- Open Access
Homogenizing effect of PEEP on tidal volume distribution during neurally adjusted ventilatory assist: study of an animal model of acute respiratory distress syndrome
Respiratory Research volume 23, Article number: 324 (2022)
The physiological response and the potentially beneficial effects of positive end-expiratory pressure (PEEP) for lung protection and optimization of ventilation during spontaneous breathing in patients with acute respiratory distress syndrome (ARDS) are not fully understood. The aim of the study was to compare the effect of different PEEP levels on tidal volume distribution and on the ventilation of dependent lung region during neurally adjusted ventilatory assist (NAVA).
ARDS-like lung injury was induced by using saline lavage in 10 anesthetized and spontaneously breathing farm-bred pigs. The animals were ventilated in NAVA modality and tidal volume distribution as well as dependent lung ventilation were assessed using electric impedance tomography during the application of PEEP levels from 0 to 15 cmH20, in steps of 3 cmH20. Tidal volume distribution and dependent fraction of ventilation were analysed using Wilcoxon signed rank test. Furthermore, airway, esophageal and transpulmonary pressure, as well as airway flow and delivered volume, were continuously measured during the assisted spontaneous breathing.
Increasing PEEP improved oxygenation and re-distributed tidal volume. Specifically, ventilation distribution changed from a predominant non-dependent to a more even distribution between non-dependent and dependent areas of the lung. Dependent fraction of ventilation reached 47 ± 9% at PEEP 9 cmH20. Further increasing PEEP led to a predominant dependent ventilation.
During assisted spontaneous breathing in this model of induced ARDS, PEEP modifies the distribution of ventilation and can achieve a homogenizing effect on its spatial arrangement. The study indicates that PEEP is an important factor during assisted spontaneous breathing and that EIT can be of valuable interest when titrating PEEP level during spontaneous breathing, by indicating the most homogeneous distribution of gas volumes throughout the PEEP spectrum.
The Acute Respiratory Distress Syndrome (ARDS) is associated with different derangements of lung physiology , such as inhomogeneity in tidal volume distribution and ventilation-perfusion (V/Q) mismatch, predominantly observed in dependent lung regions , and is marked by an elevated mortality .Tidal volume distribution inhomogeneities, deriving from local differences in time constants of the affected areas, may aggravate lung injury by developing high trans-alveolar strain forces  and potentially resulting in ventilator-induced lung injury (VILI) . Moreover the atelectatic dependent lung region impedes optimal gas exchange, by the phenomena of low V/Q or shunting , and can be susceptible to the phenomena of tidal recruitment-derecruitment [7, 8].
The relation between positive end-expiratory pressure (PEEP) and these heterogeneous alterations is complex, additionally depending on the modality of ventilation that is implemented [9,10,11].
There is an ongoing debate about the use of assisted/spontaneous breathing (SB) modes in ARDS; as both positive effects, above all the counteracting of diaphragm atrophy , and potential drawbacks, the most detrimental being the patient self-inflict lung injury (P-SILI) ), exist. The optimal setting of PEEP is proposed to be one of the most important factors determining the risk of ventilator-induced lung injury (VILI) during SB .
Neurally Adjusted Ventilatory Assist (NAVA) is an assisted mode of ventilation that uses the electrical activity of the diaphragm (Edi) to control the timing and delivery of pressure from the ventilator, in relation to the frequency and amplitude of muscle activity of the diaphragm, indirectly representing phrenic nerve activity and central breathing center [15, 16]. NAVA is widely used, however not studied to the same extent as controlled or other assisted SB modes. Furthermore, the specific effects of PEEP on ventilation distribution during NAVA ventilation have not been studied thoroughly.
Thorax electrical impedance tomography (EIT) is a well-established imaging technique  based on measure of impedance (Z), whose changes (ΔZ) between end-expiration and end-inspiration, are linearly proportional to the tidal volume during mechanical ventilation [18, 19]. Moreover EIT yields topographic information about ventilation distribution in different settings [20,21,22].
One method to analyse the data derived from EIT, is to compute the dorsal fraction of ventilation (DFV), representing the proportion of tidal volume reaching dependent lung region in relation to total tidal volume, as proposed by Brochard et al. . When DFV is 50%, ventilation can be considered homogeneously distributed between the dependent and nondependent portions of the lung [24, 25].
The aim of the present study was to test the hypothesis that increasing PEEP has a homogenizing effect on tidal volume distribution during NAVA, in an experimental animal model of ARDS.
