CURRENTOPINION Novel approaches to minimize ventilator-induced

anieri, and Luca Brazzi

injury and the pro and cons of the differentac

spiatioas

n thoraonaum

evaluation of super-protective ventilation that integrating partial or total extracorporeal support tries tominimize the use of mechanical ventilation.

Keyworacute reventilatio

INTRODUCTION

Even if mechanical vestone of treatment foclear that it can itselfage inducing the so cinjury (VILI) through

The main mecharegional lung overdistmonary pressure (strdeform above its resti

In experimental mdevelop when a lungbetween lung volumegreater than 2 is achievolume approximately greater than 20ml/kg inhealthy animals [1,2]. Thus, the smlung volume, the greater the strainvolume

Butdeleterand relapsed

Dipartimento di Scienze Chirurgiche, Universita` di Torino and Diparti-mento di Anestesiologia e Rianimazione, AOU Citta` della Salute e della

48; e-mail: luca.brazzi@unito.it

www.c

REVIEWious due to regional amplification of forcespetitive opening and closing of distal, col-lung units (atelectrauma) [3,4]. This condition

Curr Opin Crit Care 2015, 21:2025

DOI:10.1097/MCC.0000000000000172

o-criticalcare.com Volume 21 Number 1 February 2015low lung volume ventilation may also be Doglio69604 Copyright 2015logia e Rianimazione, AOU Citta` della Salute e della Scienza, Corsotti 14, 10126 Torino, Italy. Tel: +39 011 6334002; fax: +39 011change (inflation).Correspondence to Luca Brazzi, MD, PhD, Dipartimento di Anestesio-aller the restingfor a given lung

Scienza, Torino, Italydsspiratory distress syndrome, low tidal volume, respiratory mechanics, ultraprotective mechanicaln, ventilator-induced lung injury

ntilation remains the corner-r respiratory failure, it is nowaggravate or cause lung dam-alled ventilator-induced lunga variety of mechanisms.nical determinant of VILI isension due to high trans-pul-ess) that causes the lung tong volume (strain) [1].odels, VILI has been found tostrain (estimated as the ratiochange and resting volume)ved, corresponding to a tidal

has been advocated to provide augmented pulmon-ary injury when tidal ventilation starts below andends above the lower inflection point on the pres-sure/volume curve, as compared with ventilationstarting above the lower inflection point.

The biotrauma concept relies on the hypothesisthat lung tissue stretching might result in lungepithelium damage through the release of inflam-matory mediators and leukocyte recruitment. Twomechanisms are believed to be responsible forthis mechanical ventilator-induced inflammatoryresponse. The first is direct trauma to the cell withshifted from the search of optimal ventilator settings (best positive end-expiratory pressure) and to thelung injury

Pierpaolo Terragni, Vito Marco R

Purpose of reviewTo discuss the mechanisms of ventilator-induced lungapproaches proposed by literature to minimize its impsyndrome.

Recent findingsMechanical ventilation is indispensable to manage rephysiological principles and of the clinical implementshift of interest from its capability to restore normal gdamage and multisystem organ failure.

SummaryIf one of the essential teachings to young intensivists irestored being able to immediately drain a pneumothyoung intensivists is to implement protective ventilatisystemic effects of ventilator-induced lung injury (biotr Wolters Kluwer Healtht in patients with acute respiratory distress

ratory failure. The evolution of knowledge of then of mechanical ventilation is characterized by theexchange to its capability of causing further lung

e 1980s was to ensure mechanical ventilationx (barotrauma), nowadays priority we teach toto protect the lungs from the pulmonary anda). At the same time, priority of clinical research, Inc. All rights reserved.

disruptcytokinsystemvitro stcan pro[6].

Ranthe meresponmultipicallydistressing a mAlthoumediatorgans,ARDS hventilaserumnary or[10].

MaVILI: thforcespressurand thlarge nof a preductiweightsure to

However, these recommendations are chal-lenged by results of recent studies showing thatpatients with ARDS may be exposed to forces that

indauims t,1n tofe V

T

reV

ti

rimctiSe

meVhectial)tedo 6tintihe

KEY POINTS

Mechanical ventilation, although necessary to preservelife,throuthe bbasemicro

A larimprpatieapprthe o

In threprefromor ul

It is aprincasseas tostrate

Novel approaches to minimize ventilator-induced lung injury Terragni et al.

