Mini-review

Daniel MoralesFranco Laghi

Division of Pulmonary and Critical Care Medicine, EdwardHines Jr. Veterans Administration Hospital, and LoyolaUniversity of Chicago Stritch School of Medicine, Hines,Illinois, USA

Address for correspondence:Franco Laghi, MDDivision of Pulmonary and Critical Care MedicineEdward Hines, Jr. VA Hospital, 111N5th Avenue and Roosevelt RoadHines, IL 60141 - USAPhone: (708) 2022705Fax: (708) 2027907E-mail: flaghi@lumc.edu

Summary

Mechanical ventilation is necessary in most patientsaffected by the acute respiratory distress syndrome(ARDS). Unfortunately, mechanical ventilation itselfcan cause lung damage as a result of ventilator-in-duced lung injury (VILI). The cyclical recruitment andde-recruitment of atelectatic lung regions (atelec-trauma), lung overdistension (volutrauma) and de-novo inflammation caused by a combination of thetwo (biotrauma) are likely participants in the develop-ment of VILI. Increasing experimental evidence sug-gests that the risk of VILI may be decreased by care-ful titration of ventilator support guided by monitoringpulmonary mechanics. Airway pressure (Paw) is thesimplest signal available to monitor mechanics inARDS. In combination with measurements of lungvolume, Paw allows to plot volume-pressure curves(VP curves) and to record end-expiratory pressureand end-inspiratory pressure during zero flow (Pplat).In the past it was assumed that VP curves could giveaccurate information on lung recruitment andoverdistension. Those assumptions, however, havebeen proven incorrect. Similarly, it is incorrect toconsider Pplat an accurate index of overdistension.In this review we will examine some of the availabletools to monitor pulmonary mechanics in ARDS. Thecritical interpretation of the data recorded with thesetools, their limitations and the potentials use of thesedata in setting the ventilator will be discussed aswell.

KEY WORDS: Acute Respiratory Distress Syndrome;monitoring; respiratory mechanics; Ventilator-InducedLung Injury.

Introduction

The acute respiratory dis-tress syndrome (ARDS) isa form of noncardiogenicpulmonary edema that re-sults from acute damage tothe alveoli (1). Most pa-tients with this syndromewill die if they do not re-ceive supplemental oxygenand mechanical ventilation(2, 3). By reversing life-threatening hypoxemia andalleviating the work ofbreathing, mechanical ven-tilation buys time for the lungsto heal (3). Mechanical ventilation can also cause lungdamage by several mechanisms, including alveolar rup-ture and alveolar hemorrhage, especially when high air-way pressures are used for ventilation (4, 5). In these pa-tients, the damage to the lungs caused by mechanicalventilation is known as ventilator-induced lung injury (VILI)(5). Mounting experimental evidence suggests that therisk of VILI may be decreased by a careful titration of ven-tilator support guided by monitoring pulmonary mechan-ics in ARDS (5-8).

Pressure Volume curves in ARDS

A useful first step in understanding the impact of monitor-ing pulmonary mechanics in ARDS is to examine thepressure-volume relationship of the respiratory system inthese patients. As shown inFigure 1, the pressure-vol-ume curve in patients withARDS can have a sigmoidshape with two discretebends (9). The lower bendis called lower inflectionpoint (LIP) and the upperbend is called upper inflec-tion point (UIP) (9). In the past the LIP wasthought to be the criticalpressure needed to reopenmost of previously col-lapsed airways and alveoli.The UIP was thought to be the critical pressure beyondwhich alveolar overdistension occurs. That meant thattidal ventilation was thought to be safe as long as it wasdelivered within these two points. We now know thatthese are oversimplifications because recruitment ofcollapsed lung units continues above LIP (10) and aboveUIP (11).

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Ventilator-inducedlung injury (VILI) maybe considered as a"de-novo" biotraumacaused by cyclicalrecruitment and de-recruitment of atelec-tatic lung regions(atelectrauma), andlung overdistension(volutrauma).

Examination of pres-sure-volume (P-V)curves is the firststep of monitoringpulmonary mecha-nics in ARDS. Howe-ver, P-V curves aredifficult to interpretdue to many con-founders.

