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Effects of intra-abdominal pressure on respiratory system mechanics in mechanically ventilated rats
Respiratory Physiology & Neurobiology 180 (2012) 204–210
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Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Effects of intra-abdominal pressure on respiratory system mechanics in mechanically ventilated rats夽 Hanna Runck a , Stefan Schumann a,∗ , Sabine Tacke b , Jörg Haberstroh c , Josef Guttmann a a b c
Division for Experimental Anesthesiology, University Medical Center Freiburg, Germany Department of Veterinary Clinical Sciences, Clinic for Small Animals-Surgery, Justus-Liebig University, Giessen, Germany Experimental Surgery, BioMed Center, University Medical Center Freiburg, Germany
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Article history: Accepted 16 November 2011 Keywords: Intra-abdominal hypertension Pneumoperitoneum Nonlinear respiratory mechanics
a b s t r a c t We investigated the effects of intra-abdominal pressure on respiratory system compliance at different PEEP levels. 20 ventilated rats underwent four pressure levels (7, 9, 11, 13 mmHg) of helium pneumoperitoneum and were allocated to one of the four PEEP groups (0, 3, 6 and 9 cmH2 O). From the expiratory pressure–volume curve the mathematical inflection point (MIP) was calculated. Volume-dependent compliance was analyzed using the SLICE-method. MIP-pressure correlated to the intra-abdominal pressure (r2 = 0.94, p < 0.001). Peak inspiratory pressure increased with intra-abdominal pressure, and was lower after recruitment-maneuvers (p < 0.001). The compliance gain following recruitment-maneuvers depended on PEEP, intra-abdominal pressure and intratidal volume (all p < 0.001). Mean arterial pressure was independent of PEEP (p = 0.068) and intra-abdominal pressure (p = 0.293). Volume-dependent compliance courses varied according to PEEP and intra-abdominal pressure. The level of intra-abdominal pressure alters respiratory system mechanics in healthy lungs. Intratidal compliance can be used to guide the PEEP adjustment in intra-abdominal hypertension. If counterbalanced by PEEP, elevated intraabdominal pressure has no negative effects on oxygenation or hemodynamics. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Intra-abdominal hypertension (IAH) is strongly related to morbidity and mortality in critically ill patients (Cheatham, 2009; Cheatham and Safcsak, 2010). Intra-abdominal hypertension causing the abdominal compartment syndrome (ACS) is observed in severe abdominal trauma and in aftermath of major abdominal operations. Further reasons for elevated intra-abdominal pressure are morbid obesity (Pelosi et al., 1999; Lambert et al., 2005) which is known to alter respiratory system mechanics by decreasing functional residual capacity and compliance (Safran and Orlando, 1994; Iwasaka et al., 1996; Pelosi et al., 1999; Lambert et al., 2005) and artificially induced pneumoperitoneum during laparoscopy, which is applied to facilitate the minimally invasive (laparoscopic) surgery procedure. Several studies were performed to investigate the effects of a pneumoperitoneum on respiratory system
mechanics. Elevated airway pressure and reduced compliance were commonly reported (Bardoczky et al., 1993; Safran and Orlando, 1994; Iwasaka et al., 1996). There is evidence that PEEP has a positive effect on oxygenation (Pelosi et al., 1999; Hazebroek et al., 2002) in the situation of increased intra-abdominal pressure. However, the use of PEEP in the presence of pneumoperitoneum remains controversial since the application of both may reduce cardiac output (Kraut et al., 1999). In the present study we investigated the effects of different intra-abdominal pressures at different PEEP levels on intratidal nonlinear respiratory system mechanics, on hemodynamics and on oxygenation in a rat model with uninjured lungs under mechanical ventilation. The application of a pneumoperitoneum served as a model for various conditions accompanied by elevated intraabdominal pressure. 2. Materials and methods
夽 This work was supported by the Deutsche Forschungsgemeinschaft Grant #GU 561/6-2. ∗ Corresponding author at: Anästhesiologische Universitätsklinik, Sektion Experimentelle Anästhesiologie, Hugstetter Straße 55, D-79106 Freiburg, Germany. Tel.: +49 761 27023290. E-mail address: [email protected] (S. Schumann). 1569-9048/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2011.11.007
This study was approved by the review board for the care of animal subjects of the government executive (Regierungspräsidium, Freiburg, Germany; G-06/3) and was carried out in accordance with the German law for animal protection and in compliance with the animal care guidelines of the European Community (86/609/EC).
