Low Frequency Positive Pressure

Low-Frequency

Positive-Pressure

Ventilation With

_{Extracorporeal}

_CO2

Removal

in

Severe Acute

Respiratory

Failure

Luciano

Gattinoni, MD;

Antonio

Pesenti, MD;

Daniele

Mascheroni, MD;

Roberto

Marcolin,

MD;

Roberto

_Fumagalli,

MD;

Francesca

_Rossi,

MD;

Gaetano

_{lapichino, MD;}

Giuliano

_Romagnoli,

MD;

Ljli

Uziel, MD;

Angelo

Agostoni, MD;

Theodor

Kolobow, MD;

Giorgio

Damia,

MD

Forty-three

patients

wereentered inan uncontrolled

study designed

toevaluate

extracorporeal

membrane

_{lung support}

in severe acute

_respiratory

failure of

parenchymal

origin.

Most of the metabolic carbon dioxide

_production

was

cleared

through

a low-flow venovenous

bypass.

To avoid

lung injury

from

conventionalmechanical

_ventilation,

the

_lungs

were

kept

"at rest"

(three

tofive

breaths per

minute)

ata low

peak

airway

_pressureof 35to 45 cm

H2O

(3.4

to

4.4

_kPa).

The

_entry

criteria were based on gas

exchange

under standard

ventilatory

conditions

_(expected

mortality

rate,

>90%). Lung

function

improved

in

_thirty-one

_patients

(72.8%),

and 21

_patients

_{(48.8%) eventually}

survived. The

meantimeon

bypass

for the survivorswas5.4

\m=+-\

3.5

days.

Improvement

in

lung

function,

when

_present,

_always

occurred within 48 hours. Blood loss

_averaged

1800\m=+-\850mL/d. No

_major

technical accidents occurred in more than 8000

hours of

_{perfusion. Extracorporeal}

carbon dioxide removal with

_{low-frequency}

ventilation

_proved

asafe

technique,

andwe

_suggest

itasavaluabletool andan alternative to

_treating

severeacute

_respiratory

failure

_by

conventional means.

(JAMA1986;256:881-886)

EXTRACORPOREAL assist with an

artificial

lung

to

_support

a

patient

with severe acute

respiratory

failure

(ARF)

of

_{parenchymal origin}

was first re¬

ported by

Hillet

al1

in 1972.Since then

many teams have

experimented

with

this

_therapeutic

_approach

to

_"buy

time" for

_lungs

to heal. In

_1976,

Gille

For editorial comment see_p910.

and

_Bagniewski2

reviewed the world¬ wide

_experience

with

_{extracorporeal}

support

for ARF in 233 cases and

reported

an85%

mortality

rate.

From 1974 to

_1976,

the National

Heart,

Lung,

and Blood Institute sup¬

ported

a multicenter

trial3

in

severely

ill

_patients

with ARF _{to compare}

extracorporeal

venous-arterial

_support

plus

conventional continuous

positive-pressure ventilation

(CPPV)

with

CPPV alone.

The

entry

criteria for the extracor¬

poreal

membrane

_oxygénation

_(ECMO)

study3

were based on _gas

exchange

during

standard

_ventilatory

conditions. TheECMO

study

selectedan

extremely

ill

_{patient population,}

with a

mortality

rate of 91.7% in the control

_(CPPV)

group. There was no

improvement

in survival with ECMO. These _poor results inhibited use of

long-term

extracorporeal

support

for ARF for

years tocome.

In

_1979,

we

began

toassess

clinically

a method of

extracorporeal

_support

conceptually

different from

ECMO.4'5

The rationale of this

_technique

was to

prevent

further

_damage

to diseased

lungs by reducing

theirmotion

(pulmo¬

nary

rest),

although

three to five

"sighs"

were

provided

each minute to

preservethe functionalresidual

capaci¬

ty

(LFPPV

[low-frequency

positive-pressure

ventilation6]).

With this

method,

oxygen

uptake

and carbondioxide

_(C02)

removalwere

dissociated:

oxygénation

was

primarily

accomplished through

the motionless

lungs (apneic

oxygénation)7

while

C02

wascleared

through

the artificial

lung

(ECC02R

[extracorporeal

C02

remov¬

al]).

The

LFPPV-ECC02R

was

performed

atan

extracorporeal

bloodflow of20% to 30% of cardiac

_output

in a veno-venous

bypass

mode. The aim of this

article is to

report

the clinical results obtained

by LFPPV-ECC02R

in 43

patients

with ARF who met

gas-exchange

criteria similarto those used

in theECMO

_study.

PATIENTS AND METHODS

Our

_study

_group consisted of 43

patients (18

males and 25

_females;

mean _age, 26 _{years; range, 2} to 56

years)

with ARF of various

etiologies

(see below).

All

_patients

but one were referred to our institute from other

intensive care units. The mean dura¬

tion of mechanical ventilation before

bypass

was 9.0±4.6

days,

of which

approximately

half was

spent

in the

referring

hospital

and halfatourinsti¬

tute.