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Ventilation that continues beyond the UIP can cause lunginjury (5). This type of lung injury is known as “baro-trauma” or lung trauma caused by excessive pressure ap-plied to the lungs (5). Some investigators, however, pre-

fer the term “volutrauma” (lung trauma caused by exces-sive distension of the lungs) because – they note – it isnot the pressure at the airway opening that causes lunginjury but the distention of the lung (12). Ventilation that starts below the LIP is associated with cycli-cal collapse and reopening of lung units. This cyclical col-lapse and reopening causes a type of lung damage knowas “atelectrauma” (13). In addition to biophysical injury (vo-lutrauma and atelectrauma), investigators now posit that in-jurious ventilatory strategies associated with overdisten-sion of the lung and with repeated recruitment andde-recruitment of collapsed lung units can also lead to therelease of inflammatory mediators, including TNF-α, inter-leukin-6, prostaglandins, leukotrienes and reactive oxygenspecies (13). According to those investigators, these inflam-matory mediators cause a biochemical injury termed “bio-trauma” (13). At a local level inflammatory mediators canlead to recruitment of a number of cells, including neu-trophils (14). In addition, inflammatory mediators can translo-cate from the lung into the systemic circulation and this maylead to distal organ dysfunction and death (4, 13). At one time, investigators advocated obtaining pressure-volume curves to properly select ventilator settings inpatients with ARDS (15). Unfortunately, pressure-volumecurves are difficult to generate because they requireheavy sedation and paralysis (16). In addition they cancause hypoxemia at low lung volumes, derecruitment atlow levels of positive end-expiratory pressure (PEEP)and hemodynamic compromise (decrease of venous re-turn) (16). Pressure volume curves are also difficult to in-terpret due to many confounders. These confounders in-clude expiratory flow limitation (17), abnormal chest-wallmechanics (18), continuous recruitment of collapsed lungunits above LIP (10) and above UIP (11) and focal vs.non-focal distribution of ARDS (6, 19). Not surprisingly,most experts around the world use pressure-volumecurves only for research purposes but not in clinical prac-tice (Figure 2).

Figure 1 - Schematic representation of a pressure-volumecurve of the respiratory system in a patient with ARDS. Inthese patients, the pressure-volume curve can have a sig-moid shape with two discrete bends above functional resid-ual capacity. The lower bend is called lower inflection pointand an upper bend is called upper inflection point. In 1995,Roupie et al. (AJRCCM 1995;152:121) reported that usingconventional tidal volumes (9-12 mL/kg), and a mean PEEPof 10 cm H2O, more than 70% of patients with ARDS had anend-inspiratory plateau airway pressure exceeding upper in-flection point. Reducing tidal volumes to 6 mL/kg brought theend-inspiratory plateau airway pressure below upper inflec-tion point. This was the first study to demonstrate the rele-vance of reduction in tidal volume for lung protection.

Figure 2 - Pressure vol-ume curves are difficultto generate and to inter-pret. This is why mostinternational experts donot use them in theirdaily clinical practice(Franco Laghi, personalcommunication, Novem-ber 2010).

Monitoring pulmonary mechanics to limit overdistension (Volutrauma)

Following the seminal study of Amato et al. (15), theARDS Network published the result of a large multicen-ter trial of 861 patients with ARDS (20). In the study, onegroup of patients was randomized to mechanical ventila-

tion with small tidal volumes(6 ml/kg of ideal body weightor IBW) and a plateau air-way pressure (Pplat)recorded following an inspi-ratory pause of 0.5 secondsof 30 cm H2O or less. A sec-ond group of patients wasrandomized to traditionaltidal volumes (12 ml/kgIBW) and a Pplat of 50 cmH2O or less (20). The trialwas stopped when an in-terim analysis revealed that

lowering tidal volume andPplat decreased mortality by 22%. In a subsequent meta-analysis, Eichacker et al. (21) concluded that the most im-portant aspect in setting the tidal volume in ARDS is touse tidal volumes that produce a Pplat between 28 and32 cm H2O. Pplat is used to estimate transpulmonary pressure (lungstretching). A high Pplat usually signifies excessive lungstretching, and a low Pplat signifies less lung stretching.Unfortunately, the value of Pplat is determined not onlyby the stiffness of the lung but it is also determined bythe stiffness of the chest wall. In some patients, includ-ing those who are obese, pregnant or who have tenseascites, the stiffness of the chest wall can be significant.In these patients, Pplat may be very high without this sig-nifying that the lungs are truly overdistended (volu-trauma). That is, in patients with a chest wall that isstiffer than normal the simple measurement of Pplatwill cause physicians to grossly overestimate lungstretching. In these patients it may necessary to meas-ure transpulmonary pressure using esophageal pressuretracings (see below). Transpulmonary pressure is calculated by subtractingalveolar pressure from pleural pressure (Figure 3). Inclinical practice, it is unrealistic to perform direct measure-ments of alveolar pressure and direct measurements ofpleural pressure. Instead, airway pressure is used as asubstitute of alveolar pressure, and esophageal pres-sure is used as a substitute of pleural pressure. If a clinician wants to know the extent of lung stretching atend-inhalation he/she will have to record Pplat plus thecorresponding esophageal pressure at end-inhalation. Ofnote, the value of Pplat already comprises any externalPEEP applied to the patient and any intrinsic PEEP the pa-tient may have. This means that it would be wrong to in-clude in the calculation of transpulmonary pressure anycorrection for external PEEP or intrinsic PEEP. It has beenreasoned that in patients with ARDS, tidal volume shouldbe titrated to keep the transpulmonary pressure in thephysiologic range – i.e., transpulmonary pressure <25 cmH2O while the patient is in the supine position (7, 22). The use of small tidal volumes in ARDS causes a reduc-tion of CO2 clearance and a reduction in lung recruit-ment. These phenomena are responsible for an initial

