Ventilator-Induced Lung Injury

14 Pages·2011·0.97 MB·English

by  Arthur S Slutsky

2004 Donald F Egan Memorial Lecture
Ventilator-Induced Lung Injury:
From Barotrauma to Biotrauma
Arthur S Slutsky MD
Introduction
Historical Review
Key Physiologic Concepts
Biotrauma
Systemic Consequences of Biotrauma
Clinical Relevance of Biotrauma
Implications of the Biotrauma Hypothesis for Novel Treatments of
Ventilated Patients
Summary and Concluding Remarks
Introduction search;thatis,takingimportantproblemsfromtheclin-
ical arena, examining these problems in the laboratory,
IamveryhonoredtohavebeenaskedtogivetheEgan and applying the new knowledge generated to develop
Lecture,especiallyasyouarecelebratingyourgoldenan- therapeutic approaches that are then tested in patients.
niversary Congress—50 years of international respiratory
(cid:127) And,third,I’msureyouallknowofarecentpublication,
care. Donald Egan was a remarkable man. Through his
theARDSNetpublication,showingthatventilationstrate-
vision, his hard work, and his textbook, he impacted re-
gies with low tidal volumes (V ) saves lives in patients
spiratory care in a major way throughout his life, and T
with acute respiratory distress syndrome (ARDS).1 The
posthumously. In preparation for this talk, I looked over
rationale underlying that study is based on our under-
the previous Egan lecturers and was very impressed with
standing of ventilator-induced lung injury (VILI).
theindividualswhohavegiventhislectureinthepast,and
I was very humbled. In these talks, you’ve heard about SowhatI’dliketodooverthenext45minutesorsois:
everythingfromthealveolustohyperoxiatothetopofMt
(cid:127) Give you a brief historical review, dating back a few
Everest. What I’m going to talk to you about today is
centuries,ofwherewe’vecomefrominmechanicalven-
ventilator-induced lung injury: from barotrauma to bio-
tilation and resuscitation
trauma. I chose this topic for a number of reasons:
(cid:127) Talkaboutcurrentconceptsofhowmechanicalventila-
(cid:127) First of all, it’s a major interest of mine.
tion can cause lung injury, and potentially can have
(cid:127) Second, I think it’s a terrific model of translational re- systemic effects, which are potentially very important,
and, finally
(cid:127) Discusshowtheseconceptsmayleadtochangesinther-
ArthurSSlutskyMDisaffiliatedwithStMichael’sHospitalandwiththe
InterdepartmentalDivisionofCriticalCareMedicine,UniversityofTo- apyaswelookforwardoverthenextdecadeorsointhe
ronto,Toronto,Ontario,Canada. care of our patients
ThisarticleisbasedonatranscriptoftheAnnualDonaldFEganMe-
Historical Review
morialLecture,deliveredatthe50thInternationalRespiratoryCongress
oftheAmericanAssociationforRespiratoryCare,heldDecember4–7,
2004,inNewOrleans,Louisiana. Let me start first with a brief historical review. This
reviewstartswithafamous16thcenturyphysiciannamed
Correspondence:ArthurSlutsky,StMichael’sHospital,30BondStreet,
AndreasVesalius.HewasaprofessorofanatomyinPadua
QueenWing4–042,Toronto,OntarioM5B1W8,Canada.E-mail:arthur.
[email protected]. at the age of 23. In 1555 he published a remarkable ana-
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tomical treatise called de Humani Corporis Fabrica. The
bookdescribedanexperimentVesaliushadperformedon
a pig. What Vesalius wrote was, “But that life may be
restoredtotheanimal,anopeningmustbeattemptedinthe
trunk of the trachea, into which a tube of reed or cane
shouldbeput.Youwillthenblowintothissothatthelung
may rise again and take air.” This description, written
almost500yearsago,describesessentiallywhatwedoin
the intensive care unit now. We do a tracheostomy, put a
tubein,andusemechanicalventilation.Althoughthiswas
one of the first examples of a modern-day approach to
ventilation, much of what Vesalius taught us was essen-
tially forgotten for a few hundred years.
Overthesubsequentfewcenturies,akeyissueaddressed
by physicians and other practitioners was how to resusci-
tate patients. It’s important to put this into context—re-
member,thiswasbackmanyyearsagobeforetheknowl-
edge of such fundamental concepts as oxygen, carbon
dioxide, and why we breathe. During this period it was Fig.1.Schematicdrawingofoneofthefirstbody-enclosingven-
thoughtthattoresuscitateapatient,strongstimulationwas tilators,patentedbyAlfredJonesin1864.(FromReference2.)
