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British Journal of Anaesthesia 113 (3): 34659 (2014)

Advance Access publication 30 June 2014 . doi:10.1093/bja/aeu154

REVIEW ARTICLES

Corticosteroids in the management of brain-dead potential


organ donors: a systematic review
S. Dupuis 1,2,3*, J.-A. Amiel 1,2, M. Desgroseilliers 1,5, D. R. Williamson 1,3, Z. Thiboutot 6, K. Serri 4,7,
M. M. Perreault 1,2, P. Marsolais 4,7 and A. J. Frenette1,3
1

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
3
Pharmacy Department and 4 Department of Critical Care, Hopital du Sacre-Coeur de Montreal, 5400 Gouin W, Montreal, QC, Canada H4J 1C5
5
Pharmacy Department, Hopital Honore Mercier, 2750 Laframboise boul., St-Hyacinthe, QC, Canada J2S 4Y8
6
Pharmacy Department, Centre Hospitalier Universitaire de Montreal, 1560 Sherbrooke E, Montreal, QC, Canada H2L 4M1
7
Faculte de Medecine, Universite de Montreal, Pavillon Roger-Gaudry, 2900 Edouard-Montpetit, Montreal, QC, Canada H3T 1J4
2

Editors key points


The evidential basis of the
widespread use of
corticosteroids in
brain-dead organ donors
was examined by the
authors.
The evidence base
appeared to include
considerable risk of
confounding, and most
randomized studies had
neutral results.
Observational studies
appear to support the
continued use of
corticosteroids, but large,
prospective studies of the
use of corticosteroids in
the management of organ
donors are needed.

Summary. Current guidelines recommend the administration of hormonal combination


therapy including immunosuppressive doses of corticosteroids to donors with low left
ventricular ejection fractions and to consider hormonal therapy administration to all
donors. However, these recommendations are largely based on observational data. The aim
of this systematic review (SR) was to assess the clinical efficacy and safety of corticosteroids
in brain-dead potential organ donors. MEDLINE and EMBASE were searched from the
earliest accessible date up to March 2013 with a qualified librarian. Studies comparing the
effects of any corticosteroid with those of placebo, standard treatment, or another active
comparator were sought. Two independent reviewers evaluated each citation retrieved and
selected studies independently and in duplicate. A third independent reviewer resolved any
disagreement. Outcomes included donor haemodynamics and oxygenation, organ
procurement, recipient survival, and graft survival. This review included 11 randomized
controlled trials (RCTs) and 14 observational studies. The majority used methylprednisolone
and often combined it with other hormonal therapies. Ten out of the 11 RCTs yielded neutral
results. However, in observational studies, use of corticosteroids generally resulted in
improved donor haemodynamics and oxygenation status, increased organ procurement,
and improved recipient and graft survival. Overall quality of included studies was poor, as
most of them presented high risks of confounding. This SR highlights the low quality and
conflicting evidence supporting the routine use of corticosteroids in the management of
organ donors. A large trial evaluating the effect of corticosteroids on outcomes such as
organ recovery and graft survival is warranted.
Keywords: adrenal cortex hormones; brain death; human; systematic review; tissue and organ
procurement; transplantation

Organ donation saves lives and can prolong the survival of


patients with end-stage organ diseases. Unfortunately, the
gap between the number of patients on transplantation
waiting lists and the number of donors continues to widen.1
In 2011, more than 113 000 candidates were waiting for an
organ transplantation in the USA, while there were only
14 000 donors and a total of 28 500 transplantations.1
Brain death often induces a catecholamine storm followed
by haemodynamic instability leading to cardiovascular collapse. Without aggressive intervention, clinical deterioration
may account for donor loss.2 Disruption of the hypothalamic
pituitaryadrenal axis may contribute to the observed

haemodynamic instability in potential brain-dead organ


donors. Although adrenal insufficiency was observed in some
potential donors,3 7 other reports have described normal or increased adrenal function after brain death.8 Therefore, the administration of corticosteroids (CSs) to restore normal adrenal
function remains a subject of debate. Brain death has also been
identified as inducing cytokine release contributing to organ
damage.9 10 Theoretically, glucocorticoids could alleviate inflammatory neurogenic pulmonary oedema.9 11
Canadian guidelines recommend the administration of hormonal combination therapy consisting of vasopressin, methylprednisolone (MP), insulin, and thyroid hormones to donors