worsening in lung compliance and ventilation/perfusionmatching when instituting low-tidal volume ventilation(20). In other words, permissive hypercapnia and permis-sive atelectasis/hypoxemia are the trade-offs we have toaccept to improve the outcome of patients with ARDS(20). Of interest, new experimental evidence suggeststhat permissive hypercapnia may itself be lung-protective(23). Hypercapnia causes intracellular acidosis, which, inturn, has many potential protecting effects on injuredalveolar cells. These potential protecting effects includethe inhibition of xanthine oxidase (with consequent de-crease in the production of free radicals), inhibition of theactivity of NF-kB (with consequent decrease in cytokineproduction) and inhibition of capsase-3 that results inless apoptosis (23).

Monitoring pulmonary mechanics to limit cyclical recruitment-derecruitment (Atelectrauma)

The central question here is “what aspects of pulmonarymechanics should we monitor to avoid atelectrauma?”.Stated differently the question is “what aspects of pul-monary mechanics should we monitor to set PEEP inARDS?”. This is a difficult question that can be answeredonly tentatively. The various strategies used to set PEEP in ARDS include:1. Monitoring oxygenation and using a sliding-scale

(table) developed by a panel of experts to adjustPEEP and FiO2 in discrete steps to maintain ade-quate arterial oxyhemoglobin saturation (24, 25).

2. Monitoring respiratory system compliance while titrat-ing PEEP (optimal PEEP defined as the PEEP asso-ciated with maximal compliance) (26, 27).

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Figure 3 - Transpulmonary pressure or PL (lung stretching) iscalculated by subtracting alveolar pressure (PA) from pleu-ral pressure (Ppl). In clinical practice, airway pressure (Paw)substitutes alveolar pressure and esophageal pressure sub-stitutes pleural pressure.

Plateau airway pres-sure (Pplat) is usedto estimate trans-pulmonary pressure(lung stretching). Insome patients a hi-gher stiffness of thechest wall may cau-se grossly overesti-mation of lung stret-ching.

3. Monitoring the shapeof the airway pressuresignal during lung in-flation with constantairflow (optimal PEEPdefined as the PEEPassociated with a lin-ear rise in airwaypressure or “stress in-dex = 1”) (6).

4. Monitoring Pplat whiletitrating PEEP (opti-mal PEEP defined asthe highest PEEP as-sociated Pplat of 28-30 cm H2O) (28).

5. Monitoring an esti-mate of transpulmonary pressure measured with anesophageal balloon (optimal PEEP defined as thePEEP associated with positive transpulmonary pres-sure at end-exhalation while keeping transpul-monary pressure in the physiologic range of <25 cmH2O) (7).

Except for the first strategy listed above, all the otherstrategies are based on two ideas, first, to monitor the me-chanical characteristics of the individual patient withARDS and, second, set PEEP accordingly. Investigators have reported encouraging results (ten-dency to improve survival) in patients with ARDS venti-lated with a tidal volume of 6 ml/kg IBW in whom PEEPwas titrated according to the mechanical characteristicsof each individual patient (7, 28). In contrast, titratingPEEP using a sliding-scale (table) designed to adjustPEEP and FiO2 in discrete steps to maintain adequate ar-terial oxyhemoglobin saturation has not improved survival(24, 25).

