intraoperative protective mechanical ventilation for...

Copyright © 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Anesthesiology, V 123 • No 3 692 September 2015

P OSTOPERATIVE pulmonary complications (PPCs) can have an important impact on the morbidity and

mortality of patients who need major surgery.1 Approxi-mately 5% of patients undergoing general surgery will develop a PPC, and one of the five patients who developed a PPC will die within 30 days of surgery.1 Furthermore, the number of PPCs is strongly associated with postoperative length of stay and short-term and long-term mortality.1,2

There is growing evidence that intraoperative lung- protective mechanical ventilation using low tidal volumes, with or without high levels of positive end-expiratory pressure

(PEEP), and recruitment maneuvers prevents PPCs com-pared with mechanical ventilation with high tidal volumes and low levels of PEEP without recruitment maneuvers.3–6

In the current article, we review the definition of and methods to predict PPCs, the pathophysiology of ventilator-induced lung injury (VILI) with emphasis on the noninjured lung, and ventilation strategies to minimize PPCs. To identify the most recent evidence from the literature on randomized controlled trials (RCTs) addressing intraoperative mechani-cal ventilation and nonclinical as well as clinical postopera-tive outcome measures, we conducted a MEDLINE review

Copyright © 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2015; 123:692–713

ABSTRACT

Postoperative pulmonary complications are associated with increased morbidity, length of hospital stay, and mortality after major surgery. Intraoperative lung-protective mechanical ventilation has the potential to reduce the incidence of postopera-tive pulmonary complications. This review discusses the relevant literature on definition and methods to predict the occur-rence of postoperative pulmonary complication, the pathophysiology of ventilator-induced lung injury with emphasis on the noninjured lung, and protective ventilation strategies, including the respective roles of tidal volumes, positive end-expiratory pressure, and recruitment maneuvers. The authors propose an algorithm for protective intraoperative mechanical ventilation based on evidence from recent randomized controlled trials. (Anesthesiology 2015; 123:692-713)

This article is featured in “This Month in Anesthesiology,” page 1A. Corresponding article on page 501. Figures 1, 3, and 7 were enhanced by Annemarie B. Johnson, C.M.I., Medical Illustrator, Vivo Visuals, Winston-Salem, North Carolina. The first three authors contributed equally to this article.

Submitted for publication September 4, 2014. Accepted for publication January 31, 2015. From the Department of Anesthesiology and Intensive Care Medicine, Pulmonary Engineering Group, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany (A.G., T.K., P.M.S., M.G.d.A.); Program of Post-Graduation, Research and Innovation; Faculdade de Medicina do ABC (FMABC), and Department of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil (A.S.N.); Department of Intensive Care Medicine and the Laboratory for Experimental Intensive Care and Anesthesiology, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands (S.N.T.H., M.J.S.); Department of Anesthesiology and Postoperative Care Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain ( J.C.); Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (P.R.M.R.); and IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) AOU (Azienda Ospedaliera Universitaria) San Martino IST (Istituto Tumori) Hospital, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy (P.P.). All authors are members of the Protective Ventilation Network (PROVEnet, www.provenet.eu).

David S. Warner, M.D., Editor

Intraoperative Protective Mechanical Ventilation for Prevention of Postoperative Pulmonary Complications

A Comprehensive Review of the Role of Tidal Volume, Positive End-expiratory Pressure, and Lung Recruitment Maneuvers

Andreas Güldner, M.D., Thomas Kiss, M.D., Ary Serpa Neto, M.D., M.Sc., Ph.D., Sabrine N. T. Hemmes, M.D., Jaume Canet, M.D., Ph.D., Peter M. Spieth, M.D., Patricia R. M. Rocco, M.D., Ph.D., Marcus J. Schultz, M.D., Ph.D., Paolo Pelosi, M.D., F.E.R.S., Marcelo Gama de Abreu, M.D., M.Sc., Ph.D., D.E.S.A.

This article has been selected for the Anesthesiology CME Program. Learning objectives and disclosure and ordering information can be found in the CME section at the front of this issue.

ReVIew ARTICle

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Anesthesiology 2015; 123:692-713 693 Güldner et al.

EDUCATION

using the following search terms: “lower tidal volume” OR “low tidal volume” OR “protective ventilation” OR “recruit-ment maneuvers” OR “PEEP” OR “positive end expiratory pressure.” Retrieved articles, and cross-referenced studies from those articles, were screened for pertinent information.

Definition and Prediction of PPCs

Summary of Current DefinitionsPostoperative pulmonary complications are usually pre-sented as a composite, which then includes possible fatal and nonfatal respiratory events of new onset occurring in the postoperative period. Currently, there is no agreement about which of these events should be considered as PPC, for example, respiratory failure, lung injury, pneumonia, prolonged or unplanned mechanical ventilation or intuba-tion, hypoxemia, atelectasis, bronchospasm, pleural effu-sion, pneumothorax, ventilatory depression, and aspiration pneumonitis.7,8 From a clinical standpoint, it is worthwhile to present PPCs as a composite because any of these events alone or their associations has a significant impact on the postoperative outcome,1 using different definitions. How-ever, it is clear that these events can have different patho-physiologic mechanisms. For this reason, some studies have focused on single events, mainly respiratory failure9 and pneumonia.10

Postoperative pulmonary complications, to be considered as such, must be related to anesthesia and/or surgery. Fur-thermore, the time frame must be well defined. Usually, an event is only considered as PPC if it develops within 5 to 7 days after surgery.8,11

Prediction of PPCsPrediction of PPCs, or any of the single postoperative respi-ratory events that is part of that composite, can be useful to plan perioperative strategies aiming at their prevention and also to reduce health system costs.12 First, the risk factors

associated with the development of PPCs must be identified. In 2006, the American College of Physicians published a sys-tematic review of the literature listing a number of risk factors for PPCs according to their respective levels of evidence.13 In recent years, that list has been expanded to include other fac-tors found to increase the risk of PPCs. Table 1 depicts the risk factors associated with PPCs according to the current literature. Approximately 50% of the risk factors for PPCs are attributable to the patient’s health conditions, whereas the other 50% are related to the surgical procedure and the anesthetic management itself.1

Based on risk factors, different scores have been devel-oped that have the potential to predict the occurrence of PPCs,6,14–16 as shown in table 2. However, their applicability may be limited because they were derived from restricted settings,16 retrospective databases,15 or only validated for specific PPCs.6,14 The Assess Respiratory RIsk in Surgical Patients in CATalonia (ARISCAT) study was conducted in a general surgical population of Catalonia, Spain.1 After a multivariate analysis, a score based on seven risk factors was developed and underwent internal validation, showing a clinically relevant predictive capability (c-statistic, 0.90). Recently, the ARISCAT score was externally validated in a large European surgical sample (the Prospective Evaluation of a RIsk Score for Postoperative Pulmonary COmPlications in Europe study).2 Although differences in the performance of the ARISCAT score have been observed between Euro-pean geographic areas, the score was able to discriminate three levels of PPCs risk (low, intermediate, and high). Thus, at present, the ARISCAT score may represent the most valu-able tool for predicting PPCs across different countries and surgical populations.

Putative Mechanisms of VILIThe coexistence of closed, recruitable, and already overdis-tended alveolar regions makes the lung vulnerable to det-rimental effects of mechanical stress and strain induced by

Table 1. Risk Factors for Postoperative Pulmonary Complications

Patient Characteristics Preoperative Testing Surgery Anesthetic Management

Age Low albumin Open thoracic surgery General anesthesiaMale sex Low SpO2 (≤95%) Cardiac surgery High respiratory driving pressure

(≥13 cm H2O)ASA class ≥3 Anemia (Hb <10 g/dl) Open upper abdominal surgery High inspiratory oxygen fractionPrevious respiratory infection Major vascular surgery High volume of crystalloid admin-

istrationFunctional dependency Neurosurgery Erythrocyte transfusionCongestive heart failure Urology Residual neuromuscular blockadeCOPD Duration of surgery >2 h Nasogastric tube useSmoking Emergent surgeryRenal failureGastroesophageal reflux diseaseWeight loss

Respiratory driving pressure is defined as inspiratory plateau airway pressure minus positive end-expiratory pressure.ASA = American Society of Anesthesiologists; COPD = chronic obstructive pulmonary disease; Hb = hemoglobin concentration; SpO2 = oxygen saturation as measured by pulse oximetry.




Mechanical Ventilation and Postoperative Pulmonary Complications

Tab

le 2

. S

core

s fo

r P

red

ictio

n of

PP

Cs

Ref

eren

ces

Pub

lishe

dS

tud

y D

esig

nP

atie

nt P

opul

atio

nP

atie

nts,

No.

