Some points made by Appel in the recent essay “Defining death: when
physicians and families differ [1]” merit comment.
First, it is stated that critics of brain death (BD) are most
significantly in Japan and in certain religious groups. However, there is
a long list of secular commentators who point out the many problems with
the BD criterion of death.[2-11]
Some points made by Appel in the recent essay “Defining death: when
physicians and families differ [1]” merit comment.
First, it is stated that critics of brain death (BD) are most
significantly in Japan and in certain religious groups. However, there is
a long list of secular commentators who point out the many problems with
the BD criterion of death.[2-11]
Second, there seems to be a conflation of criterion and concept of
death in the discussion. As Evans points out in his reply, a definition
(concept) of death must “stand prior to the particular sets of criteria
and evidence [12].” This means that there must be a definition of death
for which brain death follows as the criterion.[13] The definition of
death in North America is the loss of integrative unity of the
organism.[13,14] The statement that “the boy’s heart may continue to beat
for weeks or even months on ‘life support’”[1] shows that the integrative
unity of the organism is not lost, as Shewmon has elegantly argued [15]
and shown.[16] Therefore, the criterion of BD does not fulfill this
definition of death.
Third, there seems to be a suggestion of the ends justifying the
means. One concern mentioned is that there may be “long term societal
damage by undermining the perceived validity of brain death.[1]” Another
concern is the “expenditure necessary to maintain lifeless bodies.[1]”
However, as Evans points out, the cost and the need for organs should be
“irrelevant to whether or not the patient on the machine is alive or dead
while still connected to it.[12]” If BD is death, it should be because it
really is death, and fulfills a definition of death; it should not be
death because we need more organs or need to save money.
There are many other inconsistencies in the criterion of BD, and to
discuss them further is beyond the scope of this letter.[2-11] As stated
by others, “the general acceptance of the practice [BD and organ donation]
since 1968 (in the US) is irrelevant to its moral rightness or
wrongness.[11]” Like the parents in the Koochin case, it may be time for
the medical community to reconsider whether BD is equivalent to death of
the patient.
References
1. Appel JM. Defining death: when physicians and families differ. J Med
Ethics 2005; 31: 641-642.
2. Truog RD. Is it time to abandon brain death? Hastings Center Report.
1997; 27(1):29-37.
3. Potts M. A requiem for whole brain death: a response to D Alan
Shewmon’s ‘The Brain and Somatic Integration’. Journal of Medicine and
Philosophy. 2001;26:479-491.
4. Youngner SJ, Bartlett ET. Human death and high technology: the
failure of the whole-brain formulations. Annals of Internal Med. 1983;
99:252-258.
5. Zamperetti N, Bellomo R, Defanti CA, Latronico N. Irreversible
apnoeic coma 35 years later: towards a more rigorous definition of brain
death? Intensive Care Med. 2004; 30:1715-1722.
6. Shewmon DA. Recovery from “Brain Death”: a neurologist’s apologia.
Linacre Quarterly. 1997; 64(1):30-96.
7. Veatch RM. Impending collapse of the whole-brain definition of death.
Hastings Center Report. 1993; 23(4):18-24.
8. Kerridge IH, Saul P, Lowe M, McPhee J, Williams D. Death, dying and
donation: organ transplantation and the diagnosis of death. J Med Ethics.
2002; 28:89-94.
9. Halevy A, Brody B. Brain death: reconciling definitions, criteria,
and tests. Ann Intern Med. 1993; 119:519-525.
11. Potts M, Evans EW. Does it matter that organ donors are not dead?
Ethical and policy implications. J Med Ethics. 2005; 31:406-409.
12. Evans HM. Reply to: Defining death: when physicians and families
differ. J Med Ethics 2005; 31: 642-644.
13. Bernat JL, Culver CM, Gert B. On the definition and criterion of
death. Annals of Internal Med. 1981;94:389-394.
14. President’s Commission for the Study of Ethical Problems in Medicine
and Biomedical and Behavioral Research. Defining Death: Medical, Legal
and Ethical Issues in the Determination of Death. Washington, D.C.; U.S.
Government Printing Office, 1981.
15. Shewmon DA. The brain and somatic integration: insights into the
standard biological rationale for equating brain death with death.
Journal of Medicine and Philosophy. 2001; 26:457-478.
16. Shewmon DA. Chronic “brain death”: meta-analysis and conceptual
consequences. Neurology. 1998;51:1538-1545.
The discussion of Global Medical Ethics, by D F-C Tsai, “Human
embryonic stem cell research debates: a Confucian argument" (1), fails to
justify the gradualist view of human personhood.
He begins with a list of flawed arguments concerning the current
status of the human embryo which fail in the following ways:
1. Many women do undergo hormonal support of early pregnancy, for
th...