The study was approved by the local ethical board for animal studies, in Uppsala, Sweden (Approval number 58 18_20174_2017), and conducted according to the European Union directive 2010/63/EU, the Helsinki convention for the use and care of animals and the National Institute of Health Guidelines. The reporting of the experiment follows the ARRIVE guidelines  on the fair use of animals in research.
10 farm-bred pigs of both sexes (28.4 ± 2.1 kg) were premedicated using tiletamine-zolazepam (6 mgkg−1, Boehringer Ingelheim, Stockholm, Sweden) and xylazine (2.2 mgkg−1, Rompun Bayer, Leverkusen, Germany) after arriving to the laboratory, and placed supine. Canulation of an ear vein was performed and anesthesia was induced and maintained, using ketamine infusion (20 mgkg−1 h−1, Ketaminol, Vetpharma, Intervet, Stockholm, Sweden), allowing spontaneous breathing. Absent reaction to a painful stimulus at the hoof was used to ensure adequate depth of anesthesia. A surgical tracheostomy was performed and a tracheal tube (tube size 9, Mallinckrodt Pharmaceuticals, Athlone, Ireland) was inserted. Mechanical ventilation was initiated using Servo-i ventilator (Maquet Critical Care, Solna, Sweden) in pressure support ventilation, using PEEP 5 cmH2O, driving pressure of 10 cmH2O above PEEP and FiO2 of 0.5, during further instrumentation. A central venous catheter and a pulmonary artery catheter (PAC, 7.0 French, Swan-Ganz Thermodilution Catheter, Baxter, Irvine, CA, United States) were introduced via the femoral vein, using ultrasound guidance. An arterial catheter (20 G, Becton–Dickinson Critical Care Systems, Mississauga, ON, Canada) was placed in the femoral artery. Except for tracheostomy, all neck tissue were left intact, reducing interference with accessory breathing muscles. An EIT electrode belt (Size XXS, 32 electrodes, Timpel, Eindhoven, The Netherlands) was placed surrounding the thorax and connected to the EIT machine (Enlight, Timpel, Eindhoven, The Netherlands). The EIT belt was positioned at a level immediately caudal to the insertion of the forelegs on the chest wall and belt size was chosen in accordance to recommendations by the manufacturer. An esophageal balloon and a gastric balloon (esophageal catheter, Erich Jaeger GmbH, Höchberg, Germany) were inserted orally and placement was controlled using an occlusion technique, described by Baydur et al. . Thereafter, a NAVA catheter (size 16F nasogastric catheter with multiple array electrodes) (Maquet, Solna, Stockholm, Sweden) was introduced orally and connected to the ventilator. Placement at the diaphragmatic dome was corrected in accordance to the guiding system provided by the ventilator, as described by Barwing et al. . A chest x-ray scan was thereafter used to ensure the correct placement of the NAVA catheter and the balloons. Furthermore, central venous pressure (CVP), heart rate (HR), arterial blood pressure, pulmonary arterial blood pressure, blood temperature and transcutaneously measured oxygen saturation, by pulse oximetry (SpO2), were continuously measured and monitored (SC 9000 XL, Siemens Medical Systems Inc., Danvers, MA, United States). A solution of Ringer´s acetate was infused at 5 ml kg−1 h−1, maintaining fluid balance.
Monitoring of respiratory mechanics
Pressure at airway opening (PAO)) together with esophageal (PESO) and gastric pressure (PGA) were continuously recorded using dedicated transducers (DigimaClic Pressure Transducers, Special Instruments GmbH, Nördlingen, Germany). Airway flow (V̇) was monitored using a Fleisch pneumotachograph (Laminar Flow Element type PT, Special Instruments GmbH, Nördlingen, Germany) positioned at the endotracheal tube and connected to a differential pressure transducer (Diff-Cap Pressure Transducer, Special Instruments GmbH, Nördlingen, Germany). Measurements and signals were digitally converted using an analog-to-digital converter card (PowerLab 16/35, AD Instruments NZ Limited, Dunedin, New Zealand) and stored on a personal computer (Intel Centrino, Intel Corp., Santa Clara, CA, United States) at a sampling frequency of 200 Hz using LabChart Software (AD Instruments NZ Limited, Dunedin, New Zealand). Transpulmonary pressure (PTP) was monitored by a continuous calculation of the difference between PAO and PESO. By integrating V̇, inspired and expired volumes (V) were calculated. For Edi-signal recording, a serial cable was connected to the personal computer and the signal was sampled at a rate of 100 Hz, by the use of Servo-tracker V 4.0 software (Maquet Critical Care, Solna, Sweden).
