Limitations on surrogate decision-making for emergent liver transplantation.

BACKGROUND: Surrogate consent is an accepted form of promoting patient autonomy when patients cannot consent, but it can lead to surrogate duress and may be unreliable. Since consent for liver transplantation in patients with fulminant hepatic failure (FHF) is typically performed by surrogates and these patients typically regain decisional capacity, we chose this population to query patients' opinion on the surrogate consent process. MATERIALS AND METHODS: We developed a questionnaire that queried transplanted patients' experience and opinion on surrogate consent, suitability of surrogates, and return of decisional capacity. This survey was then sent to consecutive survivors of liver transplantation for FHF at our institution. RESULTS: Eleven of 14 patients eligible to participate completed the questionnaire. The mean follow-up for all survivors was 41 mo, with a range of survival since transplant of 5 mo to 10 y. Although 10/11 respondents agreed with their surrogates to consent to liver transplantation, all 11 patients thought that surrogates should not be able to decline liver transplantation for this condition. In distinction, 3/11 patients believed patients could decline liver transplantation. CONCLUSIONS: This is the first study to demonstrate that liver transplant patients do not think surrogate decision-makers should be permitted to contravene physician recommendations regarding transplant. In clinical settings when patients cannot speak for themselves, it may be appropriate for surrogates and clinicians to act together according to the patients' best interest rather than attempt to determine what the patient would want. This approach might reduce surrogate distress, better represent patient preferences, and improve the decision-making process for affected patients.

In vitro preclinical cardiac assessment of tolterodine and terodiline: multiple factors predict the clinical experience.

Terodiline and tolterodine are drugs used to treat urinary incontinence. Terodiline was removed from the market in 1991 for proarrhythmia, whereas tolterodine has a generally benign clinical cardiac profile. To assess differences in the electrophysiologic actions of these drugs, we evaluated their effects on hERG current (HEK cells) and cardiac Purkinje fiber repolarization. The IC50 for hERG block (37 degrees C) by tolterodine was 9.6 nM and by terodiline was 375 nM, values near or below clinical concentrations. Tolterodine elicited concentration-dependent prolongation of the action potential duration (APD90). In contrast, terodiline depressed the action potential plateau and induced triangulation without affecting APD90. The triangulation ratios (normalized ratio of APD50 over APD90) for terodiline were 0.94 and 0.59 for 1.0 and 10 microM and for tolterodine, were 0.99 and 0.97 at 7 and 70 nM. In summary, tolterodine, a potent hERG blocker, has a benign clinical cardiac profile at therapeutic concentrations that may be due to its lack of triangulation, as well as extensive plasma protein binding. However, at supratherapeutic concentrations, preclinical data predict risk of QT prolongation. These data suggest that hERG block and triangulation are among multiple factors that must be considered in preclinical cardiac safety assessments.

The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block.

Drug-induced delayed cardiac repolarization is a recognized risk factor for proarrhythmia and is associated with block of IKr (the potassium current encoded by the human ether-a- go-go-related gene [hERG]). To evaluate the utility of 2 in vitro assays widely used to assess delayed repolarization, we compared the effects of haloperidol and 9 structurally diverse drugs in a hERG and repolarization (canine Purkinje fiber action potential duration [APD]) assay over wide concentrations. Despite potent hERG current block (IC50 = 0.174 microM), haloperidol elicited a bell-shaped concentration-response relationship for APD prolongation, with lesser prolongation (and reduced plateau height) observed with concentrations eliciting maximal hERG block, consistent with multi-channel block at higher concentrations. Consistent with this hypothesis, APD prolongation with the specific IKr blocker dofetilide was a) reduced by concomitant administration of nifedipine (calcium current block) and b) reversed by lidocaine (late sodium current block). Additional studies demonstrated prominent (>50%) hERG inhibition with most (9/10) drugs despite wide APD changes (158% prolongation - 16% shortening), consistent with multi-channel block. The poor correlation between hERG and repolarization assays suggests that the hERG assay oversimplifies drug effects on the complex repolarization process for drugs demonstrating multi-channel block and that neither assay alone adequately predicts proarrhythmic risk.