The discussion of Global Medical Ethics, by D F-C Tsai, “Human
embryonic stem cell research debates: a Confucian argument" (1), fails to
justify the gradualist view of human personhood.
He begins with a list of flawed arguments concerning the current
status of the human embryo which fail in the following ways:
1. Many women do undergo hormonal support of early pregnancy, for
threatened miscarriage or in the case of habitual miscarriage.(2) For
those women who do not choose to do submit to such therapy, society is
refrained from assault of their bodily integrity by forcing the ingestion
or injection of medication. We do not do evil to do good. In fact, the
interest of society only becomes relevant at the point of intervention by
the mother or a third person or when the child is purposefully placed in
harm’s way. In human embryology terminology, there is no such thing as a
“fertilized ova.” The human female has oocytes which cease to exist at
fertilization, when the zygotic embryo begins to exist.
2. It is interesting that, in the footnotes ("i"), the author
dismisses those cases where the parents do grieve and hold ceremonies for
the loss of unborn children. The loss of a pregnancy is experienced the
same way that all other grief is experienced: in relation to the
attachment to the one who dies. In the same way, individuals do not grieve
for thousands of strangers across the world in the same way that they
grieve for someone known for years. The fact that some murder close
relatives after birth without grief does not excuse killing and does not
define the moral status of the one killed.
3. Most, like the author, do not understand the mechanism of the
IUD.(3) In fact, it does work to inhibit fertilization by obstructing the
movement of sperm and increasing the immunological reaction to both the
sperm and (unfertilized) oocyte. When and if the device causes the death
of an embryo, it is an abortifacient. Again, Tsai uses poor terminology:
the embryo is “pre-implantation,” not a “pre-embryo” and the “egg” is
actually an “oocyte” which ceases to exist when it is fertilized and
becomes the embryo.
4. Recent publications indicate that the usual “morning after pill”
protocols work primarily to prevent ovulation, without post-fertilization
effect, although this is still in dispute.(4) As in the case of the IUD,
to the extent, if any, that such protocols are active interventions in the
normal lifespan or place the child in harm’s way, they are wrong.
5. It is irrelevant to the moral status that laws do not prohibit
abortion, since laws vary from government to government and many illicit
acts are allowed by laws in different nations. Would you excuse the
harvesting of organs for transplantation from death row inmates, since it
is legal in China? Where is the place for reform in any government if the
actions of the government make those actions licit?
6. Again, the fact that something is done does not make that action
excusable and the author is either unaware or unconcerned with the
reality that some ethicists, such as Dr. Leon Kass, have objected to the
practice of IVF all along.
The discussion of philosophers points out the problem with using
ancient knowledge, religious notions or common knowledge in determining
the moral status of the embryo: increased understanding of human
embryology informs us of the biological life span of human organisms. The
more recent philosophers mentioned, including Fletcher, Singer and
Engelhardt, give criteria (recognition of which cannot be met by the most
precocious child until 3 to 7 years of age. In fact, Singer is notorious
for his views which would push the legal status of the child up to one
year of age, depending on the wishes of his parents. Mencius’ description
of person fails all too often: Ted Bundy either never had or lost the
capacities of shame, commiseration and the feeling of right and wrong. Was
Bundy never a person or did he lose his personhood?
Tsai does not succeed in his justification of the division of human
lives into those who are persons and those who are not. He would actually
increase the confusion and dissent between those persons who are assigning
value. Remember, toddlers and young children do not meet the definitions
of personhood referenced by the author, and he admits that others such as
those with developmental impairment or other neurological abnormalities
who are counted as persons under most legal systems would have unclear
status under the “strict” personhood according to abilities criteria.
History gives us examples of definitions of personhood that were more
dependent on pigmentation and the legal status of (human) parents than on
the level of functioning or development that Tsai advocates.
The very capacity to develop "jen" as described by Tsai, and
attributed to Confucius, will always be variable, in process, and subject
to the effects of a mixture of genetics and environment, as well as valued
and measured differently in diverse cultures and according to actual
knowledge. "Jen" and "yi’" should inspire greater caution at all times
rather than the decreasing license over time and as a function of
perceived development which the author would allow for the destruction of
humans lives according to their benefit or usefulness to other humans.
The only prudent, justifiable and consistent definition of personhood -
the only one which would demonstrate "jen" and "yi'" is that which would
give full protection from active intervention in the life cycle of all
whose parents were human or whose species or nature has the capacity to
demonstrate "jen. ."
