assment oftissueoxygenation in the critically ill

8/15/2019 Assment OfTissueOxygenation in the Critically Ill

1/11

sse

ssme

nt

of

T

issue Ox

ygen

ation

in

the

Crit

ically

ll

B.

Valle

t,

B.

T

averni

er,

an

d

N.

Lund

In

troduc

tion

Dysoxia

is

inadequacy o f tis sue ox yg ena tion, th e condition when ox ygen levels are

so low

th a t m

it ocho

ndrial

r es pir

ation c

an no l

onger

be sus

tained

[

1].

t is

assu

m ed

that

tissue

dy sox i

a and

oxygen

de bt

are ma

jor fac

tors in

th e de

velopm

ent an

d the

pro

pagatio

n

o

f m

ult iple

o r gan

fai lur

e MO

F) in c r

itically

i

ll pat

ie nts.

Dysox i

a

is

the

re

su lt o

f an ab

norm a

l re la t

ionship

be tw

een ox

ygen s

upply

D0

2

)

and ox

ygen d

e

m

and. I n

or der

to p re

vent its

o c cur

rence t

he mai

nte nan

ce of a

dequa

te mea

n arter

i

al

pre ssu

re (MA

P), c a

rdiac o

utput,

and

D0

2

are

ess ent

ial goa

ls o f th

erapy.

Howev

er,

th e ad

equac

y o f th e

se goa

ls

is

ve

ry diff

icult to

de f ine

. Ultim

ately,

a norm

al rela

tion

ship

betwee

n D0

2

and o

xygen

dem an

d shou

ld be d

eterm

ined at

the m

itocho

ndrial

level.

Th e m

easure

m ent

of tissu

e bio e

nergeti

cs wou

ld pro

vid e a

nee de

d go ld

stan

dard [2]. Several s trategie s have b ee n tried re cently to avoid th e development of oxy

gen

d eb t in

in tens

ive ca

re patie

nts . Th

ese s tr

ategie

s involv

e im pr

oveme

nt of s

ystem

ic

hem o

dynam

ics an d

ox yg

en-deri

ved p a

ram ete

rs and

, m ore

rec ent

ly, have

fo cu s

ed

on

re gio

nal pa

ra mete

rs. Thi

s chap

te r pre

sents

these s

trategi

es and

as ses

ses the

ir

us

efu ln e

ss in c

urrent

practic

e.

eterm

inant

s of Tissue

Oxyg

enatio

n

E

xamin

ation

of the

anaero

bic an

d aero

bic ene

rg y cy

cles, w

hich u

se car

bon fra

g

m

ents,

shows t

hat mo

le cula

r oxyge

n

is

in

troduc

ed to th

e ele c

tron tr a

nspor

t chain

via

c

ytochro

me aa

3

in th e

m i toc

hondri

on, wh

ere it s

erves a

s a h yd

ro gen

ion acc

eptor e

s

s

ential t

o adeq

uate en

erg y p

roduct

ion (Fi

g. 1 . T

he m it

ochond

ri al e l

ectron

tran sp

ort

c

hain

is

re spo

nsible

for app

ro xim a

te ly 9

0 o f t

ota l ox

ygen u

tilizat

ion (V

0

2

;

oth

er

o

xy gen a

ses acc

ount f

or the

rem ain

ing 10

[3, 4

]. Extr

am itoc

hondri

al user

s o f m

o

le cula

r oxyge

n h ave

oxy ge

n af fin

ities th

at may

be ord

ers of m

agnit

ude les

s than

tha t

o

f c

ytochro

m e aa

3

•

Such

ox yge

n user

s may

functio

n at P

0

2

valu

es wel

l abov e

th o se

th

at lim

it aero

bic en

ergy p

ro duct

ion. T

he pat

hophys

iologi

c sign i

ficance

o f d

e

crease

d func

tion of

ox yge

nase

is

certain

ly no t

min or

bu t ob

viously

les s re

levan t

th a n

decre

ased c

yto chr

om e aa

3

-a sso

ciated

adenos

in e tri

phosph

ate

A

TP)

pr

oducti

on for

cel

l su rvi

val. If

the ele

ctron

transpo

rt cha

in is li

m it ed

by ox y

gen av

ailabil

ity,

ATP

p

roduc

tion

is

slowed

an d th

e inhi

bito ry

effect of

A

TP on pho

sphofr

uctoki

nase is

re

mov e

d so th

at glyc

olysis is

stim

ulated.