Sco

re A

cron

ymS

corin

g S

yste

mC

utof

fQ

ualit

y of

P

red

ictio

n

Pre

dic

tion

of g

ener

al P

PC

s

Can

et e

t al

. 1P

rosp

ectiv

e,

mul

ticen

ter,

obse

r-va

tiona

l co

hort

st

udy

Ad

ult

pat

ient

s un

der

goin

g no

n-ob

stet

ric s

urgi

-ca

l pro

ced

ures

un

der

gen

eral

, ne

urax

ial,

or

regi

onal

ane

s-th

esia

2,46

4 ov

er-

all;

1,62

4 d

eriv

atio

n;

837

valid

a-tio

n; 3

pat

ient

s w

ith m

issi

ng

dat

a fo

r tw

o p

aram

eter

s re

leva

nt fo

r th

e sc

ore

(Sp

O2

+ r

esp

irato

ry

infe

ctio

n d

ur-

ing

last

mon

th)

AR

ISC

ATA

ge: 5

1–80

3Le

vel/p

oint

/rat

e of

P

PC

: low

/<26

/1.6

%;

med

ium

/26–

44/1

3.3%

; hi

gh/≥

45/4

2.1%

(val

idat

ion

sub

sam

ple

)

Der

ivat

ion

coho

rt:

AU

C: 0

.89

>80

16S

pO

2%: 9

1–95

8<

9024

Res

pira

tory

infe

ctio

n d

ur-

ing

last

mon

th17

Pre

oper

ativ

e an

emia

(Hb

<

10 g

/dl)

11

Sur

gica

l inc

isio

nP

erip

hera

l1

PP

C: r

esp

irato

ry in

fect

ion,

re

spira

tory

failu

re, p

leur

al

effu

sion

, ate

lect

asis

, pne

u-m

otho

rax,

bro

ncho

spas

m,

asp

iratio

n p

neum

oniti

s

Valid

atio

n co

hort

: A

UC

: 0.8

4U

pp

er a

bd

omin

al15

Intr

atho

raci

c24

Dur

atio

n of

sur

gery

, h ≤

21

>2–

316

>3

23E

mer

genc

y p

roce

dur

e8

M

azo

et a

l.2 (v

alid

atio

n of

A

RIS

CAT

sco

re

from

the

stud

y by

Can

et e

t al

.1 in

a la

rger

, in

tern

atio

nal,

mul

ticen

ter

coho

rt)

Pro

spec

tive,

m

ultic

ente

r, ob

ser-

vatio

nal

coho

rt

stud

y

Ad

ult

pat

ient

s un

der

goin

g no

n-ob

stet

ric s

urgi

-ca

l pro

ced

ures

un

der

gen

eral

, ne

urax

ial,

or

ple

xus

blo

ck

anes

thes

ia

5,09

9A

RIS

CAT

See

ab

ove

Leve

l/poi

nt/p

red

icte

d/

obse

rved

rat

e of

PP

C:

low

/<26

/0.8

7%/3

.39%

; m

ediu

m/2

6–

44/7

.82%

/12.

96;

high

/≥45

/ 38

.13%

/38.

01%

AU

C: 0

.80 (C

ontin

ued

)




EDUCATION

Pre

dic

tion

of s

elec

ted

PP

Cs

Jo

hnso

n et

al.14

(re

eval

uate

d

in a

bro

ader

co

hort

from

the

st

udy

by

Aro

-zu

llah

et a

l.9 )

Pro

spec

tive,

m

ultic

ente

r, ob

ser-

vatio

nal

coho

rt

stud

y

Ad

ult

pat

ient

s un

der

goin

g m

ajor

gen

eral

or

vas

cula

r p

roce

dur

es p

er-

form

ed u

nder

ge

nera

l, sp

inal

, or

ep

idur

al

anes

thes

ia

90,0

55 d

eriv

a-tio

n; 8

9,94

8 va

lidat

ion

Res

pira

tory

fail-

ure

Ris

k In

dex

Typ

e of

sur

gery

Leve

l/poi

nt/p

red

icte

d/

obse

rved

pro

bab

ility

of

PR

F: lo

w/<

8/0.

2%/0

.08%

; m

ediu

m/8

–12/

1.0%

/0.8

4%;

high

/>12

/6.6

%/6

.75%

Der

ivat

ion

coho

rt:

AU

C: 0

.856

Inte

gum

enta

ry1

Res

pira

tory

and

hem

ic3

Hea

rt2

Ane

urys

m2

Mou

th, p

alat

e7

Sto

mac

h, in

test

ines

2E

ndoc

rine

2P

red

isp

osin

g fa

ctor

sM

ale

sex

1A

ge 4

0–65

2A

ge >

652

AS

A c

lass

33

AS

A c

lass

4–5

5W

ork

RV

U 1

0–17

2W

ork

RV

U >

174

Em

erge

ncy

2S

epsi

s2

His

tory

of s

ever

e C

OP

D2

Asc

ites

2P

RF:

mec

hani

cal v

entil

atio

n fo

r >

48 h

or

unp

lann

ed

rein

tub

atio

n

Valid

atio

n co

hort

: A

UC

: 0.8

63D

ysp

nea

1Im

pai

red

sen

soriu

m1

>2

alco

holic

drin

ks/d

in 2

wk

1B

leed

ing

dis

ord

ers

1W

eigh

t lo

ss >

10%

1A

cute

ren

al fa

ilure

2C

onge

stiv

e he

art

failu

re1

Sm

oker

1S

trok

e1

Wou

nd c

lass

oth

er th

an c

lean

1P

reop

erat

ive

alb

umin

<3.

51

Cre

atin

ine

>1.

52

Pre

oper

ativ

e b

iliru

bin

>1.

01

Whi

te b

lood

cou

nt

<2.

5/>

101

Pre

oper

ativ

e se

rum

so

diu

m >

145

2

Pla

tele

t co

unt

<15

01

SG

OT

>40

1H

emat

ocrit

<38

1

Tab

le 2

. C

ontin

ued

Ref

eren

ces

Pub

lishe

dS

tud

y D

esig

nP

atie

nt P

opul

atio

nP

atie

nts,

No.

Sco

re A

cron

ymS

corin

g S

yste

mC

utof

fQ

ualit

y of

P

red

ictio

n

(Con

tinue

d)





B

ruec

kman

n

et a

l.15R

etro

spec

tive,

si

ngle

-ce

nter

, ob

ser-

vatio

nal

coho

rt

stud

y

Cas

es w

ith a

sur

gi-

cal p

roce

dure

if

the

adul

t pat

ient

w

as in

tuba

ted

at

the

begi

nnin

g an

d ex

tuba

ted

at

the

end

of th

e pr

oced

ure

33,7

69 o

vera

ll;

16,8

85 d

eriv

a-tio

n; 1

6,88

4 va

lidat

ion

Sco

re fo

r P

red

ictio

n of

P

osto

per

ativ

e R

esp

irato

ry

Com

plic

atio

ns

AS

A s

core

≥3

3S

core

val

ues/

pro

bab

ility

of

rein

tub

atio

n: 0

/0.1

2%;

1–3/

0.45

%; 4

–6/1

.64%

; 7–

11/5

.86%

(val

idat

ion

sub

sam

ple

)

Der

ivat

ion

coho

rt:

AU

C: 0

.81

Em

erge

ncy

pro

ced

ure

3Va

lidat

ion

coho

rt:

AU

C: 0

.81

Hig

h-ris

k se

rvic

e2

Con

gest

ive

hear

t fa

ilure

2C

hron

ic p

ulm

onar

y d

isea

se1

Pre

dic

tion

of A

LI/A

RD

S

Gaj

ic e

t al

.6 (s

imi-

lar

to t

he s

tud

y b

y Tr

illo-

Alv

a-re

z et

al.17

but

us

ed a

larg

er,

mul

ticen

ter

coho

rt)

Pro

spec

tive,

m

ultic

ente

r, ob

ser-

vatio

nal

coho

rt

stud

y

Ad

ult

pat

ient

s w

ith

one

or m

ore

ALI

ris

k fa

c-to

rs, i

nclu

din

g se

psi

s, s

hock

, p

ancr

eatit

is,

pne

umon

ia,

asp

iratio

n, h

igh-

risk

trau

ma,

or

hig

h-ris

k su

rger

y

5,58

4 ov

eral

l; 2,

500

der

iva-

tion;

3,0

84

valid

atio

n

Lung

Inju

ry

Pre

dic

tion

Sco

re

Pre

dis

pos

ing

cond

ition

s>

4; c

utof

f for

dev

elop

men

t

of A

LI/A

RD

SC

omb

ined

: AU

C:

0.80

; sen

sitiv

ity:

0.69

; sp

ecifi

city

: 0.

78

Sho

ck2

Asp

iratio

n2

Sep

sis

1P

neum

onia

1.5

Hig

h-ris

k su

rger

yO

rtho

ped

ic s

pin

e1

Acu

te a

bd

omen

2C

ard

iac

2.5

Aor

tic v

ascu

lar

3.5

If em

erge

ncy

surg

ery

+1.

5H

igh-

risk

trau

ma

Trau

mat

ic b

rain

inju

ry2

Sm

oke

inha

latio

n2

Nea

r d

row

ning

2Lu

ng c

ontu

sion

1.5

Mul

tiple

frac

ture

s1.

5R

isk

mod

ifier

sA

lcoh

ol a

bus

e1

Ob

esity

(BM

I >30

)1

Hyp

oalb

umin

emia

1C

hem

othe

rap

y1

FIO

2 >

0.35

(>4

l/min

)2

Tach

ypne

a (R

R >

30)

1.5

Sp

O2

<95

%1

Aci

dos

is (p

H <

7.35

)1.

5D

iab

etes

mel

litus

−1,

if

sep

tic

Tab

le 2

. C

ontin

ued

Ref

eren

ces

Pub

lishe

dS

tud

y D

esig

nP

atie

nt P

opul

atio

nP

atie

nts,

No.

