm H2O and the VD/VT was measured after each PEEP decrement step. This study was aimed to realize VD/VT change induced by different PEEP levels in ARDS swine model and to explore the feasibility of VD/VT in guiding the optimal PEEP titration.
2. Materials and methods
2.1 Animals and anesthesia
This was a prospective, sham controlled and in vivo animal study. The study was approved by the animal ethics committee of Beijing Shijitan Hospital, affiliated to Capital Medical University, Beijing, China.
Twelve healthy male swine with average weight of 39.13 ± 3.27 kg were provided by the animal center of Pinggu Hospital of Capital Medical University (Licence: SYXK(B) 2010-0016). Swine were fasted for 24 hours and then orotracheally intubated (Hi-Lo Evac Tracheal Tube, Tyco Healthcare, Pleasanton, California, USA) in the supine position during deep intramuscularly anesthesia with ketamine (35 mg/kg), 3% pentobarbital sodium (30 mg/kg) and diazepam (1.5 mg/kg). A double cavity central venous catheter (ARROW, Pennsylvania, USA) was inserted into the right internal jugular vein using the Seldinger technique  and connected to the monitoring system. After line placement, the anesthetic was switched to total intravenous anesthesia with continuous infusion of pentobarbital (2 mg/kg/h), ketamine (3 mg/kg/h) and pipecurium bromide (0.03 mg/kg/h). In all swine, a 4-French gauge arterial thermodilution catheter (PICCO, Pulsion Medical Systems, Munich, Germany) was inserted via the left femoral artery. The arterial catheter was connected to a computer for pulse contour analysis using the Pulsion Medical Systems (Munich, Germany) for clinical monitoring of hemodynamic measurements. All of the punctures were under the guidance of B-sonography (M-Turbo, Sonosite, Seattle, Washington, USA).
The respiration parameters of P/F, PaCO2 and arterial O2 saturation (SaO2) were directly measured through arterial blood gas analysis  (GEM PREMIER 3000, Lexington MA, USA). Cdyn was monitored by Servo-i ventilator (Siemens Maquet Critical Care AB, Slona, Sweden).
The VD/VT was measured using the noninvasive partial CO2 rebreathing technique  (NICO Cardiopulmonary Management System, Wallingford, Connecticut, USA). With this method, the partial pressure of mixed-expired CO2 was calculated followed by the Enghoff modification of the Bohr equation as follows:
VD/VT = (PaCO2 – PeCO2)/PaCO2
Where PeCO2 represents expired CO2 . An arterial blood gas sample was obtained when the PeCO2 variability on the NICO monitor was ≤ 1 mm Hg within 5 min. The NICO sensor fitted between the Y-piece and the endotracheal tube.
The intrapulmonary shunt fraction (Qs/Qt) was calculated according to standard formulas:
CaO2 = Hb × SaO2 × 1.34 + PaO2 × 0.0031;
CvO2 = Hb × SvO2 × 1.34 + PvO2 × 0.0031;
CcO2 = Hb × ScO2 × 1.34 + PcO2 × 0.0031;
ScO2 ≈ 100%;
PcO2 ≈ PaO2;
PaO2 = PiO2 – PaCO2/R;
PiO2 = (PB – PH2O) × FiO2;
[Qs represents shunted pulmonary blood flow; Qt represents total pulmonary blood flow; Hb represents haemoglobin; CaO2 represents arterial O2 content; CvO2 represents mixed venous O2 content; CcO2 represents pulmonary capillary O2 content; PaO2 represents alveolar partial pressure of O2; PiO2 represents partial pressure of inspired O2; R represents respiratory quotient (0.8); PB represents barometric pressure (about 100 kPa on sea level); PH2O represents saturation vapor pressure (6.3 kPa at 37â„ƒ)].
The hemodynamic parameters of cardiac output index (CI), global end-diastolic volume index (GEDI), extravascular lung water index (ELWI), intra-thoracic blood volume index (ITBI), systemic vascular resistance index (SVRI) were directly measured by the thermodilution method  using the PICCO system (Munich, Germany). The central venous pressure (CVP) was monitored with the central venous catheter in the right internal jugular vein.
After intubation, lungs were ventilated in volume-controlled ventilation mode, with the following initial parameters: tidal volume (VT) of 8 ml/kg, FiO2 of 1.0, PEEP of 5 cm H2O, respiratory rate of 40 breaths/min, inspiratory to expiratory time ratio (I: E) of 1: 2. These settings were maintained for 30 min to achieve stabilization.
