No abstract

HRS is not always cured by orthotopic liver transplant. Pre-transplantation dialysis or a long waiting period should not preclude transplantation in patients with HRS. HRS may not resolve in patients with alcoholic liver disease. We were unable to accurately define that group of patients with HRS who required long-term dialysis and could theoretically benefit from combined liver-kidney transplantation.

Severe sepsis is a major healthcare problem, characterised by a high incidence, mortality and cost. New breakthroughs in treatment are quite diverse, including: (i) more effective regimens for generic, inexpensive broad anti-inflammatory agents (corticosteroids); (ii) a recombinant protein (drotrecogin-alfa [activated]); and (iii) a protocol-based treatment approach (early goal-directed therapy). Economic analyses of new sepsis agents should adopt the societal perspective, which requires prolonging the time horizon beyond that currently typically studied in sepsis trials, so that patient-centred outcomes can be more fully captured. Sepsis affects a very diverse group of patients, and if findings are to be generalisable, careful attention must be paid to study entry criteria and differences in effects and costs across different patient subgroups. Existing care patterns for sepsis are also quite diverse, with the consequence that the incremental effects on costs and outcomes could vary widely by practice pattern, again affecting generalisability. Furthermore, many sepsis patients receive multiple other therapies, which together with therapies under study may have varied and unintended, potentially costly or dangerous adverse effects, which could have a large influence on cost-effectiveness estimates. Finally, there are a number of large yet potentially hidden costs of sepsis, such as the long-term costs of managing patients who develop sepsis or the costs of introducing different interventions into clinical practice. Such costs must also be addressed in economic analyses. The search for new anti-sepsis strategies remains vigorous and exciting. We recommend wider incorporation of economic analyses into the study of potential new therapies, with appropriate attention to the caveats discussed above. Clinical demand to use new agents must be balanced against the economic consequences of their use.

No abstract

If future trials of acute lung injury/acute respiratory distress syndrome are to be rigorous, informative, and successful, a number of key design issues need to be considered. First, appropriate sample size and entry criteria must be selected. The present definitions of acute lung injury/acute respiratory distress syndrome are arbitrary and select a broad, heterogeneous patient population in which treatment effects may often be small, requiring much larger sample sizes than those of previous trials. The alternative approach, selecting a subset of patients in whom a larger benefit is anticipated, is potentially hazardous because the subset selection criteria are unproven. Second, it must be ensured that the therapy is tested against current best methods of care. To ensure that a study is considered current at completion, investigators should anticipate that recent evidence at study commencement will be considered standard at study completion. Up-to-date evidence-based medicine should therefore be encouraged for all enrolled patients and, probably, protocolized in unblinded studies. Multiple novel therapies can also be tested, but care must be paid to the particular study design choice. Third, appropriate outcomes must be chosen. The traditional end point of 28-day mortality is too short and too crude to capture all relevant patient and societal outcomes. Thus, consideration of survival over a longer duration, coupled with assessment of quality of life, functional status, and morbidity, is essential. Fourth, the study must comply with new standards for the protection of human subjects. Protecting human subjects' rights and ensuring patient safety in subjects who are critically ill and who are rarely able to provide fully informed consent is a significant challenge. However, it is essential that new studies comply with required standards without becoming so burdensome that they cannot reasonably be completed.