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* Corresponding author. E-mail: sebastien.dupuis.1@umontreal.ca

BJA

Corticosteroids in the management of brain-dead potential organ donors

with a low left ventricular ejection fraction and consideration in


all donors, whereas MP is recommended to all potential lung
donors.12 In contrast, American guidelines recommend administration of hormonal combination therapy to all
donors.13 However, these recommendations are based on
few observational studies.14 17 The aim of this systematic
review (SR) was to assess the clinical efficacy (haemodynamics, oxygenation, organ procurement, graft survival, and function) and safety of CSs in the management of brain-dead
potential organ donors compared with placebo, standard
treatments, or active comparator.

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 extraction and validity assessment


Each study was evaluated independently and in duplicate
(J.-A.A., S.D., M.D., or Z.T. and D.R.W., A.J.F., M.M.P., or K.S.).
The information was collected using a pretested standardized
form. A third independent reviewer (S.D. or A.J.F.) resolved any
disagreement. Descriptive variables for each study (language
of publication, source of funding, sample size, and study objectives) were collected.
Information regarding the study population characteristics
(donors and recipients when appropriate), pharmacological

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

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Search strategy

interventions, and outcome measures were collected and


analysed. The number of organs successfully recovered and
transplanted or mortality, morbidity, or both of the recipient
were considered as high-impact clinical outcomes. Lower impact
clinical outcomes included echocardiographic or haemodynamic changes (left ventricular ejection fraction, cardiac output,
blood pressure, vasopressor, or inotrope requirements) and
oxygenation status (PaO2 /F IO2 ratio) in the donor. Information
on all reported side effects was also collected. The risks of
hyperglycaemia in the donor and HLA mismatching between
the donor and the recipient were specifically evaluated.18 19
Methodological quality was assessed using the Downs and
Black scale for observational studies and the rating instrument
developed by the Cochrane Handbook for Systematic Reviews
of Interventions for RCTs.20 21 Power rating in the Downs and
Black scale was not assessed because of a lack of reporting of
power calculation in studies. Information regarding safety assessment method in individual studies was also collected. It
was considered appropriate if side effects were prospectively
collected or if they were a study endpoint. The method of assessing side effects had to be provided and its timing clinically relevant.22 This SR was performed according to the preferred
reporting items for systematic reviews and meta-analyses
statement (PRISMA).23

BJA

Dupuis et al.

Records identified through


MEDLINE and EMBASE searching
after duplicates removed
(n=1089)

Additional records identified


through other sources
(n=15)

Records excluded for irrelevant


topic (i.e. animal or physiological
studies)
(n=1048)

Full-text articles excluded


(n=31)
Reasons

Included studies in synthesis


(n=25)

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)

Fig 1 Flow chart of the study.

