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Università di Torino, Dipartimento di discipline Medico-Chirurgiche, Sezione di Anestesiologia e Rianimazione, Ospedale S. Giovanni Battista, Torino, Italy
CORRESPONDENCE: V.M. Ranieri, Università di Torino, Dipartimento di discipline Medico-Chirurgiche, Sezione di Anestesiologia e Rianimazione, Ospedale S. Giovanni Battista, Corso Dogliotti 14, 10126 Torino, Italy. Fax: 39 0116960448. E-mail: marco.ranieri@unito.it
Keywords: acute respiratory distress syndrome, mechanical stress, mechanical ventilation, respiratory mechanics, stress index, ventilator-induced lung injury
Supported by Cofinanziamento 2002–2004 Ministero dell'Istruzione, dell'Università e della Ricerca.
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ABSTRACT |
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 TOP ABSTRACT Biophysical characteristics of...The use of the...Analysis of the dynamic...REFERENCES |
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The volume/pressure (V/P) curve of the respiratory system in patients as well as in animal models of acute lung injury (ALI) has a characteristic sigmoid shape, with a lower inflection point (LIP) corresponding to the pressure/end-expiratory volume required to initiate recruitment of collapsed alveoli, and an upper inflection point (UIP) corresponding to the pressure/end inspiratory volume at which alveolar overdistension occurs. "Protective" ventilatory approaches have therefore set out to minimise mechanical injury by using the V/P curve to individualise positive end-expiratory pressure (PEEP) (PEEP above the LIP) and tidal volume (by setting end-inspiratory V/P below the UIP) since a large number of experimental studies correlate P/V curves to histological and biological manifestations of VILI and two randomised trials showed that protective ventilatory strategy individually tailored to the P/V curve minimised pulmonary and systemic inflammation and decreased mortality in patients with ALI.
However, despite the fact that several studies have: 1) proposed new techniques to perform pressure/volume curves at the bedside, 2) confirmed that the lower inflection point and upper inflection point correspond to computed tomography scan evidence of atelectasis and overdistension, and 3) demonstrated the ability of the pressure/volume curve to estimate alveolar recruitment with positive end-expiratory pressure, no large studies have assessed whether such measurement can be performed in all intensive care units as a monitoring tool to orient ventilator therapy. Preliminary experimental and clinical studies show that the shape of the dynamic inspiratory pressure/time profile during constant flow inflation (stress index), allows prediction of a ventilatory strategy that minimises the occurrence of ventilator-induced lung injury.
The acute respiratory distress syndrome (ARDS) is a common disease with devastating clinical effects. Mechanical ventilation is the main supportive therapy to re-establish sufficient oxygen supply to peripheral organs. As with any therapy, mechanical ventilation may expose patients to side-effects. Clinicians quickly recognised that mechanical ventilation could cause alveolar rupture and air leak, the so-called barotrauma 1. In 1974, Webb and Tierney 2 showed that mechanical ventilation could also be responsible of ultra-structural injury, independently of air leaks. The potential clinical implication of these data was not realised until a series of studies showed that, apart from the physical alveolar disruption, mechanical ventilation can induce further injury to the lung by increasing alveolar-capillary permeability through the overdistension of the lung (volutrauma) 3 and/or worsening lung injury through the tidal recruitment-derecruitment of the collapsed alveoli (atelectrauma) 4, and lead to even more subtle injury manifested by the activation of the inflammatory process (biotrauma) 6–8. All these experimental and clinical data led to the concept that all the pathophysiological mechanisms involved in ARDS (ventilation-perfusion mismatch and reduced compliance, lung oedema, atelectasis, pulmonary inflammation) may be worsened by the mechanical stress caused by inappropriate ventilator settings. In the early 1990s, an international consensus conference concluded that both tidal overdistension of normal alveoli and opening-closing of collapsed alveoli, contribute to a component of a progressive lung injury that arises not only from the disease process itself, but also from the impact of the ventilator patterns applied during the course of the disease 9. Ventilator-induced lung injury (VILI) was therefore defined as acute lung injury directly induced by mechanical ventilation in animal models whereas ventilator-associated lung injury (VALI) was defined as lung injury that resembles ARDS and that occurs in patients receiving mechanical ventilation 10.
