Controversial Points in Organ Donor Management
C. Chamorro, J.A. Falcón, and J.C. Michelena
ABSTRACT
There are still many controversial aspects regarding which method is best for managing
organ donors to prevent, lessen, or even reverse the organ alterations associated with brain
death. Fundamental aspects are the management of an adequate perfusion pressure,
hormone restoration, and opposition of the inflammatory state associated with brain
death. Once volume has been normalized, it is necessary to administer vasoactive drugs,
including catecholamines to re-establish the loss of sympathetic tone at the vascular and
myocardial level. It is impossible to define the ideal or maximal catecholamine dose
because it depends on the donor’s vascular tone, vascular reactivity, and pharmacokinetic
variability characteristic of critical patients, particularly organ donors. To control early
onset of diabetes insipidus, it is necessary to administer desmopressin. At present there are
insufficient clinical studies to show the usefulness of triiodothyronine. Furthermore, due to
its limited availability, elevated cost, and probable side effects, the use of this hormone is
not justified. More importance is being given to the negative influence of the inflammatory
state associated with brain death, which has repercussions on organ viability and probably
influences the prevalence of rejection episodes. Meanwhile in organ donor management,
we recommend the use of 15 mg/kg of methylprednisolone as soon as possible. Contrary
to triiodothyronine, the potential benefit of its immunomodulatory effects, its low cost, and
the absence of major side effects justify this recommendation.
D
URING brain death (BD) a series of hemodynamic,
hormonal, and inflammatory disorders may alter or
irreversibly damage the function of various organs,1 preventing
their use. Furthermore, the alterations may contribute to
early graft failure or rejection phenomena. Adequate organ
donor management is fundamental to preventing, reducing, or
reversing these alterations.2 Nevertheless, at present there are
controversial management aspects; even the various published
recommendations are at times contradictory.3–8
HEMODYNAMIC MANAGEMENT
During BD it is possible to differentiate 2 periods with
different hemodynamic alterations. There is an acute phase
derived from the progression of ischemia toward the medulla
oblongata, with loss of vagal nucleus activity, which is
characterized by maximum stimulation of sympathetic activity.
In this phase, called “catecholamine storm,” severe
arterial hypertension is produced together with supraventricular
or ventricular arrhythmias that may lead to cardiac
arrest. Massive release of vasoactive substances provokes
generalized vasoconstriction with reduced blood flow to the
organs, thus producing ischemia, decreased cellular energy
reserves, and, at times, organic structural damage. A rapid
progression of BD is associated with a greater intensity of
this response.9,10 Most authors agree that control of this
phase with short half-life drugs, such as esmolol, urapidil,
nicardipine, or nitroprusside, can avoid or reduce organ
damage, especially to the heart and lung.8,11
Following cessation of catecholamine release, a second
phase arises, which is characterized by hypotension secondary
to the loss of sympathetic effects at the vascular and
myocardial levels.1,12 In consequence, hemodynamic stability
is only maintained in a minority of cadaveric donors; the
natural evolution is toward progressive hypotension and
cardiac arrest. This phase may be called chronic and be
sustained during the entire donor maintenance process.
Untreated hypotension worsens organ perfusion and may
irreversibly damage the function of various organs. Active
treatment to achieve hemodynamic stability is obtained byadapting 3 basic hemodynamic pillars: preload, afterload,
and contraction.5 The contribution of fluids is fundamental
to offset the losses suffered before or after BD establishment.
On occasion, the donor may be hypovolemic either
due to the treatment to control intracranial hypertension
(mannitol, diuretics, or therapeutic hypothermia) or to
polyuria secondary to hyperglycemia or the onset of insipidus
diabetes. The contribution of fluids must aim to
normalize the preload to central venous pressure values
between 3 and 10 mm Hg. It must be adjusted to urinary
losses, or those estimated, taking into account that excess
liquid administration may worsen myocardial or pulmonary
function.13 The type of fluid administered must be determined
according to the hydroelectrolytic situation at each
phase of maintenance; habitually, it is recommended to
administer Ringer’s lactate. On occasions when there is
hypernatremia, solutions should be administered containing
more free water, such as 5% dextrose. The administration
of colloids must be performed judiciously; in excess
they may induce kidney disorders,14 coagulation disorders,
15 or even molecular capture by the hepatic reticuloendothelial
system.16 The colloids of choice are probably new
generation hydroxyethylstarch solution without surpassing
the administration of 500–1000 cc.15 Loss of sympathetic
tone at the vascular and cardiac levels must be offset by the
exogenous administration of catecholamines with _-agonist
and _1-agonist effects.12 Dopamine and preferably noradrenaline
have these effects. The doses should be those
that allow for maintaining mean arterial pressure between
70 and 90 mm Hg with an adequate level of fluid repletion.