important. So they would roll patients over barrels and
ring loud bells near to patients’ ears. They would burn
patients with hot irons, shine bright lights in their eyes,
and (one of my favorites) throw patients on their abdo-
mensacrossatrottinghorse.And,finally,ifnoneofthese
worked, they would use the famous fumigator. I don’t
knowhowmanyofyouhaveheardaboutthisdevice,and
I’mnotsureinmixedcompanyIcanreallydescribeit.Let
me just say that they used cigarette smoke and blew it up
someplacesthatwillremainunmentioned.Iwon’ttellyou
the details, but let’s just say that if this had been used
widely, lung cancer wouldn’t be the major problem with
smoking—coloncancerwould!Now,Idon’tknowwhether
therewereanyrandomizedcontrolledtrialstoseewhether
Fig.2.Anexampleofonethefirstironlungs.Thisventilator,built
any of these approaches were effective, but my guess is
byDrWoillezin1876,hadametalrodthatrestedonthepatient’s
they were probably not tested in this way; pretty difficult chest,suchthatexcursionsoftherodprovidedanestimateofthe
to blind these studies in any event. patient’stidalvolume(CourtesyofJHEmersonCompany,Cam-
One of the first ventilators was patented in the late bridge,Massachusetts.Source:TheEvolutionofIronLungs:Res-
piratorsoftheBody-EncasingType.Cambridge,Massachusetts:
1800sbyAlfredJones.2Theventilatorwasabox,andthe
JHEmersonCompany.)
patient sat in this box with only his neck and head pro-
truding outside the ventilator (Fig. 1). There was a lever
whichincreasedthepressureintheboxwhenitwaspushed Alfred Woillez was one of the first individuals to de-
in;thisincreasedpressurecompressedthechestwallofthe velop a ventilator that was similar to “modern day” iron
patient, producing exhalation. Inhalation occurred when lungs(Fig.2).3Thisventilator,developedinthelate1800s,
the lever was withdrawn. The physiologic concepts on wastobeplacedalongthebanksoftheSeineriver,tobe
which this ventilator is based are very similar to current usedtosavepatientswhohaddrowned.Thebasicconcept
concepts. Now, this was more than just a ventilator—and underlyingthisventilatorissimilartowhatwetalkedabout
I guess this was in the days before the patent offices re- earlier—thatis,achangeinpressureintheventilatorcaused
quiredreproducibledata—because,inthispatentapplica- gas to move in and out of the patient’s lung. One inter-
tionAlfredJonessaidthatwiththisventilatorhehadcured estingfeatureoftheventilatorwasametalrodthatrested
“paralysis, neuralgia, rheumatism, seminal weakness, onthepatient’schest;excursionsofthisrodwerearough
asthma,bronchitis,anddyspepsia.Ihavecuredalsodeaf- indexofV .In1931JohnEmersondevelopedanironlung
T
ness. And...when judiciously applied, many other dis- thatwassimilartotheventilatordevelopedbyWoillezbut
eases may be cured.” had the addition of a motor.3 Although these iron lungs
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units, as it was much more efficient to take care of these
patients in one location.
Thankfully,polio,whichleadstoweaknessofthemus-
cles of respiration, has been eradicated (albeit not com-
pletely)andisnotamajordiseaseforwhichwecurrently
ventilatepatients.Now,thediseasethatweareconcerned
about most in terms of mechanical ventilation, or the dis-
ease that is probably most difficult for us in terms of
ventilation is ARDS. The syndrome is characterized by
leaky, stiff lungs and severe hypoxemia.5 Essentially, all
patientsrequiremechanicalventilationortheyaregoingto
Fig. 3. Mortality rate versus month of the year for patients with
die. It’s also a disease in which the pathology is one of
paralytic polio. At the end of August 1952, Lassen introduced
inflammation. And that becomes important because key
mechanicalventilationforthesepatients.Therewasanimmediate
dropinmortality,fromover80%toaround40%.(FromReference inflammatorymediatorsarepresentinthelungsofpatients
4,withpermission.) with ARDS. As I will show you later, this has some rel-
evance for VILI.
were able to ventilate patients, the key problem was how Fromanepidemiologicalpointofview,themortalityof
tonursepatients,sinceitwasveryhardtogetaccesstothe ARDSisveryhigh—ontheorderof35–60%,depending
patient. onanumberoffactors,includingageandthepredisposing
There was an interesting solution to this problem: the factor that led to the development of ARDS. But what’s
development of a ventilation room. Essentially the iron veryinterestingisthefactthatmostpatientswhodiewith
lungwasincreasedin size untilitwas thesizeofaroom. ARDS don’t die of hypoxemia; they die of multiple-sys-
Thepatientwasplacedwithhisbody,fromtheneckdown, temorganfailure.Thishasbeenapuzzleforcliniciansfor
inaroom;thepatient’sheadwasoutsidetheroom.There alongtime.Whyshouldpatientswhohaveadiseasethat
were very large pistons in the room, and these pistons looks like it largely affects the lungs die of renal failure
caused pressure changes in the room, which moved gas and hepatic failure? The hypothesis I’ll develop is that
into and out of the lungs of the patient. The “ventilator mechanical ventilation, which is clearly life-saving, may
room” had a door, and the medical staff could come in to actuallycontributetothedevelopmentofmultiple-system
take care of the patient; it was easy to nurse the patients organ failure.
from within the ventilator.