W i th

its en tr

y in to

th e ae

robic c

ycle slo

wed,

J.-L. Vincent (ed.), Yearbook of Intensive Care and Emergency Medicine 2000

© Springer-Verlag Berlin Heidelberg 2000


2/11

716 B.Vallet et al.

ATP - -+ ADP + W + Pi

l ct te

CYTOPL SM

t

*

ITOCHONDRION

ATP

ADP W Pi

/02

oxidative c _ y t . . . _ o _ c - h r ~ o ~ e a a ~

phosphorylation ·

----r-- 3J

L ~

C0

2

Fig. 1. Cell oxygenation. ADP: adenosine diphosphate;

ATP:

adenosine triphosphate; H : hydrogen

ions; NADH: nicot inamide adenine dinucleotide; Pi: inorganic phosphate

the lactate level rises as pyruvate's role as a hydrogen ion acceptor is increased. An

aerobic energy generation by this route is much less efficient and a net energy defi

cit accumulates as V0

2

decreases, and as lactate levels and the lactate/pyruvate ratio

increase [5].

This chain of events was recently verified n vivo [6] by applying near infrared

spectrophotometry to the

hind

limb muscles

of

anesthetized pigs to record oxida

tion-reduction status

of

cytochrome aa

3

• As

limb blood

flow

was progressively

lowered, the cytochrome aa

3

oxidation state began to decrease at the

D0

2

rate

when

V0

2

could no longer be maintained. Venous lactate from the limb began to

increase. In the whole animal, Cain

[7]

showed that an increase in blood lactate

levels marked the onset

of

dysoxia whenever D0

2

became limiting to

V0

2

• This was

true whether the decreased delivery was brought about by lowering arterial oxygen

content (Ca0

2

) or by isovolemic hemodilution to decrease oxygen carried in the

blood.

D0

2

represents the amount

of

oxygen delivered to the peripheral tissues per min

ute:

D0

2

=CO X

Ca0

2

, with Ca0

2

= (Hb X 1.39 X SaOz) + 0.0031 X

Pa0

2

) 1)

Where

CO

represents cardiac output, Hb the hemoglobin level,

Sa0

2

the arterial oxy

gen saturation and Pa0

2

the arterial oxygen tension [8]. The amount

of

dissolved

oxygen is relatively small and can effectively be ignored so that D0

2

can be ex

pressed as

CO X Hb X

1.39

X SaOz

(2)

A fall in Hb

or Sa0

2

does not necessarily result in a fall in

D0

2

as cardiac output can

increase to compensate, but a fall in cardiac output will result in a fall in

D0

2

as

Hb

and

Sa0

2

cannot compensate actively [9].

V0

2

represents the sum

of

all oxidative metabolic reactions in the body (essential

ly cytochrome aa

3

-related oxygen consumption as mentioned above) and can be de

termined indirectly from the Fick equation:

V0

2

=CO X Hb X 1.39 X (Sa0

2

- Sv0

2

) (3)


3/11


4/11

718 B.

Vallet

et al.

0

2

ER

( 0

2

ERcrit) = 3/4 = 0.75. The baseline

D0

2

value in these patients was

10

ml kg/

min, i.e., 0

2

ER

= 3/10 = 0.30. The increase in 0

2

ER from 0.30 to reach an 0

2

ERcrit of

0.75 indicates preserved oxygen extraction capability

in

these patients. This result

confirmed a previous clinical case reported in 1992

of

a Jehovah's Witness in whom

the observed

D0

2

crit was 4.9 ml kg/min with

V0

2

being 2.6 ml kg/min [14]. Mean

oxygen needs

in

the awake adult human being at rest are approx. 3.5 to 4 ml kglmin

[15] resulting in a

D0

2

crit of 4.7 to 5.3 ml kglmin

if

0

2

ERcrit is 0.75. If the oxygen

need is doubled,

D0

2

crit reaches a value close to

10

ml kg/min.

A

10

ml kg/min

D0

2

crit value could therefore be chosen as a 'safe'

D0

2

value

in

the critically ill patient to titrate therapies in order to improve cardiac output, Hb,

and Sa0

2

[16]. If cardiac output can increase to balance a decrease in

D0

2

,

one may

propose (in a patient without previous cardiac disease) to allow Hb to decrease

whenever its plasma concentration value remains above 7 g/100 ml. Indeed,

if

Hb =

7 g/100 ml,

Ca0

2

=

1.39

X

7

X

100

=9.7

ml/100 ml;

if

cardiac

output=

10

1/min (mul

tiplying a baseline cardiac output by a factor

of

2),

D0

2

=

13.8

ml kg/min. Interest

ingly, the

1988

National Institute

of

Health recommendations

[17]

established a sim

ilar transfusion threshold

of

7 g/100 ml in the normal patient. Moreover, a recent

multicenter trial on transfusion strategy in the critically

ill

patient [

18]