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205 9 cmH2O
2.1. Animal preparation
2.2. Interventions After preparation, the rats were randomly allocated to one of the four PEEP levels (0, 3, 6 and 9 cmH2 O, five animals in each PEEP level). After a stabilization period of 10 min following preparation, PEEP was set to the respective level and maintained during the experiment. Mechanical ventilation was continued for 30 min without further intervention. Following baseline measurements without pneumoperitoneum a sequence of four levels of pneumoperitoneal pressures (9, 12, 15 and 18 cmH2 O, being equivalent to 7, 9, 11, 13 mmHg) was applied in random order for 30 min, respectively. For the final measurement, pneumoperitoneum was disengaged. Randomization was performed by sealed envelope technique. 2.3. Experimental protocol Following the initial stabilization period and after each 30min period a blood-gas analysis was performed, mean arterial pressure (MAP) was recorded. For recruitment of the lungs two consecutive low-flow maneuvers with an inspiratory and expiratory flow rate of 1 ml s−1 up to a maximal pressure of 40 cmH2 O were performed. Subsequently an 18 G intravenous cannula (Hospira, Inc., Lake Forest, IL, USA) was inserted into the lower right abdominal quadrant, and the abdomen was insufflated to the predefined pneumoperitoneal pressure. To avoid an impact of the insufflated gas on blood gas analysis we used helium as an inert gas for pressurizing the abdomen. 2.4. Measurements Airway pressure was measured using a piezoelectric pressure transducer (SI – special instruments GmbH, Nördlingen, Germany). Inspiratory and expiratory flow rates were measured separately using two pneumotachographs (Fleisch #3, Dr. Fenyves und Gut, Hechingen, Germany) to reduce dead space. Air volume was calculated by integration of flow. Data were recorded at a sampling rate of 400 Hz using a self-developed software package based on
12 cmH2O 15 cmH2O 18 cmH2O
12 10
V (ml)
In 20 female Wistar rats anesthesia was induced with 2% isoflurane delivered in oxygen and maintained by continuous rate infusion of 100 mg kg−1 h−1 S(+)-ketamine (Ketanest® S, Pfizer, Karlsruhe, Germany) and 4 mg kg−1 h−1 midazolam (Dormicum® , Roche, Grenzach-Wyhlen, Germany), both diluted in saline solution, which also served as volume resuscitation. The animals were tracheotomized for intubation of the trachea and the lungs ventilated with 100% oxygen using a research ventilator for rodents (FlexiVent, Scireq, Montreal, Canada). Ventilation was preset to a respiratory rate (RR) of 70 min−1 and a tidal volume of 10 ml kg−1 using volume-controlled ventilation at constant inspiratory flow rate. During the experiment RR was adjusted to maintain arterial partial pressure of carbon dioxide (PaCO2 ) within the physiological range (35–45 mmHg). Since the small blood volume in rats limits the number of blood gas analyses we did not immediately control PaCO2 after the change of ventilation settings. During animal preparation PEEP was set to 2 cmH2 O. Spontaneous breathing was suppressed by intravenous application of 1 mg kg−1 pancuronium bromide (Pancuronium® Organon, Teknika, Eppelheim, Germany). Finally, the carotid artery was cannulated with polythene tubing (Portex Non Sterile Polythene Tubing, 0.58 mm ID, 0.96 mm OD, SIMS Portex Ltd., Kent, UK). Inspiratory and expiratory flow rate, airway pressure, arterial pressure and ECG were continuously measured and recorded.
8 6 4 2 0
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P (mbar) Fig. 1. PV-loops obtained from low-flow maneuvers at different abdominal pressures. With successively increasing intra-abdominal pressures the loops are shifted downwards. Circles indicate locations of mathematical inflection points (MIPs) of the expiratory limb of the PV-curve. Vertical arrows indicate the pressure shift of the MIP when abdominal pressure is increased.
LabVIEW (LabVIEW 7.1, National Instruments Corp., Austin, TX, USA). MAP and ECG were measured via a clinical monitoring system (Sirecust, Siemens, Erlangen, Germany) from which the analogue output signal was fed into the data recording system. 2.5. Data analysis Data analysis was performed using MatLab (R2006a, The Mathworks, Natick, USA). From the low-flow maneuvers, the pressure corresponding to the mathematical inflection point (MIP) of the expiratory limb of the quasistatic pressure–volume (PV) curve was calculated as follows: from the PV-curve the expiratory limb was extracted. The MIP was identified as that point at which the second derivative of the PV-curve was zero. The MIP was compared to the given abdominal pressure. For determination of the lung’s intratidal compliance, 10 consecutive breaths before and after low-flow maneuvers were analyzed respectively. For calculation of the intratidal nonlinear compliance the SLICE-method (Guttmann et al., 1994) was used. Briefly, each tidal pressure–volume loop was divided into six adjoining volume portions (slices) of equal size. For each slice the compliance (C) was calculated via multiple linear regression analysis using the equation of motion: P = P0 +
1 V + RV˙ C
where P is the airway pressure, P0 is the dynamic pressure base, V is the volume, V˙ is the flow and R is the resistance. Like this, the intratidal course of compliance as a function of volume can be obtained by drawing the six slice-compliance values over the six volume portions. Furthermore, peak inspiratory pressure was detected for 10 breaths before and after the low-flow maneuvers respectively. 2.6. Statistical analysis For better comparison of ventilation data and abdominal pressure data, all pressure values are given in cmH2 O. Statistical analysis was carried out using two- and three-way ANOVA and paired t-test. If not otherwise indicated all values were expressed as mean ± SD. Statistical significance was set at p < 0.05.
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3. Results Application of intra-abdominal pressure resulted in characteristic changes of the pressure–volume loop of the respiratory system (Fig. 1). Increasing intra-abdominal pressure decreased the slope of the pressure–volume loop and shifted the expiratory MIP towards higher pressures. The pressure at the MIP of the expiratory limb correlated well to the applied intra-abdominal pressure (r2 = 0.94, p < 0.001, Fig. 2). Two factorial ANOVA exhibited a significant dependence of this pressure on intra-abdominal pressures (pIAP < 0.001) but no significant dependence on PEEP (pPEEP = 0.215). Intratidal compliance decreased generally with increasing intraabdominal pressure. Yet, intratidal compliance was increased after the low-flow maneuvers (Fig. 3). Three factorial ANOVA revealed a significant dependence of compliance gain on PEEP, intraabdominal pressure and intratidal volume range (all p < 0.001). The compliance–volume curves obtained before the low-flow maneuvers differed from those obtained after the low-flow maneuvers. Before application of the low-flow maneuvers the intratidal courses of compliance were slightly increasing or remained nearly constant with increasing intratidal volume at PEEP 0, 3 and 6 cmH2 O. At PEEP 9 cmH2 O we found similar compliance courses for all intra-abdominal pressures. Without pneumoperitoneum intratidal compliance courses declined with intratidal volume. After application of the low-flow maneuvers we found intratidal compliance to increase with intratidal volume at PEEP 0 and 3 cmH2 O. At PEEP 6 cmH2 O compliance increased slightly and at PEEP 9 cmH2 O the intratidal compliance decreased with intratidal volume.
Fig. 2. Correlation between intra-abdominal pressures (IAP) and pressures at the mathematical inflection point (pMIP ). The pressure values of the MIPs correlated well to the intra-abdominal pressure (r2 = 0.94, p < 0.001). The black line shows the linear regression curve (pMIP = 0.82IAP + 3.37 cmH2 O).
Fig. 3. Intratidal courses of volume-dependent compliance of the respiratory system at different PEEP levels and different intra-abdominal pressures. For the analysis each breath was divided into six equally sized portions (slices). For each slice compliance of the respiratory system was calculated separately. Top row: intratidal compliance course before low-flow maneuvers; middle row: intratidal compliance course after low-flow maneuvers; bottom row: gain in intratidal compliance course after low-flow maneuvers. PEEP levels for each column are indicated in the respective top row. Symbols indicate abdominal pressure (baseline before sequence of pneumoperitoneum was applied (0 before), at helium pneumoperitoneum of 9, 12 and 15 cmH2 O, and baseline after sequence of pneumoperitoneum was applied (0 after)) as indicated in the first graph. PEEP, tidal volume and intra-abdominal pressure were significant factors for respiratory system compliance and for compliance gain, all p < 0.001.
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Three-way ANOVA showed a significant dependence of compliance on PEEP, intra-abdominal pressure and volume range (all p < 0.001). Peak inspiratory pressure (Pmax ) increased with increasing intra-abdominal pressure and returned to its baseline value after deflation (Fig. 4). For all PEEP levels Pmax was significantly reduced after the low-flow maneuvers (p < 0.001). Two-way ANOVA revealed that Pmax depended significantly on PEEP and intra-abdominal pressure (p < 0.001). We did not observe significant changes in PaO2 after application of intra-abdominal pressure. Nevertheless, at zero PEEP, PaO2 was lower compared to the other PEEP levels (Fig. 5). Two-way ANOVA showed a significant dependence of PaO2 on PEEP (pPEEP = 0.0082) but not on intra-abdominal pressure (pIAP = 0.1534). MAP did not change significantly with intra-abdominal pressure or PEEP (pIAP = 0.2926, pPEEP = 0.0680, Fig. 6). 4. Discussion 4.1. Intratidal compliance
Fig. 4. Peak inspiratory pressures before and after low-flow maneuvers at different PEEP levels and different intra-abdominal pressures. Intra-abdominal pressures: baseline before sequence of pneumoperitoneum was applied (0 before), at helium pneumoperitoneum of 9, 12 and 15 cmH2 O, and baseline after sequence of pneumoperitoneum was applied (0 after). Black: before, white: after low-flow maneuver. PEEP levels were set as indicated in the graphs. For all PEEP levels Pmax was significantly reduced by the low-flow maneuvers (p < 0.001).
The main findings of our study demonstrate that dynamic intratidal compliance is reduced when the intra-abdominal pressure is increased by helium pneumoperitoneum. This finding is in accordance with several other studies demonstrating similar impairments of respiratory system mechanics at intra-abdominal hypertension (Bardoczky et al., 1993; Iwasaka et al., 1996; Pelosi et al., 1997; Kraut et al., 1999; Avital et al., 2008). The main reason for such effects appears to be the impeded diaphragmatic excursion. Intra-abdominal hypertension causes a cranial shift of the diaphragm and hence compression atelectasis in the basal lung regions (Safran and Orlando, 1994). The interpretation of various intratidal compliance courses was described by Mols et al. (1999). An increasing compliance course indicates ventilation on low lung volumes with repeated intratidal recruitment whereas a decreasing course indicates ventilation at high lung volumes with alveolar overdistension. At PEEP levels up to 6 cmH2 O the tidal compliance courses were almost constant across the total intratidal volume range. Only if intra-abdominal pressure was absent at a PEEP of 9 cmH2 O a declining compliance course was observed indicating ventilation at fully recruited lungs or even overexpansion of lung tissue.
Fig. 5. PaO2 at different PEEP levels and intra-abdominal pressures. PEEP levels as indicated in the graphs. Intra-abdominal pressures: baseline before sequence of pneumoperitoneum was applied (0 baseline), at helium pneumoperitoneum of 9, 12, 15 and 18 cmH2 O, and baseline after sequence of pneumoperitoneum was applied (0 endline).
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Fig. 6. Mean arterial pressure (MAP) at different PEEP levels and intra-abdominal pressures. PEEP levels as indicated in the graphs. Intra-abdominal pressures: baseline before sequence of pneumoperitoneum was applied (0 baseline), at helium pneumoperitoneum of 9, 12, 15 and 18 cmH2 O, and baseline after sequence of pneumoperitoneum was applied (0 endline).
4.2. Low-flow maneuvers It can be assumed that the passive motility of the diaphragm is the more impaired the higher the intra-abdominal pressure is, resulting in more pronounced cranial displacement and hence formation of compression atelectasis. This is in agreement to our finding that the airway opening pressure at the MIP of the expiratory PV-curve and the intra-abdominal pressure were similar. The very steep slope of the expiratory PV-curve at this point might be interpreted as a sign for alveolar collapse caused by basal compression (DiRocco et al., 2007). Reasoned by the increased intra-abdominal pressure, the abdominal compartment seems to act as a pressure limitation for the thoracic compartment, consequently smaller pulmonary gas volumes were achieved within the pressure-limited low-flow maneuvers. The reduction of compliance was accompanied by a shift of the MIP within the expiratory PV-curve towards higher pressure values. Furthermore, during volume-controlled ventilation increased maximal pulmonary pressures were observed in the presence of increased intra-abdominal pressure. 4.3. Recruitment Following low-flow maneuvers we found compliance gain accompanied by a reduction of Pmax , which we attribute to alveolar recruitment. Recruitment success of low-flow maneuvers depended strongly on intra-abdominal pressure. Low-flow maneuvers had only little recruiting effects if intra-abdominal pressure was increased. Compliance gain caused by the low-flow maneuvers was highest at zero PEEP, both with and without helium pneumoperitoneum. At PEEP 9 cmH2 O compliance gain was smaller compared to all other PEEP levels, which might be caused by an additional overdistension of the lung parenchyma. As described in other studies (Bardoczky et al., 1993; Iwasaka et al., 1996; Avital et al., 2008) we observed an increase in Pmax with increasing intra-abdominal pressure. We interpret the increase in Pmax as a result of two parameters influenced by the pneumoperitoneum. First, the applied intra-abdominal pressure counteracts the pressure applied by the ventilator to apply the targeted tidal volume during volume-controlled ventilation. In other words, the impairment of diaphragmatic excursion decreases chest wall compliance. Second there is evidence for compression atelectasis caused by intraabdominal hypertension (Liem et al., 1996; Pelosi et al., 1998; Meier et al., 2006) leading to a reduction of the accessible pulmonary gas
volume that contributes to ventilation. The latter assumption is supported by the reduction of Pmax and the increase in compliance after the low-flow maneuvers, which is likely to be caused by reduction of atelectasis. 4.4. Oxygenation The impairment of ventilation caused by an increase of intra-abdominal pressure has been visualized earlier by means of functional electrical impedance tomography (fEIT) scans in pigs (Meier et al., 2006). An increase in atelectasis decreases the number of sufficiently ventilated alveoli, resulting in a ventilation–perfusion mismatch, and a decrease in arterial oxygenation. Nevertheless, in our study intra-abdominal hypertension had no effect on oxygenation. We only observed a clearly decreased PaO2 in the absence of PEEP. This might be reasoned by the relatively mild pneumoperitoneum pressures that we induced in this study. 4.5. PEEP Larger intra-abdominal pressures counteracted full recruitment, this problem might have been resolved by the use of PEEP levels above those used in this study. The reason for the lower PaO2 is a large amount of atelectasis caused by the combination of intra-abdominal pressure and zero PEEP and probably resorption atelectasis caused by the high FiO2 . However, since ventilation with zero PEEP can per se be injurious for the lungs (Chu et al., 2004), stress-induced biotrauma in the alveolar parenchyma might also have played a role. These findings are in concordance with a study performed in rats by Hazebroek et al. (2002). In contrast to those and our findings, Liem et al. (1996) found that abdominal insufflation with CO2 or helium decreased PaO2 in piglets. However, it remains unclear if PEEP was applied during their experimental protocol or not. The authors argue that blood gases alterations in juvenile animals may occur from decreased diaphragmatic excursion and increased dead space ventilation. The postulated cause for the decrease in PaO2 is abdominal distension, resulting in alveolar collapse and pathophysiological shunting of blood. 4.6. Hemodynamics In the present study, MAP did not change in the presence of PEEP or pneumoperitoneum. In other studies negative effects of high PEEP levels (12 cmH2 O and more) on hemodynamics
H. Runck et al. / Respiratory Physiology & Neurobiology 180 (2012) 204–210
were found (Qvist et al., 1975; Schreuder et al., 1985). Others found that a relatively mild PEEP level of 5 cmH2 O had no suppressive effects on MAP (Lesur et al., 2010). The latter is in accordance with our observation, where PEEP was not higher than 9 cmH2 O. In their review article, Grabowsky et al. lined out that ‘the degree to which increased intra-abdominal pressure affects hemodynamic function is dependent on several factors, including intravascular volume, level of intra-abdominal pressure, and patient position’. The use of carbon dioxide for insufflation does also considerably influence hemodynamics (Grabowski and Talamini, 2009). Acidosis and hypercarbia can be excluded as hemodynamics-influencing factors in our study, since we used helium for insufflation and kept PaCO2 in a physiological range by adapting the respiratory rate according to blood gas analysis. We cannot make any statement about cardiac output or stroke volume because measuring these parameters was not part of our protocol. 4.7. Limitations of the study We always kept the animals in supine position and did not investigate the animals in other body positions. Furthermore, we used a gas pneumoperitoneum as a model for generally increased intraabdominal pressure. Intra-abdominal pressure caused by intraabdominal fluid accumulation, e.g. in case of ascites might result in a shifted pressure gradient inside the abdomen (Loring et al., 1994). Body position and the physical cause for increased intraabdominal pressure (incompressible fluid or compressible gas) may affect respiratory system mechanics. However, in such case the analysis of intratidal compliance would indicate atelectasis and hyperinflation in the same way as in the gas pneumoperitoneum in supine position. The study was conducted in animals with healthy lungs. If a systemic insult is added to the mechanical insult applied to the lungs, e.g. in a multiple hit model, the physiological and inflammatory responses of lungs are amplified (Bouadma et al., 2007), therefore the effects of recruitment maneuvers, PEEP and elevated intra-abdominal pressure could be different in individuals with injured lungs. This subject should be issued in further studies. 4.8. Clinical implications Analyzing intratidal compliance can be used to guide the PEEP adjustment in presence of increased intra-abdominal pressure. Several studies have previously addressed this issue and proposed strategies for setting PEEP with respect to the lower and upper inflection points of the static PV-curve as surrogates of the end of derecruitment and the beginning of overinflation, respectively (Tobin, 2001; Martin-Lefevre et al., 2001; DiRocco et al., 2007). However, it has been demonstrated that respiratory system mechanics under static conditions differ clearly from those during dynamic conditions (Stahl et al., 2006; Stenqvist et al., 2008). In this study we calculated the intratidal profile of compliance during the dynamic conditions of uninterrupted mechanical ventilation. We would like to suggest setting PEEP to a level at which the profile of intratidal compliance does not show an initial increasing part to prevent from intratidal derecruitment. Furthermore we suggest to set PEEP to a level at which the profile of intratidal compliance does not show a decreasing part at endinspiration to prevent from overdistension. In our study intratidal compliance increased up to a PEEP level of 6 cmH2 O and decreased at PEEP 9 cmH2 O (Fig. 3). This indicates that a PEEP setting to 6 cmH2 O would be preferable.
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4.9. Conclusion Intra-abdominal pressure reduces respiratory system compliance. To avoid hypoxemia and lung injury caused by compression atelectasis, PEEP should be applied to counterbalance increased intra-abdominal pressure during mechanical ventilation. The analysis of intratidal compliance could be helpful for guiding the PEEP setting to a level preventing from formation of compression atelectasis and overdistension of lung tissue during mechanical ventilation. References Avital, S., Itah, R., Szomstein, S., Rosenthal, R., Inbar, R., Sckornik, Y., Weinbroum, A., 2008. Correlation of CO(2) pneumoperitoneal pressures between rodents and humans. Surg. Endosc. 23, 50–54. Bardoczky, G.I., Engelman, E., Levarlet, M., Simon, P., 1993. Ventilatory effects of pneumoperitoneum monitored with continuous spirometry. Anaesthesia 48, 309–311. Bouadma, L., Dreyfuss, D., Ricard, J.D., Martet, G., Saumon, G., 2007. 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Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Effects of intra-abdominal pressure on respiratory system mechanics in mechanically ventilated rats夽 Hanna Runck a , Stefan Schumann a,∗ , Sabine Tacke b , Jörg Haberstroh c , Josef Guttmann a a b c
Division for Experimental Anesthesiology, University Medical Center Freiburg, Germany Department of Veterinary Clinical Sciences, Clinic for Small Animals-Surgery, Justus-Liebig University, Giessen, Germany Experimental Surgery, BioMed Center, University Medical Center Freiburg, Germany
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Article history: Accepted 16 November 2011 Keywords: Intra-abdominal hypertension Pneumoperitoneum Nonlinear respiratory mechanics
a b s t r a c t We investigated the effects of intra-abdominal pressure on respiratory system compliance at different PEEP levels. 20 ventilated rats underwent four pressure levels (7, 9, 11, 13 mmHg) of helium pneumoperitoneum and were allocated to one of the four PEEP groups (0, 3, 6 and 9 cmH2 O). From the expiratory pressure–volume curve the mathematical inflection point (MIP) was calculated. Volume-dependent compliance was analyzed using the SLICE-method. MIP-pressure correlated to the intra-abdominal pressure (r2 = 0.94, p < 0.001). Peak inspiratory pressure increased with intra-abdominal pressure, and was lower after recruitment-maneuvers (p < 0.001). The compliance gain following recruitment-maneuvers depended on PEEP, intra-abdominal pressure and intratidal volume (all p < 0.001). Mean arterial pressure was independent of PEEP (p = 0.068) and intra-abdominal pressure (p = 0.293). Volume-dependent compliance courses varied according to PEEP and intra-abdominal pressure. The level of intra-abdominal pressure alters respiratory system mechanics in healthy lungs. Intratidal compliance can be used to guide the PEEP adjustment in intra-abdominal hypertension. If counterbalanced by PEEP, elevated intraabdominal pressure has no negative effects on oxygenation or hemodynamics. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Intra-abdominal hypertension (IAH) is strongly related to morbidity and mortality in critically ill patients (Cheatham, 2009; Cheatham and Safcsak, 2010). Intra-abdominal hypertension causing the abdominal compartment syndrome (ACS) is observed in severe abdominal trauma and in aftermath of major abdominal operations. Further reasons for elevated intra-abdominal pressure are morbid obesity (Pelosi et al., 1999; Lambert et al., 2005) which is known to alter respiratory system mechanics by decreasing functional residual capacity and compliance (Safran and Orlando, 1994; Iwasaka et al., 1996; Pelosi et al., 1999; Lambert et al., 2005) and artificially induced pneumoperitoneum during laparoscopy, which is applied to facilitate the minimally invasive (laparoscopic) surgery procedure. Several studies were performed to investigate the effects of a pneumoperitoneum on respiratory system
mechanics. Elevated airway pressure and reduced compliance were commonly reported (Bardoczky et al., 1993; Safran and Orlando, 1994; Iwasaka et al., 1996). There is evidence that PEEP has a positive effect on oxygenation (Pelosi et al., 1999; Hazebroek et al., 2002) in the situation of increased intra-abdominal pressure. However, the use of PEEP in the presence of pneumoperitoneum remains controversial since the application of both may reduce cardiac output (Kraut et al., 1999). In the present study we investigated the effects of different intra-abdominal pressures at different PEEP levels on intratidal nonlinear respiratory system mechanics, on hemodynamics and on oxygenation in a rat model with uninjured lungs under mechanical ventilation. The application of a pneumoperitoneum served as a model for various conditions accompanied by elevated intraabdominal pressure. 2. Materials and methods
夽 This work was supported by the Deutsche Forschungsgemeinschaft Grant #GU 561/6-2. ∗ Corresponding author at: Anästhesiologische Universitätsklinik, Sektion Experimentelle Anästhesiologie, Hugstetter Straße 55, D-79106 Freiburg, Germany. Tel.: +49 761 27023290. E-mail address: [email protected] (S. Schumann). 1569-9048/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2011.11.007
This study was approved by the review board for the care of animal subjects of the government executive (Regierungspräsidium, Freiburg, Germany; G-06/3) and was carried out in accordance with the German law for animal protection and in compliance with the animal care guidelines of the European Community (86/609/EC).