heterogeneity. Although not reported in every study,14 16 17 24


mean age of donors was generally in the 30s or low 40s.
Two studies included paediatric patients although the exact
number is unknown.15 27 There was a slight male predominance in the donors when gender was reported.15 29 30 33
34 36 37 40 43
Only a few studies reported baseline haemodynamic29 32 and oxygenation16 31 43 status of the donors.
Causes of brain death included vascular injuries (nontraumatic intracranial haemorrhage), blunt or penetrating
traumas, and tumours. Other causes included anoxia, central
nervous system infections, or other medical causes.29 33 37 42
A total of 953 kidney recipients, 183 liver recipients, and 4726
heart recipients were included in this review. Five studies out
of 10 evaluating outcomes on recipients reported recipients
characteristics.14 34 44 Recipients in these studies were
mostly males in their 40s. Alcoholic cirrhosis, hepatocellular
carcinoma, and viral hepatitis predominated as the aetiology
of end-stage liver disease in two studies.30 Both RCTs evaluating liver recipients used two different immunosuppressive regimens: the first one combined a calcineurin inhibitor to
mycophenolate mofetil and steroids without using induction
therapy,30 whereas the second one used antithymocyte globulin and high-dose dexamethasone as induction therapy
followed by maintenance treatment with a calcineurin inhibitor.34 In one recent study evaluating kidney recipients
26 37 40

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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

Other treatments concomitantly permitted


Co-treatments are described in Tables 1 and 2. Thyroid
hormones (either liothyronine or thyroxine), insulin, and

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Full-text articles assessed for eligibility


(n=56)

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Corticosteroids in the management of brain-dead potential organ donors

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)

Corticosteroid studied and


comparator arm(s)

Clinical endpoints

Results (pretreated vs control)

Chatterjee 1977/
USA24

50/84

Treatment: MP 5 g i.v.1
Control: usual care
Comment: dopamine and
isoproterenol allowed in both groups

Graft failure at 1 and 3 months

No difference in incidence of graft


failure at 1 (37.5% vs 36.3%, PNS) and
3 months (52.5% vs 54.5%, PNS)

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

Graft survival at 6 months

No difference in graft survival at 6


months (Study 3: 40% vs 44%, PNS;
Study 2: 46% vs 48%, PNS)
Improved graft survival at 6 months in
study 1 (70% vs 38%, P,0.005) (not
randomized)

Jeffery 1978/
Canada26

NM/52

Treatment: MP 5 g i.v.+CP 7 g i.v.1


Control: usual care
Comment: dopamine allowed in both
groups

Patient and graft survival,


graft function and number of
rejections at 3, 6, and 12
months

No difference in patient and graft


survivals, graft function, and number of
rejection episodes at 3, 6, and 12
months (graft survival at 12 months:
50% vs 63.3%, PNS)

Soulillou 1979/
France27

NM/62

Treatment: MP 5 g i.v.+CP 5 g i.v.1


Control: placebo

Graft survival and function at


3, 6, and 12 months

No difference in graft survival and


function at 3, 6, and 12 months (graft
survival at 12 months: 33.3% vs 27.6%,
PNS)

Corry 1980/USA28

NM/53

Treatment: MP 60 mg kg21 i.v.+CP 80


mg kg21 i.v.1
Control: Usual care

Graft survival rate at 3, 6, 9,


and 12 months

No difference in kidney graft survival


rate at 3, 6, 9, and 12 months (graft
survival at 12 months: 59.4% vs 42.4%,
PNS)

Kainz 2010/
Austria33

269/455

Treatment: MP 1 g i.v.1
Control: placebo
Comment: vasopressors allowed in
both groups

Incidence of acute renal


failure at 7 days (defined as
need for more than 1 dialysis)
Duration of acute renal failure
Trajectories of creatinine
levels in the first week

No difference in incidence of acute renal


failure at 7 days (PNS for all
subgroups)
No difference in duration of acute renal
failure (5 days vs 4 days, P0.31)
Similar trajectories of creatinine in the
first week (P0.72)

Kotsch 2008/
Germany30

100/100

Treatment: MP 250 mg i.v.1 then 100


mg h21 until organ recovery
Control: usual care
Comment: vasopressors and insulin
(for glucose control) allowed in both
groups

Ischaemia reperfusion injury


(defined as AST/ALTelevation)
Acute rejections within the
first 6 months

Decreased ischaemia reperfusion


injury (P,0.05)
Decreased rate of biopsy-proven acute
rejections between Grades 1 and 3
within the first 6 months (22% vs 36%,
P,0.05)

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

Similar trajectories of ASTand ALT in the


first week (P0.13 and P0.40,
respectively)
Within 3 yr:
No difference in mortality [RR 0.63, 95%
CI (0.29; 1.36)]
No difference in biopsy-proven acute
rejections [RR 1.02, 95% CI (0.50; 2.10)]
No difference in graft loss (P0.41)

Kidney donors

Continued

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Liver donors

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Dupuis et al.

