Effect of intermediate care on mortality following emergency abdominal surgery. The InCare trial: study protocol, rationale and feasibility of a randomised multicentre trial.

BACKGROUND: Emergency abdominal surgery carries a 15% to 20% short-term mortality rate. Postoperative medical complications are strongly associated with increased mortality. Recent research suggests that timely recognition and effective management of complications may reduce mortality. The aim of the present trial is to evaluate the effect of postoperative intermediate care following emergency major abdominal surgery in high-risk patients. METHODS AND DESIGN: The InCare trial is a randomised, parallel-group, non-blinded clinical trial with 1:1 allocation. Patients undergoing emergency laparotomy or laparoscopic surgery with a perioperative Acute Physiology and Chronic Health Evaluation II score of 10 or above, who are ready to be transferred to the surgical ward within 24 h of surgery are allocated to either intermediate care for 48 h, or surgical ward care. The primary outcome measure is all-cause 30-day mortality. We aim to enrol 400 patients in seven Danish hospitals. The sample size allows us to detect or refute a 34% relative risk reduction of mortality with 80% power. DISCUSSION: This trial evaluates the benefits and possible harm of intermediate care. The results may potentially influence the survival of many high-risk surgical patients. As a pioneer trial in the area, it will provide important data on the feasibility of future large-scale randomised clinical trials evaluating different levels of postoperative care. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01209663.

Good penetration of moxifloxacin into human abscesses.

Abscesses are often treated with antibiotics in addition to incision or when incision is unfeasible, but accurate information about antibiotic abscess penetration in humans is missing. This study aimed at evaluating the penetration of moxifloxacin into human abscesses. After administration of a single dose of 400 mg moxifloxacin, drug concentrations were measured in 10 differently located abscesses at incision, and in plasma over 8 h. At incision performed 0.9-4.8 h after administration, moxifloxacin concentrations in abscesses ranged from ≤0.01 to 9.2 mg/l (1.9 ± 3.4 mg/l), indicating pronounced drug accumulation in some abscesses. The degree of abscess penetration could not be explained by covariates like the ratio of surface area to volume or pH of abscesses, or by moxifloxacin plasma concentrations. Concluding, moxifloxacin was detectable in most abscesses and may be a useful antibiotic for this indication. However, antibiotic abscess penetration was highly variable and unpredictable, suggesting surgical abscess incision whenever possible.

Abscess penetration of cefpirome: concentrations and simulated pharmacokinetic profiles in pus.

PURPOSE: Abscess patients frequently receive antibiotic therapy when incision cannot be performed or in addition to incision. However, antibiotic concentrations in human abscesses are widely unknown. METHODS: Pharmacokinetics of cefpirome in 12 human abscesses located in different body regions was studied. Cefpirome (2 g) was administered as an intravenous short infusion, and concentrations were measured in plasma over an 8-h period and in abscesses at incision. A pharmacokinetic two-stage model was applied. RESULTS: At abscess incision performed 158 ± 112 min after the start of the infusion, the cefpirome concentrations in the abscess fluid varied markedly, ranging from ≤0.1 (limit of quantification) to 47 (mean 8.4 ± 14.1 ) mg/L. Cefpirome was detectable in nine of 12 abscesses. Maximum concentrations were calculated to be 183 ± 106 mg/L in plasma and 12 ± 16 mg/L in the abscess. A cefpirome concentration of 2 mg/L, which is the minimum concentration inhibiting growth of 90% of the most relevant bacterial pathogens, was exceeded spontaneously in six of 12 abscesses after a single dose. Cefpirome concentrations in the abscess did not correlate with either the pH or the ratio of surface area to volume of the abscesses, nor with plasma pharmacokinetics. CONCLUSIONS: Cefpirome may be useful to treat abscess patients because it was detectable in most abscesses after a single dose. However, the penetration of cefpirome into abscesses is extremely variable and cannot be predicted by measuring other available covariates.

A combined accelerator mass spectrometry-positron emission tomography human microdose study with 14C- and 11C-labelled verapamil.