Attempts

to

_optimize

mechanical

ventilation before

_bypass

includedven¬ tilation with

_{positive end-expiratory}

pressure

(PEEP)

(up

to25 cm

H20

[2.5

kPa]),

inversed ratio

ventilation,

high-frequency jet

ventilation,

and a com¬

monly employed regimen

of medical

treatment

_(sedation,

muscle

relaxants,

control of

body

temperature,

diuretics,

vasoactive

drugs,

and

_{antibiotics).}

Entry

Criteria

Informedconsentwasobtainedfrom

the closest relative. All consecutive

patients meeting

either of the follow¬

ing

"ECMO

criteria"38

were admitted From the Istituto di Anestesia e Rianimazione _(Drs

Gattinoni, Pesenti, Mascheroni, Marcolin,Fumagalli,

Ros-si,lapichino,andDamia),the Istituto di Clinica_ChirurgiaIII

(Dr Romagnoli),and the Istitutodi ClinicaMedica V_(Drs

Uziel and _Agostoni), Universita di Milano, Milan, Italy;

and theLaboratoryof TechnicalDevelopment,National

Heart, Lung, and Blood _Institute, National Institutes of

Health, Bethesda,Md_{(Dr Kolobow).}

Reprint requests to Istituto di Anestesia e

Rianima-zione, Via F Sforza 35, 20122-Milano, Italy (Dr

35cm_H20

PEEP

Fig 1.—Cannulation and _perfusion circuit. DC indicates blood _{drainage catheter;} EC BF, extracorporealbloodflow; GF, gas flow monitor;Gl, gas inlet; GO,gas outlet; H, humidifier;ITC,

intratracheal catheter; ML, membrane _{lung; 02°/o,} venous drainage blood oxygen monitor; PML,

membranelung pressure,in-out; R,venous_{reservoir; RC,} blood return catheter; Resp, respirator;

RP,roller pump; PEEP, positiveend-expiratorypressure; andT,ambienttemperaturecontrol.

to the

study

and underwent

LFPPV-ECC02R:

(1)

fast

entry,

arterial _oxy¬

gen pressure

(Pao2)

ofless than50mm

Hg

(6.7 kPa)

for morethan two hours when measured atan

inspired

_oxygen fraction

_(Fio2)

of1.0ataPEEP of5cm

H20 (0.5 kPa)

or

greater;

and

(2)

slow

entry,

after48hours of maximalmedi¬

cal

therapy,

a

_Pao2

of less than 50mm

Hg (6.7 kPa)

for more than 12 hours

when measured at an

_Fio2

of 0.6 or

greater,

a PEEP of5cm

_{H20 (0.5 kPa)}

or

greater,

with a

right

to left shunt

greater

than 30% of cardiac

_output.

Our

_LFPPV-ECC02R

_entry

_criteria included a totalstatic

lung

_compliance

lower than 30 mL

_(centimeters

of

water)"1

(0.306

L/kPa),

not

_required

in the ECMO

study.

Total static

lung

compliance

was measured

during

_pa¬

ralysis,

and anesthesia

by

determina¬ tion of the

_{volume-pressure}

curve of

total

respiratory

system.

Although

total static

_{lung compliance}

does not

represent

the true

_{lung compliance,}

it

was chosen as an index of both

lung

elasticity

and

_{"opening pressure"}

of the

respiratory

system.9

Total

static

_lung

compliance

wasnotmeasured whenan

air leakwas

_present

(13 cases).

Exclusion Criteria

As in the ECMO

_study,

weexcluded

patients

with a

pulmonary

capillary

wedge

pressure

greater

than 25mm

Hg

(3.3 kPa),

patients

with chronic

sys-temic

_disease,

_including

_irreversible central nervous

_system

(CNS) injury,

and

_patients

with severe chronic

pul¬

monary

disease,

terminal cancer, and

major

burns.

Unlike the ECMO

_study,

the dura¬ tion of the

_pulmonary

insultor_theage of the

_patient

was notconsidered rea¬ sonsfor exclusion. Of43

patients,

four had been treated with CPPV for more

than 21

days

and three were _younger

than _{12 years.} Evaluation of Other

'Organ

System

Failures'

According

to the "additional data

collection" in the ECMO

_study,10

six

major

risk factorswereidentified: liver

dysfunction (ie,

bilirubin level>2

mg/

dL

_{[34 ¿¿mol/L]}

and/orserum transam¬

inase valves three times

normal),

renal

dysfunction (creatinine

level>2.0

_mg/

dL

_[177

_nmol/L]),

CNS

dysfunction (ie,

coma), coagulation

disorders

_(with

or

without actual

bleeding),

host defense

failure

(ie, sepsis diagnosed by positive

blood

_cultures),

and cardiovascular

failure

_(ie,

vasoactive

_drugs

were

required

to

support

systemic perfu¬

sion).

No

_attempts

weremade_{to quan¬}

tify

the

_degree

of _organ

_failure,

and

they

werenotedas

present

orabsent.

Extracorporeal

C02

Removal

This

_technique

has been

_fully

de¬

scribed

elsewhere1112

and is

_{only briefly}

summarized here

_(Fig

_1).

Vascular Access.—The

_ECC02R

was

always performed using

venovenous

bypass.

Inthe first14 cases,a

femoral-jugular

bypass

was

_employed.

We later

developed

a double-lumen

catheter13

system

where

bypass

was

performed

with a

single

_cannulation

through

_the

femoral vein

_{(ten cases).}

In _{the last}15

perfusions,

weuseda

saphenous-saphe-nousveinaccess

route.14

Duetoindivid¬

ual vascular access

problems,

other routes were used in _four cases. The

saphenous-saphenous

access was tech¬

nically

the

simplest

and didnot

_require

drainage

ofthe distalvein.

Extracorporeal

Circuit.—The

blood circuit was assembled

_using

_silicone rubber

_tubing

with

polytef

connectors.

Suitable side

ports

were

provided

for

sampling, monitoring,

and connection

to a

hemodialyzer

or

ultrafilter,

if

required.

Two membrane

_{lungs (9}

m2

total membrane surface area for adult

patients)

wereused inseries. The

prim¬

ing

volume of the blood

circuit,

includ¬

ing

the membrane

_lungs,

was

approxi¬

mately

1.8 L. The membrane

_lungs

were ventilated

separately

with a

humidified mixture

(usually

15 L/min

each)

of room air and _oxygen.

Subat-mospheric

pressurewas maintained in the _gas circuit. Blood and _gas circuits

were enclosed in a thermostated com¬

pact

system.

Monitoring

included oxy¬ gen saturation of the drained venous

blood,

blood _pressure

_drop

across the membrane

_{lung, extracorporeal}

blood

flow,

gas flow

rates,

and

system

tem¬

perature.

Low-Frequency

Positive-Pressure

Ventilation

The

_patient's

_lungs

were

inflated,

with PEEP

_ranging

from 15 to25 cm

H20 (1.5

to 2.5

_kPa).

The

_lungs

were

ventilatedthreetofive times _permin¬

ute, with

peak

airway

pressure limited to 35 to 45 cm

H20 (3.4

to 4.4

_kPa)

(representative expiratory

time,

10 to

18

_s).

Under these

_conditions,

mean

airway

pressure

approximated

PEEP.

The tidal volume was

greatly

influ¬ enced

_by

total static

lung compliance.

To

_provide

for_oxygenconsumeddur¬

ing

the

long end-expiratory

pause, we

directeda_continuousflow_ofoxygen

₍₁

to 2

_L/min)

intothetrachea

through

a

small catheteradvanced

_through

aside

port

in the trachéal tube connector.

Excess_oxygenwas vented

through

the PEEP valve.

_Despite

the continuous

oxygen

flow,

the alveolaroxygen pres¬

sure was

governed primarily by

the

Fio2

setting

on the

ventilator.6

In essence,

LFPPV-ECC02R

provided

for

apneic oxygénation

towhich mandato¬

25 20 1 15 10 Mortality,Rate % 52 50 78 14 Pneumonia Post-traumatic ARF Pulmonary Embolism Other

V77Â

Fig2.—Distribution andmortalityratebyetiolo¬

gy. Pneumonia includes viral and bacterial pneumonia; pulmonary embolism includes fat embolism and thrombotic embolism; post-trau¬

matic acute respiratory failure _(ARF) includes

patients with thoracic and/or extrathoracic

trauma; otherincludesshock,sepsis,andnear

drowning. Slashedareasof barsindicatenum¬

bers ofpatientswhodied.

Clinical

_Management

The

patients

were

paralyzed

(pancu-ronium bromide

_{given intravenously)}

and anesthetized

(alfaxolone-alphado-lone

and/or

midazolam and/or barbi¬

turates and/or

fentanyl given

intra¬

venously)

throughout

the

bypass

procedure.

The

_LFPPV-ECC02R

was

performed

using

the

_following

_guide¬

lines.

Connection

to

_{Bypass.—The}

cathe¬

ters were inserted after a dose of

intravenous

heparin,

100

_U/kg

in a

single

bolus. The

_heparinized

lactated

Ringer's

prime

solution in the

perfu¬

sion circuitwas

replaced

with warmed

whole blood and the

_perfusion

was

begun.

The blood

_temperature

in the

circuitwas

kept

at

37°C

beforeconnec¬ tionto

bypass

toavoid sudden

_cooling.

Extracorporeal

blood flowwas_progres¬

sively

raised from 200to 300 mL/min

to the selected maintenance flow of 20% to 30% of cardiac

output

over

about 20minutes.

Initially

the

Fio2

of the ventilator

and the one of _the membrane

lungs

were

kept

atthe

_prebypass

levels. The ventilation of the natural

_lungs

was

decreasedtomaintain the arterial

_C02

pressurein the normal range,to com¬

pensate

for increasein

_C02

_removal

_by

the membrane

_lungs.

Whileventilation

of the

_lungs

was

decreased,

PEEPwas

raised to maintain the mean

airway

pressure at

prebypass level,

to

_prevent

sudden

_pulmonary

edema. When the

respiratory

ratewasbelow five breaths per

minute,

we

began

a continuous slow flow of humidified 100% oxygen

intothetrachea

through

a_{small cathe¬}

ter,

asdiscussed earlier.

Maintenance

After theinitial

equilibration period,

our

goal

was to

provide

for

_adequate

gas

exchange

at the lowest

Fio2

and

airway

pressure tolerated. When oxy¬

génation improved,

we decreased the

Fio2

inthe ventilator and in the mem¬ brane

_lungs.

When

_Pao2

was

greater

than80mm

Hg

(10.7 kPa)

_atan

Fio2

of

0.4,

and the

Fio2

of the membrane

lungs

was

_0.21,

we_lowered PEEP_pro¬

gressively.

The

extracorporeal

system

thermo¬

stat was

adjusted aiming

at a normp;

patient body

temperature.

Core tem¬

peratures

between 36.5°C and 37.5°C

wereconsidered

satisfactory.

During

routine

perfusion,

gas ex¬

change

and

hemodynamic

measure¬ ments were obtained _{every hour. Vol¬} ume-pressure curve and

coagulation

testing15

weredoneonceortwicea

day.

Routine blood

chemistry

and chest

roentgenograms

were

performed

once

a

day

or whenever indicated basedon

clinical status. The

_general

_patient's

care was

unchanged16

_{from the}care of

the

_severely

ill

_patients

withARFnot on

bypass.

The main differencewas_the continuous

_{heparinization required}

to

maintain the activated

_clotting

timeat

twice thenormal

_value.15

Weaning

and

Disconnection

From

Bypass.—When

Pao2

consistently

re¬

mainedabove 80 mm

Hg

(10.7 kPa)

on an

_Fio2

of 0.40andwhenthetotalstatic

lung

compliance

rose to over 30 mL

(centimeters

of

_water)"1

_(0.306

_L/kPa)

with some

clearing

evident on chest

roentgenograms,

we

began

towean the

patient

off

_bypass.

Muscle relaxation

was first

suspended,

and the

patient

was allowed to breathe

spontaneously

with continuous

positive

airway

pres¬ sure. The

_ECC02R

was

progressively

decreased

by reducing

the gas flow to

the membrane

_lungs.

The

patient's

support

system

was

disconnected when the

_patient

wasable to maintain

_adequate

_gas

_exchange

with continuous

_{positive airway}

_pres¬ sureatan

Fio2

of 0.4 andaPEEP of10

to 15 cm

H20

(0.1

to 1.5

_kPa),

or at

low-frequency

intermittent

mandatory

ventilation foratleast six

hours,

with¬

out any gas

exchange

inthemembrane

lungs.

Staff

Requirement

Our

nurse-patient

ratio was 1:1. A

physician

or _{technician with}

expertise

in the

extracorporeal

apparatus

was

always

present.

Hematologists

and

surgeons were

always

available for

consultation. The

_daily

costof

patient

care on

bypass

was

approximately

twice the

_daily

cost of a

severely

ill

patient

receiving

standard intensive

carewith mechanical ventilation.

Statistical

Analysis

Data are

_expressed

as mean±SD.

Comparisons

between _{groups of pa¬}

tients were

performed

by

_the t testfor

unpaired

data. RESULTS

A total of 43

_patients

underwent

LFPPV-ECC02R

between

_January

1980 and

_January

1985. Five

_{patients quali¬}

fied for

_{study by}

thefast

entry

criteria

and 38

_by

the slow

_entry

_criteria.

Twenty-one patients (48.8%)

survived

1-12 13-19 20-24 25-29 30-34 35-39 40-44 45-49 50-59

Age,yr

Fig3.—Distribution andmortalityratebyage. Slashedareasof barsindicatenumbers ofpatients

Table 1.—RespiratoryParameters' Before_Bypass

VE, PEEP, Pao2, Pacoz, Rightto Cam, Group mL kg min Fio2 cm_H20(kPa) mm_Hg(kPa) mm_{Hg (kPa)} Left Shunt mL cm_{H20 (L/kPa)}

Survivors(n=21) 233.91±73.51 0.72t±0.18 11.74±2.96 51.82±15.24 44.15t±9.32 0.51±0.12 25.53±9.76

(1.15±0.29) (6.91±2.03) (5.89 ±1.24) (0.260 ±0.099)

Nonsurvivors 247.10 ±74.33 0.85t±0.12 12.91 ±4.50 52.61 ±11.85 53.49*±12.40 0.54 ±0.12 24.36 ±9.34

(n=22) (1.27±0.44) (7.01 ±1.58) (7.13±1.65) (0.248±0.095)

•Respiratory parametersinclude thefollowing: VE,minuteventilation; F102,inspiredoxygenfraction; PEEP,positiveend-expiratorypressure;Pao2,arterial oxygenpressure,

Pac02,arterial carbondioxidepressure;andCa,at,total staticlungcompliance. fP<-05. +P<.01. Table2.—HemodynamicParameters* BeforeBypasst

CI, PAP, _PCWP, PVR, _{CVP, SVR,} BP, Group L/min/sqm mm_{Hg (kPa)} mm_{Hg (kPa)} Dynes/cm5 mm_{Hg (kPa)} Dynes/cms mm_{Hg (kPa)}

Survivors(n=21) 4.12+1.21 30.90±11.17 8.40±5.25 305.95±200.66 7.59±5.79 1080.53±406.85 85.29±17.25

(4.12±1.49) (1.12±0.70) (1.01±0.77) (11.37±2.29)

Nonsurvivors 4.58±1.13 30.86±9.14 11.33±5.03 239.98±119.19 8.05±4.61 875.86±337.70 82.27±20.38

(n=22) (4.11 ±1.22) (1.51 ±0.67) 1.07±0.61) (10.97±2.72)

"

Hemodynamicparametersinclude thefollowing:CI,cardiacindex; PAP,pulmonaryarterypressure;PCWP, pulmonary capillary wedgepressure;PVR,pulmonaryvascular

resistance;CVP,centralvenouspressure;SVR, systemicvascularresistance;andBP,mean_{arterial pressure.}

tTherewas nosignificantdifference between survivors and nonsurvivors inanyof themeasurements.