Sco

re A

cron

ymS

corin

g S

yste

mC

utof

fQ

ualit

y of

P

red

ictio

n

(Con

tinue

d)




EDUCATION

mechanical ventilation.19,20 The physical forces in some alveolar regions may exceed the elastic properties of the lungs although gross measurements of airway pressures or lung mechanics as usually monitored under anesthesia still suggest mechanical ventilation is in a “safe” zone.21,22 Several mecha-nisms have been postulated to describe the development of VILI.23 Increased airway pressure (barotrauma) or the appli-cation of high tidal volumes (volutrauma) may cause damage or disruption of alveolar epithelial cells, by generating trans-pulmonary pressures (stress) that exceed the elastic properties of the lung parenchyma above its resting volume (strain).24,25 It has been demonstrated that the duration of mechani-cal stress defined as the stress versus time product affects the development of pulmonary inflammatory response.26 Although high stress versus time product increased the gene expression of biological markers associated with inflamma-tion and alveolar epithelial cell injury and low stress versus time product increased the molecular markers of endothelial cell damage, balanced stress versus time product as defined by an inspiratory to expiratory time ratio of 1:1 was associated with attenuated lung damage.26 Especially in the presence of atelectasis, mechanical ventilation may cause damage by repetitive collapse and reopening of alveolar units, a phenom-enon known as atelectrauma.27 All three mechanisms, namely barotrauma, volutrauma, and atelectrauma, may affect alveo-lar as well as vascular epithelial and endothelial cells28,29 and promote extracellular matrix fragmentation.30,31

The extracellular matrix of the lung parenchyma seems to be particularly sensitive to stress from mechanical ventila-tion, as illustrated in figure 1. Initially, the proteoglycans on the endothelial side and between the endothelial and epi-thelial lines undergo damage dependent on tidal volume,30 as well as breathing pattern.31 The mechanical fragmenta-tion of the extracellular matrix promotes interstitial edema and activation of metalloproteinases, further damaging the extracellular matrix itself. In a second step, fragments of the extracellular matrix can promote the activation of inflammatory mediators.32,33 Furthermore, the damage of the extracellular matrix induced by mechanical ventilation might be exacerbated by fluid load,34 which is not uncom-mon during general anesthesia. However, fluid overload seems to minimize the inflammatory response, likely by dilution of extracellular matrix fragments or changes in their structure, thereby down-regulating the local inflam-matory response.34 This suggests that (1) injurious mechani-cal ventilation makes the lung more susceptible to further insults; and (2) in previously healthy lungs, VILI can be induced without early increase in inflammatory mediators.

At the cellular level, physical stimuli are transformed into chemical signals, for example, proinflammatory and antiin-flammatory mediators by means of direct cell injury or indi-rect activation of cellular signaling pathways. This process is known as “mechanotransduction.”35 Some mediators may promote local effects such as proapoptotic or profibrotic actions, whereas others act as homing molecules recruiting

Kor

et

al.16

(sim

ilar

to t

he s

tud

y b

y K

or e

t al

.18, b

ut

used

a la

rger

, m

ultic

ente

r co

hort

; sec

ond

-ar

y an

alys

is o

f th

e st

udy

by

Gaj

ic e

t al

.6 )

Sec

ond

ary

anal

ysis

of a

p

rosp

ectiv

e,

mul

ticen

ter

coho

rt

stud

y

Ad

ult

pat

ient

s p

rese

ntin

g w

ith

one

or m

ore

ALI

ris

k fa

c-to

rs, i

nclu

din

g se

psi

s, s

hock

, p

ancr

eatit

is,

pne

umon

ia,

asp

iratio

n, h

igh-

risk

trau

ma,

or

high

-ris

k su

r-ge

ry a

nd u

nder

-go

ing

a su

rgic

al

pro

ced

ure

1,56

2S

urgi

cal L

ung

Inju

ry P

red

ic-

tion

2

Sur

gica

l pro

ced

ure

≥19;

cut

off f

or d

evel

opm

ent

of A

RD

SA

UC

: 0.8

4; S

en-

sitiv

ity: 0

.82;

S

pec

ifici

ty: 0

.75

Hig

h-ris

k ca

rdia

c su

rger

y7

Hig

h-ris

k ao

rtic

vas

cula

r su

rger

y11

Em

erge

ncy

surg

ery

10B

asel

ine

heal

th s

tatu

sS

epsi

s10

Cirr

hosi

s20

Ad

mis

sion

sou

rce

othe

r th

an h

ome

9P

hysi

olog

ic m

arke

rs o

f ac

ute

illne

ssR

esp

irato

ry r

ate

20–2

97

Res

pira

tory

rat

e ≥3

014

F IO

2 >

35%

13S

pO

2 <

95%

5

ALI

= a

cute

lung

inju

ry; A

RD

S =

acu

te re

spira

tory

dis

tres

s sy

ndro

me;

AR

ISC

AT =

Ass

ess

Res

pira

tory

RIs

k in

Sur

gica

l Pat

ient

s in

CAT

alon

ia; A

SA

= A

mer

ican

Soc

iety

of A

nest

hesi

olog

ists

cla

ssifi

catio

n; A

UC

= a

rea

und

er th

e cu

rve;

BM

I = b

ody

mas

s in

dex

; CO

PD

= c

hron

ic o

bst

ruct

ive

pul

mon

ary

dis

ease

; FIO

2 =

frac

tion

of in

spire

d o

xyge

n; H

b =

hem

oglo

bin

; PP

C =

pos

top

erat

ive

pul

mon

ary

com

plic

atio

n; P

RF

= p

osto

per

ativ

e re

spira

tory

failu

re; R

R =

resp

irato

ry ra

te; R

VU

= re

lativ

e va

lue

units

(a m

easu

re o

f sur

gica

l com

ple

xity

); S

GO

T =

ser

um g

luta

mic

-oxa

loac

etic

tran

sam

inas

e; S

pO

2 =

oxy

gen

satu

ratio

n as

mea

sure

d b

y p

ulse

oxi

met

ry.

Tab

le 2

. C

ontin

ued

Ref

eren

ces

Pub

lishe

dS

tud

y D

esig

nP

atie

nt P

opul

atio

nP

atie

nts,

No.

Sco

re A

cron

ymS

corin

g S

yste

mC

utof

fQ

ualit

y of

P

red

ictio

n





local and remote immune cell populations (e.g., neutro-phils and macrophages).36 These local effects as well as their immunological consequences are summarized by the term “biotrauma.”37

Besides the extracellular matrix, both the endothelial and the epithelial compartments of the alveolar–capillary unit are affected by stress and strain originating from mechani-cal ventilation. In the endothelium, high stress can lead to direct cell breaks, resulting in capillary stress failure.38,39 Fur-thermore, mechanical stress as well as inflammatory stimuli (i.e., tumor necrosis factor-α) may trigger contractions of the cytoskeleton,40 resulting in disruption of adherence junctions,41 which increase the endothelial permeability and contribute to edema formation. Similar to the pulmonary endothelium, mechanical stress and strain increase the per-meability of the alveolar epithelium,42 a phenomenon found during ventilation at high43 as well as low44 lung volumes. In addition, low lung volume ventilation can lead to repetitive collapse and reopening of lung, affecting the epithelium of small airways, yielding plasma membrane disruption,45 and epithelial necrosis and sloughing.46

Alveolar fluid clearance is essential to maintain intraalve-olar fluid homeostasis, which is usually compromised during VILI. Whereas ventilation with high tidal volumes directly decreases Na+/K+-adenosine triphosphatase activity,47 venti-lation at low lung volumes may indirectly impair fluid clear-ance due to hypoxia following increased alveolar collapse.48

Impairment of barrier function of the endothelium and epithelium, as well as of fluid clearance, leads to the

development of interstitial and alveolar edema, which sub-sequently causes surfactant dysfunction, and impairs lungs elastic and resistive properties.49 Dysfunction of the surfac-tant system makes the lung susceptible to alveolar collapse contributing to deterioration of lung mechanics and impair-ing pulmonary host defense.50

Although most evidence of gross structural alterations of endothelium and epithelium induced by mechanical ventila-tion originates from in vitro investigations of cultured cells or in vivo investigations in acute lung injury models,51 ventila-tion applying clinically relevant settings in noninjured lungs can affect the alveolar–capillary barrier function, especially in the presence of independent inflammatory triggers, mak-ing mechanical ventilation a powerful hit in the presence of systemic inflammation.29

Due to the disturbed integrity of the alveolar–capillary barrier function and consecutive systemic translocation of pathogens or inflammatory mediators, VILI may lead to a systemic inflammatory response affecting not only the lungs but the distal organs as well.52

Lung inhomogeneity, for example, due to atelectasis formation, is a major contributing factor to the develop-ment of VILI. However, most experimental evidence is derived from the acute lung injury models. Although their basic pathogenetic mechanisms may be similar, the mag-nitude and time course of atelectasis formation in acute lung injury may be very different from those of atelecta-sis occurring during anesthesia and relatively short-term intraoperative mechanical ventilation. Resorption of

Fig. 1. Alterations of the extracellular matrix in lungs during mechanical ventilation and fluid administration. CS-PG = chondroi-tin sulfate proteoglycans; HS-PG = heparan sulphate proteoglycans; ICs = inflammatory cells; IMs = inflammatory mediators; MMPs = metalloproteases; MV = mechanical ventilation; Pi = interstitial pressure; W/D = wet/dry ratio.




EDUCATION

alveolar gas53,54 and compression of lung structures55–58 may lead to atelectasis during short-term mechanical ven-tilation in noninjured lungs, whereby the former might play a more important role.

In a porcine model of experimental pneumonia, both exogenous surfactant administration and ventilation accord-ing to the open lung approach attenuated bacterial growth and systemic translocation by minimizing alveolar collapse and atelectasis formation.59 In a similar model of experimen-tal pneumonia in mechanically ventilated piglets, bacterial translocation was lowest with individually tailored PEEP levels, whereas low and high PEEP promoted bacterial translocation.60

In isolated nonperfused mouse lungs, both an “open lung approach” (tidal volume 6 ml/kg, recruitment maneuvers, and PEEP of 14 to 16 cm H2O) and a “lung rest strategy” (tidal volume of 6 ml/kg, PEEP of 8 to 10 cm H2O, and no recruitment maneuvers) were associated with reduced pul-monary inflammatory response and improved respiratory mechanics compared with injurious mechanical ventila-tion (tidal volume of 20 ml/kg and PEEP of 0 cm H2O).61 Interestingly, the “lung rest strategy” was associated with less apoptosis but more ultrastructural cell damage, most likely due to increased activation of mitogen-activated protein kinase pathways as compared with the “open lung strategy.”61

In healthy mice, mechanical ventilation with a tidal vol-ume of 8 ml/kg and PEEP of 4 cm H2O induced a revers-ible increase in plasma and lung tissue cytokines as well as increased leukocyte influx, but the integrity of the lung tissue was preserved.62 In another investigation, even least-injurious

ventilator settings were able to induce VILI in the absence of a previous pulmonary insult in mice.63 Of note, the delete-rious effects of mechanical ventilation in noninjured lungs are partly dependent on its duration.64 However, an experi-mental study demonstrated that large tidal volumes had only minor if any deleterious effects on lungs, despite prolonged mechanical ventilation.25 Possibly, this is explained by the lack of a previous inflammatory insult, as for example, sur-gery. In fact, systemic inflammation may prime the lungs to injury by mechanical ventilation.65

Mechanical Ventilation Strategies to Protect lungs during Surgery

Atelectasis and Intraoperative Mechanical VentilationAtelectasis develops in as much as 90% of patients undergo-ing general anesthesia66 and can persist to different degrees after surgery, also surrounding pleura effusion, as illustrated in figure 2. The area of nonaerated lung tissue near to the diaphragm varies depending on the surgical procedure and patient characteristics but has been estimated in the range of 3 to 6%67–69 to 20 to 25%66 and even higher if calculated as amount of tissue.

Different mechanisms have been postulated to favor atel-ectasis formation during anesthesia, including (1) collapse of small airways,70–72 (2) compression of lung structures,55–58 (3) absorption of intraalveolar gas content,53,54 and (4) impairment of lung surfactant function.73 Mechanical ventilation strategies for general anesthesia have been impor-tantly influenced by the progressive decrease in oxygenation

Fig. 2. Magnetic resonance imaging scans of lungs of three patients before and on the first day after open abdominal surgery. Images were obtained throughout spontaneous breathing and represent an average of total lung volume (TLV) during the breath cycles. (A) Minor atelectasis, (B) major atelectasis, (C) pleural effusion. Segmentation of lungs, atelectasis (red lines) and pleura effusion (blue lines), in magnetic resonance imaging scans was performed manually. Values were calculated for whole lungs. Note that the amounts of atelectasis and pleura effusion, two common postoperative pulmonary complications, are relatively low after surgery. L = left side of chest; N/A = arbitrary gray scale; PostOP = postoperative; PreOP = preoperative; R = right side of chest.





and compliance.74 Tidal volumes up to 15 ml/kg of predicted body weight were advocated to increase the end-expiratory lung volume (EELV) and counteract atelectasis in the intra-operative period.74 Provided there is no contraindication, PEEP and lung recruitment maneuvers may also contribute to revert or prevent the loss of EELV and closure of small airways during anesthesia.

Tidal Volumes for Intraoperative Protective VentilationDriven by clinical and experimental studies, tidal volumes during mechanical ventilation have been importantly reduced in patients suffering from the acute respiratory dis-tress syndrome (ARDS) to limit lung overdistension.75 Influ-enced by this practice in intensive care unit patients, a similar trend was observed in the operation room. As reported by different investigators,76,77 average tidal volumes in the range of 6 to 9 ml/kg of predicted body weight have gained broad acceptance for noninjured lungs, in spite of experimental25,78 and clinical79–81 data suggesting that higher values are not associated with increased lung damage or inflammation. Furthermore, anesthesiologists have consistently reduced tidal volumes also during one-lung ventilation. Whereas val-ues as high as 10 ml/kg have been used in the past, experi-mental,82,83 and clinical84–87 studies have suggested that tidal volumes of approximately 4 to 5 ml/kg may be more appropriate for lung protection, while still allowing adequate gas exchange. Furthermore, a small RCT showed that atel-ectasis did not increase significantly with low tidal volume without PEEP from induction of anesthesia until the end of surgery.67 This is also supported by the fact that mechanical ventilation with low tidal volume and PEEP did not result in a progressive deterioration of the respiratory system compli-ance and gas exchange during open abdominal surgery in a larger RCT.88 It must be kept in mind that “set” and “actual” (i.e., delivered) tidal volumes can differ substantially89 and that settings should be adjusted judiciously.

PEEP for Intraoperative Protective VentilationClinical studies have shown that a PEEP of 10 cm H2O is required to reduce or eliminate atelectasis,69,90,91 improve compliance without increasing dead space,92,93 and main-tain EELV during general anesthesia in both nonobese and obese patients.94 Another study in normal subjects showed that PEEP of 10 cm H2O increased lung volume but did not improve the respiratory function compared with PEEP of 0 cm H2O.56 Certainly, the level of PEEP should be cho-sen according to the patient’s particular characteristics, the particularities of the surgical approach, and patient position-ing. Several targets have been proposed for a more individ-ual titration of PEEP during general anesthesia, including the following: (1) oxygenation,95 also combined with dead space92 or EELV,93 (2) mechanical properties of the respira-tory system,96 and (3) distribution of ventilation using elec-tric impedance tomography.97,98 However, none of these has been shown to improve patient outcome.

Although controversial, an alternative approach for PEEP during general anesthesia is the so-called “intraoperative per-missive atelectasis,” when PEEP is kept relatively low and recruitment maneuvers are waived. This concept aims at reducing the static stress in lungs, which is closely related to the mean airway pressure, assuming that collapsed lung tissue is protected against injury from mechanical ventila-tion (fig. 3). Intraoperative permissive atelectasis may be lim-ited by deterioration in oxygenation, which could require higher inspiratory oxygen fractions. Also, shear stress may occur at the interface between collapsed and open tissue,20 likely resulting in lung damage and inflammation, even in presence of low global stress.99 Theoretically, intraoperative low PEEP could increase the incidence and the amount of atelectasis even in the postoperative period, resulting in fur-ther PPCs. A recent large retrospective study investigating

Fig. 3. Effects of high and low tidal volumes (VT) at end- inspiration and end-expiration with low and high positive end-expiratory pressure (PEEP) during general anesthe-sia. Atelectatic lung regions (red), overinflated lung regions (blue), normally aerated lung regions (white). During ventila-tion with low VT and low PEEP, higher amounts of atelectasis are present at end-expiration and end-inspiration with mini-mal areas of overinflation; during ventilation with high VT and low PEEP, less atelectasis is present at end-expiration and end-inspiration, with increased areas of overinflation at end-inspiration. Furthermore, a higher amount of tissue collapsing and decollapsing during breathing is present. During ventila-tion with low VT and higher PEEP, less atelectasis is present. However, higher overinflation occurs at end-inspiration and end- expiration, with minimal collapse and reopening during breathing cycling.




EDUCATION

the association between intraoperative mechanical ventilator settings and outcomes suggested that the use of “minimal” PEEP (2.2 to 5 cm H2O) combined with low tidal volumes (6 to 8 ml/kg) is associated with increased risk of 30-day mortality.79 However, a large international multicenter RCT challenged the concept that “minimal” PEEP com-bined with low tidal volumes in the intraoperative period is harmful.88 Also in elderly patients undergoing major open abdominal surgery, a strategy consisting of low tidal volume, PEEP 12 cm H2O, and recruitment maneuvers increased the PaO2 intraoperatively compared with a strategy with high tidal volume without PEEP, but this effect was not main-tained in the postoperative period.100 Even without recruit-ment maneuvers, PEEP improved oxygenation during upper abdominal surgery compared with zero end-expiratory pres-sure, but again such effects were limited to the intraoperative period and did not prevent postoperative complications.101

Lung Recruitment Maneuvers for Intraoperative Protective VentilationPositive end-expiratory pressure is most effective for pre-serving respiratory function if preceded by a recruitment maneuver, which must overcome the opening pressures of up to 40 cm H2O in nonobese102 and 40 to 50 cm H2O in obese patients,103 in the absence of lung injury. Recruit-ment maneuvers can be performed in different ways using the anesthesia ventilator, as illustrated in figure 4. Most commonly, such maneuvers are performed by “bag squeez-ing” using the airway pressure-limiting valve of the anes-thesia machine (fig. 4A). However, recruitment maneuvers are better controlled if performed during tidal ventilation, for example, using a stepwise increase of PEEP, tidal vol-umes, or a combination of these (fig. 4B). Provided there are no contraindications, the inspiratory plateau pres-sure as high as 40 cm H2O is more likely to result in full recruitment.104

In anesthesia devices that allow pressure-controlled ventilation, recruitment maneuvers can be conducted with a constant driving pressure of 15 to 20 cm H2O and by increasing PEEP up to 20 cm H2O in steps of 5 cm H2O (30 to 60 s per step). After three to five breaths at a PEEP level that allows achieving the target inspiratory pressure, PEEP and tidal volume are adjusted to the respective desired levels (fig. 4C).