Although randomised clinical trials 8 have successfully demonstrated that ventilatory strategy designed to minimise overdistension and opening-closing may reduce mortality in patients with ARDS, information regarding the bio-mechanical characteristics of stress applied to the ventilated lungs are still missing. VALI is in fact determined by the dynamic and continuous interaction between 1) the mechanical characteristics of the lung and 2) the ventilator settings. The relationship between these terms is conditioned by the dynamic variations in respiratory mechanics as determined by the status and evolution of the pathological process and by the consequences of ventilator parameters on the mechanical characteristics of the lung. Therefore clinicians have to choose tidal volume, positive end-expiratory pressure (PEEP) and recruiting manoeuvres assuming that the ventilator settings are not causing VALI but lacking a clinical tool able to identify whether or not the interaction between the currently used ventilator settings and the actual status of pulmonary mechanics is resulting in mechanical stress.
The mechanical characteristics of animal models 4 and patients 15 with ARDS have been investigated by the analysis of the static pressure/volume (P/V) curve of the respiratory system. Besides this, analysis of the P/V curve provided most of the physiological rationale explaining the pulmonary injury due to VILI/VALI. The static P/V curve is in fact characterised by a lower (LIP) and an upper (UIP) inflection point that are thought to represent the average critical opening pressure above which alveolar units start to re-open and the V/P values above which stretching and overdistension start to occur, respectively 17. Several studies demonstrated that tidal inflation starting below the LIP on the P/V curve leads to tidal recruitment/derecruitment of previously collapsed alveoli while tidal ventilation occurring above the UIP results in pulmonary overstretching both leading to a spectrum of pulmonary and systemic lesions such as air leaks 18, alterations in lung fluid balance 3, increases in endothelial and epithelial permeability 19, severe tissue damage 4, and pulmonary 6 and systemic 11 production of inflammatory mediators.
Because of this link between VILI/VALI and assessment of the P/V curve, and in an effort to make the measurement of the P/V curve available at the bedside, a growing interest in the development of new technologies, and on the clinical interpretation of the P/V curve has become evident in the last few years 22–30. However, although a large number of experimental studies correlated P/V curves to histological 4 and biological 6 manifestations of VILI, only two randomised trials showed that protective ventilatory strategy individually tailored to the P/V curve minimised pulmonary and systemic inflammation 8 and decreased mortality in patients with ALI 12. Furthermore, despite the fact that several studies have proposed new techniques to perform P/V curves at the bedside 23, confirming that the LIP and UIP correspond to computed tomography (CT) scan evidence of atelectasis and overdistension 26 and demonstrating the ability of the P/V curve to estimate alveolar recruitment with PEEP 15, no large clinical studies have assessed whether such measurement can be performed in all intensive care units as a monitoring tool to orient ventilator therapy.
This chapter will: 1) review the basic principles of mechanical stress, 2) discuss how to measure and interpret the static P/V curve to minimise VILI/VALI, 3) revise the potential advantage of the use of the dynamic P/V curve to monitor, prevent and minimise VILI/VALI.
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Biophysical characteristics of the lungs relative to mechanical stress |
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TOPABSTRACTBiophysical characteristics of...The use of the...Analysis of the dynamic...REFERENCES |
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Shear stress
Shear stress is a form of mechanical stress generated when blood or air move across a cell surface, thereby generating a force parallel to the plasma membrane that induces a tangential distortion of the cell. In damaged lungs the development of shear stress is related to the cyclic opening and closing of small airways induced by recruitment/derecruitment of alveolar units. Diseased lungs with a heterogeneous distribution of lesions may be subjected to a much greater regional stress than homogeneous lungs 4. The occlusion of small airways by exudate or apposition of their walls requires high airway pressure to restore patency, resulting in shear stress and damage of the airways, particularly if the cycle is continuously repeated 36. Airway collapse and the consequent recruitment-derecruitment may not occur in normal lungs, being favoured by surfactant deficiency and lung disease, modifying the interstitial support of the airways 35.
Stress failure
Stress failure depends on the development of excessive wall stress, defined as the ratio of alveolar wall tension to thickness. The limited strength of the alveolar-capillary barrier may explain such a mechanism of mechanical stress. It has been known that high airway pressure between the alveolus and the vascular bed during positive pressure ventilation causes the passage of air across the epithelial surface, along the bronchovascular sheath and then into the interstitial tissues 32. The endothelium, so close to the epithelial surface, is subject to stress failure determined by forces derived both from transpulmonary and intravascular pressures 32. Fu et al. 33 showed that at a constant transmural pressure, an increase of transpulmonary pressure from 5 to 20 cmH20 produced a significant increase in the number of epithelial and endothelial breaks. There was a further increase in number of breaks at the same transpulmonary pressure when capillary transmural pressure was increased. The local or regional stress induced by lung inflation may increase microvascular transmural pressures with disruption of capillaries ("capillary stress failure"), determining changes in the alveolo-capillary barrier 34. The forces generated by mechanical ventilation may therefore interact with those due to pulmonary vascular perfusion to increase lung injury.
The mechanical characteristics of the lungs are conditioned by the mechanics of its microstructure and the relative content of elastin and collagen in the alveolar walls. The alveolar septum is composed of a skeleton of collagen and elastin fibres that are interlaced with the capillary network. Many models of lung parenchyma have used various geometrical bodies to describe the volumetric structure of the alveolar region. To investigate fibre organisation and the potential distribution of mechanical deformation and stress, a two-dimensional model of the alveolar sac was proposed 37. Two-dimension electron microscope scanning showed that the traction stresses (
) at different lung volumes were detected with an analysis of internal stresses within the septal walls. Characteristics of lung tissue were evaluated through measurements of length-tension 37. The authors found the following relationship:
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| (001) |
represents the stress, 
the stretch ratio. This equation therefore identifies different traction stresses () at different lung volumes and alveolar pressures. Experimental studies showed that at 60% total lung capacity, tensions are up to 6 times higher than those at resting lung volume. In contrast, the tension stress within internal walls shared by adjacent alveoli, is nearly zero thus confirming that alveolar distortion is not uniform. |
The use of the static pressure/volume curve to minimise ventilator-induced lung injury/ventilator-associated lung injury |
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TOPABSTRACTBiophysical characteristics of...The use of the...Analysis of the dynamic...REFERENCES |
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Lower inflection point
Inflation of an excised lung requires a critical opening pressure to be applied in order to re-expand the collapsed alveoli 39. This critical pressure appears on the P/V curve as the pressure corresponding to the sudden change in slope of the curve after the initial inflation. In normal subjects, this critical opening pressure amounts to 
20 cmH2O. Similarly, in patients with ARDS, the inspiratory P/V curve shows a LIP, that is the sudden change in slope occurring at the onset of tidal inflation, when the applied pressure varies between 10–20 cmH2O. This shows that in ARDS the vast majority of the lung is collapsed at the beginning of inspiration. The pressure corresponding to the LIP should therefore represent the minimal level of PEEP that should be applied in order to have tidal inflation within an open lung. Considering that ARDS and ALI are conditions of not homogeneous lung parenchyma, densities, evaluated with CT are more concentrated in dependent lung regions, where there is a more positive pleural pressure if compared with nondependent regions (0 cmH2O and –3, –5 cmH2O respectively). The influence of this vertical gradient in pleural pressure in the supine position may be enhanced by the gravitational distribution of oedema.
Upper inflection point
The decrease of P/V curve slope indicates the end of alveolar recruitment, the beginning of alveolar overdistension and so the maximal alveolar pressure that should be applied to obtain the maximal amount of alveolar recruitment. In normal subjects, the UIP is reached at a lung volume that is 85–90% of total lung capacity (TLC); in patients with ARDS UIP occurs at a much lower volume. An increase in pressure above the UIP only gives overdistension without any other increase in volume, with a maximal stretch of lung aerated areas.