Induction of lung injury
After instrumentation, remifentanil infusion (0.25–0.5 µgkg−1 min−1, Remifentanil Orion, Orion Pharma, Espoo, Finland) was initiated and Rocuronium (20 mg, Rocuronium Fresenius Kabi 10 mg ml−1, Fresenius Kabi AB, Uppsala, Sweden) was administered to suppress breathing and movement during lung injury induction. Volume controlled ventilation, tidal volume of 8 ml kg−1, respiratory rate 30/min, PEEP 5 cmH2O, FiO2 1.0, was initiated and a mild ARDS-like condition was induced by repeated lung lavages, using 30 mlkg−1 warm saline followed by airway suctioning. The injury-inducing process was repeated until a PaO2/FiO2 of ≤ 250 mmHg was reached and maintained after 10 min of mechanical ventilation at PEEP 5 cmH2O. Thereafter remifentanil infusion was stopped and SB was reestablished.
NAVA ventilation and study protocol
After the return of spontaneous ventilation, NAVA level was titrated, in accordance to the method described by Brander et al. . The NAVA level was thereafter not changed throughout the experiment and FiO2 was kept at 1.0. NAVA ventilation was continued for 20 min, allowing stabilization prior to the initiation of the study protocol. Thereafter, an incremental and decremental PEEP protocol was initiated. PEEP was increased stepwise from 0 cmH2O to 15 cmH2O in steps of 3 cmH2O and thereafter decreased again to 0 cmH2O in steps of 3 cmH2O. Hereby, the animals were used as their own controls, and all animals underwent the same treatment. The same order of PEEP level was used for all animals, allowing for evaluation of recruiting effect of the complete maneuver, when comparing incremental PEEP levels to decremental PEEP levels. For each PEEP level, settings were kept for 10 min prior to data acquisition, allowing establishment of steady state conditions. Thereafter, EIT scans (sampling rate: 50 Hz), Edi signal, ventilator parameters, airway flow and pressure readings, esophageal and gastric pressures were acquired continuously for 1 min. In addition, arterial blood gas samples were collected. Thereafter, the PEEP level was changed according to protocol and registrations were repeated after 10 min. After the study protocol, animals were euthanized using high dose potassium chloride.
EIT data were analyzed using EIT main 8.11 (EIT analysis tool, Timpel, Eindhoven, The Netherlands). Tomographic scans were divided into four ROIs, labeled from the anterior to posterior as: anterior, mid-anterior, mid-posterior and posterior. Mean Z, relative to a machine-set zero, for each ROI was calculated. From the continuous EIT recording during non-interrupted spontaneous breathing, end-inspiratory and end-expiratory scans, for the first three breaths for each data acquisition, were identified and further analyzed. The difference between end-inspiratory and end-expiratory Z was calculated for each ROI respectively, representing ΔZ. In addition, the data was calculated in relation to total change in Z in all four ROIs, allowing for proportionate calculation of ΔZ. As ΔZ correlates linearly to change in volume, proportionate change in ΔZ was assumed to represent the relative distribution of tidal volume in each ROI. The two most anterior ROIs combined were presented as non-dependent region and the two most posterior ROIs combined were presented as dependent region.
Dependent fraction of ventilation was calculated as a percentage of total impedance change being distributed to the dependent regions, as of: DFV (%): ∆Z dependent region / ∆Z whole lung, as presented by Yoshida et al.  amongst others.
Airway pressure, airway flow and esophageal pressure during maximum transpulmonary pressure was identified and analyzed, using three representative breaths from each data acquisition. In addition, maximum airway flow and maximum airway pressure were obtained in each breath respectively.
For each of these breaths, change in esophageal pressure (ΔPESO) was calculated by subtracting the esophageal pressure PESO at end-expiration from the PESO at the point of maximum transpulmonary pressure (PTP max tracing), identified by transpulmonary pressure tracings. Maximum transpulmonary pressure (PTP max) was calculated by subtracting ΔPESO from airway pressure at PTP max tracing. As the pigs were breathing continuously and no inspiratory pause was used, transpulmonary pressure was corrected for the resistive component of the airway pressure, in order to obtain the true transpulmonary pressure acting on the alveoli.
By using the Multilinear fitting method  for PTP, V̇ and tidal volume, compliance (C) and resistance of the respiratory system (RRS) during each breath were calculated. By multiplying RRS by the flow at PTP max tracing (= V̇TP max tracing) of that same breath, the true maximum transpulmonary pressure (PTP true max) could be calculated using.
These calculations were repeated for each studied breath, as was done in previous studies .
Because ΔZ presented a non-normal distribution (Shapiro–Wilk test), we applied nonparametric tests. Wilcoxon signed rank test was used for comparing paired data and Mann Whitney test was used when comparing non-paired data. For all statistical methods, a p-value ≤ 0.05 was considered statistically significant. The dependency of ΔZ on PEEP in dependent and non-dependent lung region was also tested using linear regression analysis. All the other measurements presented a normal distribution and were analysed using student t-test (α = 0.05). To adjust for family-wise error rate when performing multiple comparison analysis, the Bonferroni correction was used for adjusting the α level.
All 10 animals survived the study protocol. For the study of ∆Z, 330 breaths and 660 EIT scans were analyzed. As for respiratory mechanics, 12 of the total 330 breaths analyzed were lost due to technical circumstances. Baseline data is presented in Table 1.
Oxygenation and transpulmonary pressure
As PEEP was increased stepwise from 0 cmH2O to 15 cmH2O, mean peak pressure increased from 6.6 ± 2.8 cmH2O to 23.5 ± 1.7 cmH2O (t-test; p < 0.01). Transpulmonary pressure increased from 6.6 ± 3.2 cmH2O to 23.7 ± 2.1 cmH2O (t-test; p < 0.01), see Fig. 1. Tidal volume increased from 153 ± 36 ml to 297 ± 63 ml (t-test; p < 0.01), see Fig. 2, and respiratory rate decreased from 75 ± 13 min−1 to 38 ± 12 min−1 (p < 0.01 t-test), see Fig. 3. Calculated compliance increased from 14.5 ± 2.2 ml·cmH2O−1 to 26.9 ± 2.7 ml·cmH2O−1 (p < 0.01 t-test). Mean minimum PaO2 was 24.9 ± 12.3 mmHg, observed at PEEP 0.9 ± 1.4 cmH2O and mean maximum PaO2 was 76.2 ± 5.6 mmHg, observed at PEEP 13.8 ± 1.5 cmH2O (p < 0.01 t-test).
Electric impedance tomography and tidal volume distribution
Stepwise increasing PEEP from 0 cmH2O to 15 cmH2O resulted in a mean anterior ∆Z decrease from 1.8 ± 1.2 to 0.31 ± 0.68 (p < 0.0033), a non-statistically significant mid-anterior ∆Z decrease from 13.0 ± 8.8 to 10.4 ± 4.0 (p > 0.0033), a mid-posterior increase in ∆Z from 6.3 ± 4.6 to 14.7 ± 5.2 (p < 0.0033) and a posterior ∆Z increase from 0.07 ± 0.09 to 0.54 ± 0.28 (p < 0.0033) when comparing PEEP 0 cmH2O to PEEP 15 cmH2O. The mentioned regional ∆Z values were calculated in proportion to the total ∆Z of the entire lung, allowing the estimation of the proportional distribution of tidal volume in the lung. As a result of increasing PEEP stepwise from 0 cmH2O to 15 cmH2O the proportional mean ∆Z in the anterior ROI decreased from 9 ± 3% to 1 ± 3% (p < 0.0033), in the mid-anterior ROI decreased from 61 ± 7% to 40 ± 8% (p < 0.0033), in the mid-posterior ROI increased from 30 ± 8 to 57 ± 8% (p < 0.0033) and in the posterior ROI increased from 0 ± 1% to 2 ± 1% (p < 0.0033), representing change in local tidal volume distribution, shown in Fig. 4.
Ventilation was predominant in the non-dependent region of the lung (anterior and mid-anterior ROI) at PEEP 0 cmH2O and gradually shifted to the dependent region of the lung (mid-posterior and posterior ROI) when PEEP was increased stepwise. The ∆Z in the non-dependent lung in relation to total ∆Z decreased from 70 ± 8% to 41 ± 9% (p < 0.0033), and the ∆Z in the dependent lung in relation to total ∆Z increased from 30 ± 8% to 59 ± 9% (p < 0.0033), when PEEP stepwise was increased from 0 cmH2O to 15 cmH2O. The stepwise change in relative distribution of ∆Z, and thereby estimated tidal volume distribution, in dependent and non-dependent region is presented in Fig. 5, with linear regression analysis, and in Fig. 6. EIT images from one representative pig are presented in Fig. 7.
The dependent fraction of ventilation (DFV) increased from 30 ± 8% to 59 ± 9% (p < 0.0033) when comparing PEEP 0 cmH2O to PEEP 15 cmH2O. PEEP 9 cmH2O, having a DFV of 47%, is the PEEP level with a DFV nearest of 50% (PEEP 12 cmH2O had a DFV of 55%). There was a statistically significant increase in DFV from PEEP 0 cmH2O to PEEP 9 cmH2O (p < 0.0033) and significant difference between PEEP 9 cmH2O and PEEP 12 cmH2O (p < 0.0033). The DFV of each PEEP step is presented in Fig. 8.