Now, one of my favorite ventilators is one that was Key Physiologic Concepts
developed in the mid-20th century. It was also a body-
enclosing device, which looked a little bit like an accor- Now, before getting into the specifics of VILI, I think
dion. The patient stood in the ventilator (with his head it’susefultodevelopsomekeyphysiologicconcepts.The
outside the ventilator) and manually pulled a lever, caus- first concept is that ARDS is a heterogeneous disease.
ingpressurechangesintheventilatorwhichcausedgasto Until the mid-1980s, based on routine chest radiographs,
moveintoandoutofthepatient’slungs.Forthoseofyou wethoughtthatthelunginjuryinpatientswithARDSwas
who are interested in the work of breathing, with this relatively homogeneous. But studies using computed to-
ventilator the muscles of respiration would have been the mography scans (Fig. 4) showed us that ARDS was a
biceps and triceps. heterogeneous disease.6 The nondependent regions of the
Themoderneraofmechanicalventilationandintensive lungarerelativelywellaerated;thedependentregionsare
care began during the polio epidemic. In 1953 Lassen collapsedandfilledwithfluid.Positiveend-expiratorypres-
published a classic paper on the use of mechanical venti- sure(PEEP)isabletorecruitsomeofthelung,butnotall.
lation in patients with paralytic polio.4 Lassen knew that The concept that there is only a small part of the lung
themortalityratefromparalyticpoliowasextremelyhigh— availableforventilationisrelevanttoourconceptofVILI,
over 80%—and he realized that patients were dying of sinceaV thatmaybefineforventilationofanormallung
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respiratory failure. So, in August 1953 he instituted me- may cause regional overdistention of parts of the lung
chanicalventilationforthesepatients.Asyoucanseefrom when only a small part of the lung is available for venti-
Figure3,mortalitydroppedvirtuallyinstantlytolessthan lation.
halfwiththeinstitutionofmechanicalventilation.Justby Now, what does a lung like this look like when you
applyingmechanicalventilationhewasabletosavethou- inflateit?Figure5isacompositeofpicturespublishedin
sandsoflivesfrompolio.Andthisledtowardscontaining The Handbook of Physiology over 40 years ago.7 It’s a
iron lungs that were used to ventilate patients with para- picture of excised cat lungs as they are being inflated,
lytic polio. This was the start of modern intensive care alongwiththecorrespondingpressure-volumecurve.The
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Fig.4.Singleslicefromacomputedtomographyscanofapatientwithacuterespiratorydistresssyndrome(ARDS)obtainedatapositive
end-expiratorypressure(PEEP)of5cmH O(left)andaPEEPof15cmH O(right).Notetheinhomogeneousdistributionofabnormalities,
2 2
withconsolidation,atelectasis,andfluidinthedependentlungzones,andrelativelywell-aeratedlunginthenondependentzones.Notethat
increasinglevelsofPEEPrecruitedpartsofthelung.(FromReference6,withpermission.)
Fig.5.Upperpanel:Pressure-volumecurveofanexcisedcatlung.Thebottompanelsrepresentphotographstakenateachpressurelevel
duringinflationanddeflation.Notethemarkedhysteresis,withmuchgreaterinflationandmorehomogeneousinflationonthedeflationlimb.
Alsonotethatrecruitmentcontinuesalongtheinflationlimbofthepressure-volumecurveaspressureincreasesabovethelowerinflection
point.(AdaptedfromReference7,withpermission.)
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Fig.6.Stillimagesobtainedfromaratlungbeingventilatedat0andthenat15cmH Opositiveend-expiratorypressure(PEEP).Thetop
2
4 images were obtained at end-expiration (exp), and the bottom 4 images were obtained at end-inspiration (insp). Note the areas of
atelectasis,evenatend-inspiration,otherthanafterthe5thbreathataPEEPof15cmH O.Fullrecruitmentofthelungstookanumber
2
ofbreaths,evenafterPEEPwasincreasedto15cmH O.Atend-inspirationfollowingthefirstbreathatPEEP15cmH Otherearestillmany
2 2
areasofatelectasis.Itwasnotuntilthe5thbreaththattheseatelectaticareaswerefullyrecruited.AfterPEEPwasreturnedtozero,the
inhomogeneity and areas of atelectasis returned within a couple of breaths. ZEEP (cid:1) zero end-expiratory pressure. EXP (cid:1) expiration.