Technique to assess the static pressure/volume curve
The super-syringe technique
The super-syringe technique was the first technique used to assess the status of elastic properties of the respiratory system in mechanically ventilated ALI/ARDS patients in supine position sedated and paralysed, to permit the slow inflation of the lung with predetermined gas volume of oxygen. The inflated volume is 100–200 mL. The syringe stops for 2–3 s, then the respiratory system is inflated with intermittent pause until a volume of 25 mL·kg–1 or an airway pressure of 40 cmH2O are reached. With this technique it is easy to detect the LIP and UIP but, on the other hand, paralysis, sedation and disconnection of the patient from the ventilator are required.
Rapid airway occlusion technique
The rapid airway occlusion technique is based on a single-breath occlusion at different inflation during mechanical ventilation. With inspiratory constant flow different volumes are achieved. Each occlusion is maintained until a plateau in the open airways pressure is obtained thus representing the static pressure of the total respiratory system. Using different volumes the static V/P curve can be constructed. Advantages of this technique include no need for patient disconnection and the ability to identify the elastic properties of the respiratory system as determined by the actual volume. Besides, the measurement does not require special devices. However, patients must be paralysed and sedated and curves are not immediately available since single data points need to be first collected and recorded and then plotted; identification of LIP and UIP is not easy.
Constant flow technique
The constant flow technique is based on the assumption that when inspiratory flow is constant during passive inflation the rate of change in the airway opening pressure is related to the elastance of the respiratory system and the resistive components are nil. There is no need to disconnect the patient from the ventilator, special devices are not required and results are available at the bedside; LIP and UIP are usually easily identified. Yet, this method requires paralysis, sedation and only a few ventilators are equipped with such a monitoring tool.
In patients with ARDS, the rapid airway occlusion technique (static V/P curve) provides the same information as the constant flow technique (with a flow of 3 L·min–1) regarding the elastic properties of the respiratory system, whereas the V/P curve obtained by the 9 L·min–1 constant flow is slightly shifted to the right 27. The slopes of the V/P curves and the LIP are not different between all methods, indicating that the resistive component induced by administering a constant flow 
9 L·min–1 is not of clinical relevance. However all methods have an intrinsic risk of adverse effects, including hypoxaemia at low lung volumes and derecruitment at low levels of PEEP 26–28. Other problems include haemodynamic changes (decrease of venous return) or complications related to sedation or paralysis required to obtain the characteristics of passive mechanics of the respiratory system. For all these reasons, P/V curves are not usually obtained in the routine clinical assessment 39.
A nonlinear model of respiratory mechanics in ARDS has recently been used to verify the physiological interpretation of the LIP and UIP and to examine their potential use in the clinical setting to set mechanical ventilation 30. This analysis showed that: 1) the initial increase in slope of the V/P curve indicates the minimal pressure at which alveolar recruitment starts to occur rather than the maximum level of PEEP able to provide maximum recruitment. Under these circumstances, a PEEP level equal to the LIP underestimates the optimal level of PEEP able to minimise end-expiratory alveolar collapse; 2) the decrease in the slope of the V/P curve does not indicate the beginning of alveolar overdistension but the end of alveolar recruitment. According to this mathematical model, the UIP is therefore unrelated to alveolar overdistension being caused by the decrease in rate of alveolar recruitment during lung inflation. Under these circumstances, the LIP will indicate the maximal alveolar pressure that should be applied to obtain the maximal amount of alveolar recruitment. Animal and clinical experiments are consistent with these data and have shown that recruitment occurs throughout the entire lung inflation from end-expiratory lung volume to TLC rather than being an "all or none" phenomenon 41.
