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1 All rights, in particular the proprietary rights of use and exploitation relating to the following contribution as well as parts thereof (including figures and tables) are the exclusive property of Springer Medizin, Springer-Verlag GmbH. Any translation, modification or adaptation is prohibited, as is public communication, presentation or performance.

2 To p i c s First EIT (Electrical Impedance Tomography)-based bedside monitoring for clinical routine Clinical applications of EIT Optimizing PEEP individually Electrical Impedance Tomography (EIT) Guiding lung protective ventilation with bedside monitoring Lung protective ventilation requires a reduced tidal volume and an adequate positive end-expiratory pressure (PEEP) level to minimize risks of ventilator-induced lung injury. Although PEEP is widely used in clinical routine, the determination of optimal PEEP is still a matter of controversy. Lung protective ventilation strategies rely largely on parameters which reflect only global lung function. The differences in the distribution of ventilation in ventral and dorsal regions of the lung are not revealed by these para meters. CT and chest X-rays can provide important morphological data, but their application for continuous bedside monitoring is limited. Electrical Impedance Tomography (EIT) has the potential to dynamically display the regional distribution of ventilation at the bedside. Clinical studies suggest that EIT monitoring may be helpful in the titration of PEEP and could play an important role in the individualization of protective ventilation strategies. Mechanical ventilation is the mainstay of therapy in patients with respiratory failure admitted to the intensive care unit (ICU). However, research over the past decades suggests that mechanical ventilation itself can exaggerate the degree of lung damage and may even be the primary factor in lung injury []. Figure Right side of patient V V V 3 V Ventral aspect 6 V 7 V V 8 V 6 V7 I 3 6 V Both lung collapse and alveolar hyperdistension can cause or perpetuate lung injury []. Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are examples of relatively common, life-threatening complications seen in ICU patients on mechanical ventilation. V V 4 V 3 Left side of patient Schematic drawing of the EIT electrodes and measurement technique: I is the first position of current application while V n shows the voltage measurements before movement of the current application to the next position Recent research has focused on the degree to which mechanical ventilation is injurious, depending on the way it is applied. In managing the routine clinical care of patients "the biggest issue is to find the optimal PEEP level at the bedside," stated Diederik Gommers, Rotterdam/Netherlands. Identifying the optimal PEEP to apply in ALI/ ARDS has been the focus of recent research involving a large number of patients [3, 4, 6]. The studies were designed to measure the clinical benefits of a protocolized ventilation strategy in a broad spectrum of patients with ALI/AR- DS. A meta-analysis recently published by Briel and colleagues used primary data from actual trials which included more than patients [6]. After adjusting for individual patient parameters, higher PEEP was associated with a 4% reduction in hospital mortality (p=.49), which was statistically significant for the subset of patients with ARDS. Dorsal aspect adpted from Drägerwerk AG & Co. KGaA

3 Individualized peep in clinical practice? Although this meta-analysis provides statistically useful answers, physicians looking for specific treatment recommendations have to consider more than five different strategies during the application of higher levels of PEEP that were evaluated in the analyzed trials [6]. "Effects of PEEP are not homogeneous neither in a single patient s lung nor in groups of patients lungs," explained Brian Kavanagh, Toronto/Canada. Against the background of clinical heterogeneities, Kavanagh pointed out that clinical trials with a more "mechanistically plausible approach can give the physician insight that a pooled analysis cannot. In terms of the most relevant clinical trials of the application of PEEP in ARDS, Amato and colleagues demonstrated that using PEEP values at a level greater than the lower inflection point on the static pressure-volume curve, as Figure EIT monitoring provides continuous quantification of changes of distribution of ventilation in the individual patient at the bedside 6% 3% 9% 54% 7% 38% well as low tidal volumes, was independently associated with better survival [7]. This protective ventilatory strategy is thought to prevent, or minimize, the risk of tidal alveolar collapse and overdistension of lung units in patients with ARDS. Furthermore, the lung-protective strategy in the same trial was shown to improve lung compliance, reported Kavanagh. Kavanagh, as well as Gommers, is in favor of individualizing PEEP in clinical practice. "In particular we should stop using tabular allocations and rather utilize the optimum PEEP in the individual patient," recommended Gommers. Nonetheless, the question of how to set an adequate PEEP level for individuals remains under debate and represents a continuous challenge in daily practice. Careful titration of PEEP following maximal lung recruitment can reverse existing collapse and prevent further alveolar closure. However, due to heterogeneity in the sick lung, the airway pressure required to keep some regions of the lung fully open can lead to alveolar hyperdistension in others, even with low tidal volumes []. In this context, a monitoring instrument which allows an estimate of the location and amount of alveolar collapse and hyperdistension during PEEP titration would be