INSP(cid:1)inspiration.
heterogeneity of lung inflation is clear. At the lower in- look like dynamically during ventilation? Figure 6 pre-
flectionpointofthepressure-volumecurve,thelungstarts sents some still pictures from a video of a rat lung that
toopenandthepressure-volumerelationshipbecomesvery is being ventilated ex vivo. As the lung is being venti-
steep.Thelungiscertainlynotfullyrecruitedatthispoint, latedatzeroPEEP,thereareareasofcollapse,andfully
or even at a few cm H O above the inflection point. As inflated areas at end-inspiration. Figure 6B represents
2
pressureincreases,thelungstartstolookrelativelyhomo- what happens as we increase PEEP to 15 cm H O, with
2
geneous, and as pressure is further increased, there is an recruitmentstartingtooccur.Butrecruitmenttakessome
upper inflection point, and the lung is fully recruited. time, and the lung is fully recruited only after a few
On the descending limb (deflation), the lung is quite breaths (see Fig. 6C). In fact, at end-inspiration, the
wellinflatedatallthesepressures.Thedifferencebetween lunglookslikeitmaybesomewhatover-inflated.When
the inflation on inspiration and expiration is termed hys- the PEEP level is subsequently decreased to zero, areas
teresis. So when one looks at a pressure-volume curve in ofcollapsestarttoappearagain,butonlyafteracouple
atextbookoratthebedside,Ithinkthatitisusefultothink of breaths. So what this tells us is that, in terms of
aboutwhatthelungactuallylookslike.Andthistellsusa recruitment,onehastomaintainarelativelyhighPEEP
coupleofthings.Firstofall,ontheinflationlimbwhenthe level if one wants to maintain the benefits of a recruit-
lung is above the inflection point does not necessarily ment maneuver. The major idea I want to get across
mean that the lung is fully recruited. The second point is here is what the lungs look like as they are being ven-
that as the lung is inflated and deflated from a relatively tilated, because, in terms of VILI, what we want to do
low pressure to a higher pressure, recruitment/derecruit- ispreventthisopeningandclosingoflungunits,andto
ment can occur. prevent the over-distention that occurs.
Now, this figure represents the static, or at least qua- Now,thefinalphysiologicconceptIwanttoexploreis
si-static properties of the lung; but what does the lung that lung distention, not airway pressures, is the critical
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Fig. 8. Pressure-volume curve of the lung, demonstrating 2 re-
gionsthatarethoughttobeassociatedwithincreasedventilator-
inducedlunginjury.Atrelativelyhighpressures,barotraumaand
volutrauma can occur, leading to gross air leaks and increased
alveolarcapillarypermeability.Whenlungsareventilatedatrela-
tively low volumes, atelectrauma can occur. With opening and
closing of lung regions, lung injury can occur due to hypoxia,
Fig.7.Plotoflungvolumeversuspressureasmusiciansplaythe effectsonsurfactant,andtherepetitiveopeningandclosingofthe
oboe, flute, or trumpet. Note that the pressure reached by the lungunits.
trumpet player is 150 cm H O. (From Reference 8, with permis-
2
sion.)
most of the pressure is dissipated in distending the chest
wall. The lung is not necessarily being over-distended.
variabledrivingVILI.Whatweoftenmeasureatthebed- So,giventhatbackground,whatarethephysicalfactors
side is pressure—either peak pressure or plateau pres- causing VILI? Well, there’s a process that we’ve called
sure—but really what’s important in terms of VILI is re- atelectrauma,9 collapse and reopening of lung units lead-
gional inflation, not airway pressures per se. High airway ingtolunginjury(Fig.8).Thereisbarotrauma,andthere
pressures do not necessarily mean that the lung is being isvolutrauma,10atermcoinedbyDreyfusstoindicatethat
subjectedtoaninjuriousventilatorypattern.Thiswaswell it’snotthepressureattheairwayopeningthat’simportant,
documented in an interesting study by Bouhuys in 1969.8 it’s the distention of the lung that’s important in causing
His interest was not mechanical ventilation; he was inter- lung injury.
ested in the physiology associated with playing musical Now, this concept of barotrauma is, in fact, not a new
instruments. Figure 7 is a graph of lung volume versus one. And I’ll go back again to the history of mechanical
pressure from Bouhuys’s study. When a musician plays ventilation and tell you about an interesting case report
theoboe,pressuresareabout25cmH O,andlungvolume thatappearedinthePhilosophicalTransactionsoftheRoyal
2
decreases relatively slowly over 30 seconds. When a mu- Society of Medicine in 1745.11 This article described the
sician plays the trumpet, pressures at the airway opening case of a patient who was revived by a physician by the
areabout150cmH O!;thetrumpetplayerblowsforonly nameofTossack.Tossackdiscoveredamanwho“...had
2
about5seconds,andthereisarapiddropinlungvolume. suffocated because of fumes from a coal pit.” The patient
Trumpetplayersgeneratethesehighpressureshundredsor was unconscious, not breathing, and pulseless. Tossack
even thousands of times a day, but they don’t get baro- resuscitated this patient by “applying his mouth close to
trauma; they don’t get VILI. the patient’s and, by blowing strongly, raised his chest
The reason is that it’s not the airway pressure per se fully. He immediately felt 6 or 7 quick beats of the heart.
