Is informed consent required for the diagnosis of brain death regardless of consent for organ donation?

In the half-century history of clinical practice of diagnosing brain death, informed consent has seldom been considered until very recently. Like many other medical diagnoses and ordinary death pronouncements, it has been taken for granted for decades that brain death is diagnosed and death is declared without consideration of the patient's advance directives or family's wishes. This essay examines the pros and cons of using informed consent before the diagnosis of brain death from an ethical point of view. As shared decision-making in clinical practice became increasingly indispensable, respect for the patients' autonomous wishes regarding how to end their lives has a significant role in deciding how death is diagnosed. Brain death, as a fully technologically controlled death, may require a different ethical framework from the old one for traditional cardiac death. With emerging and proliferating options in end-of-life care for those who suffer from catastrophic brain injury, the traditional reasoning that 'death gives no choice, hence no consent' requires another examination. Patients facing imminent brain death now have options other than undergoing the diagnostic workup for brain death, such as donation after circulatory death and withdrawal of life-sustaining treatment with maximum comfort measures for death with dignity. Nevertheless, just as in the debate over opt-in versus opt-out organ donation policies, informed consent before the diagnosis of brain death faces fierce opposition from consequentialists urging the expansion of the donor pool. This essay examines these objections and provides constructive replies along with a proposal to accommodate this morally required consent.

Informed consent for the diagnosis of brain death: a conceptual argument.

BACKGROUND: This essay provides an ethical and conceptual argument for the use of informed consent prior to the diagnosis of brain death. It is meant to enable the family to make critical end-of-life decisions, particularly withdrawal of life support system and organ donation, before brain death is diagnosed, as opposed to the current practice of making such decisions after the diagnosis of death. The recent tragic case of a 13-year-old brain-dead patient in California who was maintained on a ventilator for over 2 years illustrates how such a consent would have made a crucial difference. METHODS: Conceptual, philosophical, and ethical analysis. RESULTS: I first consider a conceptual justification for the use of consent for certain non-beneficial and unwanted medical diagnoses. I suggest that the diagnosis of brain death falls into this category for some patients. Because the diagnostic process of brain death lacks the transparency of traditional death determination, has a unique epistemic structure and a complex risk-benefit profile which differs markedly from case to case, and presents conflicts of interest for physicians and society, I argue that pre-diagnostic counseling and informed consent should be part of the diagnostic process. This approach can be termed as "allow cardiac death", whose parallel logic with "allow natural death" is discussed. I also discuss potential negative impacts on organ donation and health care cost from this proposal and offer possible mitigation. I show that the pre-diagnostic counseling can improve the possibility for well-thought-out decisions regarding organ donation and terminating life-support system in cases of hopeless prognosis. This approach differs conceptually from the pluralism of the definition of death, such as those in New Jersey and Japan, and it upholds the Uniform Determination of Death Act. CONCLUSIONS: My intention is not to provide an instant panacea for the ongoing impasse of the brain death debate, but to point to a novel conceptual ground for a more pragmatic, and more patient- and family-centered approach. By enabling the family to consent to or decline the diagnostic process of brain death, but not to choose the definition of death, it upholds the current legal definition of death.

Retrospective diagnosis of a famous historical figure: ontological, epistemic, and ethical considerations.

