Principles of antibacterial dosing in continuous renal replacement therapy

Background: Appropriate antibacterial therapy is important to maximize patient survival in sepsis. Acute renal failure complicates optimal antibiotic administration. Methods: MEDLINE search from 1986 to 2010 using the terms 'acute renal failure', 'pharmacokinetics', 'clearance', 'dosage', 'h(a)emofiltration', 'h(a)emodialysis', `h(a)emodiafiltration', `continuous renal replacement therapy', `antibiotics', `intensive care' and `critically ill'. Results: Maximal bacterial killing and minimization of side effects depend on achieving pharmacokinetic targets appropriate to the selected antibacterial agent. Volume of distribution and clearance may be altered by critical illness and/or acute kidney injury. Clearance is determined by nonrenal clearance, residual renal clearance and continuous renal replacement therapy dose. Sieving and saturation coefficients are membrane specific, but may be altered by changes in protein binding induced by critical illness. A significant proportion of studies failed to report the essential dataset required for adequate antibacterial dosage calculation. Conclusions: Individualized dosing based on first principles may be the most appropriate method of dosing, particularly when enhanced by therapeutic drug monitoring. Copyright (C) 2010 S. Karger AG, Base

Supported in part by grants GM20069, HL49277, and CA34196 from the National Institutes of Health

Purpose. To develop a protocol to measure the intraocular pressure (IOP) of living mice and to determine the IOP of genetically different mouse strains. Methods. Eyes of anesthetized animals were cannulated with a very fine fluid-filled glass microneedle. The microneedle was connected to a pressure transducer, and the pressure signal was analyzed with a computer system. Intraocular pressures of male C3H/HeJ, C57BL/ 6J, A/J, and BALB/cJ mice were determined. Results. Differences in IOP were detected between genetically distinct mouse strains maintained in virtually identical environments. C3H/HeJ was the strain with the highest average IOP (13.7 ± 0.8 mm Hg). This strain average was 1.4 mm Hg higher than that for C57BL/6J (12.3 ± 0.5 mm Hg; P = 0.14), 4.3 mm Hg higher than that for A/J (9.4 ± 0.5 mm Hg; P< 0.001), and 6 mm Hg higher than that for BALB/cJ (7.7 ± 0.5 mm Hg; P< 0.001). Conclusions. The authors have developed an accurate and reliable procedure for measuring intraocular pressure in living mice. This procedure can detect IOP differences between groups of mice that differ by genotype. Invest Ophthalmol Vis Sci. 1997;38:249-253. VFlaucoma is a group of complex diseases involving the death of retinal ganglion cells and the degeneration of the optic nerve head. Glaucoma is the leading cause of blindness in black Americans and the second leading cause of blindness in the United States. 1 It is often associated with high intraocular pressure (IOP) that results from an increased resistance to drainage of the aqueous humor. Idiopathic or primary openangle glaucoma usually exhibits multifactorial inheritance, and many studies indicate that relatives of patients with primary open-angle glaucoma have a higher risk for the disease than the general population. ' Two of the best-known risk factors for glaucoma, March 29, 1996; revised June 27, 1996; accepted August 19, 1996 Glaucoma traditionally is viewed as a disease in which deleteriously high IOP results in optic nerve damage over time. 1 Intraocular pressure, however, is not the only factor. Nerve damage does not develop in most persons who have high IOP for extended periods of time, but in others, nerve damage develops despite IOP levels in the normal range. 1 The factors determining susceptibility of the retina and optic nerve to glaucomatous damage are unknown. Some studies implicate diabetes, vascular hypertension, arterial hypotension, cardiovascular disease, sex, and race in glaucomatous neuropathy. There are, however, studies that find no association between the above factors and glaucoma, and it is unclear which factors actually interact with IOP to cause damage. 3 The genetic and pathophysiological basis of glaucoma is poorly understood. The ability to alter the mouse genome by adding transgenes or altering endogenous genes makes mice the most advanced mammalian system for assessing the function of identified genes and for assessing the consequences of mutating or overexpressing these genes. MATERIALS AND METHODS. Animal Husbandry and Experimental Design. All experiments were performed in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Male mice of strains C3H/HeJ (C3H), C57BL/6J (B6), A/J, and BALB/cJ (BALB) were obtained from the Jackson Laboratory (Bar Harbor, ME). Mice of various genetic backgrounds were used in the experiments to validate the measurement procedure and to test the effect of microneedle insertion on IOP. Mice were received 3 weeks after birth and were housed in adjacent cages covered loosely with lexon filters and containing white pine bedding. The environment was kept at 21°C with a 14-hour light

Evaluating the Appropriate Use Criteria for Coronary Revascularization in Stable Ischemic Heart Disease Using Randomized Data From the ISCHEMIA Trial

BACKGROUND: The appropriate use criteria for revascularization of stable ischemic heart disease have not been evaluated using randomized data. Using data from the randomized ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; July 2012 to January 2018, 37 countries), the health status benefits of an invasive strategy over a conservative one were examined within appropriate use criteria scenarios. METHODS: Among 1833 participants mapped to 36 appropriate use criteria scenarios, symptom status was assessed using the Seattle Angina Questionnaire-7 at 1 year for each scenario and for each of the 6 patient characteristics used to define the scenarios. Coronary anatomy and SYNTAX(Synergy between percutaneous coronary intervention with Taxus and cardiac surgery) scores were measured using coronary computed tomography angiography. Treatment effects are expressed as an odds ratio for a better health status outcome with an invasive versus conservative treatment strategy using Bayesian hierarchical proportional odds models. Differences in the primary clinical outcome were similarly examined. RESULTS: The mean age was 63 years, 81% were male, and 71% were White. Diabetes was present in 28% and multivessel disease in 51%. Most clinical scenarios favored invasive for better 1-year health status. The benefit of an invasive strategy on Seattle Angina Questionnaire angina frequency scores was reduced for asymptomatic patients (odds ratio [95% credible interval], 1.16 [0.66-1.71] versus 2.26 [1.75-2.80]), as well as for those on no antianginal medications. Diabetes, number of diseased vessels, proximal left anterior descending coronary artery location, and SYNTAX score did not effectively identify patients with better health status after invasive treatment, and minimal differences in clinical events were observed. CONCLUSIONS: Applying the randomization scheme from the ISCHEMIA trial to appropriate clinical scenarios revealed baseline symptoms and antianginal therapy to be the primary drivers of health status benefits from invasive management. Consideration should be given to reducing the patient characteristics collected to generate appropriateness ratings to improve the feasibility of future data collection

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline