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Faculte de Pharmacie, Universite de Montreal, C.P. 6128, succursale Centre-Ville, Montreal, QC, Canada H3C 3J7
Pharmacy Department, McGill University Health Centre, 1650 Cedar Avenue, Montreal, QC, Canada H3G 1A4
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Pharmacy Department and 4 Department of Critical Care, Hopital du Sacre-Coeur de Montreal, 5400 Gouin W, Montreal, QC, Canada H4J 1C5
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Pharmacy Department, Hopital Honore Mercier, 2750 Laframboise boul., St-Hyacinthe, QC, Canada J2S 4Y8
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Pharmacy Department, Centre Hospitalier Universitaire de Montreal, 1560 Sherbrooke E, Montreal, QC, Canada H2L 4M1
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Faculte de Medecine, Universite de Montreal, Pavillon Roger-Gaudry, 2900 Edouard-Montpetit, Montreal, QC, Canada H3T 1J4
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& The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
BJA
Methods
Randomized controlled trials (RCTs) and observational studies
were identified using electronic and manual search strategies.
In March 2013, MEDLINE and EMBASE were searched from the
earliest accessible date. A qualified librarian reviewed the final
search strategy. Terms defining the study treatments (CSs) and
the study population (brain death and tissue donor) were combined. No filters were used in the search but a limit to human
was applied. The bibliographies of identified studies and reviews
were manually searched for additional studies. The full MEDLINE
search strategy is available in Supplementary Appendix S1.
Eligibility criteria
Studies evaluating brain-dead potential organ donor patients,
without age restrictions, comparing the effects of the systemic
administration of any CS with those of placebo, standard treatment, or another active comparator were sought. Animal
studies and case series presenting only descriptive data or
lacking any comparison were excluded. Studies evaluating CS
efficacy on any clinical primary or secondary outcome measures, safety, or both were included. Clinical outcomes could
be evaluated on donors, recipients, or both. Studies evaluating
only biochemical markers or hormone levels were excluded.
There was no restriction for date and language of publication.
Reasons for exclusions were documented.
Study selection
Two independent reviewers (A.J.F. and D.R.W.) screened all
citations based on titles and abstracts. Full articles of selected
citations were then retrieved for eligibility assessment.
Disagreements were resolved by consensus.
Data synthesis
Sensitivity analyses were planned to evaluate the potential
effect of the following subgroups on efficacy: children vs
adults (16 yr of age or older), type of CS, concomitant active
study treatment (vasopressin, liothyronine, or other), and
year of publication. However, pooled estimates of outcome
measures were not calculated because of study clinical and
methodological heterogeneity.
Results
Included studies
The MEDLINEand EMBASE search strategies identified 1089 citations after duplicate removal. An additional, 15 records were
identified through manual search and screened. From these,
56 full-text articles were assessed for eligibility. The SR included
11 RCTs24 34 and 14 were observational studies.14 17 35 44
Reasons for exclusion are listed in Figure 1. Patient characteristics of studies are listed in Tables 1 and 2. Financial sponsorship,
when declared, was mainly from non-profit organizations or
institutes. Ten of the studies declared financial sponsorship,14
15 24 25 27 30 32 34 40
with only one of them being from a
private company.24 One study declared having received no financial support43 and no information on financial support was
provided in the remaining studies.16 17 26 28 29 31 35 39 41 42 44
Study population
The number of included donors in each study varied widely, and
studies that measured recipient outcomes did not always
report the number of donors. Patient characteristics of study
population can be found in Tables 1 and 2. Of note, variation
in patient characteristics was an important source of clinical
347
Search strategy
BJA
Dupuis et al.
No corticosteroids (n=5)
No clinical outcome (n=2)
Letter (n=1)
Living donor (n=1)
Animal study (n=2)
No control group (n=10)
Review (n=2)
No direct statistical comparison (n=8)
348
outcome, the immunosuppressive regimen consisted of a calcineurin inhibitor-based maintenance therapy with or without
induction therapy depending on different risk factors. AntiCD25s were the preferred induction agents.33 In an older
study, no induction therapy was used and the maintenance
treatment consisted of azathioprine and MP.44
Corticosteroid dose/regimen
Most studies used MP as their CS of choice (Tables 1 and 2).