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205 9 cmH2O
2.1. Animal preparation
2.2. Interventions After preparation, the rats were randomly allocated to one of the four PEEP levels (0, 3, 6 and 9 cmH2 O, five animals in each PEEP level). After a stabilization period of 10 min following preparation, PEEP was set to the respective level and maintained during the experiment. Mechanical ventilation was continued for 30 min without further intervention. Following baseline measurements without pneumoperitoneum a sequence of four levels of pneumoperitoneal pressures (9, 12, 15 and 18 cmH2 O, being equivalent to 7, 9, 11, 13 mmHg) was applied in random order for 30 min, respectively. For the final measurement, pneumoperitoneum was disengaged. Randomization was performed by sealed envelope technique. 2.3. Experimental protocol Following the initial stabilization period and after each 30min period a blood-gas analysis was performed, mean arterial pressure (MAP) was recorded. For recruitment of the lungs two consecutive low-flow maneuvers with an inspiratory and expiratory flow rate of 1 ml s−1 up to a maximal pressure of 40 cmH2 O were performed. Subsequently an 18 G intravenous cannula (Hospira, Inc., Lake Forest, IL, USA) was inserted into the lower right abdominal quadrant, and the abdomen was insufflated to the predefined pneumoperitoneal pressure. To avoid an impact of the insufflated gas on blood gas analysis we used helium as an inert gas for pressurizing the abdomen. 2.4. Measurements Airway pressure was measured using a piezoelectric pressure transducer (SI – special instruments GmbH, Nördlingen, Germany). Inspiratory and expiratory flow rates were measured separately using two pneumotachographs (Fleisch #3, Dr. Fenyves und Gut, Hechingen, Germany) to reduce dead space. Air volume was calculated by integration of flow. Data were recorded at a sampling rate of 400 Hz using a self-developed software package based on
12 cmH2O 15 cmH2O 18 cmH2O
12 10
V (ml)
In 20 female Wistar rats anesthesia was induced with 2% isoflurane delivered in oxygen and maintained by continuous rate infusion of 100 mg kg−1 h−1 S(+)-ketamine (Ketanest® S, Pfizer, Karlsruhe, Germany) and 4 mg kg−1 h−1 midazolam (Dormicum® , Roche, Grenzach-Wyhlen, Germany), both diluted in saline solution, which also served as volume resuscitation. The animals were tracheotomized for intubation of the trachea and the lungs ventilated with 100% oxygen using a research ventilator for rodents (FlexiVent, Scireq, Montreal, Canada). Ventilation was preset to a respiratory rate (RR) of 70 min−1 and a tidal volume of 10 ml kg−1 using volume-controlled ventilation at constant inspiratory flow rate. During the experiment RR was adjusted to maintain arterial partial pressure of carbon dioxide (PaCO2 ) within the physiological range (35–45 mmHg). Since the small blood volume in rats limits the number of blood gas analyses we did not immediately control PaCO2 after the change of ventilation settings. During animal preparation PEEP was set to 2 cmH2 O. Spontaneous breathing was suppressed by intravenous application of 1 mg kg−1 pancuronium bromide (Pancuronium® Organon, Teknika, Eppelheim, Germany). Finally, the carotid artery was cannulated with polythene tubing (Portex Non Sterile Polythene Tubing, 0.58 mm ID, 0.96 mm OD, SIMS Portex Ltd., Kent, UK). Inspiratory and expiratory flow rate, airway pressure, arterial pressure and ECG were continuously measured and recorded.
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P (mbar) Fig. 1. PV-loops obtained from low-flow maneuvers at different abdominal pressures. With successively increasing intra-abdominal pressures the loops are shifted downwards. Circles indicate locations of mathematical inflection points (MIPs) of the expiratory limb of the PV-curve. Vertical arrows indicate the pressure shift of the MIP when abdominal pressure is increased.
LabVIEW (LabVIEW 7.1, National Instruments Corp., Austin, TX, USA). MAP and ECG were measured via a clinical monitoring system (Sirecust, Siemens, Erlangen, Germany) from which the analogue output signal was fed into the data recording system. 2.5. Data analysis Data analysis was performed using MatLab (R2006a, The Mathworks, Natick, USA). From the low-flow maneuvers, the pressure corresponding to the mathematical inflection point (MIP) of the expiratory limb of the quasistatic pressure–volume (PV) curve was calculated as follows: from the PV-curve the expiratory limb was extracted. The MIP was identified as that point at which the second derivative of the PV-curve was zero. The MIP was compared to the given abdominal pressure. For determination of the lung’s intratidal compliance, 10 consecutive breaths before and after low-flow maneuvers were analyzed respectively. For calculation of the intratidal nonlinear compliance the SLICE-method (Guttmann et al., 1994) was used. Briefly, each tidal pressure–volume loop was divided into six adjoining volume portions (slices) of equal size. For each slice the compliance (C) was calculated via multiple linear regression analysis using the equation of motion: P = P0 +
1 V + RV˙ C
where P is the airway pressure, P0 is the dynamic pressure base, V is the volume, V˙ is the flow and R is the resistance. Like this, the intratidal course of compliance as a function of volume can be obtained by drawing the six slice-compliance values over the six volume portions. Furthermore, peak inspiratory pressure was detected for 10 breaths before and after the low-flow maneuvers respectively. 2.6. Statistical analysis For better comparison of ventilation data and abdominal pressure data, all pressure values are given in cmH2 O. Statistical analysis was carried out using two- and three-way ANOVA and paired t-test. If not otherwise indicated all values were expressed as mean ± SD. Statistical significance was set at p < 0.05.
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3. Results Application of intra-abdominal pressure resulted in characteristic changes of the pressure–volume loop of the respiratory system (Fig. 1). Increasing intra-abdominal pressure decreased the slope of the pressure–volume loop and shifted the expiratory MIP towards higher pressures. The pressure at the MIP of the expiratory limb correlated well to the applied intra-abdominal pressure (r2 = 0.94, p < 0.001, Fig. 2). Two factorial ANOVA exhibited a significant dependence of this pressure on intra-abdominal pressures (pIAP < 0.001) but no significant dependence on PEEP (pPEEP = 0.215). Intratidal compliance decreased generally with increasing intraabdominal pressure. Yet, intratidal compliance was increased after the low-flow maneuvers (Fig. 3). Three factorial ANOVA revealed a significant dependence of compliance gain on PEEP, intraabdominal pressure and intratidal volume range (all p < 0.001). The compliance–volume curves obtained before the low-flow maneuvers differed from those obtained after the low-flow maneuvers. Before application of the low-flow maneuvers the intratidal courses of compliance were slightly increasing or remained nearly constant with increasing intratidal volume at PEEP 0, 3 and 6 cmH2 O. At PEEP 9 cmH2 O we found similar compliance courses for all intra-abdominal pressures. Without pneumoperitoneum intratidal compliance courses declined with intratidal volume. After application of the low-flow maneuvers we found intratidal compliance to increase with intratidal volume at PEEP 0 and 3 cmH2 O. At PEEP 6 cmH2 O compliance increased slightly and at PEEP 9 cmH2 O the intratidal compliance decreased with intratidal volume.
Fig. 2. Correlation between intra-abdominal pressures (IAP) and pressures at the mathematical inflection point (pMIP ). The pressure values of the MIPs correlated well to the intra-abdominal pressure (r2 = 0.94, p < 0.001). The black line shows the linear regression curve (pMIP = 0.82IAP + 3.37 cmH2 O).
