Variety of non-invasive continuous monitoring methodologies including electrical impedance tomography provides novel insights into the physiology of lung collapse and recruitment – case report of an anaesthetized horse

Variety of non-invasive continuous monitoring methodologies including electrical impedance tomography provides novel insights into the physiology of lung collapse and recruitment – case report of an anaesthetized horse

Veterinary Anaesthesia and Analgesia, 2014, 41, 196–204 doi:10.1111/vaa.12098 CASE REPORT Variety of non-invasive continuous monitoring methodologi...

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Veterinary Anaesthesia and Analgesia, 2014, 41, 196–204

doi:10.1111/vaa.12098

CASE REPORT

Variety of non-invasive continuous monitoring methodologies including electrical impedance tomography provides novel insights into the physiology of lung collapse and recruitment – case report of an anaesthetized horse Yves Moens*, Johannes P Schramel*, Gerardo Tusman†, Tamas D Ambrisko*, Josep Sol a‡, Josef X Brunner§, Lidia Kowalczyk* & Stephan H Bo¨hm§ *Anaesthesiology and perioperative Intensive-Care, University of Veterinary Medicine, Vienna, Austria †Department of Anaesthesiology, Hospital privado de Comunidad, Mar del Plata, Argentina ‡CSEM Centre Suisse d’Electronique et de Microtechnique SA, Neuch^ atel, Switzerland §Swisstom AG, Landquart, Switzerland

Correspondence: Yves Moens, Anaesthesiology and perioperative Intensive-Care, University of Veterinary Medicine, Veterinaerplatz 1, 1210 Vienna, Austria. E-mail: [email protected]

Abstract Introduction The use of alveolar recruitment maneuvers during general anaesthesia of horses is a potentially useful therapeutic option for the ventilatory management. While the routine application of recruitments would benefit from the availability of dedicated large animal ventilators their impact on ventilation and perfusion in the horse is not yet well documented nor completely understood. Case history A healthy 533 kg experimental horse underwent general anaesthesia in lateral recumbency. During intermittent positive pressure ventilation a stepwise alveolar recruitment maneuver was performed. Management Anaesthesia was induced with ketamine and midazolam and maintained with isoflurane in oxygen using a large animal circle system. Mechanical ventilation was applied in pressure ventilation mode and an alveolar recruitment maneuver performed employing a sequence of ascending and descending positive end expiratory pressures. Next to the standard monitoring, which included spirometry, additionally three non-invasive monitoring techniques were used: electrical imped-

ance tomography (EIT), volumetric capnography and respiratory ultrasonic plethysmography. The functional images continuously delivered by EIT initially showed markedly reduced ventilation in the dependent lung and allowed on-line monitoring of the dynamic changes in the distribution of ventilation during the recruitment maneuver. Furthermore, continuous monitoring of compliance, dead space fraction, tidal volumes and changes in end expiratory lung volume were possible without technical difficulties. Follow up The horse made an unremarkable recovery. Conclusion The novel non-invasive monitoring technologies used in this study provided unprecedented insights into the physiology of lung collapse and recruitment. The synergic information of these techniques holds promise to be useful when developing and evaluating new ventilatory strategies in horses. Keywords capnography, compliance, electrical impedance tomography (EIT), horse, lungs, noninvasive monitoring, positive end expiratory pressure (PEEP), recruitment maneuver. 196

Novel insights into lung recruitment in a horse Y Moens et al.

Introduction It is well recognized that large (A-a) PO2 differences can develop during equine anaesthesia. As a consequence hypoxemia is reported regularly even during elective procedures in healthy horses (Hall et al. 1968; Day et al. 1995). It is also generally accepted that this potentially life-threatening disturbance of lung function with pronounced V/Q mismatching is caused mainly by atelectasis formation in dependent lung regions and concomitant right-to-left intrapulmonary shunting (Nyman et al. 1990). While intermittent positive pressure ventilation (IPPV) can correct hypoventilation and the elevated arterial carbon dioxide levels seen during anaesthesia, its effect on improving oxygenation is usually disappointing. Unfortunately, such lack of effect is also witnessed often when positive end-expiratory pressure (PEEP) is used in an attempt to treat hypoxemia. New ventilatory strategies based on the ‘Open Lung Concept’ of Lachmann (Intensive Care Med, 1992) – now commonplace in human medicine (Tusman & Belda 2010; Tusman & B€ohm 2010) – are currently being explored successfully in horses (Levionnois et al. 2006; Sch€ urmann et al. 2008; Bringewatt et al. 2011; Hopster et al. 2011; Moens & Bo¨hm, 2011; Staffieri et al. 2011). Searching the abundant human and the scarce veterinary literature for reference values to be used during lung recruitment in horses, it can be argued that the airway pressures commonly applied in horses during IPPV with and without PEEP are usually insufficient to re-expand anaesthesia-induced atelectasis. In large horses it is expected that the large superimposed gravitational gradient within the lung tissue requires recruitment pressures in excess of the 40, 50 and 60 cmH2O, the minimum plateau pressures typically employed in healthy, obese and morbidly obese humans, respectively (B€ ohm et al. 2009a,b; Tusman & Belda 2010). Thus, to open collapsed alveoli, and to keep them open, peak inspiratory pressures (PIP) of up to 80 cmH2O and PEEPs up to 25 cmH2O seem to be justified at least in some horses (Sch€ urmann et al. 2008; Bringewatt et al. 2011; Hopster et al. 2011). However, these high airway pressures inevitably induce cardiovascular and pulmonary side effects such as decreases in cardiac output and blood pressure as well as overdistension of lung parenchyma which result in augmented dead space fractions (Wettstein et al. 2006; B€ohm et al. 2009a). Therefore, the concept of ‘best or open lung PEEP’, defined as the lowest PEEP in an individual 197

patient that keeps alveoli open without overdistending them, was proposed by Suarez-Sipmann et al. (2007) and later confirmed (Tusman & Belda 2010; Tusman & B€ ohm 2010). It is highly likely that this fundamental physiological concept is also applicable for the management of equine ventilation (Moens & B€ ohm 2011). However, to implement this ventilation strategy in clinical practice appropriate monitoring tools are needed to guide therapy. This case report aims to document by a variety of continuous non-invasive monitoring means (1) the physiological effects of stepwise PEEP titrations and (2) the opening and the closing of alveoli in an anaesthetized and mechanically ventilated horse in lateral recumbency. The recruitment intervention was also recorded by electrical impedance tomography (EIT), a novel imaging technology capable of displaying changes in regional lung aeration during a tidal breathing cycle and of visualising the impact of mechanical ventilation separately for each lung. Additional monitoring consisted of electronic spirometry, volumetric capnography and respiratory ultrasonic plethysmography (RUP). To the best of the authors’ knowledge a recruitment manoeuvre has never before been documented with this unique set of non-invasive monitoring techniques and should therefore provide novel insights into the regional distribution of alveolar collapse and recruitment. Case history and methods The procedure was approved by the Institutional Ethics Committee and the National Authority according to the Law for Animal Experiments (BMWF-68.205/0059-II/3b/2011). The subject was a 533 kg warm blood horse owned by the University and free of clinically apparent lung disease. Following premedication and induction of anaesthesia with intravenous ketamine and midazolam, the horse was connected to an anaesthetic circle system. Anaesthesia was maintained with isoflurane in oxygen (inspired oxygen fraction ≥ 0.90) and a continuous rate intravenous infusion of a mixture of ketamine, xylazine and midazolam. The horse was positioned in right lateral recumbency. Clinical monitoring consisted of the continuous recording of electrocardiogram, heart rate, respiratory gas composition, arterial oxygen saturation and invasive blood pressure. Arterial blood was sampled for blood gas analysis (arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) and pH)