Most used fixed single-dose regimen varying from 1 to 5 g
of MP administered intravenously,24 27 31 34 38 39 42 whereas others used a weight-based single dose varying from 15
to 60 mg kg21.16 28 37 One study used an MP 250 mg i.v. bolus
followed by a 100 mg h21 i.v. infusion.30 One study used hydrocortisone29 and two used cortisol.17 41 Four of them did
not specify any dosing of corticosteroids used in their
studies.14 15 36 40 One study compared the use of low-dose
hydrocortisone consisting of a 300 mg i.v. bolus followed by
100 mg given every 8 h to high-dose MP at 15 mg kg21 i.v.
repeated every 24 h.43
BJA
Table 1 Characteristics and results of non-randomized studies of corticosteroid use in organ donor management. CP, cyclophosphamide; CPO,
cardiac power output; CVP, central venous pressure; D, donors; EVLWI, extravascular lung water index; HC, hydrocortisone; LVSWI, left ventricular
stroke work index; MAP, mean arterial pressure; MP, methylprednisolone; NM, not mentioned; NS, not significant; R, recipients; RVSWI, right
ventricular stroke work index; SBP, systolic blood pressure; T3, thyroid hormones (liothyronine). *Three studies are presented in the same paper:
Study 1 was a pre poststudy without randomization (n106); Study 2 was alternating allocation to treatment (n45); Study 3 was randomized
(n19)
Study/country
n (D/R)
Clinical endpoints
Chatterjee 1977/
USA24
50/84
Treatment: MP 5 g i.v.1
Control: usual care
Comment: dopamine and
isoproterenol allowed in both groups
Dienst 1977*/
USA25
NM/180
Study 1:
Treatment: MP 3 g i.v.+CP 3 g i.v.1
Control: usual care
Study 2:
treatment: MP 5 g i.v.+CP 3 g i.v.1
Control: usual care
Study 3:
Treatment: MP 5 g i.v.+CP 5 g i.v.1
Control: placebo
Jeffery 1978/
Canada26
NM/52
Soulillou 1979/
France27
NM/62
Corry 1980/USA28
NM/53
Kainz 2010/
Austria33
269/455
Treatment: MP 1 g i.v.1
Control: placebo
Comment: vasopressors allowed in
both groups
Kotsch 2008/
Germany30
100/100
Amatschek 2012/
Austria34
90/83
Treatment: MP 1 g i.v.1
Controls: placebo
Comment: vasopressors allowed in
both groups
Trajectories of transaminases
(AST/ALT) within the first week
Graft loss, mortality and
biopsy-confirmed acute
rejection within 3 yr
Kidney donors
Continued
349
Liver donors
BJA
Dupuis et al.
Table 1 Continued
Study/country
n (D/R)
Clinical endpoints
60/NM
Group 1: MP 1 g i.v.1
Group 2: MP 1 g i.v.1+T3 0.8 mg kg21
i.v.1 then 0.113 mg kg21 h21
Group 3: T3 0.8 mg/kg i.v.1 then
0.113 mg kg21 h21
Control: placebo
Comment: vasopressin (as a
vasopressor), catecholamines and
insulin (for glucose control) were
allowed in both groups. Preference for
colloids over crystalloids fluid
replacement
80/NM
Group 1: MP 1 g i.v.1
Group 2: MP 1 g i.v.1+T3 0.8 mg kg21
i.v.1 then 0.113 mg kg21 h21
Group 3: T3 0.8 mg kg21 i.v.1 then
0.113 mg kg21 h21
Control: placebo
Comment: vasopressin (as a
vasopressor), catecholamines and
insulin (for glucose control) were
allowed in both groups. Preference for
colloids over crystalloids fluid
replacement
40/NM
Change in haemodynamic
parameters (SBP, CVP,
dobutamine requirements)
New or worsening metabolic
acidosis
Probability of procurement
Lung donors
Venkateswaran
2008/UK31
Venkateswaran
2009/UK32
vasopressin were sometimes administered as part of a hormonal replacement cocktail with MP. In contrast, some studies
stated that insulin was administered in both groups for
glucose control only,29 32 43 and others administered vasopressin as a vasopressor rather than for hormonal replacement.31 32
Five studies also combined a single i.v. administration of
cyclophosphamide to MP.25 28 44 Most of the time, all these