Recent evidence for Intraoperative Protective Ventilation

Randomized Controlled Trials Using Nonclinical Primary OutcomesThe literature search identified 11 RCTs that compared a protective ventilation strategy with a nonprotective ven-tilation strategy during general anesthesia for surgery with regard to nonclinical primary outcome in patients under-going thoracic surgery,80,84,85,105,106 cardiac surgery,95,107,108

abdominal surgery,80,100,109 or spinal surgery,110 as depicted in table 3. In eight RCTs, the protective ventilation strategy consisted of both lower tidal volumes and higher levels of

Fig. 4. Illustrative fluctuation of airway pressure during three types of lung recruitment maneuvers for intraoperative me-chanical ventilation (red lines). (A) “Bag squeezing” using the airway pressure-limiting valve of the anesthesia machine. The airway pressure is difficult to control, possibly resulting in over-pressure, with the risk of barotrauma, or values lower than the closing pressure of small airways when controlled mechanical ventilation is resumed, with consequent lung derecruitment. (B) “Stepwise increase of tidal volume” during volume-controlled ventilation. Positive end-expiratory pressure (PEEP) is set at 12 cm H2O, the respiratory frequency at 6 to 8 breaths/min, and tidal volume increased from 8 ml/kg in steps of 4 ml/kg until the target opening pressure (e.g., 30 to 40 cm H2O) is achieved. After three to five breaths at that pressure, the PEEP is kept at 12 cm H2O, tidal volume reduced to 6 to 8 ml/kg, and the respiratory frequency adjusted to normocapnia. (C) Stepwise increase of PEEP at a constant driving pressure of 15 to 20 cm H2O in pressure-controlled ventilation. The PEEP is increased in steps of 5 cm H2O (30 to 60 s per step) up to 20 cm H2O. After three to five breaths at a PEEP level that allows achieving the target inspiratory pressure, PEEP and tidal volume are adjusted to the respective desired levels.





Tab

le 3

. R

and

omiz

ed C

ontr

olle

d T

rials

Usi

ng N

oncl

inic

al P

rimar

y O

utco

mes

Ref

eren

ce

Pub

lishe

dS

tud

y D

esig

nP

atie

nt P

opul

atio

n/

Num

ber

Inte

rven

tion

Gro

up(s

)C

ontr

ol G

roup

Non

clin

ical

Prim

ary

O

utco

mes

Sec

ond

ary

O

utco

mes

Thor

acic

sur

gery

W

rigge

et

al.80

Pro

spec

tive,

si

ngle

-cen

ter,

rand

omiz

ed c

on-

trol

led

tria

l

Ad

ult

pat

ient

s un

der

goin

g m

ajor

tho

raci

c su

rger

y,

n =

34

(2 e

xclu

ded

)

PV:

VT:

6 m

l/kg;

PE

EP

: 10

cm

H2O

; Paw

lim

it:

35 c

m H

2O d

urin

g TL

V

and

OLV

(n =

15)

CV:

VT:

12–

15 m

l/kg;

Z

EE

P: P

aw li

mit:

35

cm

H2O

dur

ing

TLV

and

O

LV (n

= 1

7)

Infla

mm

ator

y m

edia

tors

in

pla

sma:

no

diff

eren

ces

bet

wee

n gr

oup

s fo

r TN

Fα, I

L-1,

IL-6

, IL-

8,

IL-1

0, IL

-12

Gas

exc

hang

e: n

o d

iffer

-en

ces

bet

wee

n gr

oup

s

S

chill

ing

et a

l.84P

rosp

ectiv

e,

sing

le-c

ente

r, ra

ndom

ized

con

-tr

olle

d t

rial

Ad

ult

pat

ient

s un

der

goin

g el

ectiv

e op

en t

hora

cic

surg

ery

(n =

32)

PV:

VT:

5 m

l/kg

dur

ing

TLV

and

OLV

; PE

EP

: 3

cm H

2O, T

LV; P

EE

P:

0–2

cm H

2O, O

LV; P

aw

limit:

30

cm H

2O (n

=

16)

CV:

VT:

10

ml/k

g d

urin

g TL

V a

nd O

LV; P

EE

P:

3 cm

H2O

, TLV

; PE

EP

: 0–

2 cm

H2O

, OLV

; Paw

lim

it: 3

0 cm

H2O

(n =

16)

Infla

mm

ator

y m

edia

tors

in

BA

L: T

NFα

and

sIC

AM

lo

wer

dur

ing

PV;

no

diff

eren

ces

bet

wee

n gr

oup

s fo

r ce

ll co

unt,

P

MN

ela

stas

e, t

otal

p

rote

in, a

lbum

in, I

L-8,

an

d IL

-10

PaO

2/FI

O2:

no

diff

eren

ces

bet

wee

n gr

oup

s;

PaC

O2:

hig

her

dur

ing

PV

M

iche

let

et a

l.85P

rosp

ectiv

e,

sing

le-c

ente

r, ra

ndom

ized

con

-tr

olle

d t

rial

Ad

ult

pat

ient

s un

der

goin

g p

lann

ed e

sop

hage

c-to

my

(n =

52)

PV:

VT:

9 m

l/kg,

TLV

; VT:

5

ml/k

g O

LV; P

EE

P:

5 cm

H2O

, TLV

and

O

LV (n

= 2

6)

CV:

VT:

9 m

l/kg,

TLV

and

O

LV; Z

EE

P: T

LV a

nd

OLV

(n =

26)

Infla

mm

ator

y m

edia

tors

in

pla

sma:

IL-1

β, IL

-6,

IL-8

low

er d

urin

g P

V;

no d

iffer

ence

s b

etw

een

grou

ps

for

TNFα

Pa O

2/FI

O2

and

PaC

O2:

hi

gher

dur

ing

PV;

E

VLW

I: lo

wer

dur

ing

PV;

tim

e to

ext

ubat

ion:

sh

orte

r d

urin

g P

V

Lin

et a

l.105

Pro

spec

tive,

si

ngle

-cen

ter,

rand

omiz

ed

cont

rolle

d t

rial

Ad

ult

pat

ient

s un

der

goin

g es

opha

gect

omy

(n

= 4

0)

PV:

VT:

10

ml/k

g, T

LV; V

T:

5–6

ml/k

g O

LV; P

EE

P:

3–5

cm H

2O, O

LV (n

=

20)

CV:

VT:

10

ml/k

g, T

LV a

nd

OLV

; ZE

EP

: TLV

and

O

LV (n

= 2

0)

Infla

mm

ator

y m

edia

tors

in

pla

sma:

IL-6

, IL-

8,

low

er d

urin

g P

V

Pp

eak,

Pp

lat,

and

Raw

: low

er

dur

ing

PV

U

nzue

ta e

t al

.106

Pro

spec

tive,

si

ngle

-cen

ter,

rand

omiz

ed

cont

rolle

d t

rial

Ad

ult

pat

ient

s un

der

goin

g el

ectiv

e op

en

thor

acot

omy

(n

= 4

0)

PV:

VT:

8 m

l/kg,

TLV

; VT:

6

ml/k

g O

LV; P

EE

P:

8 cm

H2O

, TLV

and

O

LV; R

M w

ith s

tep

wis

e P

EE

P/P

aw in

crea

se u

ntil

20/4

0 cm

H2O

bef

ore

star

t of

OLV

(n =

20)

CV:

VT:

8 m

l/kg,

TLV

; VT:

6

ml/k

g O

LV; P

EE

P:

8 cm

H2O

, TLV

and

OLV

; no

RM

bef

ore

star

t of

O

LV (n

= 2

0)

Dea

d s

pac

e:

low

er d

urin

g P

VP

aO2/

FIO

2: h

ighe

r d

urin

g P

V; P

aCO

2: lo

wer

d

urin

g P

V

Car

dia

c su

rger

y

Kon

er e

t al

.107

Pro

spec

tive,

si

ngle

-cen

ter,

rand

omiz

ed c

on-

trol

led

tria

l

Ad

ult

pat

ient

s un

der

go-

ing

elec

tive

on-p

ump

co

rona

ry a

rter

y b

ypas

s gr

aftin

g su

rger

y (n

= 4

4)

(1) P

V: V

T: 6

ml/k

g; P

EE

P:

5 cm

H2O

(n =

15)

(3) C

V +

ZE

EP

: VT:

10

ml/

kg; P

EE

P: 0

cm

H2O

(n

= 1

5)

Infla

mm

ator

y m

edia

tors

in

pla

sma:

no

diff

eren

ces

bet

wee

n gr

oup

s fo

r TN

Fα a

nd IL

-6

Ppl

at: l

ower

dur

ing

PV

co

mpa

red

with

bot

h C

V

grou

ps; s

hunt

frac

tion:

lo

wer

dur

ing

PV

com

-pa

red

with

bot

h C

V +

Z

EE

P; P

aO2/

FIO

2: h

ighe

r du

ring

vent

ilatio

n w

ith

PE

EP,

(1) +

(2)

(2) C

V +

PE

EP

: VT:

10

ml/

kg; P

EE

P: 5

cm

H2O

(n

= 1

4)

Z

upan

cich

et

al.10

8P

rosp

ectiv

e,

sing

le-c

ente

r, ra

ndom

ized

con

-tr

olle

d t

rial

Ad

ult

pat

ient

s un

der

go-

ing

elec

tive

on-p

ump

co

rona

ry a

rter

y b

ypas

s gr

aftin

g su

rger

y (n

= 4

0)

PV:

VT:

8 m

l/kg;

PE

EP

: 10

cm

H2O

(n =

20)

CV:

VT:

10–

12 m

l/kg;

P

EE

P: 2

–3 c

m H

2O

(n =

20)

Infla

mm

ator

y m

edia

tors

in

pla

sma

and

BA

L: IL

-6,

IL-8

, low

er d

urin

g P

V

in b

oth

PaC

O2:

hig

her

dur

ing

PV

(Con

tinue

d)




EDUCATION

R

eis

Mira

nda

et

al.95

Pro

spec

tive,

sin

gle-

ce

nter

, ran

d-

omiz

ed c

ontr

olle

d

tria

l

Ad

ult

pat

ient

s un

der

go-

ing

elec

tive

on-p

ump

co

rona

ry a

rter

y b

ypas

s gr

aftin

g or

val

ve s

ur-

gery

(n =

62)

(1) L

ate

open

lung

: VT:

