Systematic review with meta-analysis: vasoactive drugs for the treatment of hepatorenal syndrome type 1.

BACKGROUND: Hepatorenal syndrome type 1 (HRS1) is a functional, rapidly progressive, potentially reversible form of acute kidney injury occurring in patients with cirrhosis. Characterised by intense renal arterial vasoconstriction, it carries a very poor prognosis. There is a significant unmet need for a widely approved, safe and effective pharmacological treatment. AIM: To re-evaluate efficacy and safety of pharmacological treatments for HRS1, in the light of recently published randomised controlled trials (RCTs). METHODS: MEDLINE (OvidSP), EMBASE, PubMed and Cochrane registers were searched for RCTs reporting efficacy and adverse events related to pharmacological treatment of HRS1. Search terms included: 'hepatorenal syndrome', 'terlipressin', 'noradrenaline', 'octreotide', 'midodrine', 'vasopressin', 'dopamine', 'albumin' and synonyms. Comparison of vasoactive drugs vs. placebo/no treatment, and two active drugs were included. Meta-analysis was performed for HRS1 reversal, creatinine improvement, mortality and adverse events. RESULTS: Twelve RCTs enrolling 700 HRS1 patients were included. Treatment with terlipressin and albumin led to HRS1 reversal more frequently than albumin alone or placebo (RR: 2.54, 95% CI: 1.51-4.26). Noradrenaline was effective in reversing HRS1, but trials were small and nonblinded. Overall, there was mortality benefit with terlipressin (RR: 0.79, 95% CI: 0.63-1.01), but sensitivity analysis including only trials with low risk of selection bias weakened this relationship (RR: 0.87, 95% CI: 0.71-1.06). Notably, there was a significant risk of adverse events with terlipressin therapy (RR: 4.32, 95% CI: 0.75-24.86). CONCLUSIONS: Terlipressin treatment is superior to placebo for achieving HRS1 reversal, but mortality benefit is less clear. Terlipressin is associated with significant adverse events, but infusion regimens may be better tolerated. There is continued need for safe and effective treatment options for hepatorenal syndrome.

Age and sex variation in serum albumin concentration: an observational study.

BACKGROUND: In the UK, a common reference interval for serum albumin is widely used irrespective of age or sex. Implicit in this is that laboratories produce analytically similar results. This paper challenges the validity of this approach. METHODS: A three-week collection of results sent to all primary care centres in England has been analysed by age, sex and laboratory. In all, 1,079,193 serum albumin reports were included in this analysis. RESULTS: The mean population serum albumin concentration increases to peak at around age 20 years and then decreases with increasing age. Values in females decrease more rapidly but become close to male values at 60 years. The variation between laboratories was large and potentially clinically significant. CONCLUSIONS: Reference intervals for serum albumin should be stratified by age and sex. Until there is greater methodological standardization, laboratories should determine their own reference intervals and not accept a single consensus reference interval.

Chronic kidney disease prevalence and secular trends in a UK population: the impact of MDRD and CKD-EPI formulae.

INTRODUCTION: Most UK laboratories use the MDRD4 formula to estimate glomerular filtration rate (eGFR), but this may exaggerate chronic kidney disease (CKD) prevalence. In a large adult population, we examined the impact of the more accurate CKD-EPI formulae on prevalence estimates, and on secular trends in prevalence. METHODS: We extracted all serum creatinine (SCr) results for adults, processed in our laboratory during two 1-year periods (2004, 2009-10). To minimize the effect of acute illness, a patient's lowest SCr was used for each period. eGFR (traceable to isotope dilution mass spectrometry value) was calculated using the MDRD4 and CKD-EPI formulae. Prevalence estimates were compared, with sub-group analysis by age and sex. RESULTS: In 2004, 102 322 patients had SCr tested (35.4% of the adult population), rising to 123 121 (42.3%) in 2009-10. The proportion tested rose with age to 86% of 85- to 89-year olds. The prevalence of CKD stages 3-5 was lower with the CKD-EPI formulae than the MDRD4 formula. The CKD-EPI formulae reclassified 17 014 patients (5.8%) to milder stages of CKD, most commonly from eGFR 60-89 ml/min/1.73m(2) and CKD stage 3A, in women, and in those <70 years old. 5172 patients (1.8%), mostly elderly women, were reclassified to more severe stages of CKD. Between the two time periods, the prevalence of CKD stages 3-5 rose from 5.44% to 5.63% of the population using MDRD4, but was static at 4.94% with CKD-EPI. CONCLUSION: The CKD-EPI formulae, which are more accurate than the MDRD4 formula at higher GFR, reduced the estimated prevalence of CKD stages 3-5 by 0.5% in 2004 and 0.7% in 2009-10. The greatest reclassification was seen in CKD 3A, particularly amongst middle-aged females. The minor rise in CKD prevalence between 2004 and 2009-10 seen with the MDRD4 formula was not confirmed with the CKD-EPI formulae. The CKD-EPI formulae may reduce overdiagnosis of CKD, but further assessment in the elderly is required before widespread implementation.