concomitant treatments were only administered in the treatment group. A few studies also included MP as part of a more
aggressive donor management protocols that were used
to optimize mechanical ventilation and fluid therapy for
instance.10 35 36
Efficacy outcomes
Efficacy outcomes were divided into three categories: (1)
haemodynamic and oxygenation parameters improvement,
(2) organ recovery and (3) graft survival. Pooled estimates of
outcome measures were planned for RCTs, they were not calculated because of significant clinical and methodological heterogeneity, although kidney graft survival was the primary
outcome in six of the included RCTs and liver graft survival in
350
Heart donors
BJA
Table 2 Characteristics and results of non-randomized studies of corticosteroids use in organ donor management. CI, cardiac index; CO, cardiac
output; CP, cyclophosphamide; CVP, central venous pressure; D, donors; HC, hydrocortisone; HD, high dose; HR, heart rate; LD, low dose; MAP, mean
arterial pressure; MP, methylprednisolone; NM, not mentioned; NS, Not significant; OR, odds ratio; R, recipients; RR, relative risk; SBP, systolic blood
pressure; SVR, systemic vascular resistance; T3, thyroid hormones (liothyronine); T4, thyroid hormones (thyroxine). *Actual donors were defined as
donors who were taken to the operating room for organ procurement
n
Study design
Studied
population
Clinical endpoints
Results (treatment
vs control)
Zincke
1978/USA44
Treatment:
35
control: 32
Retrospective
cohort
Successfully
transplanted
kidney
recipients
Treatment: MP 50 60 mg kg21
i.v.1+CP 60 to 80 mg kg21
i.v.1
Control: usual care
Comment: treatment group
also investigating new pulsatile
perfusion modality
Three-year patient
survival
Three-year graft
survival (failure
defined as need for
haemodialysis)
No difference in
patient survival at 3
yr (83% vs 91%,
P-value not stated)
Increased graft
survival at 3 yr (72%
vs 36%, P,0.01)
Novitzky
1987/South
Africa17
Treatment:
21
Control: 26
Historical
controls
consecutive
donors
Consecutive
potential
donors
Proportion of heart
donors
Change in
haemodynamic
and metabolic
parameters
Increased proportion
of heart donors
(100% vs 81%,
P,0.04)
Increased MAP, CO
and HR
Decrease in CVP and
bicarbonate
requirement
Decreased inotropic
support
Taniguchi
1992/
Japan41
Treatment: 4
Control: 12
Clinical trial
Patients with
cerebral death
Treatment: cortisol 3 5 mg
kg21 i.v. daily+T3 1 1.5 mg
kg21 orally daily
Control: fluids only
Follette
1998/USA16
Treatment:
80
Control: 38
Retrospective
cohort
Multi-organ
potential
donors
Exclusions: age
.55, large
steroid dose
before brain
death, hepatitis
B or C
Treatment: high-dose MP
(mean 14.5 mg kg21)1
Control: usual care
Comment: vasopressin allowed
in both groups
Number of lungs
procured
Change in
oxygenation
(PaO2 /FIO2 ) and
haemodynamic
parameters
(dopamine dose,
CVP and SBP)
Increased number of
lungs procured (31%
vs 8%, P0.005)
Improved
oxygenation and no
difference in
haemodynamic
parameters
Follette
1999/USA35
Treatment:
72
Control: 81
Pre post
implementation
of algorithm
Consecutive
potential
donors
Number of lungs
procured
Number of other
organs
procurements and
number of organs
per donor
Increased number of
lungs procured (28%
vs 1%, P0.001)
No difference in all
other organs and
number of organs
per donor (no
statistical
comparison)
McElhinney
2001/USA36
Cases: 88
lungs
transplanted
Controls: 163
lungs not
transplanted
Retrospective
study
Successful
thoracic organ
donors (heart,
lung, or both)
Predictors of
successful lung
transplantation
MP independently
associated with lung
procurement [OR 3.0,
95% CI (1.9; 4.9)]
Continued
351
Study/
country
BJA
Dupuis et al.
