Critères d’évaluation et de prélevabilité des greffons pulmonaires chez un patient

en état de mort encéphalique

Hervé

MalService de Pneumologie et Transplantation

PulmonaireHôpital Bichat, Paris

Comment résoudre le problème de la pénurie de greffons?

•

Promouvoir le don d’organes à

partir de patients en état mort encéphalique

•

Favoriser le prélèvement sur donneur à cœur arrêté

•

Augmenter la proportion de poumons prélevés

Rate of lung harvesting 2006

Australia Austria Belgium UK USA France

54% 49% 29.7% 19% 17.8% 14%

Augmenter la proportion de poumons prélevés

•

Optimisation de la formation/motivation des réanimateurs/coordinateurs en charge des donneurs en matière de prélèvement pulmonaire

•

Améliorer l’état fonctionnel des poumons de qualité médiocre

–

management médical actif des poumons de donneurs–

reconditionnement ex-vivo

•

Libéralisation des critères «

idéaux

»

de donneur pulmonaire

The « ideal » criteria•

Age 300 mmHg on FIO2

:1 •

Tobaccco history

« Ideal criteria »•

Main flaws:–

Empirical, based on opinions of experts and not on evidence

–

Doubt on the ability of the criteria to allow a a good selection

of lung donors. Suspected to lead to reject a high number of usable lungs

Physiological, histological and microbiological assessment : 29 pairs of rejected lungs : 41 % potentially suitable for LT ( Ware Lancet 2002)

•

Given the shortage of donor lungs, many centers proposed to go beyond the ideal criteria and to use lungs which do not satisfy one ore more among the «

ideal criteria

»

: marginal donors

•

Does the use of marginal donors lead to a decreased margin of safety?

Assessment of the use of marginal donors

•

Comparison of LT results using ideal donors versus marginal donors–

PGD

–

Length of stay in ICU, duration of MV–

Survival (global, early, late)

•

Identification by multivariate analysis of a donor related risk factor (age, PaO2

/FIO2

…) from large multicenter studies –

Early gas exchange

–

Survival

Comparison of LT results using ideal donors versus marginal donors

•

Liberalization of donor criteria does not affect outcome–

Sundaresan JTCS 1995 (133 donors, extended 33%)

–

Gabbay AJRCCM 1999 (112 donors, extended 57%)–

Bhorade JHLT 2000 (113 donors, extended : 46%)

–

Lardinois EJCS 2005 (148 donors, extended : 42%)–

Aigner EJCS 2005 (94 donors, extended: 24.5%)

Comparison of LT results using ideal donors vs marginal donors

•

Word of caution–

Pierre JTCS 2002 (123 donors, extended 51%)

•

30-day mortality: marginal 17.5%, standard 6% p=0.047

–

Botha JTCS 2006 (201 donors, extended 41%)•

Grade 3 PGD : 44% of marginal, 27.5% of ideal p=0.015

•

Organ specific 90-d mortality :15.7% vs 5% p=0.012

Comparison of LT results using ideal donors versus marginal donors

Critical analysis•

Retrospective

•

Single center •

Low power

•

In many studies, one of the criteria is never violated (ex : Pa02

/FIO2 Bhorade, Gabbay, Pierre)

•

Lack of precision about the extent of violation of each criterionEx: PaO2

250 mmHg vs 150 mmHg? •

The distribution of extended criteria is sometimes not mentioned

•

Methodological weakness: extended criteria group made of a mixture of criteria. Giving each of the extended criteria the same weight is against the common sense: donor of 57 yrs, or 22 pack yrs qualified as marginal as well as a donor with PaO2

/FIO2

ratio at 150 or bilateral pulmonary infiltrates

Identification of a donor related risk factor from large multicenter studies•

From the ISHLT registry or other large multicenter database

•

Multivariate analysis to assess the relationship between donor characteristics and outcome

•

Limitations–

Retrospective studies

–

The number of studied lung donor characteristics is low. ISHLT Registry: smoking history, abnormality of airway secretions, abnormality of chest radiograph or donor PaO2

/FIO2 are

not recorded

•

Donor age•

PaO2

/FIO2•

Chest radiograph

•

Purulent airway secretions•

Smoking history

•

Duration of mechanical ventilation•

Ischemic time

•

Size matching

A review of lung transplant donor acceptability criteriaOrens et al JHLT 2003

Influence of donor age

•

49 LT recipients from donors >50 yrs vs 244 recipients from younger donors (Fischer JTCS 2005)–

No incidence on early PaO2

/FIO2

or survival–

Only 6 donors >60 yrs

•

60 LT recipients from donors >60 yrs vs 407 recipients from younger donors (De Perrot JTCS 2007)–

Trend toward a higher 30-day and 10-yr mortality in the older donor group

Influence of donor age

•

ISHLT Registry–

Donor age identified as an independent risk factor of recipient 1 yr mortality in 2006 not in 2007

–

Interaction between donor age and ischemic time on survival

0

0,5

1

1,5

2

15 20 25 30 35 40 45 50 55Donor Age

Rel

ativ

e R

isk

of 1

Yea

r Mor

talit

y

.

p = 0.083

Trulock JHLT 2006 Trulock JHLT 2007

Influence of donor age

•

Lungs from donors >55 yrs can be used•

At the expense of a probable majoration of the risk for the recipient

•

Upper limit of age unknown•

Is the risk even higher in case of a combination of extended criteria?