4–

6 m

l/kg;

PE

EP

: 10

cm

H2O

sta

rtin

g at

pos

t-op

erat

ive

ICU

arr

ival

(n

= 1

8)

(3) V

T: 6

–8 m

l/kg;

PE

EP

: 5

cm H

2O (n

= 2

2)In

flam

mat

ory

med

iato

rs in

p

lasm

a: IL

-8 d

ecre

ased

af

ter

CP

B in

bot

h op

en

lung

gro

ups;

IL-1

0 d

ecre

ased

fast

er a

fter

C

PB

in e

arly

op

en lu

ng

grou

p

Evi

den

ce o

f per

iop

erat

ive

myo

card

ial i

nfar

ctio

n (C

K-M

B a

nd E

CG

): no

d

iffer

ence

s b

etw

een

grou

ps

(2) (

1) E

arly

op

en lu

ng: V

T:

4–6

ml/k

g; P

EE

P: 1

0 cm

H

2O s

tart

ing

afte

r in

tu-

bat

ion

(n =

22)

Ab

dom

inal

sur

gery

W

rigge

et

al.80

Pro

spec

tive,

sin

gle-

ce

nter

, ran

d-

omiz

ed c

ontr

olle

d

tria

l

Ad

ult

pat

ient

s un

der

go-

ing

maj

or a

bd

omin

al

surg

ery

(n =

30)

PV:

VT:

6 m

l/kg;

PE

EP

: 10

cm

H2O

; Paw

lim

it 35

cm

H2O

(n =

15)

CV:

VT:

12–

15 m

l/kg;

Z

EE

P: P

aw li

mit:

35

cm

H2O

(n =

15)

Infla

mm

ator

y m

edia

tors

in

pla

sma:

no

diff

eren

ces

bet

wee

n gr

oup

s fo

r TN

Fα, I

L-1,

IL-6

, IL-

8,

IL-1

0, a

nd IL

-12

PaO

2/FI

O2:

no

diff

eren

ces

bet

wee

n gr

oup

s;

PaC

O2:

hig

her

dur

ing

PV

Wol

thui

s et

al.10

9P

rosp

ectiv

e, s

ingl

e-

cent

er, r

and

-om

ized

con

trol

led

tr

ial

Ad

ult

pat

ient

s un

der

goin

g a

surg

ical

pro

ced

ure

in

gene

ral a

nest

hesi

a ≥5

h

(n =

46)

PV:

VT:

6 m

l/kg;

PE

EP

: 10

cm

H2O

(n =

24)

CV:

VT:

10–

12 m

l/kg

Z

EE

P: n

= 2

2In

flam

mat

ory

med

iato

rs in

p

lasm

a an

d B

AL:

low

er

mye

lop

erox

idas

e an

d

nucl

eoso

me

leve

l in

BA

L d

urin

g P

V

PaC

O2:

hig

her

dur

ing

PV;

P

PC

s: n

o d

iffer

ence

s b

etw

een

grou

ps

W

eing

arte

n

et a

l.100

Pro

spec

tive,

sin

gle-

ce

nter

, ran

d-

omiz

ed c

ontr

olle

d

tria

l

Ad

ult

pat

ient

s ag

ed

> 6

5 yr

und

ergo

ing

maj

or o

pen

ab

dom

inal

su

rger

y un

der

gen

eral

an

esth

esia

(n =

40)

PV:

VT:

6 m

l/kg;

PE

EP

: 12

cm

H2O

RM

with

st

epw

ise

PE

EP

in

crea

se u

ntil

15 c

m

H2O

(n =

20)

CV:

VT:

10

ml/k

g;

ZE

EP

: no

RM

(n

= 2

0)

Infla

mm

ator

y m

edia

tors

in

pla

sma:

no

diff

eren

ces

bet

wee

n gr

oup

s

PaO

2/FI

O2

+ P

aCO

2: h

ighe

r d

urin

g P

V; c

omp

lianc

e hi

gher

and

res

ista

nce

low

er d

urin

g P

V

Sp

inal

sur

gery

M

emts

oud

is

et a

l.110

Pro

spec

tive,

sin

gle-

ce

nter

, ran

d-

omiz

ed c

ontr

olle

d

tria

l

Ad

ult

pat

ient

s un

der

goin

g el

ectiv

e lu

mb

ar d

ecom

-p

ress

ion

and

fusi

on in

p

rone

pos

ition

und

er

gene

ral a

nest

hesi

a (n

=

26)

PV:

VT:

6 m

l/kg;

PE

EP

: 8

cm H

2O (n

= 1

3)C

V: V

T: 1

2 m

l/kg;

Z

EE

P: n

= 1

3In

flam

mat

ory

med

iato

rs in

p

lasm

a: n

o d

iffer

ence

s b

etw

een

grou

ps

PaC

O2:

hig

her

dur

ing

PV

BA

L =

bro

ncho

alve

olar

lava

ge;

CK

-MB

= m

uscl

e-b

rain

typ

e cr

eatin

e ki

nase

; C

PB

= c

ard

iop

ulm

onar

y b

ypas

s; C

V =

con

vent

iona

l ven

tilat

ion;

EC

G =

ele

ctro

card

iogr

am;

EV

LWI

=ex

trav

ascu

lar

lung

wat

er in

dex

; FI

O2

= in

spire

d fr

actio

n of

oxy

gen;

ICA

M =

inte

rcel

lula

r ad

hesi

on m

olec

ule;

ICU

= in

tens

ive

care

uni

t; IL

= in

terle

ukin

; OLV

= o

ne-l

ung

vent

ilatio

n; P

aCO

2 =

par

tial p

ress

ure

of a

rter

ial c

arb

on d

ioxi

de;

PaO

2 =

par

tial

pre

ssur

e of

art

eria

l oxy

gen;

PaO

2/FI

O2

= r

atio

of p

artia

l pre

ssur

e of

art

eria

l oxy

gen

to in

spire

d fr

actio

n of

oxy

gen;

Paw

= a

irway

pre

ssur

e; P

EE

P =

pos

itive

end

-exp

irato

ry p

ress

ure;

PM

N =

pol

ymor

pho

nucl

ear

leuk

o-cy

te; P

PC

s =

pos

top

erat

ive

pul

mon

ary

com

plic

atio

ns; P

pea

k = p

eak

pre

ssur

e; P

pla

t = p

late

au p

ress

ure;

PV

= p

rote

ctiv

e ve

ntila

tion;

Raw

= a

irway

resi

stan

ce; R

M =

recr

uitm

ent m

aneu

ver;

sIC

AM

= s

olub

le in

terc

ellu

lar

adhe

sion

mol

ecul

e; T

LV =

tw

o-lu

ng v

entil

atio

n; T

NFα

= t

umor

nec

rosi

s fa

ctor

-α; V

T =

tid

al v

olum

e; Z

EE

P =

zer

o en

d-e

xpira

tory

pre

ssur

e.

Tab

le 3

. C

ontin

ued

Ref

eren

ce

Pub

lishe

dS

tud

y D

esig

nP

atie

nt P

opul

atio

n/

Num

ber

Inte

rven

tion

Gro

up(s

)C

ontr

ol G

roup

Non

clin

ical

Prim

ary

O

utco

mes

Sec

ond

ary

O

utco

mes





PEEP80,85,100,105,107–110; in two RCTs, it consisted of either lower tidal volume,84 a higher level of PEEP.95 In one RCT, lung recruitment maneuvers were used during the protective ventilation strategy.106

The effects on inflammatory responses are slightly contra-dictory. Although four RCTs showed no difference in local levels of inflammatory mediators between patients on pro-tective and those on nonprotective ventilation,80,100,107,110 six RCTs84,85,95,105,108,109 showed that protective strategies were associated with lower levels of inflammatory mediators.

Randomized Controlled Trials Using Clinical Primary OutcomesIn total, eight RCTs were identified that compared a pro-tective ventilation strategy with a nonprotective ventilation strategy during surgery with regard to a clinical primary out-comes in patients planned for abdominal surgery,88,111–113 thoracic surgery,87,114 cardiac surgery,115 or spinal surgery,116 as shown in table 4. In four RCTs, the protective strategy consisted of both lower tidal volumes and higher levels of PEEP,112–114,116 and in the four remaining RCTs, it con-sisted of either lower tidal volumes87,111,115 or higher levels of PEEP.88

Four trials reported on PPCs in the first postoperative days, including bronchitis, hypoxemia, and atelectasis,116 pneumonia, need for invasive or noninvasive ventilation for acute respiratory failure,112 a modified “Clinical Pulmonary Infection Score,” and chest radiograph abnormalities,113 and hypoxemia, bronchospasm, suspected pulmonary infection, pulmonary infiltrate, aspiration pneumonitis, development of ARDS, atelectasis, pleural effusion, pulmonary edema, and pneumothorax.88

In a Chinese single-center RCT,116 investigators com-pared protective ventilation (tidal volume 6 ml/kg and 10 cm H2O PEEP) versus nonprotective (tidal volume 10 to 12 ml/kg and 0 cm H2O PEEP) in 60 elderly patients with Ameri-can Society of Anesthesiologists class II and III scheduled for spinal surgery. Patients receiving protective ventilation had less PPCs.

In a French multicenter trial (Intraoperative PROtec-tive VEntilation),112 protective ventilation (tidal volume 6 to 8 ml/kg and PEEP 6 to 8 cm H2O) was compared with nonprotective ventilation (tidal volume 10 to 12 ml/kg and 0 cm H2O PEEP) in 400 nonobese patients at intermediate to high risk of pulmonary complications after planned major abdominal surgery. The primary outcome (postoperative pulmonary and extrapulmonary complications) occurred less often in patients receiving “protective” ventilation. Such complications have been ascribed to the release of inflam-matory mediators by the lungs into the systemic circulation, affecting the lungs,117 as well as peripheral organs.52 These patients also had a shorter length of hospital stay, but mor-tality was unaffected.