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Novel insights into lung recruitment in a horse Y Moens et al. as required. Respiratory volumes and airway pressures were monitored via an augmented pitot tube (Horse-lite) adapted for the horse (Moens et al. 2009; Moens 2010; Datex Ohmeda S/5 multi-parameter module, GE Healthcare, NJ, USA). Additionally, mainstream volumetric capnography was performed by a standard human NICO monitor (Respironics, CT, USA), the airway adapter of which adapted by a flow divider to cope with the gas flow rates of large animals (Ambrisko et al. 2013; Schramel et al. 2013). Signals from two custombuilt RUP sensors incorporated in fluid filled tubes strapped around both, the thorax and the abdomen were transmitted wirelessly to a PC (Russold et al. 2012; Schramel et al. 2012a). Electrical impedance tomography data were acquired using the impedance tomography device ENLIGHT (Dixtal, Biomedica, Brazil) producing 50 real time images per second (Costa et al. 2009a). A dedicated 32-electrode EIT belt was placed vertically around the thorax at the level of the 6th intercostal space while electrical contact with the skin was enhanced by clipping the hair along the circumference and by applying ultrasonic gel. This way regional impedance changes corresponding to regional changes in air and blood volumes within the cross section of the thorax circumscribed by the belt were measured (Victorino et al. 2004; Schramel et al. 2012b). Following induction of anaesthesia, the horse was immediately ventilated with IPPV using the novel custom made ventilator HorseVent (VetMedUni Vienna, Austria and CSEM, Switzerland). The ventilator provided pressure controlled ventilation with a decelerating flow pattern via a computer controlled linear actuator and a standard concertina-type breathing bag (CSEM 2010). Baseline ventilation was maintained for ten minutes with a respiratory rate of 8 breaths minutes 1, PIP of 18 cmH2O with zero PEEP (ZEEP). Subsequently, an alveolar recruitment manoeuvre (ARM) as first described in humans (Tusman et al. 1999) and in ponies (Wettstein et al. 2006) was performed. The first part consisted of a sequence of PEEP increases in steps of approx. 5 cmH2O every three minutes keeping the driving pressure (PIP – PEEP) constant at approx. 20 cmH2O (Fig. 1, minutes 0–18). After three minutes at PEEP 25 cmH2O the driving pressure was temporarily raised to obtain an absolute recruitment pressure of roughly 60 cmH2O which was also maintained for three minutes (Fig. 1, minutes 18–21) to actively recruit (‘open’) collapsed lung areas. Prior to decreasing

PEEP, PIP was reduced such that the previous driving pressure was achieved and maintained there for three minutes (Fig. 1, minutes 21–24). Finally, PEEP was stepwise decreased by 5 cmH2O to zero (Fig. 1, minutes 24–39). This decremental phase served to identify the PEEP at which lung tissue started to collapse again. PaO2 and PaCO2 at baseline were 440 mmHg (58.7 kPa) and 44 mmHg (5.9 kPa) respectively. Changes of the different variables monitored over the course of the intervention are shown in Figs 1 and 2. Following anaesthesia the horse recovered without complications. Discussion Figure 1a reflects the time course of PIP and PEEP and thus the ventilator intervention with its incremental and decremental PEEP titration phases. Figure 1b shows the ARM’s effect on thoracic RUP which mirrors the stepwise changes in airway pressures. Since RUP measures static and dynamic changes in outer thoracic circumference it is capable of tracking tidal breathing and changes in chest wall volume. This is helpful to detect changes in endexpiratory lung volumes (EELV) such as the ones caused by PEEP (Valta et al. 1992; Russold et al. 2012). However, RUP does not provide an answer to the clinically important question of how much of the gain in EELV seen in this case during the incremental PEEP phase was due to a further distension of already open alveoli or to the true recruitment of previously collapsed alveoli. Therefore, a different methodology is needed. The course of the dynamic compliance (Cdyn) during the ARM is shown in Fig. 1c and resembles the one typically found in man and porcine models (Suarez-Sipmann et al. 2007; Maisch et al. 2008). In this horse, baseline Cdyn was already low (0.5 mL cm H2O 1 kg 1) and decreased even further as the increasing airway pressures caused open alveoli to overdistend. However, once airway pressures became sufficiently high to induce significant alveolar recruitment, collapsed lung tissue opened up and Cdyn increased abruptly. During the first half of the decremental PEEP phase Cdyn kept on increasing as overdistension was relieved. A maximum value of 0.8 mL cmH2O 1 kg 1 was reached at PEEP 15 cmH2O. This point – called the ‘closing point’ – at which Cdyn starts to gradually decrease with further reductions in PEEP, marked the start of alveolar re-collapse. The time course of the above

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Novel insights into lung recruitment in a horse Y Moens et al.