To our knowledge this is the first study that analyses the relation between applied PEEP and ventilation distribution during NAVA. Our main finding is that the stepwise increase of PEEP generates a homogenizing effect on the distribution of tidal volume inside the lung, by progressively shifting tidal volume from non-dependent region to dependent lung regions. In our model this effect reached its maximum at PEEP 9 cmH2O while at the extrema of PEEP spectrum the difference in ventilation between the dependent and nondependent lung was augmented.
Increasing PEEP raises peak airway pressure and the transpulmonary pressure, as end-expiratory airway pressure is increased. Simultaneously, the respiratory rate declines and tidal volume becomes higher. In other words, while PEEP gradually increases, the structure of breathing tends to change from a rapid and shallow to a slow and deep pattern, as previously shown in a similar set up . Previous studies on the effect of PEEP on Vt have shown different results. In a human study, Passath et al.  demonstrated tidal volume preservation implementing a decremental PEEP titration during NAVA ventilation, differently from the results of the present study. However, some factors may explain this difference, such as the characteristics of their studied patients in terms of lung failure at the inclusion time or the grade of chest wall involvement (40% had either thoracic trauma or surgery). In our model the chest wall was intact and all the animals had a mild/moderate lung injury. Per se, the characteristics of the animal specific breathing reflexes may also have contributed to this difference. In this respect, our results are in line with the studies by Allo et al. , where phasic Edi and ∆Peso raised in response to PEEP increase in rabbits.
Furthermore, the PaO2 raised when PEEP was increased. The demonstrated effect of PEEP on oxygenation has been known for long  and comply well with similar animal experiments , and is presumably caused by the reduction of atelectasis-induced shunting and by alveolar recruitment .
Electric impedance tomography
The difference in impedance (ΔZ) between end-expiration and end-inspiration represents the net effect of the ventilated volume (ΔV) on thorax impedance. The linear correlation between the ΔZ and ΔV [18, 19] can be used to estimate volume variation knowing impedance change.
In addition, EIT provides information about ventilation distribution [20,21,22]; in this study we have used this attribute by dividing the images in four equally spaced rectangular ROIs and observing which areas were subjected to variation of impedance due to redistribution of ventilation.
During ventilation at ZEEP, the highest tidal ΔZ is observed in the mid-anterior part of the lung. As PEEP is increased, the tidal ΔZ tends to move dorsally, to posterior ROIs. This indicates that a larger gas volume is reaching these areas. By analyzing the relative distribution of tidal volume while increasing PEEP from 0 to 15 cmH2O, it is possible to observe a significant decrease in tidal volume in anterior and mid-anterior lung sections associated to a parallel increase in tidal volume distribution to mid-posterior and posterior lung sections. The effect on shifting tidal volume dorsally may be further amplified by the increased tidal volume, as this tends to increase the distribution further posteriorly .
This indicates that increasing PEEP leads to a better ventilation, or even a recruitment, of dependent lung regions, rendering them active in the process of ventilation. This may potentially derive from the reduction of basal atelectasis or by the reduction of airway closure [37, 38].
Meanwhile, the increased PEEP causes a reduction of anterior non-dependent tidal volume, probably due to the overdistention of alveoli and the less favorable position on the compliance curve. These results conform well with prior studies  using the same experimental model, although performed using computed tomography.
Importantly, increasing PEEP during NAVA ventilation can have a homogenizing effect on the distribution of tidal volume throughout the lung. Observing the curves of Fig. 9, it is possible to notice that the progressive shift of ΔZ has opposite direction in dependent and nondependent sections of the lung. In other terms, there is a point in which these two lines intersect, which represent the point in which there is the maximal homogeneity. In our animal model of ARDS ventilated with NAVA, the point of best homogeneity is at PEEP 9 cmH2O. After this point, the lines diverge again, meaning that the main areas of ventilation become the dependent ones.
As shown in this study, the use of tidal volume distribution offers a possible technique of PEEP titration during assisted SB, as compared to the titration method previously described by Costa et al. , useful during no flow conditions.
The tidal volume distribution differs amongst various ventilatory modes, and in the case of assisted spontaneous breathing, PSV and NAVA show distribution differences, related not only to the modality per se but also to the level of their application . Correspondingly to these effects, there may be different effect of PEEP on tidal volume distribution amongst various ventilatory modes. PEEP has previously been shown to increase dependent tidal volume distribution during PSV in patients with ARDS . The specific differences of tidal volume distribution amongst assisted as wells as controlled ventilatory modes as effect of PEEP needs further investigation. However, the effect of spontaneous breathing on posterior diaphragm and dependent lung has been known for long , and spontaneous efforts have previously been shown to increase the tidal volume distribution to dependent lung regions using EIT .