The aim of this essay is to elaborate philosophical and ethical underpinnings of posthumous diagnosis of famous historical figures based on literary and artistic products, or commonly called retrospective diagnosis. It discusses ontological and epistemic challenges raised in the humanities and social sciences, and attempts to systematically reply to their criticisms from the viewpoint of clinical medicine, philosophy of medicine, particularly the ontology of disease and the epistemology of diagnosis, and medical ethics. The ontological challenge focuses on the doubt about the persistence of a disease over historical time, whereas the epistemic challenge disputes the inaccessibility of scientific verification of a diagnosis in the past. I argue that the critics are in error in conflating the taxonomy of disease (nosology) and the act of diagnosing a patient. Medical diagnosis is fundamentally a hypothesis-construction and an explanatory device that can be generated under various degrees of uncertainty and limited amount of information. It is not an apodictic judgment (true or false) as the critics presuppose, but a probabilistic (Bayesian) judgment with varying degrees of plausibility under uncertainty. In order to avoid this confusion, I propose that retrospective diagnosis of a historical figure be syndromic without identifying underlying disease, unless there is justifiable reason for such specification. Moreover it should be evaluated not only from the viewpoint of medical science but also in a larger context of the scholarship of the humanities and social sciences by its overall plausibility and consistency. On the other hand, I will endorse their concerns regarding the ethics and professionalism of retrospective diagnosis, and call for the need for situating such a diagnosis in an interdisciplinary scope and the context of the scholarship of the historical figure. I will then enumerate several important caveats for interdisciplinary retrospective diagnosis using an example of the retrospective diagnosis of Socrates for his life-long intermittent neurologic symptoms. Finally, I will situate the present argument in a larger context of the major debate among the historians of medicine and paleopathologists, and discuss the similarities and differences.

Chemoembolization-induced arterial damage: Evaluation of three different chemotherapeutic protocols using epirubicin and miriplatin.

AIM: We aimed to evaluate hepatic vascular changes following lipiodol-based transarterial chemoembolization of hepatocellular carcinoma using epirubicin (EPI), miriplatin (MPT) and miriplatin plus low-dose epirubicin (MPT+EPI). METHODS: A total of 185 arteries in 118 patients who underwent chemoembolization using EPI (67 arteries in 48 patients), MPT (64 arteries in 37 patients) and MPT+EPI (54 arteries in 33 patients) were retrospectively examined. The maximum dose limit of MPT was 140 mg and that of EPI was 50 and 20 mg for the EPI and MPT+EPI groups, respectively. Vascular changes and local recurrence were evaluated by subsequent angiography. Factors affecting arterial damage were analyzed using multivariate logistic regression analysis. RESULTS: More severe arterial damage was observed in the EPI group (88.1%) than in the MPT+EPI (72.2%) and the MPT (18.7%) groups (P = 0.044 and P < 0.001, respectively). EPI usage (hazard ratio [HR] = 12.8, P < 0.001), selective chemoembolization (HR = 5.4, P < 0.001) and MPT usage (HR = 0.28, P = 0.020) were significant predictors for arterial damage induction. The local recurrence rate was lower for the lesions exhibiting arterial occlusion after chemoembolization (39.4%) than for the lesions exhibiting no vascular attenuation (73.9%) or wall irregularity (75.8%) (P = 0.001 and P = 0.005, respectively). CONCLUSION: High-dose EPI, MPT, and low-dose EPI plus MPT usage in chemoembolization for hepatocellular carcinoma induced the greatest, the least, and intermediate vascular damages, respectively. Therapeutic occlusion of tumor feeder vessels is associated with lower local recurrence.

Clinical utility and limitations of tumor-feeder detection software for liver cancer embolization.

PURPOSE: To evaluate the clinical utility and limitations of a computer software program for detecting tumor feeders of hepatocellular carcinoma (HCC) during transarterial chemoembolization (TACE). MATERIALS AND METHODS: Forty-six patients with 59 HCC nodules underwent nonselective digital subtraction angiography (DSA) and C-arm computed tomography (CT) in the same hepatic artery. C-arm CT data sets were analyzed using the software to identify potential tumor feeders during each TACE session. For DSA analysis, 3 radiologists were independently assigned to identify tumor feeders using the DSA images in a separate session. The sensitivity of the 2 techniques in detecting tumor feeders was compared, with TACE findings as the reference standard. Factors affecting the failure of the software to detect tumor feeders were assessed by univariate and multivariate analyses. RESULTS: We detected 65 tumor feeders supplying 59 HCC nodules during TACE sessions. The sensitivity of the software to detect tumor feeders was significantly higher than that of the manual assessment using DSA (87.7% vs. 71.8%, P<0.001). Multivariate analysis showed that a tumor feeder diameter of <1.0mm (hazard ratio [HR], 56.3; P=0.003) and lipiodol accumulation adjacent to the tumor (HR, 11.4; P=0.044) were the significant predictors for failure to detect tumor feeders. CONCLUSION: The software analysis was superior to manual assessment with DSA in detecting tumor feeders during TACE for HCC. However, the capability of the software to detect tumor feeders was limited by vessel caliber and by prior lipiodol accumulation to the tumor.

Survival after C-arm CT-assisted chemoembolization of unresectable hepatocellular carcinoma.

PURPOSE: To compare patient survival after transarterial chemoembolization with and without intraprocedural C-arm computed tomography (CT) in patients with unresectable hepatocellular carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the records of 130 patients with unresectable hepatocellular carcinoma who underwent lipiodol-based chemoembolization using a C-arm cone-beam system. We compared patients who underwent chemoembolization with angiography alone (69 patients; April 2005-July 2007) to those who underwent C-arm CT-assisted chemoembolization (61 patients; July 2007-April 2010). Overall and local progression-free survivals were compared using the Kaplan-Meier estimator with log-rank testing. Univariate and multivariate analyses were performed using the Cox proportional hazards model. RESULTS: Overall survival rates of patients who underwent chemoembolization with and without C-arm CT assistance were 94% and 79%, 81% and 65%, and 71% and 44% at 1, 2, and 3 years, respectively. Local progression-free survival rates of these patients were 43% and 27%, 31% and 10%, and 26% and 5% at 1, 2, and 3 years, respectively. Patients receiving C-arm CT-assisted chemoembolization had significantly higher overall (P=0.005) and local progression-free (P=0.003) survival rates than those receiving chemoembolization with angiography alone. Multivariate analysis showed that C-arm CT assistance was an independent factor associated with longer overall survival (hazard ratio, 0.40; P=0.033) and local progression-free survival (hazard ratio, 0.25; P=0.003). CONCLUSION: C-arm CT usage in addition to angiography during transarterial chemoembolization prolongs survival in patients with unresectable hepatocellular carcinoma.

Socially and temporally extended end-of-life decision-making process for dementia patients.

There are two contrasting views on the decision-making for life-sustaining treatment in advanced stages of dementia when the patient is deemed incompetent. One is to respect the patient's precedent autonomy by adhering to advance directives or using the substituted judgement standard. The other is to use the best-interests standard, particularly if the current judgement on what is best for the incapacitated patient contradicts the instructions from the patient's precedent autonomy. In this paper, I argue that the protracted clinical course of dementia over many years requires the extended perspective of a progressive decision-making process-extended in both social space and time. The ongoing debate between these two competing views has missed this perspective by focussing on an exclusive disjunction between the competent former self and the incompetent current self. Drawing on theories of situated cognition in cognitive science, I will show that the cognition of a demented patient can be viewed as extended and embodied by her supportive social environment. As the disease progresses, the content of the mind of a demented person becomes partially constituted by such external resources along with her diminishing intrinsic mind. With this understanding, medical decision-making for a demented patient can be construed as a temporally and socially extended practice. A collective decision-making body consisting of the patient, her family and surrogates, and the clinician, should make progressive decisions as a whole over years of the disease course. Finally, I will provide a practical example of how this proposal can be applied in clinical practice.

Issues arising during the treatment of Jehovah's Witnesses by in vitro fertilisation.

Four Jehovah's Witness couples were treated between 2000 and 2009 using in vitro fertilization or intracytoplasmic sperm injection. A review of the issues encountered during their treatment, and the options chosen, was made in an attempt to provide effective treatment without compromising the moral views of the individuals concerned. Considerations specific to the Jehovah's Witness faith were identified that required departure from the standard operating procedures used in the clinic, and the development of modified protocols prior to treatment is recommended to minimize the stress and anxiety of patients and staff alike. Issues raised included the collection of semen by masturbation, the use of donor gametes, the number of oocytes inseminated, the discard of poor quality embryos conventionally thought unsuitable for transfer or embryo cryopreservation. A common request was the avoidance of blood products as a culture medium supplement. The use of recombinant human albumin circumvented this, although a recent shift by the Watchtower Bible and Tract Society of Pennsylvania in the interpretation of the Bible opens the possibility of using blood fractions if not whole blood, and so the use of standard culture medium containing human serum albumin is now acceptable to some Jehovah's Witnesses.

