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Hypothalamic-Pituitary Function in Brain Death: A Review

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The Uniform Determination of Death Act (UDDA) states that an individual is dead when "all functions of the entire brain" have ceased irreversibly. However, it has been questioned whether some functions of the hypothalamus, particularly osmoregulation, can continue after the clinical diagnosis of brain death (BD). In order to learn whether parts of the hypothalamus can continue to function after the diagnosis of BD, we performed 2 separate systematic searches of the MEDLINE database, corresponding to the functions of the posterior and anterior pituitary. No meta-analysis is possible due to nonuniformity in the clinical literature. However, some modest generalizations can reasonably be drawn from a narrative review and from anatomic considerations that explain why these findings should be expected. We found evidence suggesting the preservation of hypothalamic function, including secretion of hypophysiotropic hormones, responsiveness to anterior pituitary stimulation, and osmoregulation, in a substantial proportion of patients declared dead by neurological criteria. We discuss several possible explanations for these findings. We conclude by suggesting that additional clinical research with strict inclusion criteria is necessary and further that a more nuanced and forthright public dialogue is needed, particularly since standard diagnostic practices and the UDDA may not be entirely in accord.
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DOI: 10.1177/0885066614527410
published online 31 March 2014J Intensive Care Med
Michael Nair-Collins, Jesse Northrup and James Olcese
Pituitary Function in Brain Death: A ReviewHypothalamic
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Article
Hypothalamic–Pituitary Function
in Brain Death: A Review
Michael Nair-Collins, PhD
1
, Jesse Northrup, MA
2
,
and James Olcese, PhD
3
Abstract
The Uniform Determination of Death Act (UDDA) states that an individual is dead when ‘all functions of the entire brain have
ceased irreversibly. However, it has been questioned whether some functions of the hypothalamus, particularly osmoregulation, can
continue after the clinical diagnosis of brain death (BD). In order to learn whether parts of the hypothalamus can continue to function
after the diagnosis of BD, we performed 2 separate systematic searches of the MEDLINE database, corresponding to the functions of
the posterior and anterior pituitary. No meta-analysis is possible due to nonuniformity in the clinical literature. However, some mod-
est generalizations can reasonably be drawn from a narrative review and from anatomic considerations that explain why these find-
ings should be expected. We found evidence suggesting the preservation of hypothalamic function, including secretion of
hypophysiotropic hormones, responsiveness to anterior pituitary stimulation, and osmoregulation, in a substantial proportion of
patients declared dead by neurological criteria. We discuss several possible explanations for these findings. We conclude by suggest-
ing that additional clinical research with strict inclusion criteria is necessary and further that a more nuanced and forthright public
dialogue is needed, particularly since standard diagnostic practices and the UDDA may not be entirely in accord.
Keywords
brain death, hypothalamus, pituitary, diabetes insipidus, Uniform Determination of Death Act
Introduction
The concept of brain death (BD) is accepted nearly worldwide as
equivalent to death,
1
yet a number of controversies persist, lead-
ing one scholar to name it both ‘well settled yet still unre-
solved,’
2(p.1244)
and prompting the United States President’s
Council for Bioethics to revisit the concept in a new White Paper.
3
One issue that remains controversial is the relation of standard
diagnostic tests to the statutory definition of ‘death’ as outlined
in the Uniform Determination of Death Act (UDDA), which
states: ‘An individual who has suffered either (1) irreversible ces-
sation of circulatory and respiratory functions or (2) irreversible
cessation of all functions of the entire brain, including the brain
stem, is dead,’
4(p. 2)
For example, the editors of Nature stated
in a recent editorial:
The [UDDA] seems admirably straightforward ...In practice,
unfortunately, physicians know that when they declare that
someone on life support is dead, they are usually obeying the
spirit, but not the letter, of this law. And many are feeling
increasingly uncomfortable about it. In particular, they struggle
with three of the law’s phrases: ‘irreversible,’ ‘all functions and
‘entire brain,’ knowing that they cannot guarantee full complia-
nce ...The time has come for a serious discussion on redrafting
laws that push doctors towards a form of deceit.
5(p570)
Evidence suggests that neuroendocrine functions may be
preserved in some patients after the declaration of BD.
6
How-
ever, there are no comprehensive reviews of the clinical litera-
ture on this issue. Our purpose, therefore, is to provide such a
review. Specifically we want to know: how often is BD accom-
panied by complete hypothalamic–pituitary failure? Although
the term ‘brain death’ is sometimes used to mean irreversible
cessation of all functions of the entire brain, this implies that
continued hypothalamic function in BD is a contradiction in
terms. Nonetheless, since our purpose in this article is to inves-
tigate whether hypothalamic–pituitary function remains in
1
Department of Behavioral Sciences and Social Medicine, Florida State Uni-
versity College of Medicine, Tallahassee, FL, USA
2
Pacific Science Center, Seattle, WA, USA
3
Department of Biomedical Sciences, Florida State University College of
Medicine, Tallahassee, FL, USA
Received October 3, 2013, and in revised form December 11, 2013.
Accepted for publication December 12, 2013.
Corresponding Author:
Michael Nair-Collins, Department of Behavioral Sciences and Social Medicine,
Florida State University College of Medicine, 1115 West Call Street, Tallahassee,
FL 32306, USA.
Email: michael.nair-collins@med.fsu.edu
Journal of Intensive Care Medicine
1-10
ª The Author(s) 2014
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some patients who are declared to be brain dead, we follow the
standard usage in the clinical literature and use ‘brain death’
to mean lack of clinical functions of the brain, as judged by
apnea, brain stem areflexia, and cerebral unresponsiveness,
coupled with a known, irreversible cause of coma. We consid-
ered the functions of the posterior and anterior pituitary sepa-
rately as befitting their distinct anatomic characteristics and
embryologic origins.
Hypothalamic–Pituitary Function
Magnocellular neurons of the supraoptic and paraventricular
nuclei of the hypothalamus secrete the hormone arginine vaso-
pressin (AVP) into the peripheral bloodstream via the posterior
pituitary in response to an increase in plasma osmotic pressure
or hypovolemia. The half-life of AVP is relatively short, at
about 15 to 18 minutes, and as little as a 1% change in plasma
osmolarity can induce a change in AVP secretion. This rapid
and sensitive physiologic response is part of a negative feed-
back system that maintains plasma osmolarity within a narrow,
roughly 3% window by controlling diuresis via the kidneys.
7
In
the absence of AVP or the kidneys’ ability to respond to it, dia-
betes insipidus (DI) develops, characterized by the excretion of
large amounts of dilute urine, often accompanied by hyperna-
tremia. The clinical condition may result from primary
hypothalamic dysfunction (central DI) or from the failure of the
renal collecting ducts and distal tubules to respond to AVP
(nephrogenic DI).
By contrast, the hypothalamus controls the anterior pituitary
indirectly by secreting hypophysiotropic hormones into the
local portal circulation. The functions of the anterior pituitary
hormones, their target organs, and the peripheral hormones
they control are complex, diffuse, subject to multiple intercon-
nected feedback loops, and affect metabolic functions through-
out the body.
We operationalized the concept of preserved hypothalamic–
posterior pituitary function as the absence of DI. In contrast to
the relatively straightforward role of AVP in antidiuresis, an
inference from 1 or a few physiologic variables to a conclusion
regarding the preservation of hypothalamic–anterior pituitary
function would be less secure. Therefore, for the functions of
the anterior pituitary, the main variables of interest are direct
measurements of selected hormones or responses to anterior
pituitary stimulation tests. We used these concepts to target 2
literature reviews.
Methods
The MEDLINE database was accessed through PubMed in
September 2013. Results were restricted to English-language
articles without date restriction. For the first search, we utilized
Medical Subject Headings (MeSH) terms ‘brain death’ in con-
junction with ‘diabetes insipidus’ and with ‘posterior pitui-
tary,’ yielding 26 results and 1 result, respectively. Text
words ‘brain death,’ ‘diabetes insipidus,’ and ‘posterior
pituitary’ were combined in the same pattern to reveal 105 and
18 results. Reference lists were reviewed, and we consulted
organ donor management guidelines and bioethical reviews
to find additional studies.
Articles were included if they reported the results of an orig-
inal clinical research study that provides evidence regarding DI
or quantitative measurements of AVP in BD or brain stem
death (BSD), in a manner that allows discernment of how many
individual patients had DI or not. In accordance with common
practice, we collapse BD and BSD, the irreversible cessation of
all functions of the brain stem (a legal standard for death in the
United Kingdom), for the following reason. In practice, the
core clinical diagnostic tests for BD and BSD are the same:
brain stem areflexia, apnea, and cerebral unresponsiveness,
coupled with a known, irreversible cause of coma.
For the second search, we utilized MeSH terms ‘brain
death’ and ‘anterior pituitary,’ yielding 24 results. Text terms
‘brain death’ in conjunction with ‘endocrine failure,’ and
with ‘anterior pituitary,’ revealed 39 and 183 results, respec-
tively. Ancillary sources, as mentioned earlier, were consulted
to find additional citations. Articles were included if they
reported the results of an original clinical research study that
provided quantitative measurements of selected hormones (dis-
cussed subsequently) or responses to anterior pituitary stimula-
tion tests, in BD or BSD, reported at the individual level.
There is substantial variability in the clinical literature: the
populations are not uniform in terms of age, etiology of BD,
and the use of confirmatory diagnostic tests. The variables
measured and study methodologies are not uniform, laboratory
cutoff values are not standardized, and the key diagnostic cate-
gory of DI is not uniformly applied. These limitations preclude
the possibility of a systematic review with meta-analysis.
Instead, we provide a compilation of all studies that meet the
criteria specified earlier, in the context of a narrative review.
Results
We found a total of 32 studies that met criteria for the first
search (see Table 1).
8-40
Together, the 32 studies report on
1878 patients with BD or BSD, ranging in age from 2 months
to 89 years, of which 925 (49%) were reported to have DI. The
6 studies that report exclusively on adult patients collectively
report that 200 (60%) of 334 had DI
23,29,31,33,35,39
; for the
pediatric population, 5 studies collectively report that 145
(52%) of 279 had DI.
12,15,28,30,40
The evidenc e reg ardi ng ant eri or pituita ry fu nctio n is not
straightforward (see Ta bles 2-5). The hypophysiotropic hor-
mones luteinizing hormone-releasing hormone (LHRH),
corticotropin -rele as ing hor mone, a nd growt h horm one (GH)-
releasing hormone (GHRH) are generally detectable in periph-
eral circulation.
25,27,41
The anterior pituitary hormones
thyroid-stimulating hormone (TSH),
16,27,42-51
adrenocortico-
tropic hormone (ACTH),
27,41,51, 52 , 54
and human
GH
16,27,41, 51 , 52 ,53
are also usually detectable, mostly within a
normal range. Anterior pituitary responsiveness to stimulation
is variable. Some studies document no response to thyrotropin-
releasing hormone,
53,55
insulin-induced hypoglycemia,
41
or
2 Journal of Intensive Care Medicine
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arginine infusion,
41
whereas others document responses to
each of these anterior pituitary stimuliaswellasresponsesto
LHRH and GHRH with appropriate hormonal increases.
25,27,42
Thyroid function appears to be impaired, although the pat-
tern of thyroid hormones (low triiodothyronine [T3] and to a
lesser extent, low thyroxine [T4] with normal or high reverse
T3 and normal TSH) is more consistent with euthyroid
sick syndrome rather than central neuroendocrine fail-
ure
16,24,46,53,58,64
(see Tables 2-5 for further detail). Adrenal
function is difficult to interpret: cortisol levels show wide
variability
16,24,27,29,46,48,58,60-62
although ACTH levels are gen-
erally preserved as mentioned earlier. Diurnal variation in cor-
tisol appears universally lost.
16,27,44,63
Discussion
Interpretation of Results
These data are subject to limitations, and any quantitative esti-
mate of incidence of preserved hypothalamic function in the
Table 1. Clinical Studies Reporting on Diabetes Insipidus in Brain Death.
Publication Age BD, n DI, n DI, %
Griepp et al
8
(P) 13-52 yr 22 9 41
Jorgensen
9
(P) us 63 23 37
Jastremski et al
10
(R) 11-89 yr 176 15 9
Jorgensen and Malchow-Moller
11
(P)
a
12-86 yr 4 1 25
Outwater and Rockoff
12
(R) 5 mo to 16 yr 16 14 88
Pelosi et al
13
(P) 9-37 yr 21 6 29
Fiser et al
14
(R) 4 mo to 18 yr 34 13 38
Fackler et al
15
(R) 2 mo to 17 yr 45 5 11
Howlett et al
16
(P)
b
8-67 yr 31 24 77
Kinoshita et al
18
(P) 9-54 yr 10 10 100
Hohenegger et al
19
(P)
c
6-48 yr 11 4 36
Debelak et al
20
(R) us 181 68 38
Nygaard et al
21
(R) 6-56 yr 114 60 53
Mackersie et al
22
(R) us 99 38 38
Ali et al
23
(R) Adult 43 34 79
Gramm et al
24
(P) 9-71 yr 32 25 78
Sugimoto et al
25
(P)
d
17-61 yr 7 7 100
Rabanal et al
26
(P) us 50 20 40
Arita et al
27
(P) 9-85 yr 18 10 56
Staworn et al
28
(R) Peds 92 38 41
Amado et al
29
(P) 18-67 yr 18 5 28
Finfer et al
30
(R) Peds 77 60 78
Dominguez-Roldan et al
31
(P) Adult 59 31 53
Dosemeci et al
32
(P) 2-71 yr 94 74 79
Dominguez-Roldan et al
33
(R) Adult 50 43 86
Kim et al
34
(R)
e
13-49 yr 10 10 100
Salim et al
35
(R) Adult 69 32 46
Chai et al
36
(R)
f
17-59 yr 5 5 100
Wijdicks et al
37
(R) 2 mo to 84 yr 228 141 61
Seth et al
38
(P) 7-87 yr 55 17 31
Varelas et al
39
(R) Adult 95 55 58
Alharfi et al
40
(R) 5-17 yr 49 28 57
Total
g
2 mo to 89 yr 1878 925 49
Abbreviations: P, prospective study; R, retrospective study; BD, brain death; DI, diabetes insipidus; us, unstated; peds, pediatric (17 years and younger); adult, 18
years and older; AVP, arginine vasopressin.
a
DI was serially evaluated in patients with BD at 1, 2, 4, 8, 16, 32, 64, 128, and 256 hours postresuscitation from cardiac arrest. At these times, the following
incidence of DI in BD occurred: 1 of 4, 1 of 3, 2 of 4, 2 of 4, 4 of 8, 6 of 10, 6 of 11, 8 of 10, and 2 of 4. We have only included the first measurement in the
compilation above.
b
Keogh et al.
17
appears to report the results of the same study.
c
Of the 11, 4 had polyuria, but all had normal AVP levels. Exogenous vasopressin administered to 5 showed no or inadequate response, suggesting nephrogenic DI.
d
All 7 patients had detectable levels of AVP, suggesting nephrogenic DI or iatrogenic polyuria.
e
Of the 10 patients, 7 had a gunshot wound penetrating an area approximately 4 cm above the dorsum sella, just underneath the thalamus, crossing through the
third ventricle, the body of the corpus callosum, and the cingulum. This is very close to the hypothalamus, so it seems likely that DI was caused by direct trauma to
the hypothalamus.
f
Fifteen patients were included in this sample, but only 5 underwent apnea testing, so we have only included those 5.
g
As this is not a meta-analysis, the total only refers to the total of patients reported in this review and should not be misunderstood as implying generalizability to
the population with BD as a whole.
Nair-Collins et al 3
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population with BD in general should be taken as having
unknown confidence. However, this does not imply that no
conclusions can be drawn.
The magnocellular neurons of the hypothalamus are osmore-
ceptors, directly responsive to the osmotic pressure of their extra-
cellular environment. Although osmotically induced
depolarizations increase the likelihood that an action potential
will fire, they are not typically large enough to induce the cell
to reach its threshold voltage.
65
Normal osmoregulation requires
excitatory glutamatergic input from circumventricular areas, par-
ticularly the organum vasculosum of the lamina terminalis, creat-
ing an additive effect that allows the membrane potential to reach
spike threshold, generating an action potential down the axon and
hence inducing the secretion of AVP into the bloodstream.
65
The half-life of AVP is about 15 to 18 minutes, which allows
for a rapid physiologic response to osmotic changes. As little as
a1% change in plasma osmolarity induces a change in AVP
release, and small changes in AVP concentration in plasma
(normal range between approximately 0.5 and 5-6 pg/mL)
result in changes throughout the full range of urine osmolarity
and urine volume.
7
Thus, the osmoregulation system is sensi-
tive and rapid, with small changes in plasma osmolarity result-
ing in rapid changes in AVP secretion from the hypothalamic–
pituitary complex at a rate and level sufficient for minute-to-
minute changes in urine osmolarity and volume. In the absence
of AVP, the distal tubules and collecting ducts of the kidney’s
nephrons are nearly impermeable to water, which prevents the
reabsorption of water back into the bloodstream, resulting in
the production and release of large quantities of dilute urine.
The simplest explanation for the observation of normuria in
patients with BD is that the hypothalamic osmoregulation sys-
tem continues to function, in at least some patients.
Table 2. Overview of Hypothalamic–Anterior Pituitary Literature Review.
Variables # of Studies Findings/Comments
Selected hypophysiotropic
hormones
3 LHRH det 10/10 pts
25
; CRH and GHRH det 5/5 and 4/5
41
; GHRH det 13/23, CRH det 12/19, LHRH
det 21/22, and 1 or more of GHRH, CRH, or LHRH det 23/23
27
Selected anterior pituitary
hormones
5-12 TSH
16,27,42-51
: wnl 272/347 (78%); det 325/386 (84%)
GH
16,27,41,51,52,53
: wnl 37/60 (62%); det 102/109 (94%)
ACTH
27,41,51,52,54
: wnl 31/65 (48%); det 83/114 (73%)
Anterior pituitary
stimulation tests
6 0/36 and 0/7 responded to TRH with "TSH
53,55
0/5 responded to insulin-induced hypoglycemia or arginine with "GH
41
15/23 responded to 1 or more of TRH, LHRH, or insulin
27
2/7 and 4/5 responded to arginine and GRH with "GH
27
1/1 and 1/1 responded to TRH and LHRH
42
1/2 responded to insulin
42
4/5 responded to TRH
25
T4 (total and free) 6-7 T4
16,43,44,50,56,57
: Wnl or " 80/129 (62%)
fT4
45-50,58
: wnl or " 194/299 (65%)
T3 (total, free, and
reverse)
6-9 T3
16,43,44,50,56,57
: wnl 27/129 (21%)
fT3
44-50,56,57,59
: wnl or " 57/133 (17%)
rT3
16,45-48,50,58
: wnl or " 152/169 (90%)
Thyroid hormone patterns (including TSH) most consistent with euthyroid sick
syndrome rather than central neuroendocrine failure.
Cortisol 8 Highly variable.
16,24,27,29,46,48,58,60-62
Diurnal variation apparently lost in every case.
16,27,45,63
Abbreviations: LHRH, luteinizing hormone-releasing hormone; CRH, corticotropin-releasing hormone; GHRH, growth hormone-releasing hormone; TRH,
thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; GH, growth hormone; ACTH, adrenocorticotropin hormone; T4, thyroxine; fT4, free T4;
T3, triiodothyronine; fT3, free T3; rT3, reverse T3; wnl, within normal limits; det, detectable; ", high.
Table 3. Anterior Pituitary Stimulation Tests.
Publication Age BD, n Variables Findings
Schrader et al
42
(P) 16-56 yr 6 IH-t, LHRH-t, TRH-t IH-t þ in 1/2; LHRH-t þ in 1/1; TRH-t þ in 1/1
Koller et al
53
(P) 16-64 yr 36 TRH-t þ in 0/36
Imberti et al
55
(P) 19-62 yr 7 TRH-t þ in 0/7
Sugimoto et al
25
(P) Adult 5 TRH-t þ in 4/5
Kinoshita et al
41
(P) 17-50 yr 10 IH-t, AI-t IH-t þ in 0/5, AI-t þ in 0/5
Arita et al
27
(P) 9-85 yr 39 TRH-t, LHRH-t, IH-t, AI-t, GHRH-t 15/23 þ to 1 or more of TRH-t, LHRH-t, or IH-t; 2/4
þ in add’l LHRH-t 7 d post-BD; AI-t þ 2/7; GHRH-t þ 4/5
Abbreviations: P, prospective study; R, retrospective study; BD, brain death; adult, 18 years and older; IH-t, insulin-induced hypoglycemia test; LHRH-t, luteinizing
hormone-releasing hormone test; TRH-t, thyrotropin-releasing hormone test; þ, positive response; AI-t, arginine infusion test; GHRH-t, growth hormone-
releasing hormone test; add’l, additional; yr, years; d, days.