(a)

(b)

(c)

(d)

Figure 1 Time course of changes in respiratory parameters in an anaesthetized horse subject to an alveolar recuitment maneuver. Shaded columns represent effective recruitment and closing point airway pressures. (a) Time course of peak inspiratory pressure (PIP) and positive end-expiratory pressure (PEEP) during the incremental and decremental part of the alveolar recruitment maneuver. The numbers represent positive end-expiratory pressure values in cmH2O. (b) The effects on thoracic respiratory ultrasonic plethysmography; (c) dynamic compliance (Cdyn) (left axis, open circles) and Tidal Volume (right axis, filled circles). The numbers in the first and last column represent PaCO2 and PaO2 (mmHg 9 0.133 for conversion to kPa) and PaO2/FIO2 from top to bottom respectively. (d) Alveolar dead space fraction (VD/VTalv) (■) and CO2 elimination per breath (VTCO2) (□).

mechanical parameters illustrates how a successful recruitment leads to a more advantageous pressurevolume relationship of the recruited lung allowing larger tidal volumes to be delivered with the identical driving pressure. This is supported by spirometric values (Fig. 1c) and by the larger excursions of the RUP signals (minutes 9–12 compared with 27–30) which were achieved after the recruitment using the identical driving pressure as before. Following the therapeutic principles of the ‘Open Lung Concept’ a renewed ARM would have had to be performed as soon as the closing PEEP was identified and the subsequent PEEP set slightly (2– 199

3 cmH2O) above this closing point (not shown in this case). This ‘best or open lung PEEP’ is considered optimal for continuing ventilation treatment. None of the global lung mechanics parameters discussed so far sheds light on the efficiency of the ventilation treatment applied. While intermittent measurements of PaCO2 and the continuous noninvasive tracking of alveolar dead space and CO2 elimination are keys to optimizing ventilation, the latter parameters may also be used to identify the point of alveolar re-collapse (Tusman & B€ ohm 2010; B€ ohm & Tusman 2012). An increase in alveolar dead space can be the result of alveolar overdisten-

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Novel insights into lung recruitment in a horse Y Moens et al.

(a)

(b)

(c)

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Figure 2 The time course of global impedance change (DZ) measured by EIT (a) and the regional DZ for the non-dependent lung (b) and the dependent lung (c) during the incremental and decremental part of the alveolar recruitment maneuver. Impedance-based ‘compliances’ (DZ/DP) are shown also (solid lines) in a, b and c (rescaled right Y-axis). In (d) the time course of the ratios of DZ ventilation (open triangles) and DZ ‘pulsatility’ (solid triangles) between the non-dependent and the dependent lung are shown. Shaded columns represent effective recruitment and closing point airway pressures.

sion; in this context alveolar dead space should also be able to identify a PEEP at which alveoli are kept open without overdistending them. Although dead space fraction is usually calculated according to Enghoff’s modification of Bohr’s original equation using intermittent PaCO2 and end tidal PCO2 values (Maisch et al. 2008) a novel volumetric capnography-based way of calculating Bohr’s dead space (VDBohr) on a breath-by-breath basis has recently been described by Tusman et al. who validated this new method against MIGET (Tusman et al. 2011, 2012). The new entirely non-invasive CO2-based

method to calculate dead space has been used to find optimal PEEP and was also used in this horse (Fig. 1d). Alveolar dead space fraction (VD/ VTalvBohr) increased during the incremental PEEP phase from approx. 0.3–0.6 suggesting progressive alveolar overdistention. After effective recruitment VD/VTalvBohr decreased continuously reaching its lowest value of approx. 0.2 belatedly at PEEP 10 cmH2O (Fig. 1d minutes 30–33) while the maximum elimination of CO2 per breath (VTCO2) during the decremental PEEP titration coincided with the collapse-PEEP of 15 cmH2O already identified by the