Table3.—OrganFailures BeforeBypass

Kidney Coagulation Liver

Patients CNS* Host Defense _Dysfunction Cardiovascular Disorders Dysfunction

Survivors(n=21) 2 6 3 10 9 10

Nonsurvivors(n=22) 7 8 4 10 9 7

Mortality,% 78 67.1 57 50 50 41.2

"CNS indicates centralnervous_system.

and were

eventually

discharged.

The

etiology

of ARF and the survivalrates are shown in

Fig

2. Survivors were

obtained from all _groups ofARF. The

lowest survival rate was in

patients

with

_{post-traumatic}

ARF

_(22%).

The

age distribution of the

patients

and

related

_mortality

ratio are shown in

Fig

3.

The severity

of ARF

_immediately

before

_bypass

was

comparable

insurvi¬ vorsand nonsurvivors

(Tables

1and

2),

with the

_exception

of a

significantly

lower

_Fio2

and arterial

_C02

_pressurein survivors.

The duration of

pulmonary

insult,

although

not

_{statistically}

_different,

was somewhat shorter in survivors

(7.86

±11.7

_days)

than in nonsurvivors

(11.9

±11.6

_days).

However,

two of four

patients

with more _than 21

days

of

CPPV before

_{bypass eventually}

sur¬

vived.

The numbers of individual

failing

or

dysfunctioning

organ

systems

before

bypass

are listed in Table 3 and

Fig

4,

respectively.

The

_{highest mortality}

was

associated with CNSfailure

_(78%

)

and

the lowest

_mortality

was associated with liver

dysfunction (41%).

No

_patient

survived with five or

more _organ failures

(including

the

lungs). However,

survival was 67% in 12

_patients

with four organ

system

failures, including patients

in whom

both the artificial

_lung

and the artifi¬

cial

kidney

were _used

simultaneously

(seven

patients,

two

_survivors).

Survivors

required

5.40±3.50

_days

of

bypass

while nonsurvivors were on

bypass

a mean of 10.64 ±6.58

days

(P<.01).

Improved lung

function,

if any, was

always

seen within 48 hours after

beginning

of

_bypass.

_During

the first

six hours of the

procedure,

cardiac

index and mean

pulmonary

artery

pressure decreased

significantly

(P<.05)

toward normal

_values,

bothin

survivors and nonsurvivors

(Fig 5).

Significant

differences in

_Pao2

and

right

to left shunt between survivors

and nonsurvivors were measuredafter 12and six hoursof

_{bypass, respectively}

(Fig

6).

There were no

significant

_dif¬

ferences in central and

_systemic

hemo-dynamics

between these two groups

(Fig 5).

Irrespective

of ultimate

_survival,

31

(72.8%)

of 43

_patients

had

improved

lung

function

_{during bypass (improved}

PaOa

right

to left

_shunt,

total static

lung compliance,

and chest x-ray

films).

Irrespective

of ultimate

_survival,

the

only

differences found in the

_respirato¬

ry and

hemodynamic

parameters

be¬

fore

_bypass

between

_patients

who had

improved lung

function and those who

did not was a

significantly

lower arte¬

rial

_C02

_pressure

_(45.7

±9.5 mm

Hg

[6.1

±1.3

_kPa]

vs 57.1 ±13.7 mm

Hg

[7.6

±1.8

_{kPa], P<.01)}

and

Fio2

(0.76

±0.17vs

0.87±0.11,

P<.05).

Complications

No

_major

accidents occurredinmore

than 8000 hoursof

extracorporeal

per¬

fusion. The _average number of organ

failures was not

_higher

during bypass

than inthe

prebypass period.

In

_partic¬

ular,

the incidence

of sepsis

did not

increase

during bypass.

One

_bypass

lasting

32

_days

was

performed

_without

complications

andwas

electively

termi¬

nated aftera

lung biopsy

had revealed total interstitial and intra-alveolar fibrosis. The

_only

_{bypass-related}

ad¬ verse

finding

was

bleeding.

An_average of 1800 ±850mL/d of whole bloodwas

transfused

(including

200to 300 mL/d removed for blood

tests).

In three

MortalityRate, % 57 33 60 33 1QQ -|QQ 15 -i— 14 -13

-":

n

Lungs +1 +2 +3 +4 +5 Alone

OrganFailure,Total No. Fig4.—Distributionandmortalityratebyorgan

system failure. Slashed areasof bars indicate numbers of_patientswho died.

terminal event. Minor

bleeding,

often

requiring

a

surgical

revisionevery two tothree

_days,

occurred atthe cannula-tion sites.

_{Major bleeding}

occurred

from chest

tubes,

or

during pulmonary

surgery while on

bypass

(usually

to treat a

bronchopleural

fistula;

three

patients,

one

survivor).

On six

_occasions,

the membrane

lungs

were

replaced

_due to either a

reduced

_efficiency

in _gas

_exchange

and/or the _presence of disseminated intravascular

_{coagulation. Otherwise,}

one set of membrane

_lungs

lasted the entire

_procedure.