4 Journal of Intensive Care Medicine
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It is possible that an extracranial tumor could secrete AVP
into the bloodstream; however, this would not be subject to
inhibitory feedback, therefore, the patient would likely be oli-
guric or anuric. More importantly, this is an unusual circum-
stance and would not explain the common finding of the
absence of DI in about half of the patients reported previously.
Another possibility is that AVP passively leaks from the axonal
terminals of nonviable hypothalamic cells whose perikarya
have been destroyed (ie, posterior pituitary washout). This
source of AVP is also not subject to feedback so the patient
would more likely exhibit anuria or oliguria, followed by poly-
uria minutes after the AVP stores are depleted. However,
depending on the rate at which AVP passively leaks, it seems
plausible that passive leakage of AVP could mimic osmoregu-
lation at least while AVP stores last and so this may account for
some of the cases of lack of apparent DI.
A third possibility is that glomerular filtration rate (GFR) is
significantly decreased. This would result in the diminution of
the amount of fluid delivered to the distal tubule and hence
would limit renal water excretion and prevent polyuria.
66
The-
oretically, this phenomenon may occur even in the absence of
AVP; therefore, the absence of polyuria does not necessarily
imply function of the hypothalamic osmoregulation system.
Although this is a possibility, it cannot account for all of the
cases of lack of DI in patients with BD. Fiser et al,
14
for exam-
ple, report no significant difference in creatinine levels
between patients with BD with DI (n ¼ 13) and patients with
BD without DI (n ¼ 21), suggesting that decreased GFR cannot
account for the absence of DI in these patients. Finfer et al
30
reported mean maximum creatinine level of 1.02 + 0.7 mg/
dL in their sample. In the 17 patients without DI (of 77 with
BD in total), decreased GFR cannot account for the absence
of polyuria. Furthermore, several studies directly measured
plasma AVP, finding AVP within the normal range for osmor-
egulation in some patients with BD.
19,24,25,27
For example, 1 study followed a rigorous protocol, correlat-
ing plasma AVP with plasma osmolarity.
27
Using standardized
criteria for DI,
67
these authors found that 10 of the 18 patients
in their sample had DI, 1 had the syndrome of inappropriate
antidiuretic hormone, and the remaining 7 (39%) of the 18
demonstrated normal plasma osmolarity and normal AVP. It
should be noted that it is unlikely that passive leakage, not sub-
ject to any feedback, would account for the normal plasma
osmolarity, given the negative feedback needed to maintain a
delicate balance of plasma osmolarity within a narrow, roughly
3% window.
7
Furthermore, anatomical considerations suggest that pre-
served hypothalamic osmoregulation may be expected in BD.
The inferior hypophyseal arteries branch off the extradural seg-
ments of the internal carotids and thus are protected from
increased intracranial pressure, and these arteries supply the
posterior pituitary, the hypophysial stalk, and parts of the
hypothalamus including the median eminence.
68
Pathology
studies support this explanation. Walker and colleagues
69
Table 4. Hypothalamo–Pituitary–Thyroid Axis.
Publication Age BD, n Variables Findings
Schrader et al
42
(P)
a
16-56 yr 6 TSH TSH wnl or " 4/6
Gifford et al
56
(R) 7-54 yr 22 T4, T3 T4 wnl 10/22, det 22/22; T3 wnl 0/22, det 10/22
Macoviak et al
43
(P) 15-36 yr 22 TSH, T4, T3 TSH wnl 17/22; T4 wnl 17/22; T3 wnl 6/22
Novitzky et al
59
(P) 16-40 yr 21 fT3 fT3 wnl 1/21, det 21/21
Robertson et al
44
(P) Adult 13 TSH, T4, T3, fT3 TSH wnl 13/13; T4 wnl 10/13; T3 wnl 3/13; fT3 wnl 1/13
Montero et al
57
(P) us 21 T4, T3 T4 wnl or " 14/21, det 21/21; T3 wnl 3/21, det 21/21
Howlett et al
16
(P) 8-67 yr 31 TSH, T4, T3, rT3 TSH wnl or " 24/31; T4 wnl 18/31; T3 wnl or " 6/31; rT3 wnl or " 29/29 (15/
29 wnl and 14/29 ")
Robertson et al
58
(P) Adult 36 fT4, fT3, rT3 fT4 wnl or " 30/36; fT3 wnl or " 3/36; rT3 wnl 34/36
Masson et al
45
(P) 14-48 yr 20 TSH, fT4, fT3, rT3 TSH wnl 15/20; fT4 wnl 7/20, fT3 wnl 4/20; rT3 wnl or " 18/18 (3/18 wnl and
15/18 ")
Powner et al
46
(P) 19-60 yr 16 TSH, fT4, fT3, rT3 TSH wnl 8/16; fT4 wnl or " 15/16 (12/16 wnl and 3/16 "); fT3 wnl 1/16; rT3
wnl or " 15/16 (11/16 wnl and 4/16 ")
Arita et al
27
(P) 9-85 yr 39 TSH TSH det 39/39
Karayalcin et al
47
(P) 11-60 yr 50 TSH, fT4, fT3, rT3 TSH wnl or " 36/50, (35/50 wnl, 1/50 "), det 50/50; fT4 wnl or " 20/50 (19/50
wnl, 1/50 "); fT3 wnl 18/50; rT3 wnl or " 48/50 (44/50 wnl, 4/50 ")
Mariot et al
48
(P) us 120 TSH, fT4, fT3 TSH wnl 99/120, fT4 wnl 75/120; fT3 wnl 15/120
Goarin et al
49
(P) 15-55 yr 37 TSH, fT4, fT3 TSH wnl 35/37, fT4 wnl or " 37/37; fT3 wnl 6/37
Szostek et al
50
(P) 17-55 yr 20 TSH, T4, fT4, T3,
fT3, rT3
TSH wnl or " 13/20 (11/20 wnl and 2 "); T4 wnl or " 11/20; fT4 wnl or " 10/
20; T3 wnl or " 9/20; fT3 wnl or " 8/20; rT3 wnl or " 8/20; both T3 and T4
positively correlated with TSH
Ishikawa et al
51
(P)
b
39-70 yr 12 TSH TSH wnl 8/12
Abbreviations: P, prospective study; R, retrospective study; BD, brain death; us, unstated; adult, 18 years and older; TSH, thyroid-stimulating hormone; T4, thyr-
oxine; fT4, free T4; T3, triiodothyronine; fT3, free T3; rT3, reverse T3; wnl, within normal limits; det, detectable; ", high; #, low; yr, years.
a
‘Serum TSH was within normal range ... in the majority of the patients but was slightly elevated in case 5.’