Nevertheless, various authors and scientific societies have
recommended avoiding alpha-adrenergic drugs and limiting
the use of dopamine to a maximum dose of 10 _g/kg/min.3–5
We consider that these recommendations move away from
adequate management of the cardiovascular changes associated
with BD. It is necessary to administer vasoactive drugs to
restore the lost sympathetic tone; in addition, it is impossible
to define the ideal or maximum dose because this depends
on the residual level of the donor’s vascular tone, vascular
reactivity, and pharmacokinetic variability that all drugs
show in critical patients, such as organ donors.17 There are
no published studies that associate adequate exogenous
catecholamine administration with organ damage induced
by BD.18 In contrast, some publications associate the use of
dopamine or noradrenaline in the donor with improved
evolution of the transplanted organs.19,20 Not only the
hemodynamic effects, with normalization of perfusion pressure,
but also the immunomodulatory effects of the catecholamines
may explain this observation.21
HORMONAL MANAGEMENT
The hypothalamic/hypophyseal axis, as a central nervous
system component, is affected in BD. On occasions, hypophyseal
blood flow may be maintained by branches of the
lower hypophyseal artery, subsidiaries of the external carotid
artery, which explains why all donors do not show
hypophyseal hormonal alterations. The most usual disorder,
in up to 90% of all donors, is early onset of diabetes
insipidus, derived from the lack of antidiuretic hormone
production and release. The administration of this hormone,
or especially its derivative desmopressin (DDVAP),
is fundamental during donor management. Other hormonal
disorders are more controversial. Some authors and scientific
societies have recommended the use of thyroid hormones
or triiodothyronine (T3), or, failing that, thyroxine
for organ donor management, especially when there is
associated myocardial dysfunction.3–5,7,8 These recommendations
are based on non-comparative or retrospective
studies. However, the majority of the studies undertaken
with greater methodological and scientific rigor have not
demonstrated their usefulness.22,23 Pérez-Blanco et al in a
prospective, randomized, double-blinded controlled study
failed to observe any hemodynamic or metabolic benefit of
the use of T3 in adult cadaveric organ donors.24 A recent
revision by the United Network for Organ Sharing (UNOS)
reported that the administration to the donor of DDVAP,
diuretics, and steroids, instead of thyroid hormones, was
associated with improved organ yield.25 Thyroid disorders
associated with BD may be included in the so-called
“critical patient euthyroid syndrome,” where the administration
of these hormones has not been shown to be
beneficial.26 Only in unusual cases of prolonged donor
management, namely, longer than 24–48 hours, might
thyroid hormones have some beneficial role.
ANTI-INFLAMMATORY MANAGEMENT
During BD an inflammatory response syndrome occurs.