that’s important; what’s important is lung stretch or the In one hour, the patient began to come to himself. In 4
transpulmonarypressure—thepressureacrossthelung(air- hours,hereturnedhomeand,inasmanydays,returnedto
way pressure minus pleural pressure). And, for a trumpet work.” What was interesting was the discussion of this
player to generate such high airway pressures, he has to paper.Remember,thiswasapaperthatwaspublishedover
contracthisrespiratorymusclestogenerateahighpleural 250 years ago. What the author stated was that, in terms of
pressure, so the transpulmonary pressure (alveolar minus resuscitation (bracketed interjections mine), “a number of
pleural)isnotincreased.Sothefinalimportantconceptis individuals had suggested using a bellows to ventilate the
that lung distention, not airway pressure, is the critical patient”[similartoamechanicalventilator]....Butblow-
determinant in generating VILI. That has very important ingwouldbepreferable,[ie,mouth-to-mouthresuscitation
clinicalimplicationsinpatientswhohavestiffchestwalls would be preferable] as the lungs of one man may bear,
(eg,patientswithmassiveascites).Inthesesituations,peak without injury, as great a force as those of another man
airway pressure and plateau pressures may be high, but which by the bellows cannot always be determined.“ I
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think this is exactly the general concept we think about
whenwecontemplateVILIorbarotrauma.Highpressures
generated by a ventilator with subsequent over-expansion
ofthelungscanleadtoinjury.Andtheyrealizedover250
years ago that mouth-to-mouth resuscitation would limit
the pressures and hence limit the lung distention.
Biotrauma
WhatI’dliketofocusonnowisatypeofinjurythatis
Fig.9.Leftpanel:Schematicdiagramoftidalvolumeandpositive
relativelynew,thatcertainlywasn’tcontemplatedacouple
end-expiratory pressure (PEEP) levels used in the ex vivo venti-
hundred years ago—the concept of biotrauma, a term we latedlungmodel.Therightpaneldemonstratesthevaluesoftu-
coined to describe biochemical injury or release of medi- mornecrosisfactoralpha(TNF(cid:1))versusthe4differentventilatory
atorsthatcanbeassociatedwithmechanicalventilation.12 strategiesshownintheleftpanel.Notethatthereisabreakinthe
axisatTNF-(cid:1)valueofabout250pg/mL.C(cid:1)control.MVHP(cid:1)
We got interested in this topic about 10 years ago. Our
mediumvolume,highPEEP.MVZP(cid:1)mediumvolume,zeroPEEP.
hypothesiswasthatinjuriousventilatorystrategies—those HVZP(cid:1)highvolume,zeroPEEP.(FromReference13,withper-
strategiesthatalloweitherrepeatedrecruitment/derecruit- mission.)
mentofthelungand/oroverdistentionofthelung—could
lead to a release of inflammatory mediators, such as cy-
tokines. In our first set of studies, we used an isolated rat found in the bronchoalveolar lavage fluid (BALF). With
lung model. The movie I showed you a few minutes ago the medium-volume high-PEEP group there was a dou-
was of this model. The reason we used this model was bling or tripling of TNF-alpha, with a further doubling of
because it allowed us to use relatively large volumes that TNF-alpha when we used 0 PEEP and V 15 mL/kg.
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couldmimictheregionaloverdistentionthatoccursinpa- Finally,withrecruitment/derecruitment(0PEEP)andover-
tients(thinkbacktothatcomputedtomographyscanofthe distention(40mL/kg),therewasa50–60foldincreasein
patient with ARDS) (Fig. 4), without affecting hemody- TNF-alpha, compared to control.
namics.Thiswasimportantbecauseifoneusesveryhigh So,just2hoursofventilationisabletocausereleaseof
volumes in an in vivo situation, severe hypotension can mediators that we know from other studies are important
occur;thisbyitselfcouldpotentiallyleadtoanincreasein in sepsis and are critical in terms of organ dysfunction.