BACKGROUND AND OBJECTIVE: In microdose studies, the pharmacokinetic profile of a drug in blood after administration of a dose up to 100 µg is measured with sensitive analytical techniques, such as accelerator mass spectrometry (AMS). As most drugs exert their effect in tissue rather than blood, methodology is needed for extending pharmacokinetic analysis to different tissue compartments. In the present study, we combined, for the first time, AMS analysis with positron emission tomography (PET) in order to determine the pharmacokinetic profile of the model drug verapamil in plasma and brain of humans. In order to assess pharmacokinetic dose linearity of verapamil, data were acquired and compared after administration of an intravenous microdose and after an intravenous microdose administered concomitantly with an oral therapeutic dose. METHODS: Six healthy male subjects received an intravenous microdose [0.05 mg] (period 1) and an intravenous microdose administered concomitantly with an oral therapeutic dose [80 mg] of verapamil (period 2) in a randomized, crossover, two-period study design. The intravenous dose was a mixture of (R/S)-[14C]verapamil and (R)-[11C]verapamil and the oral dose was unlabelled racaemic verapamil. Brain distribution of radioactivity was measured with PET whereas plasma pharmacokinetics of (R)- and (S)-verapamil were determined with AMS. PET data were analysed by pharmacokinetic modelling to estimate the rate constants for transfer (k) of radioactivity across the blood-brain barrier. RESULTS: Most pharmacokinetic parameters of (R)- and (S)-verapamil as well as parameters describing exchange of radioactivity between plasma and brain (influx rate constant [K(1)] = 0.030 ± 0.003 and 0.031 ± 0.005 mL/mL/min and efflux rate constant [k(2)] = 0.099 ± 0.006 and 0.095 ± 0.008 min-1 for period 1 and 2, respectively) were not statistically different between the two periods although there was a trend for nonlinear pharmacokinetics for the (R)-enantiomer. On the other hand, all pharmacokinetic parameters (except for the terminal elimination half-life [t1/2;)]) differed significantly between the (R)- and (S)-enantiomers for both periods. The maximum plasma concentration (C(max)), area under the plasma concentration-time curve (AUC) from 0 to 24 hours (AUC(24)) and AUC from time zero to infinity (AUC(∞)) were higher and the total clearance (CL), volume of distribution (V(d)) and volume of distribution at steady state (V(ss)) were lower for the (R)- than for the (S)-enantiomer. CONCLUSION: Combining AMS and PET microdosing allows long-term pharmacokinetic data along with information on drug tissue distribution to be acquired in the same subjects thus making it a promising approach to maximize data output from a single clinical study.

A pilot study to assess the efficacy of tariquidar to inhibit P-glycoprotein at the human blood-brain barrier with (R)-11C-verapamil and PET.

UNLABELLED: Tariquidar, a potent, nontoxic, third-generation P-glycoprotein (P-gp) inhibitor, is a possible reversal agent for central nervous system drug resistance. In animal studies, tariquidar has been shown to increase the delivery of P-gp substrates into the brain by severalfold. The aim of this study was to measure P-gp function at the human blood-brain barrier (BBB) after tariquidar administration using PET and the model P-gp substrate (R)-(11)C-verapamil. METHODS: Five healthy volunteers underwent paired (R)-(11)C-verapamil PET scans and arterial blood sampling before and at 2 h 50 min after intravenous administration of tariquidar (2 mg/kg of body weight). The inhibition of P-gp on CD56-positive peripheral lymphocytes of each volunteer was determined by means of the (123)Rh efflux assay. Tariquidar concentrations in venous plasma were quantified using liquid chromatography/mass spectrometry. RESULTS: Tariquidar administration resulted in significant increases (Wilcoxon test for paired samples) in the distribution volume (DV, +24% +/- 15%) and influx rate constant (K(1), +49% +/- 36%) of (R)-(11)C-verapamil across the BBB (DV, 0.65 +/- 0.13 and 0.80 +/- 0.07, P = 0.043; K(1), 0.034 +/- 0.009 and 0.049 +/- 0.009, P = 0.043, before and after tariquidar administration, respectively). A strong correlation was observed between the change in brain DV after administration of tariquidar and tariquidar exposure in plasma (r = 0.90, P = 0.037). The mean plasma concentration of tariquidar achieved during the second PET scan (490 +/- 166 ng/mL) corresponded to 100% inhibition of P-gp function in peripheral lymphocytes. CONCLUSION: Tariquidar significantly increased brain penetration of (R)-(11)C-verapamil-derived activity due to increased influx. As opposed to peripheral P-gp function, central P-gp inhibition appeared to be far from complete after the administered tariquidar dose.