Fig. 3. Intratidal courses of volume-dependent compliance of the respiratory system at different PEEP levels and different intra-abdominal pressures. For the analysis each breath was divided into six equally sized portions (slices). For each slice compliance of the respiratory system was calculated separately. Top row: intratidal compliance course before low-flow maneuvers; middle row: intratidal compliance course after low-flow maneuvers; bottom row: gain in intratidal compliance course after low-flow maneuvers. PEEP levels for each column are indicated in the respective top row. Symbols indicate abdominal pressure (baseline before sequence of pneumoperitoneum was applied (0 before), at helium pneumoperitoneum of 9, 12 and 15 cmH2 O, and baseline after sequence of pneumoperitoneum was applied (0 after)) as indicated in the first graph. PEEP, tidal volume and intra-abdominal pressure were significant factors for respiratory system compliance and for compliance gain, all p < 0.001.
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Three-way ANOVA showed a significant dependence of compliance on PEEP, intra-abdominal pressure and volume range (all p < 0.001). Peak inspiratory pressure (Pmax ) increased with increasing intra-abdominal pressure and returned to its baseline value after deflation (Fig. 4). For all PEEP levels Pmax was significantly reduced after the low-flow maneuvers (p < 0.001). Two-way ANOVA revealed that Pmax depended significantly on PEEP and intra-abdominal pressure (p < 0.001). We did not observe significant changes in PaO2 after application of intra-abdominal pressure. Nevertheless, at zero PEEP, PaO2 was lower compared to the other PEEP levels (Fig. 5). Two-way ANOVA showed a significant dependence of PaO2 on PEEP (pPEEP = 0.0082) but not on intra-abdominal pressure (pIAP = 0.1534). MAP did not change significantly with intra-abdominal pressure or PEEP (pIAP = 0.2926, pPEEP = 0.0680, Fig. 6). 4. Discussion 4.1. Intratidal compliance
Fig. 4. Peak inspiratory pressures before and after low-flow maneuvers at different PEEP levels and different intra-abdominal pressures. Intra-abdominal pressures: baseline before sequence of pneumoperitoneum was applied (0 before), at helium pneumoperitoneum of 9, 12 and 15 cmH2 O, and baseline after sequence of pneumoperitoneum was applied (0 after). Black: before, white: after low-flow maneuver. PEEP levels were set as indicated in the graphs. For all PEEP levels Pmax was significantly reduced by the low-flow maneuvers (p < 0.001).
The main findings of our study demonstrate that dynamic intratidal compliance is reduced when the intra-abdominal pressure is increased by helium pneumoperitoneum. This finding is in accordance with several other studies demonstrating similar impairments of respiratory system mechanics at intra-abdominal hypertension (Bardoczky et al., 1993; Iwasaka et al., 1996; Pelosi et al., 1997; Kraut et al., 1999; Avital et al., 2008). The main reason for such effects appears to be the impeded diaphragmatic excursion. Intra-abdominal hypertension causes a cranial shift of the diaphragm and hence compression atelectasis in the basal lung regions (Safran and Orlando, 1994). The interpretation of various intratidal compliance courses was described by Mols et al. (1999). An increasing compliance course indicates ventilation on low lung volumes with repeated intratidal recruitment whereas a decreasing course indicates ventilation at high lung volumes with alveolar overdistension. At PEEP levels up to 6 cmH2 O the tidal compliance courses were almost constant across the total intratidal volume range. Only if intra-abdominal pressure was absent at a PEEP of 9 cmH2 O a declining compliance course was observed indicating ventilation at fully recruited lungs or even overexpansion of lung tissue.
Fig. 5. PaO2 at different PEEP levels and intra-abdominal pressures. PEEP levels as indicated in the graphs. Intra-abdominal pressures: baseline before sequence of pneumoperitoneum was applied (0 baseline), at helium pneumoperitoneum of 9, 12, 15 and 18 cmH2 O, and baseline after sequence of pneumoperitoneum was applied (0 endline).
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Fig. 6. Mean arterial pressure (MAP) at different PEEP levels and intra-abdominal pressures. PEEP levels as indicated in the graphs. Intra-abdominal pressures: baseline before sequence of pneumoperitoneum was applied (0 baseline), at helium pneumoperitoneum of 9, 12, 15 and 18 cmH2 O, and baseline after sequence of pneumoperitoneum was applied (0 endline).
4.2. Low-flow maneuvers It can be assumed that the passive motility of the diaphragm is the more impaired the higher the intra-abdominal pressure is, resulting in more pronounced cranial displacement and hence formation of compression atelectasis. This is in agreement to our finding that the airway opening pressure at the MIP of the expiratory PV-curve and the intra-abdominal pressure were similar. The very steep slope of the expiratory PV-curve at this point might be interpreted as a sign for alveolar collapse caused by basal compression (DiRocco et al., 2007). Reasoned by the increased intra-abdominal pressure, the abdominal compartment seems to act as a pressure limitation for the thoracic compartment, consequently smaller pulmonary gas volumes were achieved within the pressure-limited low-flow maneuvers. The reduction of compliance was accompanied by a shift of the MIP within the expiratory PV-curve towards higher pressure values. Furthermore, during volume-controlled ventilation increased maximal pulmonary pressures were observed in the presence of increased intra-abdominal pressure. 4.3. Recruitment Following low-flow maneuvers we found compliance gain accompanied by a reduction of Pmax , which we attribute to alveolar recruitment. Recruitment success of low-flow maneuvers depended strongly on intra-abdominal pressure. Low-flow maneuvers had only little recruiting effects if intra-abdominal pressure was increased. Compliance gain caused by the low-flow maneuvers was highest at zero PEEP, both with and without helium pneumoperitoneum. At PEEP 9 cmH2 O compliance gain was smaller compared to all other PEEP levels, which might be caused by an additional overdistension of the lung parenchyma. As described in other studies (Bardoczky et al., 1993; Iwasaka et al., 1996; Avital et al., 2008) we observed an increase in Pmax with increasing intra-abdominal pressure. We interpret the increase in Pmax as a result of two parameters influenced by the pneumoperitoneum. First, the applied intra-abdominal pressure counteracts the pressure applied by the ventilator to apply the targeted tidal volume during volume-controlled ventilation. In other words, the impairment of diaphragmatic excursion decreases chest wall compliance. Second there is evidence for compression atelectasis caused by intraabdominal hypertension (Liem et al., 1996; Pelosi et al., 1998; Meier et al., 2006) leading to a reduction of the accessible pulmonary gas