An Italian single-center trial113 investigated the effective-ness of protective ventilation (tidal volume 7 ml/kg and 10 cm

H2O PEEP with recruitment maneuvers) versus nonprotec-tive ventilation (tidal volume 9 ml/kg and zero end-expiratory pressure) in 56 patients scheduled for open abdominal surgery lasting more than 2 h. The modified “Clinical Pulmonary Infection Score” was lower in patients receiving protective ventilation. These patients also had fewer chest radiograph abnormalities and higher arterial oxygenation compared with patients receiving nonprotective ventilation.

Finally, in an international multicenter trial conducted in Europe and the United States (PROtective Ventilation using HIgh vs. LOw PEEP [PROVHILO]),88 the PROtec-tive VEntilation Network investigators compared PEEP of 12 cm H2O combined with recruitment maneuvers versus PEEP of 2 cm H2O without recruitment maneuvers in 900 nonobese patients at high risk for PPCs planned for open abdominal surgery under ventilation at tidal volumes of 8 ml/kg. The incidence of PPCs was not different between patients receiving protective ventilation and patients receiv-ing nonprotective ventilation.

Challenges of Studies Using BundlesAs shown in preceding subsections Randomized Con-trolled Trials Using Nonclinical Primary Outcomes and Randomized Controlled Trials Using Clinical Pri-mary Outcomes, most RCTs addressing intraoperative mechanical ventilation compared bundles of interventions consisting of tidal volumes and levels of PEEP, usually accompanied by a lung recruitment maneuver.112–114,116 Notably, recruitment maneuvers differed between the tri-als. In the Italian single-center RCT,113 investigators used incremental titration of tidal volumes until a plateau pres-sure of 30 cm H2O, directly after induction of anesthesia, after any disconnection from the ventilator and immedi-ately before extubation, similar as in PROVHILO.88 In Intraoperative PROtective Ventilation trial,112 recruitment was performed with a continuous positive airway pressure of 30 cm H2O for 30 s every 30 min, also known as sus-tained inflation, after tracheal intubation. Finally, in the Chinese single-center RCT,116 the recruitment maneuvers followed a similar approach, but to plateau pressures of up to 35 cm H2O, and they were performed every 15 min. It is difficult, if not impossible, to conclude from these trials what caused the benefit, tidal volume reduction or increase of PEEP or both, and to determine the role of recruitment maneuvers. Moreover, to what extent the recruitment maneuver has succeeded in reopening lung has not been analyzed in the different studies.

The results of the PROVHILO trial, however, suggest that low tidal volumes rather than PEEP combined with lung recruitment maneuvers are responsible for lung protection in the intraoperative period. This interpretation is also supported by an analysis of different studies on the odds ratios of lower tidal volumes,87,111,115 higher levels of PEEP,88 their combina-tion,112–114,116 regarding the development of PPCs (fig. 5), as well as a recent individual patient data meta-analysis.131




EDUCATION

Tab

le 4

. R

and

omiz

ed C

ontr

olle

d T

rials

Usi

ng C

linic

al P

rimar

y O

utco

mes

Ref

eren

ce

Pub

lishe

dS

tud

y D

esig

nP

atie

nt

Pop

ulat

ion/

Num

ber

Inte

rven

tion

Con

trol

Gro

upC

linic

al

Prim

ary

Out

com

esS

econ

dar

y

Out

com

es

Thor

acic

sur

gery

M

aslo

w e

t al

.114

Pro

spec

tive,

sin

gle-

cent

er, r

and

omiz

ed

cont

rolle

d t

rial

Ad

ult

pat

ient

s un

der

goin

g el

ectiv

e p

ulm

onar

y re

sec-

tion

(n =

34)

PV:

VT:

5 m

l/kg,

TLV

and

O

LV; P

EE

P: 5

cm

H2O

, TL

V a

nd O

LV (n

= 1

7)

CV:

VT:

10

ml/k

g, T

LV

and

OLV

; ZE

EP

: TLV

an

d O

LV (n

= 1

7)

Rat

e of

ate

lect

asis

: low

er

with

CV;

leng

th o

f ho

spita

l sta

y: n

o d

iffer

-en

ces

bet

wee

n gr

oup

s

PaC

O2

and

alv

eola

r d

ead

sp

ace:

hig

her

dur

ing

PV;

Cd

yn: h

ighe

r

dur

ing

CV

S

hen

et a

l.87P

rosp

ectiv

e, s

ingl

e-ce

nter

, ran

dom

ized

co

ntro

lled

tria

l

Ad

ult

pat

ient

s un

der

goin

g el

ectiv

e th

orac

osco

pic

es

opha

gect

omy

(n =

101

)

PV:

VT:

8 m

l/kg

TLV;

VT:

5

ml/k

g O

LV; P

EE

P: 5

cm

H

2O, T

LV a

nd O

LV (n

=

53)

CV:

VT:

8 m

l/kg,

TLV

; V

T: 8

ml/k

g O

LV;

ZE

EP

: TLV

and

OLV

(n

= 4

8)

PP

Cs:

low

er r

ate

with

PV;

m

orta

lity:

no

diff

eren

ce

bet

wee

n gr

oup

s

PaO

2/FI

O2

and

PaC

O2:

hi

gher

dur

ing

PV;

in

flam

mat

ory

med

ia-

tors

in B

AL:

low

er

IL-1

β, IL

-6, a

nd IL

-8C

ard

iac

surg

ery

S

und

ar e

t al

.115

Pro

spec

tive,

sin

gle-

cent

er, r

and

omiz

ed

cont

rolle

d t

rial

Ad

ult

pat

ient

s un

der

goin

g el

ectiv

e ca

rdia

c su

rger

y

(n =

149

)

PV:

VT:

6 m

l/kg;

PE

EP

/ FI

O2:

acc

ord

ing

to A

RD

S

Net

wor

k ta

ble

(n =

75)

CV:

VT:

10

ml/k

g;

PE

EP

/FIO

2: a

ccor

d-

ing

to A

RD

S N

et-

wor

k ta

ble

(n =

74)

Rat

e of

rei

ntub

atio

n:

low

er w

ith P

V; n

umb

er

of p

atie

nts

req

uirin

g ve

ntila

tion

6 h

pos

top

-er

ativ

ely:

low

er w

ith P

V

Gas

exc

hang

e: n

o d

iffer

-en

ce b

etw

een

grou

ps

Ab

dom

inal

sur

gery

Tr

esch

an e

t al

.111

Pro

spec

tive,

sin

gle-

cent

er, r

and

omiz

ed

cont

rolle

d t

rial

Ad

ult

pat

ient

s un

der

goin

g el

ectiv

e up

per

ab

dom

inal

su

rger

y la

stin

g ≥3

h u

nder

co

mb

ined

gen

eral

and

ep

i-d

ural

ane

sthe

sia

(n =

101

)

PV:

VT:

6 m

l/kg;

PE

EP

: 5 c

m

H2O

(n =

50)

CV:

VT:

12

ml/k

g;

PE

EP

: 5 c

m H

2O

(n =

51)

Rat

e of

ate

lect

asis

: low

er

with

CV

PaO

2/FI

O2:

hig

her

dur

ing

CV;

Cd

yn a

nd R

aw:

high

er d

urin

g C

V; P

aO2

at p

osto

per

ativ

e d

ay

5: h

ighe

r w

ith C

V

Futie

r et

al.11

2P

rosp

ectiv

e ra

ndom

ized

co

ntro

lled

mul

ticen

ter

stud

y

Ad

ults

pat

ient

s at

inte

r-m

edia

te t

o hi

gh r

isk

of

pul

mon

ary

com

plic

atio

ns

und

ergo

ing

maj

or a

bd

omi-

nal s

urge

ry (n

= 4

00)

PV:

VT:

6–8

ml/k

g; P

EE

P:

6–8

cm H

2O (n

= 2

00)

CV:

VT:

10–

12 m

l/kg;

Z

EE

P (n

= 2

00)

Com

pos

ite p

rimar

y ou

tcom

e of

maj

or

pul

mon

ary

or e

xtra

pul

-m

onar

y co

mp

licat

ions

: lo

wer

with

PV

Red

uced

rat

e of

ate

lec-

tasi

s, p

neum

onia

, ne

ed fo

r ve

ntila

tion

with

in 7

day

s an

d s

ep-

sis

with

PV.

Red

uced

le

ngth

of h

osp

ital s

tay

with

PV

S

ever

gnin

i et

al.11

3P

rosp

ectiv

e, s

ingl

e-ce

nter

, ran

dom

ized

co

ntro

lled

tria

l

Ad

ult

pat

ient

s un

der

goin

g el

ectiv

e op

en a

bd

omin

al

surg

ery

≥2 h

n

= 5

6 (1

exc

lud

ed)

PV:

VT:

7 m

l/kg;

PE

EP

: 10

cm

H2O

(n =

28)

CV:

VT:

9 m

l/kg;

Z

EE

P (n

= 2

7)P

ulm

onar

y fu

nctio

n te

sts:

im

pro

ved

with

PV

Mod

ified

Clin

ical

Pul

mo-

nary

Infe

ctio

n S

core

: lo

wer

with

PV;

PaO

2 at

pos

top

erat

ive

day

s 1,

3, a

nd 5

: hig

her

with

PV.

Rat

e of

che

st

rad

iogr

aph

abno

rmal

i-tie

s: lo

wer

with

PV.