helpful at the bedside. First eit-based monitoring for clinical routine However, bedside monitoring of distribution of ventilation was not available for routine clinical practice until recently. Techniques which provide parameters of global lung function, such as arterial blood gas analysis or airway pressure-volume curves, have the disadvantage that regional inspiratory overdistension of lung units or end-expiratory collapse may still go undetected. Computed tomography (CT) provides a snapshot of regional ventilation. However, due to radiation exposure and the impact on workflow, CT is not suitable for continuous regional lung monitoring at the bedside. Hence, Gommers welcomed the recently introduced lung function monitor (Pulmo Vista 5, Dräger Medical GmbH) as a true bedside technique, which provides information about regional distribution of ventilation. With this monitor, a non-invasive and radiation-free imaging method based on EIT is now available for clinical use for the first time. This bedside lung function monitor was specially designed for clinical routine and does not interfere with the workflow of ICUs. EIT enables visualization of lung function (Fig.) at the bedside and provides continuous information about regional distribution of ventilation in the form of images, waveforms and parameters. EIT requires minimal preparation; monitoring can be established in a few minutes and is easy to maintain during ongoing monitoring. To perform bioimpedance measurements an EIT electrode belt with 6 integrated electrodes is placed around the thorax. Most of the time we are interested in the basal part of the chest, so that the electrode belt is usually placed at the 5th or 6th parasternal intercostal space, explained Gommers. Additionally, one reference electrode has to be attached to a central point on the body preferably on the patient s abdomen, ensuring that all measurements at different electrode pairs are referenced to the same electric potential. 8% 7% 9% % Figure 3 Z PEEP EIT tracing during PEEP optimization: A horizontal tracing corresponds to a stable end-expiratory lung volume, i.e. optimal PEEP 6% 34% PEEP PEEP 5 PEEP Time modified from Erlandsson et al. (6) Springer Insert for Intensive Care Physicians

4 The electrode belt is connected to an EIT device for visualization of the generated data. Bioimpedance data are generated when a small electrical current is applied to sequential pairs of electrodes (Fig. ) and the resulting surface potential voltage difference is measured at all other neighboring electrode pairs. One rotation of current application generates voltage profiles at 6 electrode positions, each consisting of 3 voltage measurements. The resulting values are used to reconstruct one cross-sectional EIT image. Figure 4 a Non dependent pixel Dependent pixel Pixel compliance ( Z/cmHO) b Decremental PEEP steps (cmh O) a) Two pixels in different locations and b) their respective best compliances during decremental PEEP titration modified from Costa et al. (9) EIT displays regions of interest The monitoring screen displays a 'dynamic image' showing impedance changes due to tidal ventilation in a thoracic cross-section. If one is interested in a certain area of lung to evaluate regional ventilation distribution, the EIT image can be divided into four regions of interest (ROI) of user-defined size, either horizontally or as quadrants. A regional impedance waveform shows the relative impedance changes that occur in each of the four ROIs. CT images display lung regions filled with air in black and tissue- and fluid-filled lung regions in white; EIT displays non ventilated regions in black while ventilated regions are shown as dark blue through to white; the darkest blue areas show where the least ventilation occurs, while the white regions show where most of the ventilation occurs. The clinician can follow changes in distribution of ventilation during recruitment maneuvers, as shown in the sequence of screen shots in Figure. Clinical applications of eit Knowledge about the distribution of ventilation can help the clinician to optimize ventilation settings, such as PEEP, for the individual patient. Researchers have already started to describe various approaches to the extraction of diagnostic information from EIT data. There are two approaches to the visualization of changes in PEEP, in the opinion of Gommers: "You can use the baseline or the regional compliance." The former method was used during a study by Erlandsson et al. to evaluate whether EIT could be used to optimize PEEP in order to maintain normal functional residual capacity (FRC) and oxygenation in morbidly obese patients during surgery [8]. For this purpose, 5 patients were studied while under anesthesia for laparoscopic bypass surgery. The development of the end-expiratory lung impedance was assessed at various PEEP levels over time. PEEP was titrated according to the baseline of the EIT waveform; an upward slope indicated recruitment and a downward slope indicated derecruitment. Optimal PEEP was determined by adjusting PEEP stepwise to obtain a horizontal baseline on the EIT waveform (corresponding to a stable FRC) (Fig. 3). Thus the study of Erlandsson et al. demonstrated that EIT can provide information continuously, which is valuable for optimizing PEEP and achieving a more homogeneous distribution of ventilation. In this study the optimal PEEP Figure 5 Without lung disorder With lung disorder PEEP: f EIT f EIT PEEP: f EIT f EIT to to 5 5 to 5 5 level needed to maintain a stable end-expiratory lung volume was around 5 cm H₂O [8]. Another study presented a novel algorithm for estimating recruitable alveolar collapse and hyperdistension based on EIT during a decremental positive end-expiratory pressure (PEEP) titration []. For that, Costa and colleagues focused on very small regions of interest: Because EIT tracks changes in ventilation in small regions, antagonistic responses such as hyperdistension and alveolar collapse can also be observed within each pixel according to the range of PEEP settings (Fig. 4). The authors used the changes in compliance in each pixel during a decremental PEEP trial to estimate collapse and hyperdistension. In the associated case reports, col- 5 4 increase 3 No change decrease The effect of a decremental PEEP trial on regional ventilation shown in two representative patients (with and without a lung disorder) modified from Bikker et al. () Springer Insert for Intensive Care Physicians 3