1070-529ion of cell walls, resulting in the release ofes into both the alveolar space and theic circulation [5]. Regarding the second, in-udies have shown that most pulmonary cellsduce cytokines in response to cyclic stretch

ieri et al. [7] were the first to suggest thatchanical ventilator-induced inflammatoryse may contribute to development of

canplateandmise[1,14

Iconsimiz

PRO

Diffemize

Low

ExpereduARDversyvolufrom

Tredua tid(PBWdebaset tresullated

T

can itself aggravate or cause the so called VILIgh a variety of mechanisms resulting in injury toloodgas barrier (endothelial, epithelial, andment membrane) with consequent increase invascular permeability and lung rupture.

ge number of trials tried to identify strategies toove the outcome of mechanically ventilatednts but only studies based on the physiologicaloaches for minimizing VILI really improvedutcome.

e last years, the most important innovation issented by the progressive change of approach,basic mechanical respiratory support, to protectivetraprotective noninjurious ventilation.

dvisable for clinicians to integrate physiologicaliples with clinical data through a runningssment of respiratory mechanics at the bedside soset up the most protective (tailor made) ventilatorygy. Copyright 2015 Wolters Kluwer Hea

le system organ dysfunction seen in mechan-ventilated patients with acute respiratorysyndrome (ARDS) by initiating or propagat-alignant, systemic inflammatory response.

gh it remains unclear how inflammatoryors exert their detrimental effects on distalexperimental studies and clinical trials inave shown that the application of protectivetor strategies is associated with decreasedcytokine levels [8,9], decreased extrapulmo-gan dysfunction [7], and decreased mortality

ny factors contribute to the development ofe type, duration and intensity of physicalgenerated by the ventilation (volume ande) as well as the cause, timing of lung injurye general progression of the disease, and aumber of trials reported the clinical efficacyrotective ventilatory strategy based on theon of tidal volume to 6ml/kg of ideal bodyand the limitation of end-inspiratory pres-30 cmH2O.

the ammightvolumeimagintomogrtionalwhichtime cument or tidal overdistension [18

&&

]. Of note, patientswith ARaggravacontrolwith A150mmHg, Papazian et al. [20] found that theadjustewho re48h thout anpreciseunclearserumneurom

5 Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.lth, Inc. All rights reserved.

d 90-day mortality was lower among thoseceived a neuromuscular blocking agent foran among those who received placebo, with-y increase in residual muscle weakness. Themechanism for the decreased mortality is[19] but a previous study showed reduced

cytokine levels among patients receiving auscular blocking agent [21].

www.co-criticalcare.com 21DS often fight the ventilator, and this mayte VILI [19]. In a recent multicenter, placeboled, randomized trial involving 340 patientsRDS and a PaO2 : FiO2 ratio of less thanuce injurious ventilation despite values ofpressure (Pplat) of 30 cmH2O or less [1113];pairment of chest wall mechanics compro-he ability of Pplat to reflect overdistension5].he present study, we will discuss the pros andthe different approaches proposed to min-ILI in patients with ARDS.

ECTIVE VENTILATORY STRATEGIES

nt approaches have been proposed to mini-ILI in patients with ARDS.

dal volume

ental and clinical data showed that aon of tidal volume reduced mortality inventilated patients [10,16,17] but contro-xists regarding the extent to which tidalshould be reduced to protect the lungs

ILI.ARDSnet study demonstrated that a 22%

on in mortality could be obtained by usingvolume of 6ml/kg predicted body weightinstead of 12ml/kg PBW [10]. But it is stillwhether the tidal volume should be strictlyml/kg PBW in all patients with ARDS, as theg strain will depend on the amount of venti-ssue rather than on PBW [11].development of tools for measurement of

ount of lung open to ventilation at bedsideallow for individual adjustment of tidal. These include promising noninvasiveg methods, such as electrical impedanceaphy and lung ultrasound, but also func-dynamic indexes, such as the stress index,describes the shape of the airway pressure-rve profile and may indicate tidal recruit-

lth

High positive end-expiratory pressure

Early trials comparing lower with higher levels ofpositive end-expiratory pressure (PEEP) in patientswith Abetweehypoxerecruitmtive venmore, ttrial destrategypressurnumbeorgansuggestpatientrecentsignificthe usePEEP in the subset of patients with PaO2:FiO2 lessthan 20with leto a pwhichthe mo

Recrui

Althouthat wabovestrategyretrieved from heart-beating donors [27], the roleof recremaineffect ocationsmotho

Prone

Proneways: fibutionlung, seare suthird,ing, thoxygen

Des[3134reductieven ifroutinebenefitoxygen

efficacy only in a selected category of very hypo-xemic patients lowering absolute mortality. Startingfrom these assumptions, Guerin et al. [39

&

] designedsptoioAvin5

lesoving%

-f

remomad

latory vr mionhilause aaygh

spulmonary pressure

S pinhomareas n

ioninalo

y sethbauniffurrminant of VILI [44].hestint008dctichexHin

Respiratory system

22 Copyright 2015 Wolters Kluwer Hea

ruitment maneuvers in clinical practices uncertain because of questions about itsn outcomes and concerns regarding compli-(e.g., hemodynamic compromise or pneu-

rax) [28].