Freedman's 'clinical equipoise' and sliding-scale all-dimensions-considered equipoise'.

It is often claimed that a clinical investigator may ethically participate (e.g., enroll patients) in a trial only if she is in equipoise (if she has no way to ground a preference for one arm of the study). But this is a serious problem, for as data accumulate, it can be expected that there will be a discernible trend favoring one of the treatments prior to the point where we achieve the trial's objective. In this paper, I critically evaluate Benjamin Freedman's 'clinical equipoise' solution to this dilemma. I argue that Freedman actually puts forth at least two distinct contrasts--one in terms of community vs. individual equipoise, and another concerning clinical vs. theoretical equipoise--and that neither of them resolves the dilemma. I then make a proposal for a more adequate account of how to think about the circumstances under which entering subjects in trials would be justified--a 'sliding-scale equipoise' that arises out of a discussion of patients' values.

Research ethics. Managing risks of arthropod vector research.

Field research with vectors is an essential aspect of vector biology research and vector-borne disease prevention and control. This type of research, which brings experimental vector manipulations into endemic areas, can present risks to human populations. This paper seeks to stimulate a full discussion within the medical entomology community of the risks associated with vector field research. Such discussions will promote development of a consensus, among investigators, sponsoring agencies and the communities within which the work is done, so that appropriate steps can be taken to minimize and manage the risks, and adequate oversight can be maintained.

Serum cytokine levels in patients with neutropenia.

Serum samples from 76 patients with neutropenia and 34 control subjects were analyzed for levels of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin 1 alpha, and tumor necrosis factor beta. Clinical correlates and duration of neutropenia were determined insofar as possible. Systemic acute inflammatory disease was present in only two patients. In most cases, the neutropenia was considered idiopathic or medication related. Significantly elevated serum granulocyte colony-stimulating factor levels were found in the patient group, regardless of the apparent cause of the neutropenia. Increased levels of granulocyte-macrophage colony-stimulating factor, interleukin 1, and tumor necrosis factor were seen in only one patient with sepsis.

Serum levels of erythropoietin and selected other cytokines in patients with anemia of chronic disease.

Serum levels of erythropoietin and five other cytokines potentially operational in erythropoiesis were determined in patients with anemia of chronic disease. No correlation between erythropoietin levels and severity of anemia was found. A spectrum of abnormality was encountered among patients in whom there was less than expected erythropoietin response to increased levels of erythropoietin and among others in whom the erythropoietin levels were subnormal for their degree of anemia. Increased serum levels of interleukin-3, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor were encountered in limited numbers of patients, especially those with increased erythropoietin levels. Deficient erythropoietin production is concluded to be the major cause of anemia of chronic disease.

Complex genetic causation of human disease: critiques of and rationales for heritability and path analysis.

This paper examines some criticisms that have been made of two standard genetic methodologies: heritability and path analysis. I conclude that the criticisms should be taken seriously, concerning both the accuracy of heritability measures and their significance. In light of the fact that such studies remain prominent in the literature, I consider what possible rationale they can retain consistent with these criticisms. In particular, I consider (1) a role in the identification of high-risk individuals and (2) a heuristic role in the planning of research strategy.

The conflict between randomized clinical trials and the therapeutic obligation.

The central dilemma concerning randomized clinical trials (RCTs) arises out of some simple facts about causal methodology (RCTs are the best way to generate the reliable causal knowledge necessary for optimally-informed action) and a prima facie plausible principle concerning how physicians should treat their patients (always do what it is most reasonable to believe will be best for the patient). A number of arguments related to this in the literature are considered. Attempts to avoid the dilemma fail. Appeals to informed consent and mechanisms for minimizing the resulting harm are important for policy, but informed consent is problematic and mechanisms for minimization of harm do not address the dilemma. Appeals to some sort of contract model of justification are promising and illuminating.

KIE: The assumption that randomized clinical trials are the best way to get reliable knowledge about the efficacy of treatments leads to conflict with the physician's therapeutic obligation to treat patients in the way that will be most beneficial to them. This dilemma arises whenever the evidence for the superiority of one treatment is approaching, but has not yet reached, the significance level. Considerations of different ways of obtaining informed consent, determining ways of minimizing harm, and justifications for violating the therapeutic obligation are discussed but found unsatisfactory in many respects. Contract models of justifying randomized trials seem to be the most promising models to assess; however, more research is needed on the methodologies of human experimentation to determine whether some combination of random and historical controls or some statistical or procedural changes could give reliable results with less harm to patients.