clearly dem

onstrated that red cell transfusion for a higher Hb threshold than 7 g/100 ml was of

no benefit, and was even associated with more serious adverse events. In contrast, it

might be necessary to keep a

10

g/100 ml Hb concentration threshold in the patient

without cardiac reserve. Indeed,

ifHb= 10

g/10 ml (Ca0

2

=

13.9

ml oxygen/100 ml),

and if

cardiac output remains 5 1/min (i.e., 5/70 = 71.4 ml kg/min),

D0

2

= 71.4

X

3.9 =

10

ml oxygen/kg/min, keeping

D0

2

around the 'safe' value.

Reaching Supra

normal

Values

of Systemic

Oxygen

Delivery and

Uptake?

Should we do more than titer cardiac output, Hb

and Sa0

2

to maintain

D0

2

above its

potential critical value? Should we use 'supranormal'

D0

2

values to optimize

our

treatment

in

the critically ill patient? This strategy was proposed long ago by Shoe

maker et al. [ 19]. Their message was rather simple: The 'normal' hemodynamic val

ues are 'abnormal ' in a critically ill patient. This arose from the consistent observa

tion that critically ill patients who survived,

had

higher cardiac output

and D0

2

val

ues than those found in non-survivors, and higher than standard physiological

values. The consequence of this observation was to push hemodynamics up to val

ues that were found to be the threshold values which better discriminate between

survivors

and

non-survivors. One very important question was raised when multi

center trials tested the hypothesis that supranormal hemodynamics,

D0

2

and V0

2

could improve survival:

Is

there any particular relationship between the ability to in

crease

D0

2

and V0

2

with respect to treatment

and

outcome?

In fact, we

[20]

demonstrated that failure to respond to treatment is an indicator

of poor

prognosis

in

patients with sepsis, and that survivors

had

a significantly

greater percentage increase in cardiac index,

D0

2

and

V0

2

in response to a

60

min

infusion

of

dobutamine (dobutamine test,

10

p.glkg/min) than did the non-survi

vors. In particular,

V0

2

did

not

increase in non-survivors in this study. Rhodes et

al.

[21], and more recently Hayes et

al.

[22], confirmed these results. These studies have


5/11


6/11

720 B.Vallet et al.

i.e., decreased APC0

2

,

whereas

V0

2

remained unchanged. I f gastric pHi or APC0

2

is

a better indicator of hypoperfusion than related increases in V0

2

, then catechola

mine titration should be optimized by this method, which might help to enhance

survival rates

in

critically

ill

patients [26].

Veno Arterial C0

Difference:

Marker of

Tissue

Dysoxia?

Bowles et al. [27],

Vander

Linden et al. [28], and Zhang and Vincent

[29]

have de

scribed animal models in which they reduced D0

2

by reducing cardiac output

in

protocols

of

progressive hemorrhage

or

cardiac tamponade.

As V0

2

remained con

stant, Bowles et al.

[27]

reported

an

elevation in veno-arterial APC0

2

from

4.2

to

14.9

mmHg following the reduction in

D0

2

; Vander

Linden et al. [28] measured an

increase in veno-arterial APC0

2

from 4.3 to

12.9

mmHg;

and

Zhang

and

Vincent [29]

made the same type

of

observation. In this situation

of

oxygen supply-independen

cy and stable

C0

2

production, elevation

of

veno-arterial APC0

2

following flow re

duction can be explained simply by

C0

2

stagnation. A veno-arterial APC0

2

value

of

15

mmHg may therefore

be

considered as the maximal value to

be

accepted.

In those studies, when

D0

2

was further reduced below its critical value, a decrease

in V0

2

was observed, suggesting oxygen supply-dependency and appearance of an

aerobic metabolism. When measured, an increase

in

lactate concentration con

firmed this assumption

[28,

29]. The progressive widening of veno-arterial APC0

2

,

observed before

D0

2

had reached the critical point, was magnified by a sharp in

crease

in

PvC0

2

when

D0

2

decreased below that point (with veno-arterial APC0

2

approx.

30

mmHg). The authors

[28,

29] assumed that this steep increase

in

APC0

2

can

be

used as a reliable marker

of

tissue dysoxia since

D0

2

crit calculated by either

using the V0

2

to

D0

2

,

lactate to

D0

2

,

or APC0

2

to

D0

2

dual-regression analysis gave

the same result. However,

in

a recent review, Teboul et al.