2.4 ARDS induction
After recording pre-injury hemodynamic, gas exchange, respiratory mechanics measurements and oxygen metabolism in the supine position at the ventilatory settings as described previously, 0.2 ml·kg-1 oleic acid (Sigma-Aldrich inc. St. Louis, MO, USA) in 40 ml saline was slowly (within 15min) injected in the right atrium via the central venous catheter. After a 90-min injury stabilization period, the experimental protocol was initiated. A successful model of ARDS was defined by P/F < 200 mm Hg for 90 min after oleic acid injection . Each swine were infused a continuous intravenous saline at a rate of 100 ml/h.
The swine were stabilized for 15 min on the following ventilator settings followed by data gathering: pressure control ventilation (PCV) peak pressure 35 cm H2O, PEEP 20 cm H2O, inspiratory time 0.6 s, rate 40/min, FiO2 1.0. Then PEEP was set to 20 cm H2O and pressure control set to a peak airway pressure of 40 cm H2O. These settings were maintained for 2 min, followed by a 15-min stabilization period with peak pressure 35 cm H2O. Data were gathered if PaO2 + PaCO2 > 400 mm Hg. If PaO2 + PaCO2 < 400 mm Hg, the PEEP setting remained unchanged and pressure control was increased to obtain a peak airway pressures of 45 cm H2O. This pattern was sustained for 2 min, followed by a 15-min stabilization period with peak pressure 35 cm H2O. If PaO2 + PaCO2 > 400 mm Hg, the lung recruitment was considered complete [9, 23].
2.6 PEEP titration
After PaO2 + PaCO2 > 400 mm Hg, all swine underwent a decremental PEEP titration in volume control mode. PEEP was decreased in 2 cm H2O steps (from 20 to 0 cm H2O) and maintained at each level for 10 minutes. Cdyn was measured at each step using a VT of 8 ml/kg and a frequency of 40/min. Additionally, the physiologic data including Cdyn, VD/VT, P/F etc. were gathered after each step . The optimal open-lung PEEP was identified by thelowest VD/VT method, which was achieved as determined by a decrease in VD/VT and then a rise with each PEEP step.
The study consisted of the following seven experimental periods:
i) Pre-injury period. Introduction of catheters and mechanical ventilation using the initial parameters;
ii) Injury period. ARDS was induced by the intravenous administration of oleic acid;
iii) PEEP period 1 (Po – 4). 4 cm H2O below the optimal PEEP;
iv) PEEP period 2 (Po – 2). 2 cm H2O below the optimal PEEP;
v) PEEP period 3 (Po). The optimal PEEP;
vi) PEEP period 4 (Po + 2). 2 cm H2O above the optimal PEEP;
vii) PEEP period 5 (Po + 4). 4 cm H2O above the optimal PEEP period.
2.7 Statistical analysis
All data were analyzed using statistics software IBM-SPSS 19.0 (Armonk, New York, USA) and were expressed as mean ± standard deviation (SD). Analysis of non-parametric repeated-measures ANOVA test was used for comparison of all variables collected during seven assessment periods. The P < 0.05 was considered statistically significant.
3.1 Optimal PEEP
The optimal PEEP identified by the lowest VD/VT method was: 13.25 ± 1.36 cm H2O.
3.2 VD/VT change induced by different PEEP levels
There was a significant (P < 0.05) increase in VD/VT from the pre-injury period (34.83 ± 10.70%) to the injury period (67.67 ± 9.78%). After RM, VD/VT decreased to the lowest value of 44.33 ± 7.96% (vs injury P < 0.05) at the optimal PEEP. When PEEP decreased to Po – 4cm H2O, VD/VT significantly increased to 59.58 ± 7.28%. But at the optimal PEEP + 4 cm H2O, VD/VT was higher (64.33 ± 10.28%) (Figure 1 and Table 1).
3.3 Change of P/F during PEEP decrement
There was a statistically significant (P < 0.05) decrease in P/F from the pre-injury period (562 ± 162 mm Hg) to the injury period (75 ± 21 mm Hg). After RM, P/F values significantly increased from 166 ± 109 mm Hg to 365 ± 133 mm Hg when PEEP increased from the optimal P – 4cm H2O to optimal P + 2 cm H2O. But P/F decreased again at the optimal P + 4 cm H2O (Figure 2 and Table 1).
3.4 Changes of Cdyn and Qs/Qt during PEEP decrement
Compared to the pre-injury and another PEEP station after RM, Cdyn value was significantly (P < 0.05) higher on the pressure level of optimal PEEP. But Qs/Qt values were significantly (P < 0.05) lower on the pressure level of optimal PEEP. (Figure 3, Figure 4 and Table 1).