mediators,whichmaynotbestrictlyduetothemechanical Wheredothesecytokinescomefrom?Weobtaineddataa
forces on the lung. few years ago suggesting that the cytokines, to some ex-
Wetookthelungs,ventilatedthemfor2hours,andused tent or maybe to a large extent, come from the epithelial
4 different ventilatory strategies.13 One strategy, which surface of the lung.14 Remember, the epithelial surface
was the control, consisted of a relatively low level of areaofthelungishuge.Thecross-sectionalareaisthesize
PEEP (3 cm H O) and a V of 7 mL/kg—a relatively of a tennis court and, if each one of the epithelial lining
2 T
small V . The second group had a PEEP of 10 cm H O cellsproducesalittlebitofTNF-alphaorothercytokines,
T 2
andV of15mL/kg.Thethirdgrouphad0PEEPandV suchasinterleukin6(IL-6),thetotalcanbequitesubstan-
T T
of 15 mL/kg, and the final group had 0 PEEP and a very tial. Figure 10 represents in situ hybridization for TNF-
large V of 40 mL/kg, such that the end-inspiratory ex- alpha, which looks at message levels of TNF-alpha. We
T
pansionwasroughlythesameingroups2and4.Now,you also looked at the protein level within cells, using immu-
mightlookatthislastV andsay,“Well,that’sridiculous. nohistochemistry(seeFig.10B).Andinbothcasesitwas
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We would never use a V of 40 mL/kg in our patients,” the epithelial lining that lit up markedly, demonstrating
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and that’s certainly true. However, some patients have that these cells were producing the cytokines. Other stud-
such bad disease that only about a quarter of their lung is ies have addressed this issue, but I don’t have time to
availableforventilation(worsethanthepatientinFig.4). discuss them. Most, but not all, studies are supportive of
So, if a V of 10 mL/kg is applied to that patient, the thisconceptthatinjuriousventilatorystrategiescanleadto
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regional overdistention in the quarter of the lung that’s release of mediators.
open is equivalent to the distention that would occur in a
normal lung ventilated with 40 mL/kg. Systemic Consequences of Biotrauma
At the end of 2 hours of ventilation, we measured a
number of things, including concentrations of tumor ne- I’m not going to talk any more specifically about the
crosisfactoralpha(TNF-alpha).Thisisakeycytokinethat lung. I’d like to now focus on what I think may be more
is a central mediator in the sepsis cascade. As shown in importantintermsoftheoutcomesofourpatients—thatis
Figure9,undercontrolconditionsverylittleTNF-alphais the systemic consequences of biotrauma. It’s not just the
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Fig.10.Left:Dark-fieldimageofinsituhybridizationfortumornecrosisfactoralpha(TNF-alpha)messengerribonucleicacid(mRNA)with
aventilatorystrategyusingmediumvolumesandzeropositiveend-expiratorypressure(PEEP).Thewhitedenotescellsthatarepositive
forTNF-alpha.NotethatthemessagelevelsofTNF-alphaappearstobelargelyinepithelialcells.Right:Immunohistochemicalstainingfor
TNF-alphaproteininthelungsventilatedwiththemediumtidalvolumeandazero-PEEPstrategy.NotethattheTNF-alphaprotein(reddish
color)appearslocalizedlargelytothealveolarepithelium.(FromReference14,withpermission.)
release of mediators in the lung. If these mediators can
translocate from the lung and get into the systemic circu-
lation, they can potentially cause damage to other end
organs.15
The lung is unique in that virtually all of the systemic
blood flow traverses the lung. It has a huge vascular bed
andmanyneutrophilsmarginateorstickinthelung,wait-
ing to be activated. It also has a huge surface area that is
open to the environment and can be a portal of entry of
manypathogens,suchasbacteria.Thelungisalsoamet-
abolically active organ. As I showed you, the epithelium
producesTNF-alphaandIL-6,aswellasothersubstances,
Fig.11.Leftpanel:Fourventilatorystrategieswereusedtoven-
andsodoestheendothelium.Ifthesecellsproducemedi- tilateratsfollowingintratrachealacidaspiration:HVZP(cid:1)highvol-
ators that then are released into the systemic circulation, ume, zero positive end-expiratory pressure (PEEP); HVP (cid:1) high
that can potentially cause problems. volume, 5 cm H O PEEP; LVZP (cid:1) low volume, zero PEEP; and
2
We examined the hypothesis that ventilatory strategy LVP (cid:1) low volume, 5 cm H2O PEEP. Tidal volume (VT) was 16
mL/kg.Rightpanel:Serumlevelsoftumornecrosisfactoralpha
could lead to the release of cytokines from the lung into
(TNF-(cid:1)) versus time for the different ventilatory strategies. Note
the systemic circulation. We used an in vivo model of themarkedincreaseinTNF-(cid:1)withtimeinthestrategywithhigh
acutelunginjury,inwhichintra-trachealacidwasinjected volumeandzeroPEEP.(FromReference16,withpermission.)
into rats.16 This is a pretty good model of what occurs in
patientswhoaspirate—notanuncommoncauseofARDS.
We then ventilated these animals with 4 different ventila- only the lung, but could possibly impact other organs by
tory strategies: V 16 mL/kg, 0 PEEP; V 16 mL/kg, release of various mediators into the circulation.