position

positioning may mitigate VILI in three keyrst, by providing amore homogeneous distri-of transpulmonary pressure throughout thecond, by resting anterior lung units, whichbjected to the most overdistension, andby improving ventilation-perfusion match-ereby allowing for a decrease in the inspiredconcentration [29,30].pite this, four randomized clinical trials] have so far failed to demonstrate aon in mortality with its routine use in ARDSfour meta-analyses concluded that althoughprone position ventilation offers no survivalin patients with ARDS, it does improveation [3538]. One more demonstrated the

effusopennormareaslatorof thfromlatoraccothe dpressdete

Tadjupatiein 2founreduat suend-10 cmrema

www.co-criticalcare.com0mmHg. No such benefit was seen in thosess severe hypoxemias [25]. This adds weightrevious subgroup analysis of earlier trials,concluded that higher levels of PEEP benefitst-hypoxemic patients with ARDS [26].

tment maneuvers

gh such maneuvers were used in some trialsere included in the meta-analysis described[25] and were implemented in a protective

that increased the number of lungs

loweventwhicventto cacomairwin ri

Tran

ARDRDS found no difference in mortalityn the two groups. However, lower rates ofmia were observed when higher PEEP andentmaneuvers were combined with protec-tilation in an open lung strategy. Further-he results of a large randomized controlledmonstrated that an increased recruitment, wherein PEEP was used to reach a plateaue of 2830 cm H2O, resulted in a greaterr of ventilator-free days and days free offailure [2224]. There is some evidence tothat higher levels of PEEP may benefit

s with a greater degree of lung injury. Onemeta-analysis demonstrated a statisticallyant reduction in hospital mortality withof higher PEEP when compared with lower

a protrialpositwithreceileastwasimprtion32.8

High

Theominirand419, Inc. All rights reserved.

importance of transpulmonary pressure inng mechanical ventilation setting in ARDSs has even been studied by Talmor et al. [45]. In a randomized, single-center trial, theyan improvement in oxygenation and aon in 28-day mortality by setting the PEEPa level that transpulmonary pressure duringpiratory occlusion ranged between 0 and

2O and during end-inspiratory occlusioned lower than 25 cmH2O.

Volume 21 Number 1 February 2015atients are particularly prone to VILI due toogeneous parenchyma damage that presentsot aerated (with atelectasis, infiltrates, ors), areas with low ventilation in which theg-closing phenomenon is prevalent, areasly aerated without signs of stress, and lastlyverinflated. In this context, the best venti-trategy should be ideally adapted to the sizeaerated lung. It is hence necessary to movee selection of mode and setting of the venti-sed on a fixed set of numbers, to take intot the transpulmonary pressure [43

&&

], that is,erence between alveolar pressure and pleurale, which is considered by some as the mainective, multicenter, randomized controlledexplore whether early application of pronening would improve survival among patientsRDS who, at the time of enrollment, wereg mechanical ventilation with PEEP of atcmH2O and in whom the PaO2/FiO2 ratios than 150 mmHg. The trial confirmed theement in patient survival with prone posi-reducing the rate of 28-day mortality from

(supine group) to 16.0% (prone group) [39&

].

requency oscillatory ventilation

tically, this technique should be ideal forizing VILI [40]. In a meta-analysis of eightized, controlled trials involving a total ofults with ARDS [41], high-frequency oscil-entilation-treated patients had significantlyortality than did patients treated with con-al ventilation (risk ratio, 0.77; P0.03),suggested that high-frequency oscillatorytion might improve survival and is unlikelye harm. Unfortunately, these benefits usuallyt the expense of markedly increased meanpressures [42] and the potential deteriorationt heart function and organ perfusion.

ea

Different methods have been proposed in liter-ature to estimate transpulmonary pressure:

(1) PplPpl

(2) Ppl

Recently, Chiumello et al. [46] reported that thetwo mtranspumateddisconnpossibldue to

SUPESTRAT

Extracoas extraextracoprovide[47].Valast demore bMoreovtectivevolume

lth

generation ECCO2R devices, will improve clinicaloutcomes.

Ackno

None.

Financ

None.

Confli

V.M.R.at Hemand Far

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utsk3:1paz

spirarelam

ndroowepiraEngeadelumr acuntroercaultsndomiel Messundroattinuteasciganndomowetienntila:25pperfus94;mmprov0:1

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Novel approaches to minimize ventilator-induced lung injury Terragni et al.

1070-529 Copyright 2015 Wolters Kluwer H5 Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.lth, Inc. All rights reserved.www.co-criticalcare.com 25