Similar results are possible to achieve by computing the so-called dorsal fraction of ventilation (DFV) as proposed by Brochard et al. . By analyzing the proportion of the tidal volume distributing to the dependent lung, the homogeneity of tidal volume distribution may be estimated. The concept of DFV is similar to that of impedance ratio (IR)  and anterior–posterior ratio , able to detect lung recruitment and tidal volume distribution homogenization during PEEP increase. However, DFV is not to be confused with the concept of center of ventilation (COV), describing the center of distribution of tidal volume in relation to the chest geometry . In this study, we show that, by increasing PEEP in NAVA ventilation, there is a gradual change from predominantly low dependent activity (DFV < 50%) to predominantly low non-dependent activity (DFP > 50%) and that the DFV closest to 50% is reached at PEEP 9 cmH2O. These findings are in line with the results from Katira et al. , in which they use a similar experimental set up, but studying controlled ventilation. The results show similar effect of non-dependent to dependent ventilation shift with a DFV ≈ 50% at PEEP 9 cmH2O, indicating that the effect of PEEP on tidal volume distribution may be similar when using controlled ventilation and NAVA, although further studies are needed.
Ultimately, the PEEP level must be set aiming at either reducing dependent atelectasis or reducing non-dependent overinflation, in relation to the present DFV and the clinical situation. The goal of balancing these impairing phenomena may be achieved by aiming at a DFV of 50%, in which the level of stress is more uniformly distributed throughout the lung.
To titrate the PEEP in order to get the most homogeneous distribution of lung volumes, the EIT is exceptionally helpful.
The findings in this paper suggest that during NAVA ventilation, and potentially other assisted breathing modes, EIT can be used for continuous monitoring of tidal volume distribution. Thereby, the technique can potentially be used for PEEP level selection and titration, guided by either signs of dependent lung recruitment and non-dependent hyperinflation, or by the use of dependent fraction of ventilation. The results in this paper stress the effect and the importance of carefully choosing the PEEP level in spontaneously breathing subjects, as the consequences on lung ventilation are considerable.
The present study has different limitations. An animal model of mild ARDS was used, by inducing lung injury through lavage and pulmonary suctioning. This may vary from the authentic condition seen in human patients, and may possibly be more recruitable. In addition, more severe ARDS may be less suitable for the use of assisted spontaneous breathing. Regarding the use of animals, it is important to notice that respiratory drive and respiratory reflexes may differ amongst species. This indicates that the results may not be directly transposed to the clinical settings nor be extrapolated to severe ARDS. Furthermore, the PEEP levels were not randomized. However, this was intentional as incremental and decremental PEEP levels could be compared, testing for differences amongst incremental and decremental levels indicating time dependent reduction of effect of lung injury or a permanent recruitment effect of high PEEP, however this effect was not observed. In the present study, the analysis of tissue histology and inflammatory markers was not performed although it could have contributed to collect additional information about the studied model.
As previously shown, increased Vt shifts tidal volume distribution dorsally. Hence, in this study showing increased Vt as an effect of increasing PEEP, a contributing effect of Vt changes on the tidal volume distribution cannot be ruled out. However, DFV shows statistically significant differences between PEEP levels only having minor differences in tidal volume, indicating that Vt alone is not responsible of tidal volume distribution changes.
Furthermore, this study evaluates the effect of PEEP on lung mechanics and tidal volume distribution and may not conform to other modes of assisted spontaneous breathing.
Regarding EIT analysis, there is an important phenomenon resulting from the effect of increasing PEEP that needs to be noted. As PEEP is increased from 0 to 15 cmH2O, the lung is expanded inferiorly, shifting the parenchyma adjacent to the EIT belt. However, in relation to the dimension of the lungs of the pigs used, EIT generates images pertaining to approximately half of the cranio-caudal extension of the lung . From previous studies on porcine models of the same size and comparable lung inflation (see Perchiazzi et al., supplementary material ) it is possible to conclude that EIT maintains in view the same lung structures throughout the increasing PEEP sequence used in the present paper. For this reason, any possible flaws deriving for the downward shift of lung parenchyma were considered not affecting the results of our analysis.
Availability of data and materials
The datasets analysed during the current study are available from the corresponding author on reasonable request.
Wheeler AP, Bernard GR. Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet. 2007;369:1553.