The author should consider his understanding about why Shun would
carry his father on his back rather than violate justice or cause a death,
even though it would mean the loss of a kingdom. Since the author used a
New Testament Bible quote, I'll use one, too: “For what is a man profited,
if he shall gain the whole world, and lose his own soul? or what shall a
man give in exchange for his soul?”(Mat 16:26 KJVR. E-sword.com)
References
(1) D F-C Tsai. "Human embryonic stem cell research debates: a
Confusian argument." Journal of Medical Ethics 2005; 31:635-640.
http://jme.bmjjournals.com/cgi/content/full/31/11/635 (accessed November
4, 2005)
Allen B Shaw suggests that individuals commenting on the BMA Guidance
on male circumcision should declare if they are bereft of, or the proud
possessors of a prepuce. He also says that 'surely there must be some
bold spirits among the circumcised, articulate enough to protest about the
violation of their own rights in childhood. Yet no sound is heard.'
Allen B Shaw suggests that individuals commenting on the BMA Guidance
on male circumcision should declare if they are bereft of, or the proud
possessors of a prepuce. He also says that 'surely there must be some
bold spirits among the circumcised, articulate enough to protest about the
violation of their own rights in childhood. Yet no sound is heard.'
First therefore I will declare that I was circumcised for no medical
reason and have no memory of having an intact body. I consider that I
have been genitally mutilated. Unlike Allen B Shaw however, I am fully
aware of my loss. I do not need to have lost a limb to know that I would
be at a disadvantage if I was without one. The same reasoning applies to
a foreskin.
With regard to his comments that 'No sound is heard', I am the
General Manager of NORM-UK, a registered charity formed to help men who
have been damaged either physically or psychologically by circumcision.
We have now handled in excess of 5,000 enquiries. The sound is there if
people are prepared to listen.
Following the publication of the Fox and Thomson report, our Chairman
Dr John Warren has written to the All Party Group on Men's Health asking
them to investigate the situation. We agree that the Medical Ethics
Committee of the BMA has more work to do in this respect.
I do not consider that circumcision has in itself protected me from
HIV. Frankly I would rather have kept my foreskin and taken my chances
with the virus.
The paper of K. Devolder[1] is very interesting and stimulating.
Unfortunately, the author takes for granted some value premises,
which are not so widely accepted.
The first one is that embryos are just lumps of cells, biological
matter without any dignity apart from being of some utility to us. If this
is true, the consequences are obvious. Their coming to life will be
justified only...
The paper of K. Devolder[1] is very interesting and stimulating.
Unfortunately, the author takes for granted some value premises,
which are not so widely accepted.
The first one is that embryos are just lumps of cells, biological
matter without any dignity apart from being of some utility to us. If this
is true, the consequences are obvious. Their coming to life will be
justified only by the benefits we can derive from them. If no benefit can
come to us (no possible HLA-matching), they can be destroyed. Or perhaps
used for other any other (possibly lucrative) purpose.
The second one is that everything, which is technically possible, may
be done, if economically profitable and if no major risks (valued
according to the first assumption) derive for the involved subjects. The
fact that embryos are not accorded any moral status and that newborn
children (derived or not from pre-implantation HLA typing) are incompetent
and can not oppose any refusal (while adults are free to refuse to become
bone-marrow or simply blood donors) opens the doors to alternative ghastly
scenarios. So, banking of HLA typed embryos, which foreshadows a sort of
embryos supermarket where anyone can buy, "adopt the embryo and carry it
to term, ... or use the embryo in vitro as a source of stem cells", is
presented as "a valuable option". And the insurance policy scenario
("using preimplantation HLA typing to ensure that all of one's children
will be HLA identical, in case one of them needs a transplant") is laid
aside (for the time being) only because of its financial costs.
The whole paper leaves the bitter taste of a view of science in which
those who can are allowed to do almost everything, and in which the rights
of the weakest are much less important than the interests of the
strongest.
We believe that the new tools that medicine continues to offer must be
used with extreme prudence and attention, and only for the wellbeing and
in the interests of all the subjects involved. In case of incompetent
subjects (as in the case of the newborn, and - for many of us - even
embryos), prudence should be much greater.
Centuries ago, Immanuel Kant taught us to treat no one merely as a means
to an end, but only and always as an end in his/herself. We believe that
this is still the only way in which medicine and science can really serve
humanity and not the other way round.
References:
1. Devolder K. Preimplantation HLA typing: having children to save
our loved ones. J Med Ethics 2005;31:582-586.
Author Address:
Nereo Zamperetti, MD
Department of Anesthesia and Intensive Care Medicine
San Bortolo Hospital, Via Rodolfi, 37
36100 Vicenza
Italy
e-mail: zamperetti.n@medicivi.org
Rinaldo Bellomo, MD
Department of Intensive Care,
Austin & Repatriation Medical Center,
Heidelberg, Victoria
Australia
e-mail: Rinaldo.bellomo@austin.org.au
I am delighted that Trevor Perry agrees that the debate about the
medical aspects of male circumcision is not closed, because most
correspondents think that it is.
One correspondent argues that removal of the richly innervated
prepuce delays ejaculation. Now rapid ejaculation may have had
evolutionary benefit, when wild animals or rivals often interrupted
coitus. In more civilised times we wo...