•

Caution in case of older donor and long ischemic time

Chest radiograph (CXR) abnormality•

Although the presence of abnormal CXR is the most frequent extended criterion noted in the studies comparing ideal and marginal donors, no series provide outcome data

•

No firm guidelines regarding utilization of such donors•

Analysis of donor CXR: a very subjective form of assessment–

Great interobserver variability (Bolton EJCS 2003) : difficulty of lecture of CXR in ICU

•

CXR abnormality may disappear after optimization of the donor (Straznicka 2002, Mc Cowin 2005, Angel 2006)

•

Probably not the same problem if atelectasis, infiltrates, pleural effusion

•

CT scan: detection of emphysema, bronchiectasis, atelectasis, infiltrates, nodule

•

Is the traditional limit of PaO2

at 300 mmHg on FIO2

1 PEEP 5 cmH2

O too strict?

•

PaO2

/FIO2

: apparently the only objective tool in the evaluation of donors but in fact one of the most challenging issue

•

In several studies comparing ideal vs marginal donors, this criterion was not violated (Gabbay, Bhorade, Pierre)

•

Few studies have focused on donors with PaO2

/FIO2ratio

Multivariate analysis to assess the relationship between donor characteristics and outcome

•

French multicenter experience–

785 LT from 1988 to 1998 in 7 centers

–

No effect of donor age on outcome

–

PaO2

/FIO2

before harvest significantly associated with early gas exchange, duration of MV, long-term survival

–

Steep increase in RRisk of death when PaO2

/FIO2

< 350

Thabut JHLT 2005

Donor PaO2

•

Physiological, histological and microbiological assessment of 29 rejected lung

•

Lungs from donor with PaO2

Effect of donor management on gas exchange

•

Effective management can improve arterial gas exchange in donors with initial poor oxygenation

–

Gabbay AJRCCM 1999–

Straznicka JTCS 2002

–

Angel AJRCCM 2006(At the time of procurement, all patients had PaO2

/FIO2ratio>300

•

ex vivo reconditioning

•Frequent discrepancy between arterial PaO2

in ICU and pulmonary vein PO2

obtained intraoperatively during harvesting

•Among 182 donor lungs evaluated (91 donors): 40 lungs with pulmonary vein P02

>300 mmHg whereas PaO2

Critères d’évaluation du greffon pulmonaire

•

Age•

Données anamnestiques (tabagisme chiffré, maladie respiratoire, antécédents chir thoracique, durée MCE, notion d’inhalation)

•

Poids/taille•

Gazométrie récente en FIO2

100%, PEP 5cmH20 (obtenue en réa et non pendant le prélèvement)

•

RxP (TDM si possible)•

Aspect des sécrétions (fibro souhaitable mais pas indispensable)

Critères absolus de non prélevabilité

•

Age du donneur >70 ans•

Images alvéolaires bilatérales

non

réversibles après une fibroaspiration ou une déplétion hydrosodée

•

Rapport PaO2

/FIO2

Critères ne constituant pas une contre- indication absolue au prélèvement

pulmonaire •

Age >55-60 ans

•

Présence de sécrétions purulentes dans les voies aériennes•

Notion d’inhalation

•

Anomalie radiologique unilatérale non réversible après «

optimisation

»: Possibilité

d’utiliser un seul poumon

•

Tabagisme >20paquets

/années•

Antécédents de maladie asthmatique

•

Durée d’ischémie totale prévisionnelle longue

Nécessité

d’une discussion au cas par cas

•

Donor PaO2

should be interpreted according to CXR P

PaO2

after optimization

Conclusions•

Selection of donors based on ideal criteria is effective but this assesment is imprecise and subjective leading to the rejection of usable lungs

•

Current data suggest that it is possible to use lungs with extended criteria

•

The extended criteria are also subjective and imprecise. Up to which limits each criterion could be violated?.

•

The weight of each criterion is probably not the same. Many groups consider that some criteria should not be violated at the time of procurement

•

Little is known on the effect of combined extended criteria. Donor score?

•

Some criteria may be modified by an active management•

Development of reliable tools allowing an objective assessment

Lung donor score•

Age

•

Smoking history•

CXR

•

Secretions•

PaO2

/FIO2

(double weighting)

-

Relation found between score and early post transplant outcome (PaO2

/FIO2

, PGD, intub hours…) in Melbourne (Oto et al Ann Thorac Surg 2007)

-

No relation found in Toronto (Cypel et al, ISHLT 2008)

A novel strategy to assess donor lung based on a reliable biological marker ?