Table 1 Continued
Study/country

n (D/R)

Corticosteroid studied and


comparator arm(s)

Clinical endpoints

Results (pretreated vs control)

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

Change in PaO2 /F IO2 ratio


Change in EVLWI
Lung suitability for
transplantation

No change in PaO2 /F IO2 ratio


Less increase in EVLWI (post hoc
analysis)
Increased lung suitability for
transplantation (trial cohort: 43% vs
non-trial cohort: 27%, P0.016)

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

Cardiac index prerecovery


Haemodynamic parameters
(RVSWI, LVSWI, CPO)

No difference in cardiac index or other


haemodynamic parameters

40/NM

Treatment: HC 100 mg i.v.+T3 2 mg i.v.


every 30 60 min until adequate CVP
and SBP
Control: placebo
Comment: insulin (for glucose control),
dobutamine, and low-dose dopamine
(for diuresis) allowed in both groups

Change in haemodynamic
parameters (SBP, CVP,
dobutamine requirements)
New or worsening metabolic
acidosis
Probability of procurement

No difference in SBP,CVP or dobutamine


requirements
No difference in acidbase status
No difference in probability of
procurement (100% vs 90%, no direct
statistical comparison)

Lung donors
Venkateswaran
2008/UK31

Venkateswaran
2009/UK32

Any organ donors


Mariot 1991/
France29

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

two. Clinical heterogeneity resulted mostly from timing of


graft survival measurement, difference in type of organ
studied, and co-treatments administered. A majority of these
studies were also from the 1970s and were of low quality.
A summary of results is presented in Tables 1 and 2 and
Figure 2. Predetermined sensitivity analysis did not provide
any further information.

Haemodynamic and oxygenation parameters


Three RCTs evaluated changes in haemodynamic parameters
as their primary outcome.29 31 32 One study concluded that
hydrocortisone associated with liothyronine boluses did not
result in an improved cardiac output or decreased need for
dobutamine in treated donors.29 A second study including
heart donors obtained similar results.32 The latter group also
found in another trial that MP did not change the PaO2 /F IO2
ratio in lung donors compared with those not receiving MP
(either liothyronine or placebo), although they found in a
post hoc analysis that extravascular lung water index
increased less in the MP group.31

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Heart donors

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Corticosteroids in the management of brain-dead potential organ donors

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

Corticosteroid studied and


comparator arm(s)

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

Treatment: cortisol 100 mg i.v.


hourly according to
response+T3 2 mg i.v. every
1 2 h+insulin 20 units every
1 2 h
Control: usual care
Comment: vasopressin and
calcium allowed in both groups

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

Time from cerebral


death until cardiac
death
Change in
haemodynamic
parameters

Increased time from


cerebral death until
cardiac death (11.5
days vs 4.3 days,
P,0.05)
Increased HR, MAP,
CI and SVR

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

Treatment: protocol including


high-dose corticosteroids
(agent and dosing schedule not
specified)+T4 20 mg i.v.1
then 20 to 50 mg h21 i.v.
infusion, lung protective
ventilation, bronchoscopy,
conservative fluid
management
Control: usual care

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)

Treatment: MP (any dosing)


Control: N/A

Predictors of
successful lung
transplantation

MP independently
associated with lung
procurement [OR 3.0,
95% CI (1.9; 4.9)]

Continued

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Study/
country

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Dupuis et al.