I am delighted that Trevor Perry agrees that the debate about the
medical aspects of male circumcision is not closed, because most
correspondents think that it is.
One correspondent argues that removal of the richly innervated
prepuce delays ejaculation. Now rapid ejaculation may have had
evolutionary benefit, when wild animals or rivals often interrupted
coitus. In more civilised times we would wish to prolong coitus to enhance
female satisfaction. Perhaps it is a sacrifice that man should make for
his mate, if not his maker. On the other hand removal of the clitoris
reduces female sexual pleasure, its unjustifiable purpose. Those
circumcised for medical reasons, whose predilection is variety not
constancy, should also remember that circumcision offers some protection
against HIV. Students will forgive an old doctor for reminding them that
yesterday’s dogma is today’s anathema, and may yet be dogma tomorrow.
I am also grateful to Trevor Perry for following my lead in coming
out of the closet. But our frankness is useless until all contributors
follow suit. I am also grateful to him for reminding me that the important
issue is whether those circumcised for religious, not medical reasons,
object to what was done. Unless he can show that many of those object,
then Fox and Thomson are indeed patronising them, however learned they
might be.
Otherwise Trevor Perry is misguided. I quoted Fox and Thomson, when I
said that men may wish their sons to resemble them, and they quoted four
other authors. Perhaps he should read their article.
Finally Fox and Thomson are not just unwise, they are unrealistic. No
government in Europe, with its Moslem population, nor in America, with its
Jewish population, would ban circumcision. You cannot compare it to
slavery, because the slaves never willingly enslaved their sons. They are
not just unwise and unrealistic, they are unethical. Proscription would
cause more distress than it could possibly relieve. Why do they not return
to the ethical path of persuading parents that currently the benefits of
circumcision are questionable, and forget proscription?
Allen Shaw's suggestion, that Fox and Thomson have made an "unwise"
proposal in urging legal sanctions against male circumcision, is poorly
founded.
His first premise is muddled. In hypothetical language, Shaw
suggests that the presence or absence of an author's prepuce "may" lead
papers to be "rationalisations of emotional attitudes." Primarily, this
argument should be discounted becaus...
Allen Shaw's suggestion, that Fox and Thomson have made an "unwise"
proposal in urging legal sanctions against male circumcision, is poorly
founded.
His first premise is muddled. In hypothetical language, Shaw
suggests that the presence or absence of an author's prepuce "may" lead
papers to be "rationalisations of emotional attitudes." Primarily, this
argument should be discounted because he provides no substantial evidence
that males do indeed "all wish others of our sex to resemble us." This,
the lynchpin of the premise, is an assumption. Shaw's argument would be
better served if he could cite actual subjectivity on the part of the
authors in the text, instead of conjecturing about the possibility of
subjectivity.
Shaw's second premise is as wanting. He misconstrues the authors as
assuming "that the medical case against circumcision is beyond doubt."
First, the authors have not made this assumption. Instead, they have
cited authoritative evidence, based on empirical observations, that at
best, the harm to benefit ratio is difficult to ascertain, and at worst,
the harms outweigh the benefits. Included in Fox and Thomson's analysis
is the link to medical responsibility with regard to surrogate consent.
Shaw's own words, that "it is hard to know the balance," confirm the
authors' message: there is not enough medical justification for surrogate
consent to be acceptable. At the very least there ought to be a
moratorium on infant circumcision until substantial and clear knowledge is
gained. Again we find that Shaw has not proven Fox and Thomson's proposal
to be "unwise."
His next opposition to legal restrictions is as conjecturally
misguided as his first. The perpetuation of the practice of genital
mutilation is not self-justifying. Considering that unnumbered voices,
contrary to Shaw's assumption, are being heard condemning circumcision,
that the majority of males living today are not circumcized, and that
annual circumcision rates are declining in the United States, we have
reason to believe, using Allen's logic, that people, including males, are
recognizing the ethically questionable nature of circumcision, including
its harms. Shaw is even welcome to consider me "some bold spirit among
the circumcised, articulate enough to protest about the violation of their
own rights in childhood." As for Fox and Thomson being "patronising," it
is fair to consider them as learned bioethicists whose duty is to inform
popular opinion, medicine, and law. Their criticism of the BMA is within
this duty.
Shaw's last point includes an unjustified attack against Fox and
Thomson. The relationship between law, religion, and invasive procedures
has already been outlined, and Fox and Thomson have properly included
analysis on this. While it may be
true that further discussion about the acceptance, by religious persons,
of outlawing circumcision is merited, this alone is simply not enough to
justify the status quo, particularly when the entire dilemma of genital
mutilation is considered. In sum, Fox and Thomson's proposal is very wise
indeed.
Holms, writing in June 2004, laments that there is a “singular lack” of medical evidence regarding the harm of early circumcision on which to form an opinion regarding the ethical status of child circumcision.[1]
We submit that that is not the case. We affirm there was enough evidence in 2004 regarding the inherent harm of circumcision on which to make a decision. We furth...
Holms, writing in June 2004, laments that there is a “singular lack” of medical evidence regarding the harm of early circumcision on which to form an opinion regarding the ethical status of child circumcision.[1]
We submit that that is not the case. We affirm there was enough evidence in 2004 regarding the inherent harm of circumcision on which to make a decision. We further submit that additional evidence has emerged in the past year to further support the sexual harm of child circumcision.
Winkelmann, as early as 1959, showed that the prepuce is a “specific erogenous zone” with nerve endings arranged in rete ridges.[2] Moldwin & Valderrama (1989) reported “an extensive neuronal network within prepucial tissue.”[3] Taylor et al. (1996) further described the tissue that is excised by circumcision, finding that more than one-half of the skin and mucosa of the penis is excised by circumcision and, moreover, that this includes a highly innervated and vascularized circular band of ridged tissue, which he named the ridged band.[4] With so much sensory tissue extirpated, one would expect to find decreased sensory input to the central and autonomic nervous systems with adverse effects on sexual function.
Demonstrated adverse effects of circumcision on erection and ejaculation supply proof of injury. A survey from South Korea (where circumcision has been practiced since the Korean War as a result of American cultural influence) found that men were twice as likely to report “diminished sexuality rather than improved sexuality.”[5] Coursey et al. report that the adverse effect of circumcision on erectile function is equivalent to that of anterior urethroplasty.[6] Fink et al. report a statistically significant reduction in erectile function after circumcision and a loss of sensitivity.[7] Shen et al. report weakened “erectile confidence” and prolonged intercourse after circumcision.[8] Senkul et al. report statistically significant increase in ejaculatory time after circumcision.[9] Masood et al. report degraded erectile function.[10]
Circumcision also causes changes in sexual behaviour. Laumann et al. report higher incidence of oral sex, anal sex, and masturbation in circumcised men.[11] Dave et al. report circumcised males are more likely to have homosexual experience and partners from abroad.[12]
Nineteenth century doctors were well aware of the sexual nature of the prepuce, therefore they promoted circumcision in hope of eliminating masturbation.[13]
Coursey et al., Fink et al., and Masood et al. argue that men should be told of the probable adverse effect on sexual function as part of pre-circumcision informed consent counseling.[6] [7] [10]
Although Holm attempts to draw a distinction between adult circumcision and childhood circumcision, [1] there is no reason to believe that the age at the time of circumcision has any effect on the reported sexual changes associated with extirpation of sensory tissue from the penis.
Dr Howard Mann[1] discusses the "intense controversy about the
scientific and ethical validity" that followed the publication of a
government sponsored lung ventilation experiment conducted on 861
critically ill patients suffering from acute respiratory distress syndrome
(ARDS) or acute lung injury. However, he does not address the violation of
the first and foremost tenet of acceptable research involvin...
Dr Howard Mann[1] discusses the "intense controversy about the
scientific and ethical validity" that followed the publication of a
government sponsored lung ventilation experiment conducted on 861
critically ill patients suffering from acute respiratory distress syndrome
(ARDS) or acute lung injury. However, he does not address the violation of
the first and foremost tenet of acceptable research involving human
subjects: "the voluntary, informed consent of the human subject is
absolutely essential." (Nuremberg Code).
In their published report in The New England Journal of Medicine
(2000) the ARDS Network[2] investigators stated: "informed consent was
obtained from the patients or surrogates at all but one hospital, where
this requirement was waived. " [p. 1302]
However, an investigation by the federal Office of Human Research
Protection (OHRP) [3] determined that "at nearly all" the prestigious
ARDS Network sites informed consent standards had been violated. And OHRP
found that most of these patients were enrolled without legally effective
consent by a legally authorized surrogate. Some patients were enrolled
without anyone's consent. For example, at the University of Washington[4]
(Seattle), 71 subjects 'were unable to provide legally effective informed
consent, and consent for 55 of these subjects was obtained and documented
from another individual." And, OHRP acknowledged that for 16 of the 71
subjects, the IRB waived consent altogether.
OHRP found that ARDS Network sites had not only failed to obtain
informed consent but when consent was obtained it violated essential
requirements:
"at nearly all study sites the informed consent documents failed to
adequately describe the purpose of the research... failed to adequately
describe the nature of the experimental design...failed to include death
as one of the risks of the research." In particular, there was no
statement that the subject could have a higher risk of death depending on
which of the experimental groups he or she was assigned to, in comparison
to not entering the trial and thereby receiving individualized care based
upon the best clinical judgment of the subject?s physicians. " And "
subjects in each experimental group" of the trial "may have been
disadvantaged compared to patients treated according to concurrent routine
clinical practice." [3]
The ARDS Network IRBs approved informed consent documents that "failed to describe the reasonably foreseeable risks and discomforts."
Patients and families were misled with false reassurances. For example,
the University of Utah consent document made unsubstantiated claims:
?risks will be minimized by close monitoring and by a computer protocol."
The computer protocols which will be used to standardize care in both
treatment groups have been extensively tested and been associated with a
four-fold increase in survival for patients with severe lung disease."[5]
The most disturbing aspect of this is that the exact opposite was shown to
be true.[6] Who should bear responsibility for such violations?
An article co-authored by a principle ARDS investigator from the
University of Utah, Dr. Alan Morrison,[7] and two pediatric critical
care physicians affiliated with Harvard (the site of the ARDSNet
statistics analysis) argued in 1999, in the NEJM that explicit informed
consent for research should not be required in experiments such as the
ARDS trial:
"We believe that as with clinical care, in the case of many
randomized, controlled trials, the patient's participation can and should
be considered to be authorized by his or her general consent for treatment
and that specific consent should not be required...In addition, there is a
price that is paid when one insists on specific informed consent for all
randomized, controlled trials. Many worthwhile studies will not be
conducted if investigators are required to obtain specific informed
consent."
Although their utilitarian argument was roundly criticized by federal
officials, physicians and ethicists,[8] it is most disturbing that OHRP?s
investigation revealed that the ARDS Network had, in fact, largely
dispensed with federal informed consent requirements.
The controversial design of this multi-site experiment, in which
patients were withdrawn from the individualized ventilation settings
prescribed by a critical care specialist (i.e. following standard
practice), then randomly assigned to one of two fixed ventilator settings-
-a low 6 ml/kg vs. a high 12 ml/kg--is being heatedly debated. The
American Journal of Respiratory Critical Care Medicine and Critical Care
Medicine, have seen fit to give equal opportunity to both sides of the
debate--but not The New England Journal of Medicine.
In this contested trial design, the investigators substituted
individualized standard treatment with a randomly assigned, fixed
ventilation setting, while failing to include a control group against
which the two tested methods could be compared. But what is the value (or
justification) for conducting an experiment that puts human beings at
increased risk if the findings will not answer the important clinical
question: Which of the two tested methods of ventilation is better than
current practice?
The appropriate control group for ARDS patients would have been a
group of patients receiving standard care which allows physician to select
a tidal volume setting from a range of possible settings, depending upon
the severity of injury to the lung and condition of the patient. At the
time of the ARDS experiment that range in standard care was between 6.5
ml/kg and 14.5 ml/kg. [See: Mann, Fig 1]
Prior to being randomized to either fixed tidal volume, most patients
in the ARDS Network were receiving 9.5 ml/kg to 11.5 ml/kg tidal volume.
Without a control group, it is not possible to know whether one or the
other tested method of ventilation--i.e., 6 ml/kg or 12 ml/kg--is as good
as, better than, or worse than the setting prescribed in current
practice.. As Dr. Mann correctly points out, "An inappropriate choice may
nullify the clinical value of a trial that otherwise meets the requirement
of internal validity." [p. 550]
Dr. Mann makes three recommendations: first, a systematic review of
the relevant literature. It is hard to believe that the standards of
approval for clinical trial have not yet reached the point at which we can
reasonably expect that IRBs would have ensured 'prior to approval' that
investigators have conducted a systematic review of the relevant
literature to ascertain risk.
Two additional steps recommended prior to IRB approval include a
formal survey of relevant clinical experts to document current practices;
and publication of the trial's protocol to solicit critical appraisal of
its rationale and design. To ensure against bias, flawed trial design, as
well protecting human subjects from unjustified risks in invalid
experiments will require accountability.
The ARDS Network experiment is a disturbing case study revealing
current unethical practices at major US universities, and thereby
demonstrating the ineffectiveness of the regulatory protection system that
is supposed to prevent experiments that unnecessarily expose human
subjects to increased risk of death. Only one IRB in the ARDS Network
raised substantive concerns about the inability of eligible patients to
give informed consent. The University of Washington (Seattle) IRB
questioned the ventilator trial design: "What if a subject assigned to the
lower tidal volume group cannot tolerate this level and needs to go to the
higher tidal volumes? Would such a person be dropped from the study?" Yet,
after raising substantive concerns, the IRB approved the research and
approved a waiver of informed consent. This government sponsored trial
cost taxpayers $48 million.
References
[1] Mann, H. Controversial choice of a control intervention in a
trial of ventilator therapy in ARDS: standard of care arguments in a
randomised controlled trial. Journal of Medical Ethics, 2005; 31:548-553.
[2] The Acute Respiratory Distress Syndrome Network. Ventilation with
lower tidal volumes as compared with traditional tidal volumes for acute
lung injury and the acute respiratory distress syndrome. New Engl J Med
2000;342:1301?8.