Socrates and temporal lobe epilepsy: a pathographic diagnosis 2,400 years later.

PURPOSE: Some enigmatic remarks and behaviors of Socrates have been a subject of debate among scholars. We investigated the possibility of underlying epilepsy in Socrates by analyzing pathographic evidence in ancient literature from the viewpoint of the current understanding of seizure semiology. METHODS: We performed a case study from a literature survey. RESULTS: In 399 BCE, Socrates was tried and executed in Athens on the charge of "impiety." His charges included the "introduction of new deities" and "not believing in the gods of the state," because he publicly claimed that he was periodically and personally receiving a "divine sign," or daimonion, that directed him in various actions. We found textual evidence that his daimonion was probably a simple partial seizure (SPS) of temporal lobe origin. It was a brief voice that usually prohibited Socrates from initiating certain actions. It started when he was a child, and it visited Socrates unpredictably. Moreover, we found at least two descriptions of Socrates' unique behavior that are consistent with complex partial seizures (CPSs). The fact that Socrates had been experiencing both SPSs and CPSs periodically since childhood makes the diagnosis of temporal lobe epilepsy (TLE) likely. CONCLUSIONS: We hypothesize that Socrates had a mild case of TLE without secondary generalization. This is the first report in 2,400 years to present a pathographic diagnosis of TLE in Socrates based on specific diagnostic features in the ancient textual evidence. Our study demonstrates that the knowledge of modern epileptology could help understand certain behaviors of historic figures.

The role of the medial prefrontal cortex in human religious activity.

Although religious practices are ubiquitous and universal throughout human history, their biological basis is little understood, particularly at the neural level. In this paper, I will first review the current understanding of the neural basis of human religious activity, and then present a hypothesis that the medial prefrontal cortex plays a vital role in the integrity of religious activity. In this hypothesis, optimal functions of the medial prefrontal cortex, such as error detection, compliance to social norms, self-reflection, and theory of mind, are a key prerequisite to the maintenance of integrated religious activity. Hyperreligiosity may result from the hyperfunction of the medial prefrontal cortex, including rigid legalism (excessive error detection), excessive concern over one's existence (excessive self-reflection), and delusional interpretation of God's mind (excess of theory of mind). Future research based on this hypothesis is proposed, and the potential implication of this hypothesis on our society is also discussed.

Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells.

BACKGROUND: The formation of methylglyoxal (MG), a highly reactive dicarbonyl compound, is accelerated through several pathways, including the glycation reaction under diabetic conditions, presumably contributing to tissue injury in diabetes. On the other hand, apoptotic cell death of glomerular cells has been suggested to play a role in the development of glomerulosclerosis in various types of glomerular injuries. We therefore examined whether MG was capable of inducing apoptosis in rat mesangial cells to address the possible mechanism by which hyperglycemia-related products accelerated pathologic changes in diabetic glomerulosclerosis. METHODS: Rat mesangial cells were incubated with 0 to 400 micromol/L MG, followed by the detection of apoptosis by both TUNEL method and electrophoretic analysis for DNA fragmentation. In addition, we investigated intracellular mechanisms mediating MG-induced apoptosis, focusing especially on the p38 mitogen-activated protein kinase (MAPK) pathway. RESULTS: MG induced apoptosis in rat mesangial cells in a dose-dependent manner and was accompanied by the activation of p38alpha isoform. Aminoguanidine and N-acetyl-l-cysteine inhibited the MG-induced p38 MAPK activation, as well as apoptosis in rat mesangial cells, suggesting the involvement of oxidative stress in these phenomena. SB203580, a specific inhibitor of p38 MAPK also suppressed the MG-induced apoptosis in rat mesangial cells. CONCLUSIONS: These results suggest a potential role for MG in glomerular injury through p38 MAPK activation under diabetic conditions and may serve as a novel insight into the therapeutic strategies for diabetic nephropathy.