Le

ngth

of h

osp

ital

stay

: no

diff

eren

ce

bet

wee

n gr

oup

s

(Con

tinue

d)





Certainly, these conclusions are only valid for the studied population, that is, nonobese patients at risk of PPCs under-going elective abdominal surgery. Other patient populations could still benefit from higher levels of PEEP and recruit-ment maneuvers.

Challenges of Composite Outcome MeasuresComposite outcome measures offer the benefit of an increased event rate, which is helpful to ensure adequate statistical power of a trial.8 It is reasonable to combine related outcomes that rep-resent different aspects of a single underlying pathophysiologic process, such as PPCs for VILI. There are, though, two major limitations regarding the use of composite outcomes. First, the component variables can differ importantly in terms of severity and frequency. Second, differences in the frequency of compo-nent variables in a composite outcome may be masked.

Drawbacks of Protective VentilationThe term “protective” in the context of mechanical ventila-tion implies a decrease in the major components of VILI, namely atelectrauma, volutrauma, and biotrauma. However, a strategy that is protective to lungs may also cause harm to other organ systems. The potential for harm caused by protective ventilation was reported in PROVHILO trial,88 in which patients receiving higher PEEP and lung recruit-ment maneuvers developed intraoperative hypotension more frequently and needed more vasoactive drugs. These findings are at least in part in line with the finding that protective ventilation was associated with a higher incidence of intra-operative hypotension in the French trial.112

Standard of Care versus Unusual Settings: Were the Control Groups of Recent Trials Representative of Clinical Practice?In RCTs addressing intraoperative protective mechanical ventilation, the strategy used to treat control groups can play an important role when drawing conclusions for daily practice of general anesthesia. Meta-analyses suggest that lower tidal volumes are protective not only during long-term ventilation in critically ill patients118,119 but also short-term ventilation during general anesthesia for surgery.119 Accord-ingly, anesthesiologists have been using tidal volumes of approximately 8 to 9 ml/kg on average, and seldom higher than 10 ml/kg,76 as also illustrated in figure 6A. In contrast to this practice, the tidal volumes used in the control groups of recent RCTs were as high as 9113 to 12 ml/kg,112 except to PROVHILO88 (fig. 6B), which used a tidal volume of 7 ml/kg both in the intervention and in the control group. Similarly, levels of PEEP in the control arms of three of four recent RCTs112,113,116 on protective mechanical ventilation were much lower than the standard of care at the moment the respective studies were designed (fig. 6, C and D). Taken together, these facts suggest that, among the most impor-tant recent RCTs on intraoperative protective mechani-cal ventilation, only the PROVHILO trial used a control

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EDUCATION

group that reproduced the standard of anesthesia care at the time it was conducted. Accordingly, the PROVHILO trial addressed a major question regarding mechanical ventila-tion during anesthesia, namely whether the combination of high PEEP with recruitment maneuvers confers protection against PPCs. In this study, high PEEP was not individual-ized, but based on previous findings from computed tomog-raphy69,90,91 and physiological studies.92,94

Intraoperative Mechanical Ventilation According to the Utmost Recent evidenceA number of reviews and commentaries have suggested that intraoperative mechanical ventilation for surgery should consist of low tidal volumes (6 to 8 ml/kg), mod-erate levels of PEEP (6 to 8 cm H2O), and periodic lung recruitment maneuvers (e.g., every 30 min).5,123–125 How-ever, previous reviews and recommendations have been based on bundles, which do not permit to infer on the contribution of individual measures. Furthermore, the results of the largest RCT in this field (PROVHILO) could not be taken into account. Also, a recommenda-tion regarding the use of positive pressure ventilation dur-ing induction and emergence of anesthesia, as proposed recently,124 is not supported by outcome data. Currently, the only recommendations that can be given for clinical practice are summarized in figure 7. In nonobese patients without ARDS126 undergoing open abdominal surgery, mechanical ventilation should be performed with low tidal volumes (approximately 6 to 8 ml/kg) combined with low

PEEP (≤2 cm H2O) because higher PEEP combined with recruitment maneuvers does not confer further protection against PPCs and can deteriorate the hemodynamics. If hypoxemia develops and provided that other causes have been excluded (e.g., hypotension, hypoventilation, and pulmonary embolism), the FIO2 should be increased first, followed by increase of PEEP, and recruitment maneuvers based on stepwise increase of tidal volume during regular mechanical ventilation, according to the rescue algorithm described in the PROVHILO trial,88 provided no contra-indication is present. In patients with ARDS126 undergo-ing open abdominal surgery, intraoperative mechanical ventilation should be guided by the ARDS network pro-tocol,127 whereby higher PEEP values128 may be useful in more severe ARDS.129 If the target PaO2 (55 to 80 mmHg) or SpO2 (88 to 95%) cannot be achieved, a maximal lung recruitment maneuver with a decremental PEEP trial can be considered.130

Future Perspectives Despite the increasing number of highly qualitative RCTs on intraoperative mechanical ventilation, a number of issues remain unaddressed. Although meta-analyses strongly sug-gest that low tidal volumes during intraoperative mechani-cal ventilation protect against postoperative pulmonary events, no single RCT has been able to prove this claim. Because meta-analyses in this field frequently include the studies that tested intervention bundles, for example, low tidal volume and high PEEP with recruitment maneuvers

Fig. 5. Odds ratios for postoperative pulmonary complications of “protective” versus “nonprotective” ventilation in trials com-paring different tidal volumes,87,111,115 different tidal volumes and positive end-expiratory pressure (PEEP),112–114,116 and different levels of PEEP.88 df = degrees of freedom; M-H = Mantel-Haenszel.





versus high tidal volumes without PEEP, the estimation of the effects of single measures, for example, low tidal volume or PEEP, is prone to criticism. Therefore, RCTs are most relevant for clinical practice if they test single interven-tions, and if control groups reproduce current standards. Whereas direct testing of the hypothesis that intraoperative low tidal volumes protect against PPCs is still lacking, ethi-cal issues preclude such a trial.

Despite convincing evidence that PEEP and recruitment maneuvers do not confer further protection and may even impair hemodynamics during a ventilatory strategy based on low tidal volumes in open abdominal surgery, we do not know whether patients with obesity or undergoing one-lung anesthesia procedures may benefit from those inter-ventions. Also, we cannot rule out the possibility that an individual PEEP titration targeted on lung function could yield different results. Furthermore, it remains unclear how

postoperative atelectasis, the most frequent of the differ-ent PPCs, influences the development of pulmonary infec-tions and severe respiratory failure and affects other relevant outcome measures, including hospital length of stay and mortality. In addition, further studies should shed light on the potential contributions of ventilatory strategies during induction and emergence of anesthesia, as well as in the postoperative period (e.g., noninvasive ventilation). Accord-ingly, the potential of perioperative nonventilatory measures (e.g., muscle paralysis, use of short-acting neuromuscular-blocking agents, and monitoring and reversal of muscle paralysis, early mobilization, and respiratory therapy) for reducing PPCs should be investigated. Such studies are nec-essary to support future guidelines on the practice of peri-operative mechanical ventilation and adjunctive measures in a broad spectrum of patients as well as surgical interven-tions, both open and laparoscopic.

Fig. 6. Settings of tidal volume (VT) (A) and positive end-expiratory pressure (PEEP) (C) according to observational studies of mechanical ventilation in the operation room (in Canada,120 France,121 and the United States3,76,77,122); settings of VT (B) and PEEP (D) in “nonprotective” ventilation (red) and “protective” ventilation (blue) groups in four recent randomized controlled trials (Severgnini et al.,113 Intraoperative PROtective VEntilation trial [IMPROVE],112 Ge et al.,116 and PROtective Ventilation using HIgh vs. LOw PEEP [PROVHILO]88). PBW = predicted body weight.




EDUCATION

ConclusionsThe potential of intraoperative lung-protective mechanical ventilation to reduce the incidence of PPCs is well estab-lished. RCTs have suggested that low tidal volumes, high PEEP, and recruitment maneuvers may be protective intra-operatively, but the precise role of each single intervention has been less clearly defined. A meta-analysis taking the utmost recent clinical data shows that the use of low tidal volumes, rather than PEEP, recruitment maneuvers, or a combination of these two, is the most important deter-minant of protection in intraoperative mechanical venti-lation. In nonobese patients without ARDS undergoing open abdominal surgery, mechanical ventilation should be performed with low tidal volumes (approximately 6 to 8 ml/kg) combined with low PEEP because the use of higher PEEP combined with recruitment maneuvers does not confer further protection against PPCs and can deteri-orate the hemodynamics. If hypoxemia develops, and pro-vided that other causes have been excluded, for example, hypotension, hypoventilation, and pulmonary embolism, the FIO2 should be increased first, followed by increase of PEEP, and recruitment maneuvers based on stepwise increase of tidal volume during regular mechanical ventila-tion. Further studies are warranted to guide intraoperative mechanical ventilation in a broader spectrum of patients and surgical interventions.

AcknowledgmentsThe authors are indebted to Anja Braune, M.Sc., and Lorenzo Ball, M.D., from the Pulmonary Engineering Group, Department of Anesthesiology and Intensive Care Medicine, University Hospital Dresden, Technische Universität Dres-den, Dresden, Germany, for segmentation and calculations of atelectasis and pleura effusion volumes in magnetic reso-nance imaging scans.

Support was provided solely from institutional and/or departmental sources.

Competing InterestsThe authors declare no competing interests.

CorrespondenceAddress correspondence to Dr. Gama de Abreu: Pulmo-nary Engineering Group, Department of Anesthesiology and Intensive Care Medicine, University Hospital Dresden, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. [email protected]. This article may be accessed for personal use at no charge through the Journal Web site, www.anesthesiology.org.

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