[3] See, OHRP Letter of determination to ARDS Network. July 3, 2003.
Online at: http://www.hhs.gov/ohrp/detrm_letrs/YR03/jul03a.pdf
[5] Informed consent documents were obtained by the Alliance for
Human Research Protection (AHRP) under the Freedom of Information Act.
[6] Mechanical ventilation in ARDS: One size does not fit all*,
Editorial by Katherine J. Deans, Peter C. Minneci, Steven M. Banks,
Charles Natanson, Peter Q. Eichacker, Critical Care Medicine, 2005;
33(5):1141.
[7] Truog, RD, Robinson, W., Morris, AH. Is informed consent always
necessary for randomized, controlled trials? The New England Journal of
Medicine, 1999; 340 (10):804-807.
[8] New England Journal of Medicine, 1999; 341:448-450, Aug 5, 1999.
Correspondence
Harris raises important concerns about NICE’s QALY methodology. The
rational for rationing treatments is opportunity cost; the alternative
better uses of scarce resources. If opportunity cost is king, why does
NICE not examine the opportunity cost of drugs, the resources (factor
costs) taken to manufacture them, i.e. the ex patent costs rather than the
supplier price, in its calculations, certainly wit...
Harris raises important concerns about NICE’s QALY methodology. The
rational for rationing treatments is opportunity cost; the alternative
better uses of scarce resources. If opportunity cost is king, why does
NICE not examine the opportunity cost of drugs, the resources (factor
costs) taken to manufacture them, i.e. the ex patent costs rather than the
supplier price, in its calculations, certainly within sensitivity
analysis? NICE economic methodology is entirely static, ignoring the
dynamics of the drug market completely.
The Alzheimer example is pertinent. The appraisal report gives a QALY
range of £40-80,000 for Aricept et al. It will probably become "cost
effective" to treat in 7 years time when the drugs go ex patent and
typically, halves or more. (NB there is much data and experience to
forecast price changes ). It is odd that the NICE Social Value Judgement
paper (SVJ) does not even mention this issue, central though it clearly
is.
Most volume drugs are not expensive to manufacture, and costs come
down with improved techniques, so it is equally strange that there is
apparently no background information on drug cost trends published during
the appraisal process. The Technology Advisory Committee is expected to
use its judgement on the "broad balance of costs and benefits ", but does
not seem to be given this essential factual background. The share of drugs
in the NHS bill is also falling, both absolutely, and relatively, since
the last PPR round. There was a £112 million reduction between January -
May 2005 over 2004, largely the result of major drugs going ex patent.
This does put recent draft negative decisions in perspective.
The patent premium represents society’s way of funding research and
launch costs. The NHS, via NICE, is effectively seeking to avoid
contributing its fair share of global R&D costs through denying some
patients until the post patent price drop. As Harris says, this is
discrimination against those for whom treatment is intrinsically
difficult, and arguably unethical in a more global sense.
An example from Scotland demonstrates rather clearly why it is
seriously misguided to use QALY’s to select patients, rather than compare
treatment paths. The SMC, NICE Scottish counterpart, has provisionally
rejected pegvisomant as the 3rd line treatment for acromegaly. This is a
rare endocrine disease, usually diagnosed in early adulthood but across a
wide range of ages. Pegvisomant appears to be a very effective but very
expensive drug, approximately £18,000 p.a. – but these patients will have
exhausted the wide range of cheaper treatments for this condition. The
best evidence is that ineffectively treated acromegalics lose around 9.5
years of good quality life expectancy, dying at typically 65 rather than
75. This suggests the additional life expectancy should be QALY valued at
up to £300,000. SMC did not do a detailed study, but clearly, using basic
NICE principles, a patient diagnosed at 25 (50 years at £18,000) has no
hope, one at 58 is at the margin, (£306,000) and older patients would be
"profitable". There are just 31 such patients in Scotland, but these,
unlike the children with vastly expensive metabolic disease removed by
NICE from its SVJ, itself a breathtakingly arbitrary value judgement,
won’t make headlines. The bias against low profile disease is only too
clear.
NICE controversies would disappear if, like other administrations, it
adopted an inclusive principle," at least one" effective treatment, where
it exists. It is time that NICE methodology is independently reviewed.
Such a review might also seek to commission a QALY estimate of the loss of
welfare and stress caused to patients and carers by its periodic ill-
judged negative and delayed decisions.
Dr. Mann's 20/20 hindsight discloses the availability of some of the
alternative research designs that might have answered the question
addressed by the ARDSNET researchers. However, the choice among
alternatives in face of uncertainty is not itself controversial. What is
and should be controversial in all such cases is the failure to disclose
to the unknowing patients or their surrogates the nature o...