Pro-inflammatory cytokines, such as TNF-_, interleukin
(IL)-1, IL-6, and IL-8, as well as leukocyte activation and
intercellular adhesion molecules (ICAM-1) or vascular
adhesion molecule (VCAM-1) expression are increased
both in blood and locally, in various organs.27,28 This
inflammatory response may be of cerebral origin or from
ischemia-reperfusion and free radical activation at the
organ level during the herniation process.2,10 The inflammatory
activity may contribute to hemodynamic and organic
deterioration, leading to immunologic changes that
favor the subsequent appearance of rejection phenomena in
the recipient.2,29 This observation may explain the wellknown
greater incidence of rejection among recipients who
receive organs from BD donors compared with living
donors or even from donors following cardiac arrest.30
Early administration of steroid at the time of establishment
of BD may inhibit the release or prevent the alterations
produced by pro-inflammatory cytokines, in addition to
being able to stabilize cell membranes, produce a downward
trend in adhesion molecule expression, and interfere with
the lipid peroxidation that occurs after ischemia. Kuecuek
et al31 demonstrated that steroid administration to donors
was associated with a significant decrease in inflammatory
cytokines, both in the serum and locally in various harvested
organs. These effects may lessen the incidence of early graftfailure and of subsequent rejection episodes. A retrospective
analysis performed by UNOS on 14,616 cadaver kidney
transplant recipients showed that steroid administration
produced a 10% decrease in renal graft loss at 1 year after
implantation.32 At an experimental level, steroid use prior
to BD or early after its establishment avoids deterioration
of myocardial contraction by decreasing the release of
pro-inflammatory cytokines.33 Some authors have recommended
early use of 15 mg/kg of methylprednisolone during
pulmonary donor management. Nonetheless, this recommendation
is based on a single published retrospective
study and a historic series.34,35 A recent study designed to
show its usefulness in pulmonary donor management only
demonstrated reduction of lung water accumulation among
steroid-treated donors.36 However, despite the absence of
prospective studies that demonstrate the usefulness of
steroids, their potential beneficial immunomodulatory effects,
as well as their low economic cost, and the absence of
adverse effects justify their administration.37
REFERENCES
1. Smith M: Physiologic changes during brain stem death–
lessons for management of the organ donor. J Heart Lung Transplant
23(9 suppl):S217, 2004
2. Martins PN, Chandraker A, Tullius SG: Modifying graft
immunogenicity and immune response prior to transplantation:
potential clinical applications of donor and graft treatment.
Transpl Int 19:351, 2006
3. Zaroff JG, Rosengard BR, Armstrong WF, et al: Consensus
conference report: maximizing use of organs recovered from the
cadaver donor: cardiac recommendations, March 28–29, 2001,
Crystal City, Va. Circulation 106:836, 2002
4. Rosendale JD, Kauffman HM, McBride MA, et al: Aggressive
pharmacologic donor management results in more transplanted
organs. Transplantation 75:482, 2003
5. Wood KE, Becker BN, McCartney JG, et al: Care of the
potential organ donor. N Engl J Med 351:2730, 2004
6. Boulard G, Guiot P, Pottecher T, et al: Management of
brain-dead subjets for organ harvesting. Organ Tissues 3:185, 2005
7. Novitzky D, Cooper DK, Rosendale JD, et al: Hormonal
therapy of the brain-dead organ donor: experimental and clinical
studies. Transplantation 82:1396, 2006
8. Shemie SD, Ross H, Pagliarello J, et al: Organ donor management
in Canada: recommendations of the forum on medical management
to optimize donor organ potential. CMAJ 174:S13, 2006
9. Shivalkar B, Van Loon J, Wieland W, et al: Variable effects of
explosive or gradual increase of intracranial pressure on myocardial
structure and function. Circulation 87:230, 1993
10. Takada M, Nadeau KC, Hancock WW, et al: Effects of
explosive brain death on cytokine activation of peripheral organs in
the rat. Transplantation 65:1533, 1998
11. Audibert G, Charpentier C, Seguin-Devaux C, et al: Improvement
of donor myocardial function after treatment of autonomic
storm during brain death. Transplantation 82:1031, 2006
12. Herijgers P, Flameng W: The effect of brain death on
cardiovascular function in rats. Part II. The cause of the in vivo
haemodynamic changes. Cardiovasc Res 38:107, 1998
13. Pennefather SH, Bullock RE, Dark JH: The effect of fluid
therapy on alveolar arterial oxygen gradient in brain-dead organ
donors. Transplantation 56:1418, 1993
14. Cittanova ML, Leblanc I, Legendre C, et al: Effect of
hydroxyethylstarch in brain-dead kidney donors on renal function
in kidney-transplant recipients. Lancet 348:1620, 1996
15. Chamorro C, Romera MA, Márquez J: Farmacologı´a de los
coloides sintéticos. Emergencias 15:S5, 2004
16. Christidis C, Mal F, Ramos J, et al: Worsening of hepatic
dysfunction as a consequence of repeated hydroxyethylstarch infusions.