5 Figure 6 Changes in regional compliance in patients without (left) and patients with (right) lung disorders Regional compliance (AU) 3 Non-dependent 5 lapse, estimated by EIT and CT, was shown to be comparable in terms of amount and spatial location for all levels of PEEP. Optimizing peep individually Gommers described the use of ventilation distribution change maps, based on functional EIT (feit) images, to evaluate the effect of four PEEP levels (5,, 5 and cm H O) in 4 ICU patients with and without lung disorders [9]. Figure 5 shows the effect of PEEP on the regional distribution of ventilation, as visualized in a patient with a lung disorder and in a patient without a lung disorder. Maps of changes of distribution of ventilation between PEEP levels (ΔfEIT) were created by subtracting feit before each PEEP step from feit after each PEEP step. The increase or decrease in regional ventilation between the different PEEP steps is displayed in a color-coded matrix (red indicating increase and blue indicating loss of ventilation). Each EIT image represents a cross-section of the chest, with the N 5 PEEP (cm H O) *p<.5; p<.; AU: Arbitrary Units modified from Bikker et al. () Dependent Regional compliance (AU) 5 5 Non-dependent D * Dependent 5 5 PEEP (cm H O) ventral lung regions at the top and dorsal parts at the bottom. Between the two patients a difference in response to changes in PEEP in the non-dependent and dependent lung regions was demonstrated (Fig. 5). The trial also demonstrated that EIT is suitable for bedside monitoring of regional compliance during decremental PEEP steps: During pressure-controlled ventilation with constant driving pressure the tidal impedance change per pixel was regarded as regional compliance change per pixel (Fig. 4). Analysis of the response of regional tidal impedance to PEEP in all patients showed a significant difference from 5 to cm H O (p=.) and from to 5 cm H O (p=.) between patients with and those without lung disorders. As Gommers reported, "regional compliance of the dependent regions in patients without lung disorders decreased when when the PEEP level was lowered from 5 to cm H O, whereas it first increased in the non-dependent regions and then de- creased" (Fig. 6). In group D, including patients with lung disorders (Fig. 6 right), tidal impedance variation was significantly lower compared with group N (Fig. 6 left) in both regions. "These patients probably need more PEEP", said Gommers. He added: "Further studies are needed to answer the question of what PEEP is really optimal. In addition, differences in response to decremental PEEP steps were observed not only between patient groups but also within groups. This may indicate that the optimal PEEP should be titrated individually and cannot be generalized for a group of patients [9]. Conclusion EIT (PulmoVista 5) offers continuous realtime dynamic images of regional distribution of ventilation at the bedside. EIT displays changes in end-expiratory lung volume and allows optimization of PEEP settings so that lung regions remain open throughout the breath cycle, this may avoid the problems associated with cyclic recruitment in the individual patient. EIT provides a method of monitoring lung function and is therefore helpful in guiding a strategy of lung protective ventilation. C References [] Ricard JD et al. () Curr Opin Crit Care 8: [] Costa ELV et al. (9) Intensive Care Med 35: 3 37 [3] ARDSnet. () N Eng J Med 34: 3 38 [4] Brower RG et al. (4) N Engl J Med 35: [5] Meade MO et al. (8) JAMA 99: [6] Briel M et al. () JAMA 33: [7] Amato MBP et al. (998) N Eng J Med 338: [8] Erlandsson K et al. (6) Acta Anaesthesiol Scand 5: [9] Bikker IG et al. () Critical Care 4: R Imprint PEEP levels in ARDS: Using EIT as a guide and what do we know about PEEP? Scientific Presentation at the Annual ISICEM Conference 4th March, Brussels/Belgium Coverage: Yuri Sankawa, Stuttgart Cover Picture: Drägerwerk AG & Co. KGaA Printers: Druckpress GmbH, Leimen This publication is supported by Drägerwerk AG & Co. KGaA, Lübeck Corporate Publishing (responsible): Ulrike Hafner, Dr. Katharina Finis, Dr. Friederike Holthausen, Sabine Jost, Dr. Claudia Krekeler, Inge Kunzenbacher, Dr. Sabine Lohrengel, Dr. Annemarie Musch, Dr. Monika Prinoth, Dr. Petra Stawinski, François Werner, Teresa Windelen Insert "Intensive Care Medicine" Volume 36, Issue 6, June Springer Medizin Springer-Verlag GmbH Tiergartenstraße 7 69 Heidelberg Springer is part of Springer Science+Business Media Springer-Verlag GmbH Some commercial names, trade names and trademarks etc. used in this text are designated as such. However, neither the presence nor absence of such designation means that these names should not be regarded in accordance with the copyright and trademark laws or that they are for general use. Product liability: The printers and publishers cannot be held liable for information on dosage and methods of application. Information of this nature should be reviewed for accuracy in each case by the reader, using other sources of reference Springer Insert for Intensive Care Physicians