42(p241)
We have transcribed this statement into our
compilation as the lowest number of cases possible such that the majority was within the normal range (ie, 4 of 6).
b
Hormones were measured at autopsy, 4 to 25 days post-BD. All patients were autopsied within 12 hours of cardiac arrest. Blood was taken from the right cardiac
chamber.
Nair-Collins et al 5
at FLORIDA STATE UNIV LIBRARY on April 1, 2014jic.sagepub.comDownloaded from
reported finding some intact regions of the hypothalamus with
relatively well-preserved neurons, intermingled with neurons
with lytic changes, in patients with coma de´passe´ (a diagnostic
precursor to BD: all patients were comatose, apneic, and with
isoelectric encephalograms). In a more recent pathology study
of 41 patients with BD,
70
moderate to severe ischemic changes
in brain stem and higher brain structures were found in only
about 34% to 68% of patients (with variability in different brain
areas). Of these 41 patients, 16 of the pituitary glands were
examined, with 55% of those showing mild or absent ischemic
changes.
Polyuria alone is not sufficient evidence of dysfunctional
hypothalamic control of plasma osmolarity, yet the majority
of studies did not rule out confounding factors nor corroborate
urine output with laboratory values. There are a number of
iatrogenic reasons for polyuria, including diuretics or fluid
resuscitation. To illustrate, Fiser and colleagues
14
report that
26 of the 34 patients were polyuric, yet only 13 had DI while
the remaining 13 did not have hypernatremia, serum hyperos-
molarity, or urine hyposmolarity. Polyuria was determined to
be due to the administration of furosemide, mannitol, or con-
trast solution for computed tomography. In 2 studies,
12,26
DI
was found to spontaneously resolve in some patients without
administration of exogenous vasopressin, suggesting reperfu-
sion or a decrease in edema, or both, to the hypothalamic–pitui-
tary complex after an initial insult that rendered the area
temporarily nonfunctional.
Regarding anterior pituitary function, measurement of
hypophysiotropic hormones in peripheral circulation is not
entirely reliable due to pulsatility of the hormones and the min-
ute amounts secreted. However, finding preserved anterior
pituitary hormones, which depend on hypophysiotropic
hormones for their secretion, corroborates the finding of pre-
served hypophysiotropic hormones. Responsiveness to stimu-
lation suggests viability of the anterior pituitary as well as
preserved blood flow. Thyroid and adrenal functions, while
impaired, are not absent. If there were central neuroendocrine
failure, the pattern of thyroid hormones would be very differ-
ent, with significant hypothyroidism as well as undetectable
TSH. These data suggest variable preservation of some areas
of the hypothalamus and anterior pituitary. Furthermore, they
serve as corroborating evidence for the preservation of
hypothalamic osmoregulation, by suggesting preservation of
circulation to the pituitary and parts of the hypothalamus.
Although the data have limitations, we believe the following
modest conclusions are justified. At least some of the patients
in these studies who were normuric had some preserved brain
function through hypothalamic osmoregulation. The various
findings consistent with preservation of hypothalamic control
of the anterior pituitary corroborate this by suggesting pre-
served blood flow to the area, and suggest some hypothala-
mic–anterior pituitary function as well although often in the
presence of peripheral endocrine insufficiency. Anatomical
considerations explain why these findings are to be expected,
and pathology studies corroborate this explanation. It is to be
emphasized that this is not a meta-analysis and no specific inci-
dence estimates are offered for the general population of
patients with BD.
General Discussion
The results of this review suggest that some basal parts of the
brain can continue to function in a nontrivial proportion of
patients who are declared dead on the basis of neurological
Table 5. Hypothalamo–Pituitary–Adrenal Axis and GH.
Publication
Age
yr, years BD, n Variables Findings
Schrader et al
42
(P) 16-56 yr 6 GH GH wnl or " 5/6
Howlett et al
16
(P) 8-67 yr 31 GH, cort GH wnl 10/31, det 27/31; cort wnl 5/21, det 20/21
Robertson et al
58
(P) Adult 36 Cort Cort wnl 27/30
Powner et al
46
(P) 19-60 yr 16 Cort Cort wnl or " 10/11
Kinoshita et al
41
(P) 17-50 yr 10 GHRH, GH, CRH, ACTH, cort All hormones det in all patients, except GHRH det 4/5
Arita et al
27
(P) 9-85 yr 39 GHRH, GH, CRH, ACTH, cort,
LHRH
GHRH det 13/23; CRH det 12/19; LHRH det 21/22; 1 or
more of GHRH, CRH, or LHRH det in every case; GH
det 38/39; ACTH det 33/39; mean concentration all
hormones wnl except GH was ". Cortisol wnl 23/30
Mariot et al
48
(P) us 120 Cort Cort wnl 101/120
Fitzgerald et al
54
(P) 25-61 yr 11 GH, ACTH, cort GH wnl 11/11; ACTH wnl 9/11, det 10/11; cort wnl 10/
11
Dimopoulou et al
60
(P) Adult 17 Cort Cort wnl 5/17
a
Ishikawa et al
51
(P)
b
39-70 yr 12 GH GH wnl or " 11/12
Nicolas-Robin et al
52
(P) Adult 42 ACTH ACTH wnl 17/42, det 25/42
Abbreviations: P, prospective study; R, retrospective study; BD, brain death; us, unstated; adult, 18 years or above; LHRH, luteinizing hormone-releasing hormone;
GHRH, growth hormone-releasing hormone; GH, growth hormone; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropin hormone; cort, cor-
tisol; wnl, within normal limits; det, detectable; ", high; yr, years.
a
‘Within normal limits’ is here considered to be above 10 mg/dL. Although this is high, it is considered normal in the context of acute stressful illness.
b
Hormones were measured at autopsy, 4 to 25 days post-BD. All patients were autopsied within 12 hours of cardiac arrest. Blood was taken from the right cardiac
chamber.
6 Journal of Intensive Care Medicine
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criteria. Given that the UDDA and all state laws based on it
describe the statutory definition of ‘death’ as ‘irreversible
cessation of all functions of the entire brain,’ it follows that
any patient who retains neuroendocrine regulation does not,
strictly speaking, meet the statutory standard for death by neu-
rologic criteria in the United States (nor any other nation with
similar ‘whole-brain death’ laws). Therefore, we make 2
suggestions.