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Analysis of the dynamic pressure/time curve during constant flow: a "stress index" to minimise ventilator-induced lung injury/ventilator-associated lung injury |
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TOPABSTRACTBiophysical characteristics of...The use of the...Analysis of the dynamic...REFERENCES |
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During constant flow conditions and if resistances are constant, airway opening pressure (Pao) changes linearly with time when compliance does not change with increasing lung volume. When compliance decreases, Pao is concave upward and when compliance increases Pao is concave downward with respect to the time axis 15. Such an analysis of the P/t relationship is based on the assumption that during volume controlled ventilation with a constant flow inflation, the rate of change of pressure is related to the changes in pulmonary compliance 15. Under these circumstances, the Pao profile as function of inspiratory time (t) can be described by a power equation (fig. 1
):
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| (002) |
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1. The threshold value for the stress index that discriminated best between lungs with and without histological and inflammatory evidences of VILI ranged between 0.90–1.10. For such threshold values, the sensitivity of the stress index to identify noninjurious ventilatory strategy was 1.00. A second study 49 examined the impact of different ventilatory strategies on the development of ischemia-reperfusion injury following lung transplantation and evaluated whether a ventilatory strategy aimed to maintain a stress index of 1 would minimise pathophysiological indices of ARDS in the setting of lung transplantation. In a rat lung transplant model, animals were randomised into two groups defined by the ventilatory strategy during the early reperfusion period.
In the conventional mechanical ventilation group the transplanted lung was ventilated with a VT equal to 50% of the inspiratory capacity of the left lung and a low PEEP. In the minimal mechanical stress ventilation group the transplanted lung was ventilated with a VT equal to 20% of the inspiratory capacity of the left lung and PEEP adjusted according to the shape of the P/t curve to obtain a stress index of 1. After 3 h of reperfusion, oxygenation from the transplanted lung was significantly higher in animals ventilated with a stress index of 1 than in animals ventilated with conventional ventilation. In addition, elastance, cytokine levels, and morphological signs of injury were significantly lower in the group ventilated with a stress index of 1. This study demonstrates that the mode of mechanical ventilation used in the early phase of reperfusion of the transplanted lung can influence ischemia-reperfusion injury, and a protective ventilatory strategy based on a stress index of 1 can lead to improved lung function after lung transplantation. In a rabbit ARDS model, Nakane et al. 50 compared efficacy to minimise VILI of a ventilatory strategy aimed to maintain a stress index of 1 to the National Institutes of Health (NIH) protective ventilatory strategy 13. Animals were randomly ventilated for 3 h using one of the following ventilatory strategies: stress index group: VT 6 mL·kg–1, PEEP adjusted so that b=1; NIH group: VT 6 mL·kg–1, PEEP set according to the table created by NIH ARDSNet; Injurious group: VT 10–12 mL·kg–1, PEEP 1–2, inspiratory oxygen fraction was adjusted so that arterial oxygen tension was 55–80 in all groups. Respiratory mechanics worsened with time only in animals ventilated with the NIH and the injurious ventilatory strategies while they were maintained at the baseline levels only in animals ventilated with a stress index of 1. After 3 h of mechanical ventilation, lung homogenate concentration of interleukin-8 in the dependent region was significantly lower in animals protected by VILI using the stress index strategy than in animals protected using the NIH strategy; histological exams showed significantly lower incidence of VILI in the stress index group compared to the other groups. In eight pigs lung injury was induced with lung lavage 51. Each animal was ventilated in random order with three ventilator settings aimed to obtain a stress index =1 a stress index >1 and a stress index <1. At the end of each experimental condition the current authors measured respiratory mechanics, gas exchange and quantified tidal recruitment and tidal overinflation with spiral CT scan and multiple inert gas elimination technique (MIGET). As can be seen in table 1, CT evidences of intratidal alveolar collapse and/or overdistension are mirrored by the stress index. Preliminary data in patients with ARDS 52 show that the use of the stress index is feasible also in the clinical scenario and that, compared to the gold standard protective ventilatory strategy (NIH protocol), patients ventilated with a stress index of 1 have lower elastance and higher recruitment of collapsed alveoli.
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