[30]

noticed that aerobic

production

of C0

2

is theoretically reduced when tissue dysoxia

is

present (as

VC0

2

=

R

X

V0

2

,

and proposed that an explanation

of

venous and tissue hypercar

bia in low-flow states emerges from the curvilinearity

of

the Fick equation.

As

men

tioned above,

if

anaerobic

C0

2

production occurred under conditions

of

tissue dys

oxia, it would result from buffering of excess

H+

by

HC03.

However, as underlined

by Teboul et al.

[30],

all studies that have addressed the issue

of

detecting tissue dys

oxia by analysis

of

APC0

2

used experimental protocols

of

reducing blood flow. The

presence

of

a decrease in cardiac output acts as a confounding variable,

and

results

in difficulties in drawing any definitive conclusions. The authors suggested the need

for experimental studies

in

which cell dysoxia would be created by a mechanism

other than reducing blood

flow.

For example, a decrease

in

D0

2

may

be

obtained by

lowering Ca0

2

•

We

used the well-described

n

situ isolated, innervated canine

hind

limb model

[31]

to address this issue. In this model, the femoral artery was isolated, cannulated,

and

perfused with a roller pump-membrane oxygenator circuit that originated

in

the opposite femoral artery.

We

decreased D0

2

by either decreasing flow (ischemic

hypoxia, IH)

or

arterial

P0

2

(hypoxic hypoxia, HH)

in

this isolated

hind

limb. Dur

ing hypoxia, total

D0

2

was significantly lowered beyond

D0

2

crit in both groups

and


7/11

Assessment

ofTissue Oxygenation

in the

Critically

Ill

72

hind limb

V0

2

decreased significantly. Regional vena-arterial APC0

2

was altered in

a very different fashion

in

IH and HH and increased only when flow was decreased,

even though the limbs of both groups experienced the same oxygen deficit. From

these results we concluded that absence

of

increased vena-arterial APC0

2

does not

preclude the presence of tissue dysoxia. As anticipated, decreased flow appeared to

be a major determinant

of

increased APC0

2

•

Mucosal

to Arterial C0

Difference: Marker of

Regional

Tissue

Dysoxia?

Our attention then focused on gut production of C0

2

during hypoxia since an in

crease in gastrointestinal mucosal

PC0

2

(PmC0

2

)

was proposed:

1)

as an early mark

er

of

inadequate oxygen supply in shock states; and 2) to indicate risk of gut epithe

lial dysfunction

[32]

that may facilitate the passage

of

enteric bacterial endotoxin

into the circulation, which would ultimately lead to

MOF

[33]. Schlichtig

and

Bowles

[34]

presented convincing evidence that changes in mucosal

PC0

2

,

which mirror

changes in V0

2

during progressive flow stagnation, most likely represent dysoxia. In

deed, the authors observed that tonometer-estimated mucosal

PC0

2

increased to

values nearly threefold higher than that predicted with the Dill nomogram. Analysis

of

the Dill blood nomogram shows the aerobic relationship between PvC0

2

and

Sv0

2

• If PvC0

2

is known, Sv0

2

is predictable from the Dill blood nomogram

S v o ~ m ) .

An

v o ~ m

that agrees with measured Sv0

2

therefore indicates appearance

of

dissolved

C0

2

purely

on

the basis

of

aerobic metabolism, whereas

an v o ~ m l e s s

than

measured Sv0

2

represents conversion

of

HC03

to dissolved

C0

2

by anaerobic

processes [34]. Moreover, Schlichtig and Bowles [34] also observed that

PmC0

2

markedly exceeded

PC0

2

values in portal venous blood when flow was decreased

below the critical

D0

2

(200 versus

75

mmHg at zero flow), and that only a maximal

mucosal-arterial APC0

2

gradient around 25-35 mmHg was consistent with aerobic

C0

2

•

The authors assumed that, above this value, a further increase

in

mucosal-arte

rial APC0

2

was consistent with mucosal dysoxia. However, in this particular study,

low flow remained as a confounding variable. Again, to this date, whether increased

C0

2

gap represents dysoxia,

or

impaired washout

of C0

2

at the level

of

the gastroin

testinal mucosa, remains unknown.