Gattinoni L, et al. Relationships between lung computed tomographic density, gas exchange, and PEEP in acute respiratory failure. Anesthesiology. 1988;69(6):824–32.
Bellani G, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788.
Perchiazzi G, et al. Regional distribution of lung compliance by image analysis of computed tomograms. Respir Physiol Neurobiol. 2014;201:60–70.
Bellani G, et al. Lung regional metabolic activity and gas volume changes induced by tidal ventilation in patients with acute lung injury. Am J Respir Crit Care Med. 2012. https://doi.org/10.1164/rccm.201008-1318OC.
Ralph DD, Robertson HT, Weaver LJ, Hlastala MP, Carrico CJ, Hudson LD. Distribution of ventilation and perfusion during positive end-expiratory pressure in the adult respiratory distress syndrome. Am Rev Respir Dis. 1985;131(1):54–60.
Gattinoni L, Pelosi P, Crotti S, Valenza F. Effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome. Am J Respir Crit Care Med. 1995;151(6):1807–14.
Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369(22):2126–36.
Meier T, et al. Assessment of regional lung recruitment and derecruitment during a PEEP trial based on electrical impedance tomography. Intensive Care Med. 2008;34(3):543–50.
Gattinoni L, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006;354(17):1775–86.
Maggiore SM, Jonson B, Richard J-C, Jaber S, Lemaire F, Brochard L. Alveolar derecruitment at decremental positive end-expiratory pressure levels in acute lung injury: comparison with the lower inflection point, oxygenation, and compliance. Am J Respir Crit Care Med. 2001;164(5):795–801.
Levine S, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327–35.
Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimize progression of lung injury in acute respiratory failure. Am J Respir Crit Care Med. 2017;195(4):438–42.
Goligher EC, et al. Clinical strategies for implementing lung and diaphragm-protective ventilation: avoiding insufficient and excessive effort. Intensive Care Med. 2020;46(12):2314–26.
Lourenço RV, Cherniack NS, Malm JR, Fishman AP. Nervous output from the respiratory center during obstructed breathing. J Appl Physiol. 1966;21(2):527–33.
Sinderby C, et al. Neural control of mechanical ventilation in respiratory failure. Nat Med. 1999;5(12):1433–6.
Brown BH. Electrical impedance tomography (EIT): a review. J Med Eng Technol. 2003;27(3):97–108.
Frerichs I, Hahn G, Hellige G. Thoracic electrical impedance tomographic measurements during volume controlled ventilation-effects of tidal volume and positive end-expiratory pressure. IEEE Trans Med Imaging. 1999;18(9):764–73.
Adler A, Amyot R, Guardo R, Bates JHT, Berthiaume Y. Monitoring changes in lung air and liquid volumes with electrical impedance tomography. J Appl Physiol. 1997;83(5):1762–7.
Costa EL, et al. Bedside estimation of recruitable alveolar collapse and hyperdistension by electrical impedance tomography. Intensive Care Med. 2009;35(6):1132–7.
Bachmann MC, et al. Electrical impedance tomography in acute respiratory distress syndrome. Crit Care. 2018;22(1):1–11.
Frerichs I, et al. Chest electrical impedance tomography examination, data analysis, terminology, clinical use and recommendations: consensus statement of the TRanslational EIT developmeNt stuDy group. Thorax. 2017;72(1):83–93.
Brochard L, Yoshida T, Amato M. Reply to Frerichs et al. Am J Respir Crit Care Med. 2020;201(3):388.
Yoshida T, Piraino T, Lima CAS, Kavanagh BP, Amato MBP, Brochard L. Regional ventilation displayed by electrical impedance tomography as an incentive to decrease positive end-expiratory pressure. Am J Respir Crit Care Med. 2019;200(7):933–7.
Katira BH, et al. Positive end-expiratory pressure, pleural pressure, and regional compliance during pronation: an experimental study. Am J Respir Crit Care Med. 2021;203(10):1266–74.
Kilkenny C, Browne W, Cuthill I, Emerson M, Altman D. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLOS Biol. 2010;8(6): e1000412.
Baydur A, Behrakis PK, Zin WA, Jaeger M, Milic-Emili J. A simple method for assessing the validity of the esophageal balloon technique. Am Rev Respir Dis. 1982;126(5):788–91.
Barwing J, Pedroni C, Quintel M, Moerer O. Influence of body position, PEEP and intra-abdominal pressure on the catheter positioning for neurally adjusted ventilatory assist. Intensive Care Med. 2011;37(12):2041–5.