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PEEP 5 cm H O; and then a small V 5 mL/kg without Wewereinterestedinstudyingthemechanismsbywhich
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and with PEEP. And then, in addition to measuring lung mediator release could lead to organ dysfunction in other
lavagecytokines,wemeasuredserumcytokines.Figure11 organs. Last year we published an article in JAMA,17 in a
isagraphofserumTNF-alphaversustime.Inmostgroups new section called “Translational Medical Research.”18
there is very little change in TNF-alpha over time. But in Weusedtheacidaspirationmodelinanesthetizedrabbits.
one group (large V , zero PEEP) there was a marked The animals were then randomized and ventilated for 8
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increaseinTNF-alpha.Interestingly,PEEPwasprotective hours. One group received an injurious ventilatory strat-
inthismodel:withPEEPinthelarge-V grouptherewas egy, with high V and 0 PEEP; other animals received a
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no large increase in serum levels of TNF-alpha. So this relativelynoninjuriousventilatorystrategy,withrelatively
study showed that mechanical ventilation can impact not lowV andhigherPEEPlevels.Wemeasuredanumberof
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VENTILATOR-INDUCED LUNG INJURY: FROM BAROTRAUMA TO BIOTRAUMA
injuriousgrouphadamuchhigherapoptoticindexinkid-
ney and the villi of the gut in the animals ventilated with
the injurious strategy.
To summarize, cells in the kidney are dying from apo-
ptosisinthegroupventilatedwiththeinjuriousventilatory
strategy.Idon’thavetimetogiveyoudetailshere,butin
thisstudywealsosuggestedthatitwasFasligandthatwas
important. We took serum from the rabbits and applied
thisserumtocellcultureandshowedthatwecouldblock
Fas ligand and could block the increased apoptosis.
Clinical Relevance of Biotrauma
Atthispointyoumightbesayingtoyourself,“Well,all
this is very nice, but in my intensive care unit we don’t
Fig. 12. Plot of soluble Fas ligand (sFasL) in patients with acute
ventilate rats. We don’t ventilate rabbits. We take care of
respiratory distress syndrome who went on to live or die. (From
Reference19,withpermission.) humans.” So does any of this have any relevance at the
bedsidetoourpatients?Isthisofanyrelevancetopatients
with ARDS? Well, I think that there are increasing data
factors, including hemodynamics, enzymes, and blood suggesting that these concepts do have clinical relevance.
gases,butwefocusedonsomethingcalledapoptosisusing About5yearsago,incollaborationwithMarcoRanieri,
TUNEL (terminal deoxyribonucleotidyl transferase-medi- we published a paper in JAMA in which we performed a
ateddeoxyuridine5-triphosphate-digoxigeninnickendla- randomized controlled trial in patients with ARDS, com-
beling) assay, and electron microscopy. paring a minimal-stress ventilatory strategy to a conven-
Now I’m going to take a bit of a tangent to tell you a tionalventilationstrategy,andmeasuredcytokinesinthese
littlebitaboutapoptosis,becauseIknowthatthat’ssome- patients.21SomeresultsareshowninFigure14.Thegroup
thingthatmanyofyoumaynotbefamiliarwith.Cellscan treated with the minimal-stress ventilatory strategy had
die in a couple of ways. They can die by necrosis, with a markedly lower BALF cytokines, and lower serum cyto-
breakdown of the cell’s plasma membrane and release of kines at 24 and 36 hours, compared to the conventional
thecell’scontents—aprocessthatcausesaninflammatory group.Thesedataareveryreminiscentoftheanimaldata
reaction.Theotherwaythatcellscandieisbyapoptosis— thatIshowedyouearlier,demonstratingthataventilatory
alsoknownasprogrammedcelldeath.Thisanorderlyway strategythatminimizedVILIwasassociatedwithdecreased
for cells to die. Key mediators here are caspases, which cytokine concentrations. In fact, ventilatory strategy can
canbetriggeredbychemicalsorsubstancescalledFasand impact cytokine levels within a very short time frame.
Fas ligand. Figure 15 is from a study by Stuber et al, in which they
Well,areapoptosisandFasimportantinARDS?Figure ventilatedpatientswithARDSwithalung-protectivestrat-
12 presents data from a group in Seattle, which suggest egy for a period of time, then changed to a lower PEEP/
thattheymaybeimportant.PatientswithARDSwhowent higher-V strategy for a few hours.22 When the more in-
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ontolivehadlowerlevelsofsolubleFasligandthanthose jurious strategy was used, there was an increase in
who died.19 It certainly doesn’t prove that this is an im- concentrationofcytokines;thisoccurredwithinanhourof
portant molecule in ARDS, but it certainly indicates that changingventilatorystrategy.Whentheychangedbackto
thereissomerelationshipbetweensolubleFasligandand thelung-protectivestrategy,therewasarapiddecreasein
clinicaloutcomes.Otherstudiesfromthisgrouphaveshown these cytokines. The fact that these mediators can be re-
thattheBALFfromARDSpatientstriggersapoptosis,and leased relatively quickly after a change in strategy brings
theapoptosiscanbeblockedbymoleculesthatblockFas.20 up an interesting possibility. Maybe we can use some of
Nowlet’sgetbacktoouranimalstudy.Bloodpressure these markers to decide when we have optimized ventila-
was identical for the injurious group and the noninjurious torystrategyinapatientwithARDS.Perhapsinthefuture
groups, so what I’m going to show you here in terms of we will titrate ventilatory strategy to serum mediator re-
kidneyfunction,intermsofkidneyapoptosis,isnotdueto lease.