First, further clinical research is needed, with well-designed
studies (including stricter inclusion criteria) aimed at ascertain-
ing the nature and incidence of preserved brain function in
patients who meet standard diagnostic tests for BD. In addition
to neuroendocrine function, electrophysiology studies suggest
that the integrity of a variety of neural pathways may be pre-
served as manifested by evoked potentials as well as organized
cortical activity.
6
It is to be emphasized that the triad of unre-
sponsiveness, brain stem areflexia, and apnea are tests—they
do not define the nosological category of BD itself. Legally
in the United States, BD is the irreversible cessation of all func-
tions of the entire brain; hence, if a patient satisfies clinical
tests while maintaining, for example, hypothalamic osmoregu-
lation, then that is a false positive.
Second, a forthright public dialogue is needed, which better
takes into account the complexities of this topic. This should
include frank discussion of the biomedical science underlying
BD and its diagnosis, including the possibility of minimal brain
function in some patients declared ‘dead by neurologic cri-
teria.’ If, as it would appear, diagnostic practices and the
UDDA are not entirely in accord, then there should be an open
public conversation. Whether those laws that ‘push doctors
toward a form of deceit’ need to be redrafted, as the editors
of Nature suggested,
5
or whether more stringent diagnostic
practices should be used is a question with important medical,
ethical, social, and legal components and therefore should be
publicly vetted.
For example, the diagnosis of BD has important legal and
ethical implications for organ transplantation, since brain dead
organ donors remain the primary source of transplantable
organs. One well-accepted legal and ethical principle is known
as the ‘dead donor rule,’ which states that organ donors must
be dead before vital organs are procured.
3
However, the results
of this review suggest the possibility that some patients who are
declared dead may maintain some minimal brain function and
therefore, at least in a strict sense, do not meet legal standards
for death by neurologic criteria. Were such patients to become
organ donors, adherence to the dead donor rule could be called
into question. The ethical issues related to BD and organ dona-
tion are complex, however, and cannot be adequately addressed
in this context (see Nair-Collins for a review of the philosophi-
cal and ethical literature on this topic).
71
It should suffice to
point out that there are clear ethical, legal, and social implica-
tions of the diagnosis of BD, which reach beyond rather tech-
nical concerns regarding AVP secretion and osmoregulation;
and therefore, an informed public dialogue is needed.
One might reply that ‘BD is a clinical diagnosis,’ and only
those functions that are clinically ascertainable are relevant to
the determination of death.
72,73
But this is a nonsequitur. The
UDDA is clear and straightforward: an individual that has any
brain function cannot be said to satisfy the UDDA’s definition
of irreversible cessation of all functions of the entire brain,
regardless of whether the preserved function is clinically obser-
vable or not. Furthermore, normuria is a clinically observable
sign of brain function just as much as pupillary constriction
or spontaneous inspiration.
One might also point to the immediately following phrase in
the UDDA: ‘A determination of death must be made in accor-
dance with accepted medical standards.’ Since brain stem
areflexia, apnea, and cerebral unresponsiveness constitute
long-accepted medical standards upon which to diagnose BD,
perhaps it follows that the use of such diagnostic standards is
in accordance with the UDDA. However, ‘accepted medical
standards’ refers to the tests to be used to identify those
patients who have irreversibly lost all functions of the entire
brain, and this was made explicit by the authors of the
UDDA.
4(pp78-79)
Although it is accepted practice to not test for
certain brain functions (particularly neurohormonal functions),
this does not show that doing so is consistent with the UDDA in
either letter or spirit, since both the UDDA and the President’s
Commission’s report upon which it is based are explicit in
insisting that all brain functions must be lost.
Finally, we have not discussed in any depth the diagnostic
tests that were used in these studies. Given that there is varia-
bility in diagnostic practices,
1,74
perhaps it is simply the case
that many of the patients reported in these studies were mis-
diagnosed and that, with stricter diagnostic criteria, no patient
with neuroendocrine function would be classified as brain
dead. This response is also a nonsequitur, since the question
of misdiagnosis is precisely the point. We wished to address,
in light of continued controversy over BD and its diagnosis,
whether some patients who are in fact declared to be dead by
neurologic criteria nonetheless maintain some brain function.
The results of our review suggest an affirmative answer, and
potentially almost half of the patients reported in the cited stud-
ies should be classified, in a strict sense, as false positives. It
therefore follows that diagnostic practices—variable they may
be—might not be entirely in accord with legal standards such
as the UDDA (note 1). Whether to alter diagnostic practices,
for example by insisting on direct tests of hypothalamic func-
tion (a practice that is not routinely used anywhere, to our
knowledge), or whether to redraft the laws is a question that
should be addressed explicitly.
We conclude by reiterating that further clinical research is
needed in this area. Furthermore, a serious and forthright public
dialogue is in order, which takes into account the medical, ethi-
cal, and legal complexity and nuance of these issues.
Acknowledgments
The authors are grateful to Ms Sydney Green for assistance with liter-
ature reviews and to Dr Les Beitsch, MD, JD, for critical reading of the
manuscript and thoughtful comments. Dr Nair-Collins is grateful for
financial support received from The Council on Research and Creativ-
ity at Florida State University. The Council on Research and
Nair-Collins et al 7
at FLORIDA STATE UNIV LIBRARY on April 1, 2014jic.sagepub.comDownloaded from
Creativity played no role in the design and conduct of the study; col-
lection, management, analysis, and interpretation of the data; and pre-
paration, review, or approval of the manuscript. All authors have had
full access to all the data in the study. Dr Nair-Collins takes full
responsibility for the integrity of the data and accuracy of analysis.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship and/or publication of this article: Dr Nair-
Collins received financial support from the Council on Research and
Creativity at Florida State University.
Note
1. For thoroughness, the absence of diabetes insipidus (DI) cannot be
simply attributed to variable diagnostic practices: 18 of the stud-
ies
8-10,12,14,15,18,19,21,24,25,27,29,32,35,38-40
cited in the first review
explicitly listed diagnostic criteria that are in accord with standard
consensus guidelines, such as the American Academy of Neurol-
ogy’s guidelines for diagnosing brain death
75
and most used addi-
tional confirmatory tests such as electroencephalography or
angiography, in addition to standard clinical criteria. Collectively
those studies report that 539 (58%) of the 928 patients did not have
DI. Therefore, the appearance of preserved hypothalamic function
cannot be dismissed as a result of diagnostic variability or impreci-
sion in the cited studies.
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at FLORIDA STATE UNIV LIBRARY on April 1, 2014jic.sagepub.comDownloaded from
... Further problems presented themselves for the PC's consensus with clinical evidence that hypothalamic activity often continues for a time in patients declared dead by neurological criteria [13]. Anatomically, the hypothalamus is part of the brain, and one of its functions is the regulation of electrolyte concentration in the blood, a process involving osmoreceptor cells (i.e., neurons) in the anterior hypothalamus [13]. ...