Table 2 Continued
n
Study design
Studied
population
Clinical endpoints
Results (treatment
vs control)
Rosendale
2003/USA15
Treatment:
701
Control: 9591
Retrospective
cohort
Any donor
Treatment:
steroids+vasopressin+T3 or
T4
Control: none, one, or two
hormones
Comment: not clear whether
insulin was administered
Organs
transplanted per
donor
Predictors of organ
procurement
Increased number of
organs transplanted
per donor (,40 yr
old: 4.2 vs 3.8 organs/
donor, P,0.01 and
.40 yr old: 3.1 vs 2.5
organs/donor,
P,0.01)
Treatment
independently
associated with
increased probability
of kidney, heart, liver,
lung, and pancreas
procurement
Rosendale
2003/USA14
Treatment:
394
Control: 4149
Retrospective
cohort
Heart
recipients
Treatment:
steroids+vasopressin+T3 or
T4
Control: none, one, or two
hormones
Combination
treatment:
improved 1 yr
survival (89.9% vs
83.9%, P,0.01)
Reduced odds of
death within 30 days
[OR 0.54, 95% CI
(0.31; 0.92)]
Reduced odds of
early graft
dysfunction [OR 0.52,
95% CI (0.33; 0.81)]
Steroids only:
No difference in odds
of death within 30
days [OR 0.75, 95%
(0.53; 1.05)]
Reduced odds of
early graft
dysfunction [OR 0.67,
95% CI (0.50; 0.90)]
Van Bakel
2004/USA42
Group 1: 19
Group 2: 36
Control: 64
Retrospective
cohort
Donors with
successful
organ recovery
Group 1: MP 1 to 2 g i.v.1
Group 2: MP 2 g i.v.1+regular
insulin 20 units i.v.1+T4 20
mg i.v.1 then 10 mg h21 i.v.
infusion
Control: usual care
Comment: catecholamines and
vasopressin allowed in the
three groups
Adrenergic support
Number of organs
procured
Decreased
adrenergic support in
Group 2, no
difference in Group 1
(both vs control)
No difference in
number of organs
procured (3.0 vs 3.0
vs 2.8, P0.60)
Salim 2005/
USA39
Controls
(pre): 214
Treatment
(post): 255
Pre post
protocol
implantation
Consecutive
potential
donors with
successful
organ retrieval
Exclusions:
children ,10
and undefined
excessive
adrenergic
support
Treatment: MP 2 g i.v.1+rapid
insulin 20 units i.v.1+T4 20
mg i.v.1 then 10 mg h21 i.v.
infusion (for patients requiring
vasopressors only, N is
unknown) as part of an
aggressive donor management
protocol
Control: usual care
Number of actual
donors*
Number of donors
loss because of
cardiovascular
collapse
Number of
procured organs
Increased number of
actual donors (82%
increase, P0.001)
Decreased number
of donors lost
because of
cardiovascular
collapse (87%
decrease, P0.001)
Increased number of
procured organs
(71% increase,
P0.001)
Continued
352
Study/
country
BJA
Table 2 Continued
n
Study design
Studied
population
Clinical endpoints
Results (treatment
vs control)
Salim 2006/
USA38
Controls
(pre):1667
Treatment
(post): 313
Retrospective
cohort
Consecutive
potential
donors
Treatment: MP 2 g i.v.1+rapid
insulin 20 units i.v.1+T4 20
mg i.v.1 then 10 mg h21 i.v.