Brander L, et al. Titration and implementation of neurally adjusted ventilatory assist in critically ill patients. Chest. 2009;135(3):695–703.
Iotti GA, et al. Respiratory mechanics by least squares fitting in mechanically ventilated patients: applications during paralysis and during pressure support ventilation. Intensive Care Med. 1995;21(5):406–13.
Widing CH, Pellegrini M, Larsson A, Perchiazzi G. The effects of positive end-expiratory pressure on transpulmonary pressure and recruitment-derecruitment during neurally adjusted ventilator assist: a continuous computed tomography study in an animal model of acute respiratory distress syndrome. Front Physiol. 2019;10:1392.
Passath C, Takala J, Tuchscherer D, Jakob SM, Sinderby C, Brander L. Physiologic response to changing positive end-expiratory pressure during neurally adjusted ventilatory assist in sedated, critically ill adults. Chest. 2010;138(3):578–87.
Allo JC, Beck JC, Brander L, Brunet F, Slutsky AS, Sinderby CA. Influence of neurally adjusted ventilatory assist and positive end-expiratory pressure on breathing pattern in rabbits with acute lung injury. Crit Care Med. 2006;34(12):2997–3004.
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967;290(7511):319–23.
Morais CCA et al. High positive end-expiratory pressure renders spontaneous effort non-injurious. AJRCCM Artic Press, pp. 201706–1244.
Borges JB, Cronin JN, Crockett DC, Hedenstierna G, Larsson A, Formenti F. Real-time effects of PEEP and tidal volume on regional ventilation and perfusion in experimental lung injury. Intensive Care Med Exp. 2020;8(1):1.
Chen L, et al. Airway closure in acute respiratory distress syndrome: an underestimated and misinterpreted phenomenon. Am J Respir Crit Care Med. 2018;197(1):132–6.
Hedenstierna G, Chen L, Brochard L. Airway closure, more harmful than atelectasis in intensive care? Intensive Care Med. 2020;46(12):2373.
Blankman P, Hasan D, van Mourik MS, Gommers D. Ventilation distribution measured with EIT at varying levels of pressure support and Neurally Adjusted Ventilatory Assist in patients with ALI. Intensive Care Med. 2013;39(6):1057–62.
Mauri T, et al. Topographic distribution of tidal ventilation in acute respiratory distress syndrome. Crit Care Med. 2013;41(7):1664–73.
Froese AB, Bryan AC. Effects of anesthesia and paralysis on diaphragmatic mechanics in man. Anesthesiology. 1974;41(3):242–55.
Blankman P, Van Der Kreeft SM, Gommers D. Tidal ventilation distribution during pressure-controlled ventilation and pressure support ventilation in post-cardiac surgery patients. Acta Anaesthesiol Scand. 2014;58(8):997–1006.
Kunst PWA, et al. Monitoring of recruitment and derecruitment by electrical impedance tomography in a model of acute lung injury. Crit Care Med. 2000;28(12):3891–5.
Jang GY, et al. Integrated EIT system for functional lung ventilation imaging. Biomed Eng Online. 2019;18(1):1.
Rabbani KS, Kabir AMBH. Studies on the effect of the third dimension on a two-dimensional electrical impedance tomography system. Clin Phys Physiol Meas. 1991;12(4):393–402.
The authors express their sincere gratitude to Kerstin Ahlgren, Agneta Roneus, Liselotte Pihl, Mariette Andersson and Maria Swälas for their assistance and support during the experiments at the Hedenstierna Laboratory.
Open access funding provided by Uppsala University. This work was supported by the department of Anaesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden. GP was supported by: the Swedish Research Council Grant (2018-02438); the Swedish Heart and Lung foundation (20200877 and 20200825) and the Alvar Gullstrand research Grant (ALF-938050).
Ethics approval and consent to participate
The study was approved by the local ethical board for animal studies, in Uppsala, Sweden (Approval number 58 18_20174_2017), and conducted according to the European Union directive 2010/63/EU, the Helsinki convention for the use and care of animals and the National Institute of Health Guidelines. The reporting of the experiment follows the ARRIVE guidelines  on the fair use of animals in research. As the PEEP protocol was not considered safe for critically ill patients the porcine experimental model was chosen, offering relevant similarities to human respiratory physiology.
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Widing, H., Chiodaroli, E., Liggieri, F. et al. Homogenizing effect of PEEP on tidal volume distribution during neurally adjusted ventilatory assist: study of an animal model of acute respiratory distress syndrome. Respir Res 23, 324 (2022). https://doi.org/10.1186/s12931-022-02228-x
- Positive end-expiratory pressure
- Assisted breathing
- Spontaneous breathing