In a series

of

experiments we explored the issue

of

detecting tissue dysoxia by

analysis of APC0

2

in

another animal model of hypoxia where both vena-arterial

C0

2

gap (P(v-a)C0

2

)

and gut mucosal-arterial

C0

2

gap (P(r-a)C0

2

)

were measured

[35]. In a first group

of

six anesthetized, ventilated and instrumented (Swan-Ganz

catheter-Baxter, NGS tonometer-Tonometries) pigs, the inspired oxygen fraction

was progressively reduced every

30

min.

in

five

steps (step 1 to step 5), from

0.21

to

0.08 (hypoxic hypoxia, HH). In a second group of 5 pigs, blood was removed every

hour

(25% at step

1, 15

at step 3,

10

at step

5)

providing progressive ischemic

hypoxia (IH). Gut wall blood flow

(GBF)

was measured with a mucosal surface laser

probe (PF219-Perimed) that was placed close to the tonometer in a loop of the small

intestine. Both groups exhibited a biphasic

V0

2

to

D0

2

relationship suggesting oxy

gen supply dependency with a critical

D0

2

at 7 ml kglmin. Moreover, oxygen supply

dependency was confirmed by a sharp increase in arterial lactate when D0

2

de-


8/11


9/11

Assessment ofTissue Oxygenation

in the

Critically

Ill

723

intestinal intramucosal pH (pHi). In all published studies

of

patients admitted to

ICUs,

an

abnormally low pHi has been found to be common and associated with a

poor

outcome (for a review see [43]). However, many

flaws

in the determination of

pHi have been described,

and

in order to solve them the difference between arterial

pH (pHa) and pHi,

or

the arterial

PC0

2

(PaC0

2

) and tonometer

C0

2

have been pro

posed as more useful indices

of

gut mucosal perfusion [43]. It has been stated that

the pHi to pHa gap is illogical since

pH

scale is logarithmic [43]. The C0

2

gap seems

to be the most logical since the gut luminal

PC0

2

is a true measure, and normalizing

it to PaC0

2

solves any interpretational problem caused by respiratory acidosis

oral-

kalosis (for a review see [

43] ).

Automated tonometric measurement is now proposed

to provide regional

PC0

2

(PrC0

2

)

on

a semi-continuous basis. The Tonocap (Tono

metries & Datex) utilizes a tonometer balloon filled with air rather than saline. The

gas is automatically sampled after an equilibration period of

15

min, and measured

with

an

infrared sensor. The Tonocap automatically keeps track

of

end-tidal

C0

2

(PetC0

2

)

and

PrC0

2

. The monitoring

of

PetC0

2

is

interrupted at regular intervals to

allow for the determination

of

PrC0

2

from the tonometric catheter. Blood gas values

may be entered via the Tonocap keyboard for the calculation of pHi, with

pHi=

pHa

log

(PrC0

2

/PaC0

2

). The Tonocap trend screen can display both

PrC0

2

and

PetC0

2

to indicate any P(r-et)C0

2

gradient. PetC0

2

s

used as a noninvasive index of

PaC02.

The Tonocap is currently undergoing laboratory

and

human investigations

and

seems to be a reliable and an easy-to-use technique. The Tonocap allows semi-con

tinuous monitoring of P(r-et)C0

2

gap throughout the patient's stay

in

the ICU and

may therefore provide a useful monitor to trigger appropriate interventions. Consid

ering the results

we

obtained with regional capnometry at the level

of

the gut, in

both ischemic and hypoxic hypoxia (i.e., an increase in P(r-a)C0

2

), we

feel that gas

trointestinal tonometry, in particular with automated on-line tonometry, remains a

promising approach to establish clinical interest in the monitoring

of

gut perfusion

and associated dysoxia.

We

used gastrointestinal automated on-line air tonometry to

monitor gastric perfusion in patients at risk of circulatory failure after cardiopulmo

nary bypass (CPB) [44]. In this study, circulatory failure was prospectively defined as

requirement for vasoactive support to maintain MAP

~

70 mmHg after optimal fill

ing. Hemodynamic variables,

D0

2

,

V0

2

, venous-to-arterial [P(v-a)C0

2

], gastric-to

arterial [P(r-a)C02]

and

gastric-to-end-tidal [P(r-et)C02]

PC0

2gap were retrospec

tively compared

in

14

patients with

or

without circulatory failure during a 12-hour

post-bypass period

(HO

to H12). In contrast to patients without circulatory failure

(n = 7), in patients with circulatory failure (n =

7)

increased

vo2

was not associated

with an increase in

D0

2

. P(r-a)C0

2

was larger at

HO

in circulatory failure patients

and was the sole parameter to be different between the two groups at this time.

P(v-a)C0

2

did not vary significantly in both groups while P(r-a)C0

2

increased to a

larger extent from

HO

to H12 in patients with circulatory failure suggesting selective

gastrointestinal hypoperfusion in this group. P(r-et)C0

2

provided comparable in

formation to P(r-a)C0

2

. Hospital length of stay was 4 days longer (p


10/11


11/11

Assessment

ofTissue Oxygenation

in the

Critically Ill 725

19. ShoemakerWC, Appel PL, Waxman K, Schwartz

S,

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