Table 2 Continued
n

Study design

Studied
population

Corticosteroid studied and


comparator arm(s)

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

One year survival


rate in heart
recipients
Recipient death
within 1 month
Early graft
dysfunction (graft
failure within 14
days or prolonged
graft dysfunction
before discharge)

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

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Study/
country

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Corticosteroids in the management of brain-dead potential organ donors

Table 2 Continued
n

Study design

Studied
population

Corticosteroid studied and


comparator arm(s)

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

Treatment: any steroid


Control: usual care
Comment: desmopressin and
T4 evaluated in the model as
potential predictors

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

Treatment: MP 15 mg kg21 i.v.


bolus, repeated if needed after
24 h+T4 20 mg i.v.1 then 10
mg h21 i.v.
infusion+vasopressin 1 unit
i.v.1 then 0.5 4.0 units h21
i.v. infusion as part of a protocol
Control: usual care

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

Pre post steroid


dose
modification

Consecutive
potential
donors
Exclusions:
children and
.65 yr

HD: MP 15 mg kg21 i.v. every 24


h
LD: HC 300 mg i.v.1 then 100
mg every 8 h
Comment: vasopressors,
vasopressin and T4
administered in both groups as
part of a standardized protocol.
Key physiologic metrics control
included in protocol

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

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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

Randomized controlled trials

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

difference in mortality, biopsy-proven acute rejections, or


graft loss within 3 yr posttransplant.34 The six other trials
evaluating graft outcomes only included pretreated kidney
donors.24 28 33 They all found no difference in kidney graft
function or survival either at 1-week posttransplantation33 or
up to 12 months posttransplantation.24 28 Kidney graft
failure was defined as the need for dialysis, an increase in
serum creatinine, or an acute rejection. Four of these studies
also used cyclophosphamide in the active treatment arm.25 28
Two observational studies assessed patient and graft survival. An older study evaluating kidney recipients from pretreated donors found no difference in 3-yr patient survival,
but an improvement in graft survival.44 In a large retrospective
cohort study looking at heart recipients, pretreatment of
donors with an hormonal combination therapy consisting of

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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

Corticosteroids in the management of brain-dead potential organ donors

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

steroids, vasopressin, and thyroid hormones was associated


with an improved 1 yr patient survival and a reduced odd of
early graft dysfunction.14

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

outcome.43 They found an improvement in glycaemic target


achievement 4 h after the dose was administered and an
overall decrease in insulin requirements in the low-dose
group. They found no difference in haemodynamics or oxygenation parameters between those two regimens, and also in
lung procurement and recipient or graft survival.

Risk of bias/quality of the studies


Risks of bias of selected studies are presented in Tables 3 and 4.
Most RCTs demonstrated a high risk of bias; only three studies
had an overall low level of bias.32 34 Allocation concealment
was often not mentioned in these RCTs and six studies had
no power calculation.24 29 Six of them did not use placebo or
did not blind properly the study treatments24 28 30 and

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Study

BJA

Dupuis et al.

External
validity (/3)

Internal validity

in heart recipients from pretreated donors.14 No meta-analysis


could be performed because of significant clinical heterogeneity between studies. Clinical heterogeneity arose from
included populations, treatments, clinical outcomes, and
timings.

Bias
(/7)

Confounding
(/6)

Possible mechanism of action of corticosteroids

Table 4 Risk of bias and methodological quality assessment of


included observational studies (by using the Downs and Black
checklist)
Study

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

possible confounding biases were present in four studies.24 28


Sequence generation was problematic in two RCTs.25 28
One RCT based its conclusion on post hoc analyses.31 Observational studies were also generally of poor quality. Most of these
presented high risk of confounding bias or other risks of biases
inherent to the study design.