•

Association between proinflammatory cytokines in the donor lung and subsequent development of severe I/R injury (Fisher AJRCCM 2001)

•

mRNA expression of various pro and anti- inflammatory cytokines in 169 lung donors biopsies

obtained before implantation (Kaneda AJT 2006)–

The most predictive risk factor of 30-day mortality: IL6/IL10

–

Identification of group with a high risk of mortality: those highest IL6/IL10 ratio

DONOR AGE DISTRIBUTION FOR LUNG TRANSPLANTS BY ERA

05

10152025303540

0-11 12-17 18-29 30-39 40-49 50-59 60-64 65+

% o

f tra

nspl

ants

1985-1994 (N = 4,658)1995-1999 (N=7,116)2000-6/2006 (N=11,851)

p < 0.0001

ISHLT 2007J Heart Lung Transplant 2007;26: 782-795

Limitations

•

Retrospective studies•

The number of lung donor characteristics studied is low. No record of:–

smoking history not recorded

–

abnormality of airway secretions–

abnormality of chest radiograph

–

donor PaO2

/FIO2

Is there a place for a lung donor score?

•

None of the selection criteria is unquestionable•

The weight of each criterion in the decision making process is not clear

•

Some criteria may probably be extended. What is the influence of the combinaison of extended criteria?

•

Lung donor score–

Improve decision making

–

Allow data comparison among centers

•

Age ischemic time•

Optimisation gabbay

•

Le score •

Ya peut être une aug de risque Tout depend de la severité

du pt

•

C’est deja integre (registre) notament sur l’age•

Est ce que les critères sont la bonne façon dévaluer un lung donor

•

La photo d’un donneur•

Le fait que l’austarlie prelève autant montre que els critères sont pas bons

•

Le tdm•

Que sait-on de l’interaction des critères entre eux?

Indirect guments showing that the current criteria are not appropriate

•

australie taux de preleveme,nt

•

Ware •

fisher

47,1

41,6

32,629,0 28,5

27,023,3

19,118,0 17,3 15,7

10,3 8,2

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Taux

de

Tran

spla

ntat

ions

pul

mon

aire

s pa

r do

nneu

r pré

levé

Autric

he

Austr

alie/

NZ

Suiss

e

Cana

da

Scan

dinav

ie

Belgi

que L

ux UK

Allem

agne

Moye

nne

USA

Pays

Bas

Espa

gne

Franc

e

Marginal donor

•

Definition: one or more among the «

deal

» criria is not satistified

ADULT LUNG TRANSPLANTS

(1/1995-6/2005) Risk Factors for 1 Year Mortality

Donor Age

0

0,5

1

1,5

2

15 20 25 30 35 40 45 50 55

Donor Age

Rel

ativ

e R

isk

of 1

Yea

r Mor

talit

y

.

p = 0.083

ISHLT 2007J Heart Lung Transplant 2007;26: 782-795

Thabut JHLT 2005

Multivariate analysis to assess the relationship between donor characteristics and outcome

•

French multicenter experience–

785 LT from 1988 to 1998 in 7 french centers

–

No effect of donor age PaO2

/FIO2

before harvest significnatly associated with early gas exchange , duration of MV, long-term survival

–

Steep increase in RR of death when PaO2/FIO2< 350

Thabut

JHLT 2005

Critères d’évaluation et de prélevabilité des greffons pulmonaires chez un patient en état de mort encéphaliqueComment résoudre le problème de la pénurie de greffons?Rate of lung harvesting�2006Augmenter la proportion de poumons prélevésThe « ideal » criteria« Ideal criteria »Assessment of the use of marginal donorsComparison of LT results using ideal donors versus marginal donorsComparison of LT results using ideal donors vs marginal donorsComparison of LT results using ideal donors versus marginal donors�Critical analysisIdentification of a donor related risk factor from large multicenter studiesDiapositive numéro 12Influence of donor ageInfluence of donor ageInfluence of donor ageChest radiograph (CXR) abnormalityDiapositive numéro 17Diapositive numéro 18Diapositive numéro 19Is the traditional limit of PaO2 at 300 mmHg on FIO2 1 PEEP 5 cmH2O too strict?Multivariate analysis to assess the relationship between donor characteristics and outcomeDonor PaO2Effect of donor management on gas exchangeDiapositive numéro 24Critères d’évaluation du greffon pulmonaireCritères absolus de non prélevabilitéCritères ne constituant pas une contre-indication absolue au prélèvement pulmonaire Diapositive numéro 28ConclusionsDiapositive numéro 30Lung donor scoreA novel strategy to assess donor lung based on a reliable biological marker ?Diapositive numéro 33Diapositive numéro 34Diapositive numéro 35DONOR AGE DISTRIBUTION FOR �LUNG TRANSPLANTS BY ERALimitationsIs there a place for a lung donor score?Diapositive numéro 39Indirect guments showing that the current criteria are not appropriate�Marginal donor�ADULT LUNG TRANSPLANTS (1/1995-6/2005) �Risk Factors for 1 Year Mortality�Donor AgeDiapositive numéro 43Diapositive numéro 44Multivariate analysis to assess the relationship between donor characteristics and outcome