... Further problems presented themselves for the PC's consensus with clinical evidence that hypothalamic activity often continues for a time in patients declared dead by neurological criteria [13]. Anatomically, the hypothalamus is part of the brain, and one of its functions is the regulation of electrolyte concentration in the blood, a process involving osmoreceptor cells (i.e., neurons) in the anterior hypothalamus [13]. The posterior pituitary, or neurohypophysis regulates the body's water content: a vital homeostatic process [14]. ...
... As Nair-Collins has pointed out, hypothalamic functioning is "at least as physiologically vital for life, if not more so, than a corneal blink reflex or a gag reflex-both of which, if present, would preclude a diagnosis of brain death." [13] It would seem that the persistence of hypothalamic function would necessarily invalidate a diagnosis of brain death made under an "all functions of the entire brain" definition of brain death. This is why Nair-Collins has suggested that, taking endocrine function into account, "half of patients declared dead under UDDA criteria are still alive under UDDA criteria [15]". ...
Article
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The definition of death as “irreversible coma” was introduced in 1968 by the Harvard University Medical School. It was developed largely in diagnostic terms as the “irreversible cessation of all functions of the entire brain, including the brainstem.” In its review of brain death in 1981, The President’s Commission for the Study of Ethical Problems in Medicine argued that brain death is consonant with circulatory death because the loss of certain brain functions results in the “loss of integrative unity of the organism,” leading to cardiac arrest. This picture of a unified conception of death was challenged by subsequent clinical evidence suggesting that, with proper treatment, circulatory death is not the inevitable result of brain death. Here, it is argued that, if death, in the morally relevant sense, is defined as irreversible loss of consciousness, a unitary conception of death can be maintained. However, significant theoretical and methodological obstacles remain in diagnosing irreversible loss of consciousness.
Chapter
Ethical challenges in medical decision making are commonly encountered by clinicians caring for patients afflicted by neurological injury or disease at the end of life (EOL). In many of these cases, there are conflicting opinions as to what is right and wrong originating from multiple sources. There is a particularly high prevalence of impaired patient judgment and decision-making capacity in this population that may result in a misrepresentation of their premorbid values and goals. Conflict may originate from a discordance between what is legal or from stakeholders who view and value life and existence differently from the patient, at times due to religious or cultural influences. Promotion of life, rather than preservation of existence, is the goal of many patients and the foundation on which palliative care is built. Those who provide EOL care, while being respectful of potential cultural, religious, and legal stakeholder perspectives, must at the same time recognize that these perspectives may conflict with the optimal ethical course to follow. In this chapter, we will attempt to review some of the more notable ethical challenges that may arise in the neurologically afflicted at the EOL. We will identify what we believe to be the most compelling ethical arguments both in support of and opposition to specific EOL issues. At the same time, we will consider how ethical analysis may be influenced by these legal, cultural, and religious considerations that commonly arise.
Chapter
The persistence of some degree of hypothalamic function is common in patients who meet all other preconditions to test for the determination of death by neurologic criteria with approximately 50% of such patients not developing diabetes insipidus. This may be difficult to reconcile with the whole-brain criterion for death that requires the loss of all functions of the entire brain including the brainstem. The determination of death must also be made in accordance with accepted medical standards. In most countries, these standards are not set in legislation, but are developed by appropriate professional bodies. Professional standards worldwide and international consensus statements accept that the absence of diabetes insipidus is compatible with a determination of death by neurologic criteria. This mismatch in legal and clinical requirements will continue to raise philosophical, legal, professional, and ethical arguments until the mismatch is resolved. Meanwhile, it remains true that no patient who meets the conditions for determination of death by neurologic criteria ever regains consciousness or breathes independently again, irrespective of the presence or absence of neuroendocrine function.
Chapter
This chapter examines concepts and criteria of death and the coherence of their associations. Concepts of death fall into two broad categories: non-ontological and ontological. Non-ontological concepts include death as a cluster kind and death as a process; the corresponding criteria are stipulative, based on pragmatic concerns. Ontological concepts are essentially either psychological (cessation of “personhood,” equated with capacity for thinking and self-awareness) or biological (cessation of the human organism). The psychological concept corresponds to a “higher brain” criterion, namely irreversible, permanent nonfunction (destruction) of bilateral thalami (the sufficiency of neocortical destruction alone being uncertain); anatomically broader criteria are sufficient but not necessary. The biological concept corresponds to a criterion of irreversible, permanent cessation of circulation of oxygenated blood (irreversible cessation of brain function being necessary but not sufficient). Irreversible apneic unconsciousness is best understood not as a concept of death but as a stipulative criterion. Concepts of life and death and their corresponding criteria derive from fundamental worldviews, on which there has been no consensus for over two millennia, nor is there likely ever to be. Respect for deeply held fundamental worldviews requires allowance for personal specification of circulatory or brain-based criteria.
Chapter
In this chapter, we discuss whether death requires permanent or irreversible cessation of function. We argue that death requires only permanent cessation of function, ultimately focusing on the application of this argument to determining death by neurologic criteria. Throughout history, we have relied on permanent cessation of function. The genuine possibility of reversing the cessation of function became real only from about the 1700s. The gradual introduction of the requirement of irreversibility reflects the ethical norm that everything should be done to revive a patient where this is possible and appropriate. However, this norm does not apply to patients for whom resuscitation is not appropriate. Since permanence covers both patient cohorts, it is a sound criterion for declaring death. Influential defenses of irreversibility, such as that of Don Marquis, are subjected to critical scrutiny.
Chapter
The whole-brain criterion for death requires the absence of all functions of the entire brain. It follows logically that the preservation of any function of any part of the brain is not consistent with the whole-brain criterion for death. The hypothalamus is a part of the brain and has been shown to continue functioning in up to 50% of patients declared dead by neurologic criteria. Therefore, up to 50% of patients declared dead under the whole-brain criterion for death are false-positive misdiagnoses. Numerous responses have been offered to explain why preserved hypothalamic function is consistent with the whole-brain criterion for death. All these responses fail.
Chapter
The conceptual basis for the brain criterion of death is the permanent cessation of the human organism-as-a-whole. This holistic concept relies on principles of organized hierarchies, emergent functions, biological mereology, and self-integration as applied to brain functions. It grants that many parts of the human organism can remain alive by technological support despite the cessation of the organism-as-a-whole. This rationale, endorsed by scholars and two US ethics commissions, remains vague, relies on intuition, and needs a more detailed analysis. Cases of mismatch between the whole-brain criterion of death and the test battery accepted in the United States could be lessened by changing the whole-brain criterion of death to the brain-as-a-whole criterion. Although many physicians conceptualize brain death using the brain-as-a-whole criterion, it remains in an early developmental stage and needs reasoned accounts of which brain functions characterize the brain-as-a-whole and why. There is noncongruence between the biological concept of death as irreversible and the accepted medical practice of determining death at a time when the vital functions have ceased permanently but not irreversibly. This noncongruence has long been accepted by society but recently has triggered disputes over death determination in organ donors after the circulatory determination of death. The reality of the noncongruence should be recognized and laws should state the prevailing medical standard of permanent vital function cessation for death determination, irrespective of organ donation.