J Hepatol 35:726, 2001
17. Chamorro C, Silva JA, Romera MA: Cardiac donor management:
another point of view. Transplant Proc 35:1935, 2003
18. Chamorro C, Silva JA, Segovia J, et al: Use of catecholamines
in cardiac donors: what is the real limit? J Heart Lung
Transplant 23:916, 2004
19. Schnuelle P, Yard BA, Braun C, et al: Impact of donor
dopamine on immediate graft function after kidney transplantation.
Am J Transplant 4:419, 2004
20. Cuende N, Miranda B, Cañón JF, et al: Donor characteristics
associated with liver graft survival. Transplantation 79:1445, 2005
21. Schaub M, Ploetz CJ, Gerbaulet D, et al: Effect of dopamine
on inflammatory status in kidneys of brain-dead rats. Transplantation
77:1333, 2004
22. Powner DJ, Hernandez M: A review of thyroid hormone administration
during adult donor care. Prog Transplant 15:202, 2005
23. Falcon JA, Chamorro C, Peraza V, et al: Mitos o realidades
con el uso de hormonas tiroideas en el manejo del donante de
órganos. Rev Esp Trasp 16:216, 2007
24. Pérez-Blanco A, Caturla-Such J, Cánovas-Robles J, et al:
Efficiency of triiodothyronine treatment on organ donor hemodynamic
management and adenine nucleotide concentration. Intensive
Care Med 31:943, 2005
25. Selck FW, Deb P, Grossman EB: Deceased organ donor
characteristics and clinical interventions associated with organ
yield. Am J Transplant 8:965, 2008
26. Bennett-Guerrero E, Jimenez JL, White WD, et al: Cardiovascular
effects of intravenous triiodothyronine in patients undergoing
coronary artery bypass graft surgery. A randomized, doubleblind,
placebo-controlled trial. JAMA 275:687, 1996
27. Stangl M, Zerkaulen T, Theodorakis J, et al: Influence of
brain death on cytokine release in organ donors and renal transplants.
Transplant Proc 33:1284, 2001
28. Skrabal CA, Thompson LO, Potapov EV, et al: Organspecific
regulation of pro-inflammatory molecules in heart, lung,
and kidney following brain death. J Surg Res 123:118, 2005
29. Pratschke J, Wilhelm MJ, Kusaka M, et al: Brain death and
its influence on donor organ quality and outcome after transplantation.
Transplantation 67:343, 1999
30. Terasaki PI, Cecka JM, Gjertson DW, et al: High survival
rates of kidney transplants from spousal and living unrelated
donors. N Engl J Med 333:333, 1995
31. Kuecuek O, Mantouvalou L, Klemz R, et al: Significant
reduction of proinflammatory cytokines by treatment of the braindead
donor. Transplant Proc 37:387, 2005
32. McBride MA, Peters TG, Henderson JM, et al: Expanded
donor study. In UNOS Report to the Health Resources & Services
Administration, 17, 1997
33. Lyons JM, Pearl JM, McLean KM, et al: Glucocorticoid
administration reduces cardiac dysfunction after brain death in
pigs. J Heart Lung Transplant 24:2249, 2005
34. Follette DM, Rudich SM, Babcock WD: Improved oxygenation
and increased lung donor recovery with high-dose steroid
administration after brain death. Heart Lung Transplant 17:423, 1998
35. McElhinney DB, Khan JH, Babcock WD, et al: Thoracic
organ donor characteristics associated with successful lung procurement.
Clin Transplant 15:68, 2001
36. Venkateswaran RV, Patchell VB, Wilson IC, et al: Early
donor management increases the retrieval rate of lungs for transplantation.
Ann Thorac Surg 85:278, 2008
37. Michelena JC, Chamorro C, Falcón JA, et al. Hormonomodulación
del donante de órganos. Utilidad de los esteroides.
Med Intensiva 33:251, 2009
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Controversial Points in Organ Donor Management