infusion (for patients requiring
vasopressors only, N is
unknown) as part of an
aggressive donor management
protocol
Control: usual care
Incidence of
cardiovascular
collapse
Number of
procured organs
per donor
Decreased incidence
of cardiovascular
collapse
Increased number of
procured organs per
donor (2.4 vs 2.1,
P0.02)
Selck 2008/
USA40
Whole
registry:
14 125
Retrospective
cohort
Potential
donors with
successful
organ retrieval
Predictors of
number of organs
transplanted per
donor
Steroid
administration
independently
associated with
organ yield
(P0.005) and
improved
oxygenation
(P,0.001)
Nath 2010/
USA37
Controls
(pre): 273
Treatment
(post): 301
Pre post
protocol
implantation
Consecutive
potential
donors
Thoracic organs
recovery (hearts
and lungs)
Increase in thoracic
organs recovery
(64% increase,
P,0.001)
Dhar 2013/
USA43
HD (pre): 60
LD (post): 72
Consecutive
potential
donors
Exclusions:
children and
.65 yr
Oxygenation in
lung donors
Vasopressor use
glycaemic control
(target control
,140 mg dl21)
Number of organs
transplanted per
donor
Ejection fraction
One year heart or
lung graft/patient
survival
No difference in PaO2
improvement
No difference in
vasopressor weaning
Improvement in
glycaemic target
achievement after 4
h and less insulin
requirements in LD
No difference in lung
procurement [OR 1.2,
95% CI (0.45; 3.2)] or
other organ
procurement
No difference in
ejection fraction
No difference in
graft/patient survival
(LD: 92% vs HD: 79%,
P0.6)
Seven observational studies assessed haemodynamic oroxygenation outcomes.16 17 38 42 Three studies found an increase
either in mean arterial pressure or in cardiac output or a decrease in adrenergic or inotropic support,17 41 42 whereas
another one did not find any improvement in haemodynamics.16 Taniguchi and colleagues found a 7-day increase in time
from cerebral death until cardiac death when cortisol and
liothyronine were administered to their patients.41 Salim and
colleagues showed a reduced number of donors who were lost
because of cardiovascular collapse.38 39 Two studies associated
MP with an improvement in oxygenation (PaO2 /F IO2 ).16 40
Organ recovery
No RCTs directly evaluated organ recovery with CS use,
although one RCT did state that there was no difference in
organ recovery, without presenting any statistical comparison.29 31 In a post hoc observational analysis of an RCT,
Venkateswaran and colleagues found an increased number
of lungs transplanted in those participating in the trial compared with a cohort of donors excluded from that trial.31
Ten observational studies evaluated organ procurement as
their outcomes.15 17 35 40 42 Nearly all of them with the exception of one that presented neutral results42 associated the use
353
Study/
country
BJA
Dupuis et al.
Patient survival
Graft outcomes
Receiver
outcomes
Any organ procurement
Heart procurement
Lung procurement
Oxygenation
Haemodynamics
Donor outcomes
K
K
K
K
K
Zincke 197844
Novitzky 198717
Taniguchi 199241
Follette 199816
Follette 199935
McElhinney 200136
Rosendale 200315
Rosendale 200314
Van Bakel 200442
Salim 200539
Salim 200638
Selck 200840
Nath 201037
Dhar 201343
K
L
K
K
H
H*
Fig 2 Summary of findings of included studies. Green: exposure to corticosteroids associated with a positive result; blue: exposure to corticosteroids
associated with a neutral result; and white: outcome has not been assessed in study. A: any organ recipient; H: heart transplant recipient; K: kidney
transplant recipient; and L: Liver transplant recipient. *Neutral result with methylprednisolone alone, but positive result with combined hormonal
therapy.
of CS (or a hormonal combination therapy) with an improvement in the number of organs procured.
Graft outcomes
Eight RCTs measured graft survival as their primary
outcome.24 28 30 33 34 Two trials studying liver recipients
from pretreated donors presented opposite results.30 34 The
first found a decreased rate of ischaemia reperfusion injury
defined as an increase in liver enzyme values (AST/ALT),30
whereas the second showed that liver enzymes had a similar
trajectory posttransplantation.34 Again, Kotsch and colleagues
found a decrease in the rate of grade one to three biopsyproven acute rejections within the first 6 months posttransplantation,30 whereas Amatschek and colleagues found no
354
Chatterjee 197724
Dienst 197725
Jeffery 197826
Soulillou 197927
Corry 198028
Mariot 199129
Kotsch 200830
Venkateswaran 200831
Venkateswaran 200932
Kainz 201033
Amatschek 201234
Non-randomized studies
BJA
Table 3 Risk of bias and methodological quality assessment of included RCTs (by using Cochrane Collaborations Tool for assessing risk of bias).