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

Hypothalamicpituitary injury occurring after brain death may


be characterized by adrenal insufficiency.3 7 Lower levels of
circulating cortisol could therefore be explained by the injury
and the inability of the adrenal glands to respond adequately
to stress.6 Supplementation with stress doses of CS could theoretically improve haemodynamic stability and clinical outcomes in brain dead donors. However, as recently reported
by Boonen and colleagues, the true metabolism and pharmacokinetics of cortisol in critically ill patients is not fully understood.45 Although brain-dead organ donors were not part of
this study, this may highlight the lack of understanding of the
true cortisol metabolism in organ donors.
Brain death is also characterized by a catecholaminergic
storm in which a pro-inflammatory environment develops
through release of TNF-a, IL-1, IL-6, and IL-8. These
pro-inflammatory markers may be associated with poor outcomes in donors.10 46 47 Blunting this inflammatory reaction
by glucocorticoids could theoretically permit better outcomes
in donors. Although it remains unclear, effects of CS could
vary depending on the type of organ transplantation studied.
Interestingly, one recent study compared the use of
low-dose hydrocortisone with high-dose MP,43 using the
same hypothesis as in sepsis where hydrocortisone has been
shown to reduce the need for vasopressors,48 thus raising controversy regarding the optimal dosing and timing of steroids in
organ donation.

Strengths and limitations


To our knowledge, this is the first SR evaluating the efficacy and
safety of CS in brain-dead organ donor management.
Strengths of this SR include rigorousness in methodology, assessment of the most important clinical outcomes, and focus
on the quality of identified studies. Limitations include the
lack of homogenous data to perform a meta-analysis and
provide more objective conclusions.
Decision to administer CS to the brain dead donors cannot
be solely based on RCTs because of the poor quality of evidence
described above. In fact, although RCTs usually provide more
valuable data on patient outcomes, brain death and organ donation may be considered as a rare event, and RCTs may
become less feasible and provide less convincing results. Decision to include observational studies in this SR was based on
this fact, as these may become the best quality of evidence
available to guide decisions made in a clinical setting of rare
events. In addition, the RCTs were small and often of low methodological quality, whereas some of the observational studies
were of a much larger scale.
The reason why CSs did not seem to provide any benefits in
the different RCTs and were associated with better donor

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Zincke 197844

BJA

Corticosteroids in the management of brain-dead potential organ donors

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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and recipient outcomes in observational studies is unclear. Our


results are similar to those found by Macdonald and
colleagues,49 who evaluated the efficacy of thyroid hormones
on organ donor management independently from the
co-administration of other hormones. They concluded that
there was no clear evidence to support the routine use of
thyroid hormones in the context of organ donor management.49 An SR from Rech and colleagues also concluded that
there was poor evidence to support the use of either thyroid
hormones or desmopressin.50 Although it also reviewed CSs,
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One major difficulty in analysing the clinical effect of CSs is
isolating their effects from other potentially active drugs
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CS has already been described in sepsis. Their synergistic
anti-inflammatory effects may be associated with improved
survival.57 Vasopressin, even if sometimes used for diabetes
insipidus, could potentially improve blood pressure and
reduce the need for vasopressors.
Strategies to improve organ availability need to be
addressed in future studies. As reported in our review and
others, equipoise warrants performing a large RCT evaluating
the independent components of hormone therapy, including
CSs.49 50 Most of the prospective studies in this review were
single-centred, limiting the statistical power necessary to
evaluate clinically relevant outcomes. An adequately
powered multi-centred RCT is feasible and should evaluate
the effect of CS on important clinical outcomes such as organ
recovery and graft survival.
In conclusion, this SR highlights that evidence supporting
the routine use of CS in the management of organ donors is
conflicting and of poor quality. RCTs tend to show that the administration of CS in potential brain-dead organ donors provides no benefit, while observational studies suggest that
they may be associated with improved donor and recipient outcomes. Current recommendations regarding the administration of CSs in this population originate from low-quality
evidence, as observational studies do provide some evidence
to support their use.12 13 Future studies should aim at evaluating independent components of hormonotherapy, including
CSs. Adequately powered multi-centred RCTs evaluating the
effect of CS on clinical outcomes such as organ recovery and
graft survival would be of higher impact.

BJA

358

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