COMMENT

Survival from ARF

_depends

on the

severity

of

lung injury,

the nature of the

_underlying

_disease,

and the number of _associated

_failing

_organs.17

The

impaired

gas

exchange

is

only

part

of the

_problem.

When the

_underlying

dis¬

easedoesnot

_respond

to

_{drug therapy,}

surgery, or an

early

favorable natural

evolution,

survivalis

_unlikely

whatever

themode of

_respiratory

support.

Inthis

_study

we

_report

ontheeffec¬

tiveness of

_LFPPV-ECC02R

in 43

patients

withsevereARFof

parenchy-mal

_origin,

selected

_{primarily by}

_the

criteria of the

_previous

ECMO

study.

The ECMO

_{study produced}

an overall

mortality

rateof 91% in

_1977,8

with48

patients

treated with CPPV and 42

patients

treated with venous-arterial

bypass

and CPPV.

When similar criteria were used in

another

_population

of

_patients

with

o- 4 E 3 ^» _i ¡3 2 1 0 40 30 20 10h J_I_I_I_I_I_I_L Basal 6 12 18 24 _{30 36 42 48} Hours

Fig 5.—Cardiac index (CI) and mean pulmo¬

naryarterypressure(PAP) before (basal)and

duringfirst 48 hours ofbypass. Open squares indicate survivors; closed squares, nonsurvi¬

vors.

ARF treated

conventionally,

the mor¬

tality

rate was

_reported

as 93%

.18

In

1985,

a review of 72

patients meeting

ECMO_criteria on admissionor

during

theircourse in the intensive care

unit,

butnot on

ECMO,

_showed a

mortality

of 91.7%

_{(W. Zapol, MD,}

written com¬

munication,

June

_5,

_1985).

In our 43

patients

with severeARFevaluated

by

the same criteria and _{treated with}

LFPPV-ECC02R,

the

mortality

rate was 51.2%. _We

_recognize

_that we lack an

indigenous

control

population;

_how¬

ever, after our first novel and success¬

ful clinical

_applications

of

LFPPV-ECC02R,19

we decided we could not

ethically

organize

a randomization in

moribund

_{patients. First,}

wewished to

explore

the clinicaloutcomeand obtain

experience

with this

_therapy.

More¬

over,

bypass therapy

was neveroffered

asanalternative

treatment,

but

always

as alast

resort,

after CPPV and other

nonconventional forms of

_treatment,

such as inverted-ratio ventilation or

high-frequency jet ventilation,

had failedto

_improve

gas

exchange.9

Since the

_{expected mortality}

ratefor

patients

meeting

ECMO

entry

criteria

was

consistently

_greater

_than

_90%,

why

did

_LFPPV-ECC02R

result in a

lower

_mortality?

If the

_impairment

of

gas

exchange

was

similar,

then the

observeddifferencemay havebeendue to a different

patient population

or may have been due to an

improved

lung

therapy

with

_{LFPPV-ECC02R.}

170, 160 150 140 130 O) I120

I

110 s100 a ₉₀ 80 70 60 50 40 30 20 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 p—¿r' ù—_Ûv "à-,_¿y' _1_I_I_L

:

ThrnTt

_I_I_I_I_I_I_I_I_L_ Basai 6 12 18 24 30 36 42 48 Hours

Fig 6.—Arterial oxygen pressure (Pao2) and shunt fraction before(basal)andduringfirst 48 hours ofbypass. Open squares indicate survi¬

vors; closed squares, nonsurvivors; andaster¬ isks, P<.05.

The mean _{age of} our

patients

was lower than inthe ECMO

_study,

butwe

found no

relationship

_{between age}and

mortality (Fig

3).

Differences in ARF

patient population

may neverbe com¬

pletely

ruled out.

_However,

the _etiolo¬

gies

seen in our

patients

were _similar to those

_reported

_{in the ECMO}

_trial.8

Pneumonia in both studies was the

major

causeofARF

(23

inour

_study—

14 viraland nine

_bacterial).

We

_report

a

slightly

higher

incidence of

post-traumatic ARF

_(nine

vs

two)

while

pulmonary

embolism,

sepsis,

and shock were almost

equally represented.

The number of

_{"organ failures"}

_may have had an

important

effect on

mortality

asshown in the"additionaldata collec¬

tion" of the ECMO

_study.

That

_study

found a

major

correlation between

mortality

and the number of

_failing

organs.10

In our

patients,

38of 43 had

one ormoreadditional

"organ failure,"

highly

indicative of a

severely

ill

patient population

(Fig

4).

Hence,

the

_improvement

in _survival

obtained

_{by LFPPV-ECC02R}

_compared

with CPPV-ECMO_maylie inthetech¬

nique

itself. Both the

_bypass

mode and

the

respiratory

treatments were, in

fact, different.

The choice of the venovenous route

instead of the venous-arterial route may

play

a role.

During

venovenous

bypass, pulmonary

hemodynamics

re¬

main

_unaffected,

while

_during

venous-arterial

_{bypass (as}

in

_ECMO)

_there

maybe

significant pulmonary

hypoper-fusion.20

It has been

_suggested

that

reducing lung perfusion during

ARF

may lead to

pulmonary

thrombosis,21

and it is

important

to recall that the

terminal

respiratory

units are nour¬

ished

primarily by pulmonary

blood flow and not

_by

bronchial blood flow.