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other methods (Fig. 1d minutes 27–30). The highest elimination of CO2 at this PEEP gives rise to the speculation that the largest area for gas exchange and the most favourable global V/Q matching were reached in this animal. However, deeper insights into the regional ratios of ventilation and perfusion such as the ones provided by EIT are needed to substantiate this speculation. Graphs showing impedance changes (DZ) separately for the non-dependent and the dependent lung and with the corresponding functional EIT images are presented in Fig. 2. Just as RUP, EIT is also able to track tidal breathing and when the baseline is considered, indirectly also changes in EELV (Fig. 2a) (Givans et al. 2011; Schramel et al. 2012b). Visual inspection of the functional images and calculation of the non-dependent/dependent lung (ND/D) ratio of DZ during baseline IPPV at ZEEP reveal that in this laterally recumbent horse tidal volumes were unevenly distributed between the two lungs (Fig. 2b–d) with less air reaching the dependent lung. This is as findings obtained by Kunst et al. (2000) and by selective spirometry in anaesthetized horses (Moens et al. 1994, 1995). In this horse, the ARM caused profound changes in this partition. During the incremental phase where both, PEEP and PIP were increased (Fig. 2, minutes 0–18) an increasing fraction of tidal ventilation was redirected towards the dependent lung as shown by decreasing ND/D DZ ratios from 4.7 to 2.8 (Fig. 2d). This obvious downward shift in the centre of ventilation provides indirect evidence for the redistribution of ventilation towards the dependent lung (Radke et al. 2012). However, in this horse repartition remained incomplete during the incremental PEEP titration. Only when PIP exceeded 45 cmH2O a sudden and dramatic increase in global DZ amplitude (total ventilation in Fig. 2a, minutes 18–21) as well as in DZ amplitude of the dependent lung occurred (Fig. 2c). ND/D DZ became inverted (0.8) now showing more ventilation in the dependent than in the non-dependent lung. This event suggests that collapsed alveoli were effectively recruited by the elevated airway pressures (PIP/PEEP = 60/25 cm H2O) allowing tidal ventilation to be directed also to the dependent lung. When PEEP was decreased ND/D DZ increased again indicating that regional ventilation shifted once more towards the non-dependent lung to approach at ZEEP baseline condition (before the ARM). This suggests a gradual re-collapse of previously recruited alveoli within the dependent lung. The effects of PIP and PEEP on the distribution 201

of ventilation seen in EIT are in line with the findings obtained by selective spirometry in horses (Moens et al. 1998). The pressures which finally recruited the dependent lung and the PEEP level at the closing point found in this study were in the order of magnitude of those reported to improve oxygenation in clinical equine cases where ventilatory management included an ARM strategy (Levionnois et al. 2006; Sch€ urmann et al. 2008; Hopster et al. 2011; Bringewatt et al. 2011). Advanced post-hoc analysis of the EIT signal provided even more insights into the dynamic processes which took place within the lungs during the intervention (Lowhagen et al. 2012). First, impedance-based ‘compliance’ can be studied dividing DZ – as a surrogate for tidal volume – by the driving pressure DP (Costa et al. 2009a,b; Dargaville et al. 2010). Whereas Fig. 2a shows global ‘compliance’ changes, Fig. 2b,c illustrate the marked differences in the time course of ‘regional compliances’ for the non-dependent and the dependent lung, respectively. During the incremental phase there is a gradual decrease in ‘compliance’ in the non-dependent lung, while that of the dependent lung remains relatively unaltered until, at the highest airway pressures, it suddenly increases indicating the opening of collapsed lung regions, while ‘compliance’ of the non-dependent lung continues to decrease as a result of further overdistension. Although overall compliance is given by the sum of regional compliances, the maximum of the latter does not appear at the same PIP/PEEP levels as the maximum of the overall compliance as revealed exclusively by EIT (Fig. 2). In particular the improvement of overall compliance induced by the ARM is mainly due to the opening of the dependent lung. However, the non- dependent lung is more prone to compliance changes than the dependent lung notably when major parts of the latter are closed. Electrical impedance tomography can distinguish also between ventilatory and circulatory phenomena. This is due to the fact that the total DZ signal is composed of a dominant ventilatory component generated by the cyclic changes in regional air content during tidal breathing and to a lesser extent of a circulatory component caused by the cyclic changes in local blood volume during the cardiac cycle. By applying frequency-based filtering techniques, ventilation and cardiac-related DZ can be separated, the latter being called ‘pulsatility’ (Fagerberg et al. 2009; Nguyen et al. 2012). Global EIT pulsatility correlates well with stroke volumes as

© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 196–204

Novel insights into lung recruitment in a horse Y Moens et al. measured by thermodilution while its regional fractions can be assumed to reflect fractions of the stroke volume directed towards the respective lung regions (Vonk-Noordegraaf et al. 2000). However, it is worth noticing that regional pulsatility might not be an adequate measure of local forward blood flow or lung perfusion as pulsatility is greatly influenced by regional resistances of the pulmonary vessels as well as size, compliance and patency of the pulmonary microvascular bed. Therefore, if real perfusion were to be measured reliably by EIT an indicator dilution technique based on the first pass kinetics of a bolus of hypertonic saline should be considered, as has been demonstrated experimentally in piglets by Borges et al. (2012). Nevertheless, changes in pulsatility distribution along the protocol may still serve as a surrogate for changes in the spatial distribution of the pulses generated by the right heart. Figure 2d shows the time course of the ND/D ratio for DZ ventilation and pulsatility signals, respectively. During the incremental PEEP titration phase the gradual shift of ventilation towards the dependent lung is accompanied by a parallel development of pulsatility. Alveolar recruitment then induces an abrupt equilibration of ventilation and pulsatility within both lungs in the range of 1:1. The sequence of events in this figure is suggestive of the fact that the effective reopening of the collapsed dependent lung is matched by some circulatory adaptation such as the relief of hypoxic vasoconstriction. Different types of ARM including repeated sustained inflation have been reported and are also explored in horses today (Levionnois et al. 2006; Wettstein et al. 2006; Sch€ urmann et al. 2008; Staffieri et al. 2011). The profound effects of a sudden and sustained application of high airway pressures and the lack of cycling between PIP and PEEP can lead to pronounced decrease in cardiac output in humans (Nielsen et al. 2005) and in animals (Odenstedt et al. 2005). In contrast, stepwise increase of PIP and PEEP allow the cardiovascular system to adapt to higher intrathoracic pressures. In the case presented here mean arterial blood pressure did not change substantially during the ARM. Despite the lack of cardiac output data in this patient, but based on previous clinical experience with recruitment procedures and reports from human anaesthesia in morbidly obese (B€ ohm et al. 2009a,b) it is highly recommended to obtain an euvolemic state and a mean blood pressure no <70 mmHg before starting an ARM in horses.

Interestingly, in this 533 kg healthy horse gas exchange was unexpectedly well preserved as indicated by low (A-a) PO2 and high PaO2 and PaO2/ FIO2 during IPPV at ZEEP (Fig. 1c). This is especially remarkable in lieu of the massive hypoventilation of the dependent lung at ZEEP. Ventilation/perfusion mismatch in general and maldistribution of ventilation in particular have traditionally been associated with atelectasis and shunt in dependent less ventilated lung regions as witnessed by an impaired gas exchange (Nyman et al. 1990; Schatzmann 1995). In this adult horse direct morphologic evidence for the presence of atelectasis e.g. from computed tomography (Borges et al. 2006; Muders et al. 2011) or from histology (Hedenstierna et al. 1989) was not possible to obtain nor was shunt measured. However, EIT and the various other parameters measured in this study provide indirect evidence for substantial lung collapse in the dependent lung. Furthermore, the association of interregional changes in ventilation and pulsatility and blood gases support the idea that maldistribution of ventilation is not necessarily accompanied by an impaired gas exchange. In fact this points towards the existence of effective powerful adaptive regulatory mechanisms, such as hypoxic vasoconstriction, which optimize V/Q matching and limit right-to-left shunt despite widely varying degrees of lung collapse predominantly in the dependent lung (Hall 1983). Conclusions In summary, the synopsis of data in this report showcases the physiology of lung collapse and re-expansion. The different monitoring techniques support and visualize the basic principles of the ‘Open Lung Concept’ according to which high PIP opens the lung and PEEP keeps it open. This report also illustrates the clinical usefulness of novel noninvasive monitoring technologies which can easily be applied during anaesthesia in horses. Respiratory ultrasonic plethysmography, VC and electronic spirometry provide continuous information on changes in EELV, tidal volumes, compliance, dead space and thus efficiency of both, ventilation and gas exchange. The more advanced technology of EIT is able to shed light onto the pathophysiological phenomena at a regional level. Together these techniques form a promising never-heard-of toolkit for future studies aimed at optimizing ventilatory management in general and at improving our understanding of the physiological impact of novel

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ventilatory strategies such as ARM during equine anaesthesia. A holistic approach to monitoring may furnish more keys to the understanding of the pathophysiologic mechanisms underlying the clinical variability of gas exchange and to better adapt treatments to the individual needs of each patient.

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