changesinbloodpressure.Figure13presentstheresultsof Other evidence suggesting that these concepts may be
a TUNEL assay in kidney and gut from animals in the relevant to patients is based on the results from the
injurious and noninjurious groups. The apoptotic-positive ARDSNet study I mentioned previously, which demon-
cellsarestainedyellow-green.Theresultsinthe2groups strated a 22% relative decrease in mortality in the group
werequantifiedinablindedfashion(rightofFig.13);the treatedwithaV of6mL/kgpredictedbodyweight,ver-
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654 RESPIRATORY CARE•MAY 2005 VOL 50 NO 5
VENTILATOR-INDUCED LUNG INJURY: FROM BAROTRAUMA TO BIOTRAUMA
Fig. 13. Left: Terminal deoxyribonucleotidyl transferase-mediated deoxyuridine 5-triphosphate-digoxigenin nick end labeling (TUNEL)
stainingofkidneyandsmallintestinefromrabbitsventilatedwithanoninjuriousstrategy(lowtidalvolume,relativelyhighpositiveend-
expiratorypressure[PEEP])andaninjuriousventilatorystrategy(largetidalvolume,zeroPEEP).NotethatthereweremanymoreTUNEL
positivecells(indicatedbythearrows)inthekidneyandinthevilliofthesmallintestineintheinjuriousventilatorystrategy.Right:The
apoptoticindexwascalculatedforeachoftheorgansshownontheleft,aswellasthelung.Therewasdecreasedapoptosisinthelungs
ofanimalsventilatedwiththeinjuriousventilatorystrategy,butanincreaseinapoptosisinthekidneyandthevilli.(FromReference17,with
permission.)
sus 12 mL/kg.1 We don’t know the mechanism for the I say that is the tremendous spatial heterogeneity of the
decreasedmortalityinthesmaller-V group,butitwasnot lung disease that exists in patients with ARDS. Figure 16
T
duetoreducedbarotrauma,astheincidenceofbarotrauma is taken from a study by Gattinoni et al.24 The X axis is
wasessentiallyidenticalinbothgroups.Itwasnotdueto PEEPlevel,andtheYaxisrepresentsgastissueratio.The
differences in oxygenation; in fact, the lower-V group, upperpanelrepresentsthenondependentregion;thelower
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which had the better survival, had lower P /fraction of panelisthedependentregion;andthemiddlepanelisthe
aO
2
inspiredoxygenratiosforthefirstcoupleofdaysthandid mid-lung region. If one were to set the PEEP level to
thehigher-V group.TheARDSNetinvestigatorssuggested minimize VILI and optimize oxygenation for the middle
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that this difference in mortality may be related to differ- region, one might pick a value of PEEP somewhat above
encesinmediatorrelease;levelsofIL-6decreasedsignif- the inflection point—about 16 or 18 cm H O. This might
2
icantly more quickly over time in the lower-V group.1,23 beadequateforthisregion,butifoneexamineswhatthis
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So maybe the biotrauma hypothesis explains the decrease wouldmeanfortheother2regions,onecanseetheprob-
in mortality in this study. lem. For the dependent region the lung is essentially still
collapsed. Examination of the nondependent region sug-
Implications of the Biotrauma Hypothesis for Novel geststhatthislevelofPEEPmightleadtoover-distention
Treatments of Ventilated Patients of this portion of the lung. So, based on these and other
data, I think in some patients it will not be possible to
Does the biotrauma hypothesis suggest any novel non- develop a ventilatory strategy that is noninjurious in all
ventilatoryapproachestomitigateVILI?Areasonablefirst lungregions.Thereareotherapproachesthansimplychang-
question to ask is, why do we need novel nonventilatory ingPEEP,butwhetheroneusesthepronepositionoruses
therapies? One could argue that we have the ARDSNet high frequency or whatever, in patients with very severe
studythatdemonstratedadecreaseinmortality.Let’sjust ARDS, VILI will still occur in some lung regions.
optimize the ventilatory strategy and we won’t need any- So in these patients with severe lung injury we might
thing else. In fact, this would be ideal, but the problem is think about targeting mediators, since the patients are dy-
that it’s going to be difficult to obtain a completely non- ing of multiple-system organ failure, perhaps due to a
injurious ventilatory strategy in every patient. The reason release of mediators. Could this approach be effective?
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