3.5 Hemodynamic change induced by different PEEP levels
The CI, ITBI, GEDI, SVRI did not change significantly during the pre-injury, injury and variable PEEP periods, but a downtrend was observed in CI with the increase of PEEP. For CVP, a significant (P < 0.05) increment was observed during the variable PEEP period relative to the pre-injury and injury period, besides, CVP increased obviously with PEEP increasing. Compared to the pre-injury period, EVLWI values were notably higher during the injury and variable PEEP periods (P < 0.05) (Table 2).
Previous study has reported that the increased VD/VT is one of the marks of early ARDS, besides, an elevated VD/VT is related to an increased risk of death . In the present trial, PEEP was decreased after an RM in swine with ARDS. We observed that PEEP caused a significant change of VD/VT, Qs/Qt, Cdyn and P/F. The results suggested that VD/VT might become a clinically useful tool for assessing collapsed alveolar opening and titrating the optimal PEEP in ARDS.
A markedly elevated VD/VT can be found early in the course of ARDS, which may be due to the obstruction of pulmonary blood flow in the extra-alveolar pulmonary circulation , and increasing areas with a low ventilation, which may impair CO2 clearance . Importantly, the injury of pulmonary capillaries by inflammation and thrombus can also result in the increase of VD/VT [26, 27]. As shown in Figure 1, VD/VT increased significantly during the injury period than during the pre-injury period.
With the increase of PEEP, VD/VT showed a trend of decline. But higher PEEP may lead to the increase of VD/VT because of the over-distention of well ventilated alveoli, which was mentioned in a controlled study by Fengmei et al. . They also figured that the PEEP level corresponding to the minimal VD/VT after the RM was 12 cm H2O.
In our study, the optimal PEEP identified by lowest VD/VT was 13.25 ± 1.36 cm H2O, which reached to the maximum compliance and optimal oxygenation. Our data were in agreement with the findings of Maisch et al. , who showed that different PEEP levels after RM caused significant changes in VD/VT, P/F as well as compliance in ARDS patients.
As can be seen from the calculating formula of VD/VT, VD/VT is inversely related to the CO2 elimination. The CO2 elimination by lung is influenced by effective alveolar surface area, alveolar ventilation, and cardiac output [29, 30]. After the recruitment and optimal PEEP, the CO2 elimination capacity of lung is increased, because alveolar ventilation significantly increased. Our study also showed that in the PEEP levels ranging from Po – 4 to Po, there was a decreasing trend in VD/VT. But when the PEEP levels ranged from Po + 2 to Po + 4 cm H2O, VD/VT increased again. Previous study also demonstrated that VD was significantly increased in the higher PEEP (20 cm H2O) group, which was induced by hyperinflated lung region .
In ARDS, the alveolar collapse causes alveolar ventilation deficient while blood flow not significantly decreasing and VD/VT increasing, which leads to the decline of ventilation/blood flow and increase of Qs/Qt. In the present study, the Qs/Qt achieved the maximum with the increase of VD/VT in ARDS conditions. Under the application of PEEP, the Qs/Qt showed a trend of decline to close to the base value with the decrease of VD/VT, besides, Qs/Qt reached to the minimum under the optimal PEEP state.
Furthermore, higher PEEP increases VD/VT by the reduction in cardiac output [32, 33]. In our study, after the application of PEEP, CVP showed a trend of rise with the increase of PEEP, indicating that PEEP significantly affected the function of right atrium to reduce the returned blood volume. The increase of CVP might be owing to the augment of intrapleural pressure and vena cava reflux resistance which were induced by the high PEEP levels. Moreover, the reduction of returned blood volume gives rise to the decrease of left atrium cardiac output, which is in accordance with our findings that the CI gradually declined with the increase of PEEP. Specially, CI had no obvious statistical difference in each PEEP state, because the PEEP ranged in our study was less than 20 cm H2O.
In conclusion, measurement of VD/VT is valuable in assessing the effects of lung recruitment. The minimal VD/VT can be used as one of many choices to assess PEEP titration in ARDS. In the context of RM and a PEEP titration procedure, a reduction in VD/VT and Qs/Qt, and an increase in Cdyn and P/F indicate a maximum amount of effectively expanded alveoli. The VD/VT may be prospectively used in future clinical trials, particularly when the goal is to evaluate the benefit of an open-lung protective ventilation strategy in patients with ARDS.
However, there are some limitations in our study. In the context of RM and PEEP, alveolar ventilation volume could not be assessed by direct computed tomography methods. In addition, we did not evaluate PEEP more than 20 cm H2O after RM in the ARDS model, so we cannot comment on the effect of higher PEEP on VD/VT, Qs/Qt etc. under those circumstances. Finally, the sample size of twelve swine is relatively small, and arguably underpowered to detect an important effect.