Monitoring pulmonary mechanics to limit biotrauma

To posit that monitoring a particular aspect of pulmonarymechanics can give an insight to the risk of developingbiotrauma implies the existence of a not yet well identifiedlink between pulmonary mechanics and biotrauma. Mon-itoring tools that have triggered interest in this regard in-clude the quantification of the end-inspiratory strain of thelung (29, 30) and the computation of the so-called drivingpressure (31). 1. End-inspiratory strain: according to continuum me-

chanics, a branch of classic mechanics that dealswith solids and fluids, the transformation of a bodyfrom a reference configuration to a current configu-ration is called deformation. This is quantified as thedisplacement between particles in the body relativeto a reference length or strain. In the case of thelungs undergoing mechanical ventilation end-inspira-tory strain is defined as the change in lung volumerelative to the resting volume (29, 30). This meansthat to calculate the end-inspiratory strain of the lungit is necessary to measure the end-expiratory lungvolume and tidal volume (30). In mechanically ven-tilated patients, measurements of end-expiratory lungvolume can be performed using the helium dilutiontechnique, the nitrogen washout/washin technique

and with spiral computed tomography (32, 33).(Whether strain should be calculated while patientsare on PEEP or not remains controversial) (34).Cyclical end-inspiratory strain associated with infla-tion to total lung capacity is injurious to healthy lungs(29). This occurs when the resting lung volume (thebaby lung in case of ARDS) is increased by two-foldto three-fold (29, 35). In patients with ARDS damagehas been reported with end-inspiratory strains wellbelow this upper limit (29). Such observation impliesthe presence of inhomogeneous distribution of localend-inspiratory strain (29).

2. Driving pressure: thispressure is calculatedas the difference be-tween Pplat andPEEP. This meansthat one of the deter-minants of drivingpressure is end-inspi-ratory lung strain: thegreater the strain thegreater the drivingpressure. Post-hoc analysis ofseveral clinical inves-tigations suggeststhat driving pressuresabove 15-20 cm H2Oare conducive to increased mortality in ARDS (Fig-ure 4) (4, 7, 15, 20, 24, 25, 28, 36-40). It would betempting to speculate that the excess mortality inthose studies was due, at least in part, to excessivestrain and biotrauma. For several reasons such spec-ulation cannot be either accepted or refuted. First, thelink between strain and driving pressure is indirect.Second, the value of Pplat required to calculate driv-ing pressure is not only a function of lung mechan-ics but it is also a function of chest wall mechanics(see section on volutrauma). Third, no study hasprospectively determined the impact of different driv-ing pressures on ARDS outcome. Fourth, ventilatorsettings (such ventilator mode, as PEEP, respira-tory rate, FiO2) in the investigations summarized inFigure 4 varied from study to study (4, 7, 15, 20, 24,25, 28, 36-40). This makes it impossible to dissectthe effect of driving pressure from other ventilatorvariables on patient outcome. In other words, whileit would seem reasonable to aim for a driving pres-sure below 15-20 cm H2O (5, 15, 41) it is necessaryto bear in mind that such threshold is based on con-jecture, biological plausibility and post hoc analysisof studies not designed to identify the ideal drivingpressure to use in patients with ARDS.

Conclusion

In patients with ARDS mechanical ventilation can be life-saving yet it can also exacerbate lung injury (VILI). Cur-rent knowledge suggests that preventing VILI during me-chanical ventilation requires avoidance of cyclical openingand closing of unstable lung units and avoidance of ex-cessive stretching of lung parenchyma. Growing experi-mental evidence suggests that these goals may be

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Investigators havereported encoura-ging results (ten-dency to improvesurvival) in patientswith ARDS ventila-ted with a tidal volu-me of 6 ml/kg IBW inwhom PEEP was ti-trated according tothe mechanical cha-racteristics of eachindividual patient.

The quantificationof the end-inspira-tory strain of thelung and the com-putation of the so-called driving pres-sure has been sug-gested to limit bio-trauma, but the linkbetween pulmonarymechanics and bio-trauma has not yetbeen identified.

achieved by a careful titration of ventilator support guidedby monitoring pulmonary mechanics (5-8).

Acknowledgements and disclosures

The article is supported by grants from the Veterans Ad-ministration Research Service.

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Figure 4 - Mortality of patients with ARDS plotted against driv-ing pressure in twelve clinical studies designed to comparesome type of conventional ventilation against different lung-protective strategies (4, 7, 15, 20, 24, 25, 28, 36-40). For eachstudy, the circle indicates the combination of mortality anddriving pressure recorded with protective strategy and the starindicates the combination of mortality and driving pressurerecorded with conventional ventilation. In blue are studieswhere there was no difference in mortality between protec-tive strategy and conventional ventilation. In red are studieswere the mortality with conventional ventilation was greaterthan with protective strategy. In most instances, mortality wasthe highest when driving pressure of the conventional venti-lation group was more than 20 cm H2O and it was the lowestwhen driving pressure of the lung-protective strategy groupwas less than 15 to 20 cm H2O (Modified from Bugedo andBruhn) (41).

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