Moreover,

Kolobowet

al22

induced

_pul¬

monary infarction in

healthy

sheep

after six hours of total venous-arterial

bypass

with the heart in ventricular fibrillation.

They

suggested

that ele¬ vated focal

lung

tissue

_pH

caused

by

the ventilation of

_nonperfused

alveoli

was the direct cause of

pulmonary

infarction. These factorsmay decrease

the

_possibility

of

_{lung repair}

_during

venous-arterial

bypass.

Astothe

respi¬

ratory treatment,

neither LFPPV nor

CPPV cures the

injured

lungs.

The most we can

_expect

_{from the "best"}

respiratory

treatmentisto

support

gas

exchange

without further

damage

to

the

_lungs.

We believe it

_possible

that CPPV

_damages

the

_lungs

more than LFPPV does. Insevere

ARF,

high

_Fio2

and PEEP are

required

for _oxygéna¬

tion,

while

_{high peak}

pressure and

minute _ventilation are

mandatory

_for

C02

removal.

Experimental

evidence

demonstrates that

high

Fio^23

peak

pressures,24"27

anda

high

minute venti¬

lation2829

are noxious to the

_lung.

To

maintain gas

exchange during

severe ARFwith

CPPV,

these noxious factors

are directed to the healthiest gas

exchange regions

of the

injured lungs.

With

_LFPPV,

the

_lungs

are able to

rest,

thereby avoiding high peak

pres¬

sures and

large

minute

ventilation,

allowing

fora more

"gentle

_treatment" of the

_lung.

For thisreasonweaddeda low total static

_{lung compliance}

as an

indication for

bypass.

The reduced

mortality

rateinour

patients

_maythen

reflect a reduced

lung damage

from LFPPV

_compared

with CPPV.

Irrespective

of

_survival,

the acute response to

bypass therapy

deserves

comment.

_Thirty-one

of 43

_patients

experienced

consistent

improvement

in

their

_lung

function.

Uniformly,

any

improvement

occurred within48hours

after

_{beginning bypass.}

Thismayhave

important practical

consequences al¬

lowing

the withdrawal of

_bypass

if no

response is observed within two or

three

_days.

These

_patients

who didnot

experience improvement

of their

lung

function had a

significantly higher

arterial

C02

pressurein the

prebypass

period.

This may reflect a more

advanced

lung

disease.

_However,

the

duration of

pulmonary injury

was not

different between

_patients

who

experi-enced

improved lung

function and

patients

who didnot.Increasedarterial

C02

pressure may indicate a more severe

injury

to the

_pulmonary

micro-circulation. This

_point

needs to be

clarified.

We believe

LFPPV-ECC02R

to be a

safe

technique,

with a

relatively good

outcome in otherwise almost

hopeless

acute

respiratory

failure.

However,

the

lack of an

early improvement

in a

significant

number ofour

patients

_sug¬

gests

that

lung damage

had advanced

to a

stage

beyond

which _recoverymay

no

longer

be

possible. Hence,

the con¬

tinued adherence to ECMO criteria

mayneedtobe reevaluated. Now is the

time toconduct a randomized

study

to

confirm the effectiveness of

LFPPV-ECC02R.

This work was supported in part by Special Project on Biomédical and Clinical Engineering

contracts_{83.00504.57, 83.00547.57,84,02098.57,}and

84.02053.57, Consiglio Nazionale delle Ricerche, Rome; and Ministers Pubblica Istruzione _grant

1982-83.

This researchwasperformedinthe framework of theEuropeanEconomicCommunityConcerted Action_ProjectII.2.1"ReplacementofBodyFunc¬ tions."

We thank Kontron, SPA, Milan, Italy, for

providing us with the extracorporeal _apparatus system(LSS 6000).

We thank PeterSuter,MD,for his contribution in reviewing the manuscript, the medical and

nursingstaffofthe Anesthesiology Department

forcontinuous and dedicatedwork,and the Trans¬ fusion and Transplant Immunology Center of

Policlinico, Milan,Italy,for their invaluable_sup¬

port.

References

1. Hill JD, O'Brien TG, Murray JT: Prolonged extracorporeal oxygenation for acute

post-trau-maticrespiratory failure (shock-lung syndrome). NEnglJ Med1972;286:629-634.

2. Gille JP, Bagniewski A: Ten years of use of extracorporealmembraneoxygenation(ECMO)in

treatment of acute respiratory insufficiency.

Trans AmSoc ArtifIntern Organs 1976;22:102\x=req-\

108.

3. Protocol_{for Extracorporeal Support for} Respi-ratory Insufficiency. Bethesda, Md, National

Heart, Lung,and BloodInstitute,1974.

4. Gattinoni L, Kolobow T, Damia G, et al:

Extracorporealcarbon dioxide removal(ECCO2R):

Anewform ofrespiratoryassistance. Int JArtif Organs1979;2:183-185.

5. Gattinoni L, Kolobow _T, Agostoni A, et al: Clinical application of low frequency positive pressure ventilation with extracorporeal CO2

removal (LFPPV-ECCO2R) in the treatment of adultrespiratorydistresssyndrome (ARDS).Int J

Artif Organs1979;2:282-283.