Dr. Mann's 20/20 hindsight discloses the availability of some of the
alternative research designs that might have answered the question
addressed by the ARDSNET researchers. However, the choice among
alternatives in face of uncertainty is not itself controversial. What is
and should be controversial in all such cases is the failure to disclose
to the unknowing patients or their surrogates the nature of the risk into
which the researchers would put them. Interestingly, Dr. Mann's focus and
survey of the expert clinicians to establish the "probative" value of an
experimental design lacking representation of the applicable, albeit
putative, standard of care in the situation entirely misses the point that
the ARDSNET researchers failed to satisfy the ethical and legal
requirement pursuant to 45 CFR 46 of obtaining the informed consent of the
patients or their surrogate decision-makers.
The Alliance for Human Research Protection (AHRP) that Dr. Mann cites
as one of the critics of the ARDSNET trial complained to the Office of
Human Research Protection (OHRP) about the lack of informed consent for a
substantial number of the human subjects, which the OHRP itself had drawn
to the attention of the ARDSNET researchers.
The ordinary "standard of care" requires the physician to explain the
benefits and risks of the intended treatment before undertaking it. This
essential step makes the difference at law between authorized treatment
and a battery committed on the person of the patient.
The question that remains to be addressed in all of this is "If the
researchers were so muddled and uncertain about what they were doing, how
could they have possibly conveyed the possible benefits and risks to their
patients or surrogate decision-makers?" That this should have been done is
uncontroversial, and fixing this deficiency was one of the stipulations in
the OHRP permission for the ARDSNET researchers to resume the suspended
trial in question.
Dear Editor
Some points made by Appel in the recent essay “Defining death: when physicians and families differ [1]” merit comment.
First, it is stated that critics of brain death (BD) are most significantly in Japan and in certain religious groups. However, there is a long list of secular commentators who point out the many problems with the BD criterion of death.[2-11]
Second, there seems t...
Dear Editor
The discussion of Global Medical Ethics, by D F-C Tsai, “Human embryonic stem cell research debates: a Confucian argument" (1), fails to justify the gradualist view of human personhood.
He begins with a list of flawed arguments concerning the current status of the human embryo which fail in the following ways:
1. Many women do undergo hormonal support of early pregnancy, for th...
Dear Editor
Allen B Shaw suggests that individuals commenting on the BMA Guidance on male circumcision should declare if they are bereft of, or the proud possessors of a prepuce. He also says that 'surely there must be some bold spirits among the circumcised, articulate enough to protest about the violation of their own rights in childhood. Yet no sound is heard.'
First therefore I will declare that I...
Dear Editor,
The paper of K. Devolder[1] is very interesting and stimulating.
Unfortunately, the author takes for granted some value premises, which are not so widely accepted.
The first one is that embryos are just lumps of cells, biological matter without any dignity apart from being of some utility to us. If this is true, the consequences are obvious. Their coming to life will be justified only...
Dear Editor
I am delighted that Trevor Perry agrees that the debate about the medical aspects of male circumcision is not closed, because most correspondents think that it is.
One correspondent argues that removal of the richly innervated prepuce delays ejaculation. Now rapid ejaculation may have had evolutionary benefit, when wild animals or rivals often interrupted coitus. In more civilised times we wo...
Dear Editor
Allen Shaw's suggestion, that Fox and Thomson have made an "unwise" proposal in urging legal sanctions against male circumcision, is poorly founded.
His first premise is muddled. In hypothetical language, Shaw suggests that the presence or absence of an author's prepuce "may" lead papers to be "rationalisations of emotional attitudes." Primarily, this argument should be discounted becaus...
Dear Editor:
Holms, writing in June 2004, laments that there is a “singular lack” of medical evidence regarding the harm of early circumcision on which to form an opinion regarding the ethical status of child circumcision.[1]
We submit that that is not the case. We affirm there was enough evidence in 2004 regarding the inherent harm of circumcision on which to make a decision. We furth...
Dear Editor
Dr Howard Mann[1] discusses the "intense controversy about the scientific and ethical validity" that followed the publication of a government sponsored lung ventilation experiment conducted on 861 critically ill patients suffering from acute respiratory distress syndrome (ARDS) or acute lung injury. However, he does not address the violation of the first and foremost tenet of acceptable research involvin...
Dear Editor,
Harris raises important concerns about NICE’s QALY methodology. The rational for rationing treatments is opportunity cost; the alternative better uses of scarce resources. If opportunity cost is king, why does NICE not examine the opportunity cost of drugs, the resources (factor costs) taken to manufacture them, i.e. the ex patent costs rather than the supplier price, in its calculations, certainly wit...
Dear Editor,
Dr. Mann's 20/20 hindsight discloses the availability of some of the alternative research designs that might have answered the question addressed by the ARDSNET researchers. However, the choice among alternatives in face of uncertainty is not itself controversial. What is and should be controversial in all such cases is the failure to disclose to the unknowing patients or their surrogates the nature o...
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