H, high risk of bias; L, low risk of bias; U, unknown risk of bias; MP, methylprednisolone
Sequence
generation
Allocation
concealment
Blinding
Incomplete
outcome data
Selective outcome
reporting
Other threats to
validity
Chatterjee
197724
H
No use of placebo
H
Sixteen kidneys are
discarded for
unknown reason
H
Possible confounding
bias
No power calculation
Dienst 197725
H
U
No randomization
in Study 1
Alternate allocation
in Study 2
H
No blinding nor
placebo in Studies
1 and 2
H
No mention of
exclusions or
information on
donors
L
No power calculation
Jeffery 197826
U
No use of placebo
L
No power calculation
Soulillou 197927
H
No mention of
sequence
generation
L
No power calculation
Corry 198028
H
Alternate donors
receive MP
U
No use of placebo
H
Possible confounding
bias
No power calculation
Mariot 199129
L
No power calculation
Kotsch 200830
H
Only surgeon was
blinded, not the
treating physician
H
Possible confounding
bias
Sample size
calculated on a
surrogate endpoint
Venkateswaran
200831
H
Title and conclusion
not based on
prespecified analysis
H
Modification of
analysis because of
lack of power
Post hoc analysis
Possible confounding
bias (MP group is
younger)
Venkateswaran
200932
Kainz 201033
Amatschek
201234
Safety
Treatment safety was barely discussed in any of the randomized trials. Four studies mentioned using insulin to maintain
normoglycaemia in both treatment and control groups, but
did not report hyperglycaemia as a side effect.29 32 Only one
study reported that the treatment arm required significantly
more insulin to maintain normoglyacemia compared with
the control group.29
One trial comparing low-dose hydrocortisone with highdose MP assessed glycaemic control as their primary
355
Study
BJA
Dupuis et al.
External
validity (/3)
Internal validity
Bias
(/7)
Confounding
(/6)
Reporting
(/11)
Novitzky
198717
Taniguchi
199241
Follette
199816
Follette
199935
McElhinney
200136
Rosendale
200315
Rosendale
200314
Van Bakel
200442
Salim 200539
Salim 200638
Selck 200840
Nath 201037
Dhar 201343
10
30 31
Discussion
Summary of review findings
In this SR, 11 RCTs and 14 observational studies evaluating the
clinical effects of CS in potential donor management were
identified. No clear clinical benefit from the administration of
MP to potential donors could be drawn from the RCTs. Although
one low-quality RCT resulted in decreased ischaemia and
reperfusion injury and in decreased biopsy-proven acute rejections in liver donors,30 the other trials yielded neutral results.
Overall, the quality of the included RCTs was poor, with high
risk of bias identified in the majority.
On the other hand, multiple observational studies have
found beneficial effects of CS on haemodynamic or oxygenation parameters.16 17 41 42 Furthermore, most of these
observational studies found better outcomes in organ recovery.14 17 35 40 One large retrospective audit reported a positive
correlation between CS administration as part of a hormonal
combination therapy and increased patient and graft survivals
356
Zincke 197844
BJA
Supplementary material
Supplementary material is available at British Journal of
Anaesthesia online.
Authors contributions
S.D. and A.J.F.: study design, search strategy development,
data analysis, writing up of the first draft, and revisions.
J.-A.A. and M.D.: study design, search strategy development,
data analysis, and writing up of the first draft. D.R.W.: study
design, search strategy development, data analysis, and critical revision of the manuscript. Z.T., K.S., M.M.P., and P.M.: data
analysis and critical revision of the manuscript.
Acknowledgement
The authors thank Patrice Dupont M.Sc., professional librarian
at the Universite de Montreal Medical Library, for his help in
developing the search strategy.
Declaration of interest
None declared.
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