volume that contributes to ventilation. The latter assumption is supported by the reduction of Pmax and the increase in compliance after the low-flow maneuvers, which is likely to be caused by reduction of atelectasis. 4.4. Oxygenation The impairment of ventilation caused by an increase of intra-abdominal pressure has been visualized earlier by means of functional electrical impedance tomography (fEIT) scans in pigs (Meier et al., 2006). An increase in atelectasis decreases the number of sufficiently ventilated alveoli, resulting in a ventilation–perfusion mismatch, and a decrease in arterial oxygenation. Nevertheless, in our study intra-abdominal hypertension had no effect on oxygenation. We only observed a clearly decreased PaO2 in the absence of PEEP. This might be reasoned by the relatively mild pneumoperitoneum pressures that we induced in this study. 4.5. PEEP Larger intra-abdominal pressures counteracted full recruitment, this problem might have been resolved by the use of PEEP levels above those used in this study. The reason for the lower PaO2 is a large amount of atelectasis caused by the combination of intra-abdominal pressure and zero PEEP and probably resorption atelectasis caused by the high FiO2 . However, since ventilation with zero PEEP can per se be injurious for the lungs (Chu et al., 2004), stress-induced biotrauma in the alveolar parenchyma might also have played a role. These findings are in concordance with a study performed in rats by Hazebroek et al. (2002). In contrast to those and our findings, Liem et al. (1996) found that abdominal insufflation with CO2 or helium decreased PaO2 in piglets. However, it remains unclear if PEEP was applied during their experimental protocol or not. The authors argue that blood gases alterations in juvenile animals may occur from decreased diaphragmatic excursion and increased dead space ventilation. The postulated cause for the decrease in PaO2 is abdominal distension, resulting in alveolar collapse and pathophysiological shunting of blood. 4.6. Hemodynamics In the present study, MAP did not change in the presence of PEEP or pneumoperitoneum. In other studies negative effects of high PEEP levels (12 cmH2 O and more) on hemodynamics
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were found (Qvist et al., 1975; Schreuder et al., 1985). Others found that a relatively mild PEEP level of 5 cmH2 O had no suppressive effects on MAP (Lesur et al., 2010). The latter is in accordance with our observation, where PEEP was not higher than 9 cmH2 O. In their review article, Grabowsky et al. lined out that ‘the degree to which increased intra-abdominal pressure affects hemodynamic function is dependent on several factors, including intravascular volume, level of intra-abdominal pressure, and patient position’. The use of carbon dioxide for insufflation does also considerably influence hemodynamics (Grabowski and Talamini, 2009). Acidosis and hypercarbia can be excluded as hemodynamics-influencing factors in our study, since we used helium for insufflation and kept PaCO2 in a physiological range by adapting the respiratory rate according to blood gas analysis. We cannot make any statement about cardiac output or stroke volume because measuring these parameters was not part of our protocol. 4.7. Limitations of the study We always kept the animals in supine position and did not investigate the animals in other body positions. Furthermore, we used a gas pneumoperitoneum as a model for generally increased intraabdominal pressure. Intra-abdominal pressure caused by intraabdominal fluid accumulation, e.g. in case of ascites might result in a shifted pressure gradient inside the abdomen (Loring et al., 1994). Body position and the physical cause for increased intraabdominal pressure (incompressible fluid or compressible gas) may affect respiratory system mechanics. However, in such case the analysis of intratidal compliance would indicate atelectasis and hyperinflation in the same way as in the gas pneumoperitoneum in supine position. The study was conducted in animals with healthy lungs. If a systemic insult is added to the mechanical insult applied to the lungs, e.g. in a multiple hit model, the physiological and inflammatory responses of lungs are amplified (Bouadma et al., 2007), therefore the effects of recruitment maneuvers, PEEP and elevated intra-abdominal pressure could be different in individuals with injured lungs. This subject should be issued in further studies. 4.8. Clinical implications Analyzing intratidal compliance can be used to guide the PEEP adjustment in presence of increased intra-abdominal pressure. Several studies have previously addressed this issue and proposed strategies for setting PEEP with respect to the lower and upper inflection points of the static PV-curve as surrogates of the end of derecruitment and the beginning of overinflation, respectively (Tobin, 2001; Martin-Lefevre et al., 2001; DiRocco et al., 2007). However, it has been demonstrated that respiratory system mechanics under static conditions differ clearly from those during dynamic conditions (Stahl et al., 2006; Stenqvist et al., 2008). In this study we calculated the intratidal profile of compliance during the dynamic conditions of uninterrupted mechanical ventilation. We would like to suggest setting PEEP to a level at which the profile of intratidal compliance does not show an initial increasing part to prevent from intratidal derecruitment. Furthermore we suggest to set PEEP to a level at which the profile of intratidal compliance does not show a decreasing part at endinspiration to prevent from overdistension. In our study intratidal compliance increased up to a PEEP level of 6 cmH2 O and decreased at PEEP 9 cmH2 O (Fig. 3). This indicates that a PEEP setting to 6 cmH2 O would be preferable.
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4.9. Conclusion Intra-abdominal pressure reduces respiratory system compliance. To avoid hypoxemia and lung injury caused by compression atelectasis, PEEP should be applied to counterbalance increased intra-abdominal pressure during mechanical ventilation. The analysis of intratidal compliance could be helpful for guiding the PEEP setting to a level preventing from formation of compression atelectasis and overdistension of lung tissue during mechanical ventilation. References Avital, S., Itah, R., Szomstein, S., Rosenthal, R., Inbar, R., Sckornik, Y., Weinbroum, A., 2008. Correlation of CO(2) pneumoperitoneal pressures between rodents and humans. Surg. Endosc. 23, 50–54. Bardoczky, G.I., Engelman, E., Levarlet, M., Simon, P., 1993. Ventilatory effects of pneumoperitoneum monitored with continuous spirometry. Anaesthesia 48, 309–311. Bouadma, L., Dreyfuss, D., Ricard, J.D., Martet, G., Saumon, G., 2007. 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