Chapter
Proof of irreversible brain dysfunction (IHA, „brain death“) is the legal prerequisite for post-mortem organ donation, but its determination is generally independent of a possible organ donation. Because not all patients with a severe brain injury that could cause brain death are formally diagnosed, the exact epidemiology of brain death is not known. The current version of the associated guideline of the German Medical Association is binding for formal brain death diagnostics. Independently of each other, at least two physicians check the preconditions for diagnosing brain death in the 1st step, then, in the 2nd step, record the clinical findings and, in the 3rd and final step, prove the irreversibility of the clinical symptoms of failure. The findings must be documented using the protocol sheets specified in the guideline.
Article
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The controversy surrounding the dead donor rule and the adequacy of neurological criteria for death continues unabated. However, despite disagreement on fundamental theoretical questions, I argue that there is significant (but not complete) agreement on the permissibility of organ retrieval from heart-beating donors. Many disagreements are rooted in disputes surrounding language meaning and use, rather than the practices of transplant medicine. Thus I suggest that the debate can be fruitfully recast in terms of a dispute about language. Given this recasting, I argue that the language used to describe organ donation is misleading and paternalistic. Finally, I suggest that the near-agreement on the permissibility of heart-beating organ retrieval ought to be reconsidered. If the paternalism is not justified, then either the language used to describe organ transplantation must change radically, or it would seem to follow that much of the transplant enterprise lacks ethical justification.
Article
Objective: To survey brain death criteria throughout the world. Background: The clinical diagnosis of brain death allows organ donation or withdrawal of support. Declaration of brain death follows a certain set of examinations. The code of practice throughout the world has not been systematically investigated. Methods: Brain death guidelines in adults in 80 countries were obtained through review of literature and legal standards and personal contacts with physicians. Results: Legal standards on organ transplantation were present in 55 of 80 countries (69%). Practice guidelines for brain death for adults were present in 70 of 80 countries (88%). More than one physician was required to declare brain death in half of the practice guidelines. Countries with guidelines all specifically specified exclusion of confounders, irreversible coma, absent motor response, and absent brainstem reflexes. Apnea testing, using a PCO2 target, was recommended in 59% of the surveyed countries. Differences were also found in time of observation and required expertise of examining physicians. Additional provisions existed when brain death was due to anoxia. Confirmatory laboratory testing was mandatory in 28 of 70 practice guidelines (40%). Conclusions: There is uniform agreement on the neurologic examination with exception of the apnea test. However, this survey found other major differences in the procedures for diagnosing brain death in adults. Standardization should be considered.
Article
Hormonal replacement therapy is a new concept in the perioperative management of the heart-beating cadaveric donor. The objective of this study was to examine haemodynamic and endocrine changes in potential organ donors in an attempt to substantiate previous reports of low free T3 and T4 levels associated with haemodynamic instability.
Hydromineral metabolism and serum arginine-vasopressin (AVP) levels were investigated in 11 patients who sustained brain death. They showed various degrees of polyuria with low osmolality and low fractional sodium excretion. Urine osmolality was always below that of serum, and AVP levels were between 1.3 and 50.0 pg/ml vs 0.7-8.0 pg/ml in ten normal subjects. Thus central diabetes insipidus was excluded. A renal mechanism inducing water diuresis has to be assumed. The type of renal lesion, however, remains unclear.
Article
Objectives: To determine the occurrence rate of central diabetes insipidus in pediatric patients with severe traumatic brain injury and to describe the clinical, injury, biochemical, imaging, and intervention variables associated with mortality. Design: Retrospective chart and imaging review. Setting: Children's Hospital, level 1 trauma center. Patients: Severely injured (Injury Severity Score ≥ 12) pediatric trauma patients (>1 month and <18 yr) with severe traumatic brain injury (presedation Glasgow Coma Scale ≤ 8 and head Maximum Abbreviated Injury Scale ≥ 4) that developed acute central diabetes insipidus between January 2000 and December 2011. Measurements and main results: Of 818 severely injured trauma patients, 180 had severe traumatic brain injury with an overall mortality rate of 27.2%. Thirty-two of the severe traumatic brain injury patients developed acute central diabetes insipidus that responded to desamino-8-D-arginine vasopressin and/or vasopressin infusion, providing an occurrence rate of 18%. At the time of central diabetes insipidus diagnosis, median urine output and serum sodium were 6.8 ml/kg/hr (interquartile range = 5-11) and 154 mmol/L (interquartile range = 149-159), respectively. The mortality rate of central diabetes insipidus patients was 87.5%, with 71.4% declared brain dead after central diabetes insipidus diagnosis. Early central diabetes insipidus onset, within the first 2 days of severe traumatic brain injury, was strongly associated with mortality (p < 0.001), as were a lower presedation Glasgow Coma Scale (p = 0.03), a lower motor Glasgow Coma Scale (p = 0.01), an occurrence of fixed pupils (p = 0.04), and a prolonged partial thromboplastin time (p = 0.04). Cerebral edema on the initial computed tomography, obtained in the first 24 hrs after injury, was the only imaging finding associated with death (p = 0.002). Survivors of central diabetes insipidus were more likely to have intracranial pressure monitoring (p = 0.03), have thiopental administered to induce coma (p = 0.04) and have received a decompressive craniectomy for elevated intracranial pressure (p = 0.04). Conclusions: The incidence of central diabetes insipidus in pediatric patients with severe traumatic brain injury is 18%. Mortality was associated with early central diabetes insipidus onset and cerebral edema on head computed tomography. Central diabetes insipidus nonsurvivors were less likely to have received intracranial pressure monitoring, thiopental coma and decompressive craniectomy.
Article
1. Postmortem examinations were made on 240 of the 459 cases succumbing 52 percent of the deaths in the Collaborative Study on Cerebral Survival; the central nervous system was examined in 226 cases. 2. The autopsy was performed on an average of 15.3 hours after death. 3. The mean weight of the brains was 1450 +/- 196 grams; the mean weight of the brains of patients on whom resuscitation was stopped, presumably on the basis of "cerebral death," was greater than that of the patients succumbing to cardiac failure. There was a tendency for the brain to increase in weight about 24 hours after the initiation of resuscitative measures. At that time, swelling, discoloration, softening, congestion, and brain herniations also became more prominent. 4. On the basis of a survey of American neuropathologists and the data from this study, the entity commonly termed "respirator brain" may be confirmed. This is a dynamic process that is complicated by concurrent postmortem changes. The respirator brain requires time approximately 24 hours for maturation; many patients die a cardiac death during the metamorphosis. If the patient survives for 3 to 4 days, the percentage dying with typical respirator brains is less, and more patients have electroencephalograms with biological activity. (C) 1975 American Association of Neuropathologists, Inc