6.Gattinoni L, Kolobow T, Tomlinson T, et al: Lowfrequency positivepressureventilation with extracorporeal carbon dioxide removal (LFPPV\x=req-\ ECCO2R): An experimental study. AnesthAnalg

1978;57:470-477.

7. Frumin _MJ, Epstein RM, Cohen G: Apneic oxygenation in man. Anesthesiology _{1959;20:789\x=req-\}

798.

8. _ZapolWM,SniderMT,HillJD,etal:

Extracor-poreal membrane oxygenation in severe acute respiratoryfailure. JAMA1979;242:2193-2196.

9. GattinoniL,Pesenti_A,Caspani ML,etal: The role of total staticlung compliancein the manage-mentofsevereARDSunresponsiveto convention-altreatment.IntensiveCare Med_{1984;10:121-126.}

10.ExtracorporealSupport for Respiratory Insuf-ficiency. A Collaborative _Study in Response to

RFP-NHLBI-73-20.Bethesda, Md,National_Heart,

Lung,and BloodInstitute,1979.

11. Pesenti A, Pelizolla_A, Mascheroni D, etal: Low_{frequencypositive pressure}ventilation with

extracorporealCO2removal(LFPPV-ECCO2R)in

acute_respiratoryfailure(ARF):Technique.Trans Am SocArtifInternOrgans1981;27:263-266.

12.Gattinoni L,Pesenti A, KolobowT, etal: A

new look at therapy of the adult respiratory

distress syndrome: Motionlesslungs. IntAnaesth

Clin1983;21:97-117.

13.Pesenti A,KolobowT,Riboni_A,etal:Single

vein cannulation for extracorporeal respiratory

support.Life Support Syst 1982;1(suppl):165-167.

14. PesentiA,RomagnoliG,FoxU,etal: Saphe-no-saphenous cannulation for LFPPV-ECCO2R (lowfrequency positive pressureventilation with extracorporealCO2 removal),inTenthCongress of European Society of Artificial Organs. Bologna,

Italy,European Societyof ArtificialOrgans,1983, p 97.

15. Uziel_L,AgostoniA,Pirovano_E,etal:

Hema-tologicsurveyduringlowfrequency positive

pres-sureventilation withextracorporeal_CO2removal. TransAm Soc _ArtifIntern Organs 1982;28:359\x=req-\

363.

16. _{Iapichino G,}Pesenti A, Radrizzani D, et al: Nutritional_supportto_longtermanesthetized and

curarized_patientsunder_{extracorporeal}

respirato-ry assist for terminal pulmonary failure. JPEN

1983;7:50-54.

17. Suter PM: Syndromede detresse respiratoire aigue d l'adulte: Moyens therapeutiques, in Lemaire M_(ed):Lesyndromede detresse respira-toire_aiguede l'adulte._{Paris, Masson, 1984,}pp111\x=req-\ 123.

18. Greene _R, Zapol W, SniderMT,et al: _Early bedside detection ofpulmonaryvascular occlusion

duringacute_respiratory failure. Am RevRespir

Dis1981;124:593-601.

19. Gattinoni L, Agostoni A, Pesenti A, et al: Treatment ofacute_respiratory failure with low

frequency positivepressureventilation and extra-corporealCO2removal.Lancet_{1980;2:292-294.} 20. ZapolWM,SniderMT,Schneider R:

Extracor-porealmembraneoxygenationforacute respirato-ryfailure.Anesthesiology1977;46:272-285.

21. Ratliff_JL,Hill_JD,Fallat_RJ,etal:

Complica-tionsassociated with membrane_{lungsupportby}

veno-arterial perfusion. Ann Thorac Surg 1975;

19:537-539.

22. Kolobow T, Spragg R, Pierce J: Massive pulmonary infarction during total cardiopulmo-nary bypass in unanesthetized spontaneously

breathinglambs. Int JArtif Organs1981;4:76-81.

23. Deneke SM, FanburgBL: Oxygentoxicityof the lung: An update. Br JAnaesth 1982;54:737\x=req-\

749.

24. Webb H, Tierney DF: Experimental pulmo-naryedema duetointermittentpositivepressure

ventilation withhighinflation pressures: Protec-tionby positive end-expiratorypressure.Am Rev

RespirDis1974;110:556-565.

25. Kolobow T, Moretti M, Fumagalli R, et al:

Adult respiratory distress syndrome following

mechanical pulmonary ventilation at high peak airwaypressures,abstracted. Am RevRespirDis 1985;131(suppl):137.

26. WoodringJH: Pulmonaryinterstitial

emphy-semain theadultrespiratorydistresssyndrome.

Crit Care Med1985;13:786-791.

27. _DreyfussD,BassetG,SolerP,etal:

Intermit-tent_{positivepressure}hyperventilationwithhigh

inflationpressuresproduces pulmonary

microvas-cular injury in rats. Am Rev Respir Dis 1985;

132:880-884.

28. MascheroniD,KolobowT,FumagalliR,etal:

Respiratoryfailurefollowinginduced

hyperventi-lation: An experimental study. Crit Care Med

1985;13:330.

29. Wyszogrodski I, Kyei-Aboagye K, Taensch HW_Jr,etal: Surfactant inactivationby

hyperven-tilation: Conservationby end-expiratorypressure.