Interstitial Fluid Of Subcutaneous Tissue Research Articles

Perioperative administration of cefazolin and metronidazole in obese and non-obese patients: a pharmacokinetic study in plasma and interstitial fluid.

To assess plasma and tissue pharmacokinetics of cefazolin and metronidazole in obese patients undergoing bariatric surgery and non-obese patients undergoing intra-abdominal surgery. Fifteen obese and 15 non-obese patients received an IV short infusion of 2 g cefazolin and 0.5 g metronidazole for perioperative prophylaxis. Plasma and microdialysate from subcutaneous tissue were sampled until 8 h after dosing. Drug concentrations were determined by HPLC-UV. Pharmacokinetic parameters were calculated non-compartmentally. In obese patients (BMI 39.5-69.3 kg/m2) compared with non-obese patients (BMI 18.7-29.8 kg/m2), mean Cmax of total cefazolin in plasma was lower (115 versus 174 mg/L) and Vss was higher (19.4 versus 14.2 L). The mean differences in t½ (2.7 versus 2.4 h), CL (5.14 versus 4.63 L/h) and AUC∞ (402 versus 450 mg·h/L) were not significant. The influence of obesity on the pharmacokinetics of metronidazole was similar (Cmax 8.99 versus 14.7 mg/L, Vss 73.9 versus 51.8 L, t½ 11.9 versus 9.1 h, CL 4.62 versus 4.13 L/h, AUC∞ 116 versus 127 mg·h/L). Regarding interstitial fluid (ISF), mean concentrations of cefazolin remained >4 mg/L until 6 h in both groups, and those of metronidazole up to 8 h in the non-obese group. In obese patients, the mean ISF concentrations of metronidazole were between 3 and 3.5 mg/L throughout the measuring interval. During the time of surgery, cefazolin concentrations in plasma and ISF of subcutaneous tissue were lower in obese patients, but not clinically relevant. Regarding metronidazole, the respective differences were higher, and may influence dosing of metronidazole for perioperative prophylaxis in obese patients.

Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study.

Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used fAUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 ± 11.2 kg/m2) and 15 non-obese (23.9 ± 2.1 kg/m2) patients were analyzed. AUC0–8 in ISF decreased by −1.69 mg*h/L (95% CI: −2.59 to −0.79, p < 0.001) for every 10 kg increase in weight. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs. 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs. 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC ≥ 1 mg/L in ISF and ≥ 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC ≥ 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients.

Plasma and target-site subcutaneous tissue population pharmacokinetics and dosing simulations of cefazolin in post-trauma critically ill patients.

The objective of this study was to describe the population pharmacokinetics of cefazolin in plasma and the interstitial fluid of subcutaneous tissue of post-trauma critically ill patients and provide clinically relevant dosing recommendations that result in optimal concentrations at the target site. This was a pharmacokinetic study in a tertiary referral ICU. We recruited 30 post-trauma critically ill adult patients and collected serial total and unbound plasma cefazolin concentrations. Interstitial fluid concentrations were determined using in vivo microdialysis. Population pharmacokinetic analysis and Monte Carlo simulations were undertaken with Pmetrics(®). Fractional target attainment against an MIC distribution for Staphylococcus aureus isolates was calculated. The mean (SD) age, weight, APACHE II score and CLCR were 37.0 (14.1) years, 86.8 (22.7) kg, 16.9 (5.3) and 163 (44) mL/min, respectively. A three-compartment linear population pharmacokinetic model was most appropriate. Covariates included in the model were CLCR on drug clearance and serum albumin concentration and body weight on the volume of the central compartment. The fractional target attainment for a 1 g intravenous 8-hourly dose for a CLCR of 50 mL/min was 88%, whereas for a patient with a CLCR of 215 mL/min, a dose of 2 g 6-hourly achieved 84% fractional target attainment. Clinicians should be mindful of the effects of elevated CLCR and serum albumin concentrations on dosing requirements for post-trauma critically ill patients.

Open flow microperfusion: pharmacokinetics of human insulin and insulin detemir in the interstitial fluid of subcutaneous adipose tissue.

To compare the time profile of insulin detemir and human insulin concentrations in the interstitial fluid (ISF) of subcutaneous adipose tissue during constant i.v. infusion and to investigate the relationship between the pharmacokinetics of both insulin molecules in plasma and the ISF of subcutaneous adipose tissue. During a 6-h hyperinsulinaemic-euglycaemic clamp (plasma glucose level 8 mmol/l) human insulin (21 and 42 pmol/min/kg) or insulin detemir (209 and 417 pmol/min/kg) were infused i.v. in eight rats per dose level. Open flow microperfusion (OFM) was used to continuously assess interstitial insulin concentrations in subcutaneous adipose tissue. At the lower infusion rate, insulin detemir appeared significantly later in the ISF than in the plasma (p < 0.05) and also appeared later in the ISF relative to human insulin (p < 0.005). By using OFM we were able to monitor albumin-bound insulin detemir directly in the ISF of subcutaneous tissue and confirm its delayed transendothelial passage to a peripheral site of action.

Overview of a Novel Sensor for Continuous Glucose Monitoring

The core element of a continuous glucose monitoring (CGM) system is the glucose sensor, which should enable reliable CGM readings in the interstitial fluid in subcutaneous tissue for a period of several days. The aim of this article is to describe the layout and constituents of a novel glucose sensor and the rationale behind the measures that were used to optimize its performance. In order to achieve a stable glucose sensor signal, special attention was paid to the sensor materials and architecture, i.e., biocompatible coating of the sensor, limitation of glucose flux into the working electrode, low oxidation potential by use of manganese dioxide, and a tissue-averaging sensor design. A series of in vitro and in vivo evaluations showed that the sensor enables stable and accurate glucose sensing in the subcutaneous tissue for up to 7 days. Parallel measurements with four sensors in a single patient showed a close agreement between these sensors. In summary, this high-performance needle-type glucose sensor is well suited for CGM in patients with diabetes.

Continuous monitoring of glucose in subcutaneous tissue using microfabricated differential affinity sensors.

We describe miniaturized differential glucose sensors based on affinity binding between glucose and a synthetic polymer. The sensors possess excellent resistance to environmental disturbances and can potentially allow wireless measurements of glucose concentrations within interstitial fluid in subcutaneous tissue for long-term, stable continuous glucose monitoring (CGM). The sensors are constructed using microelectromechanical systems (MEMS) technology and exploit poly(N-hydroxy-ethyl acrylamide-ran-3-acrylamidophenylboronic acid) (PHEAA-ran-PAAPBA), a glucose-binding polymer with excellent specificity, reversibility, and stability. Two sensing approaches have been investigated, which respectively, use a pair of magnetically actuated diaphragms and perforated electrodes to differentially measure the glucose-binding-induced changes in the viscosity and permittivity of the PHEAA-ran-PAAPBA solution with respect to a reference, glucose-unresponsive polymer solution. In vivo characterization of the MEMS affinity sensors were performed by controlling blood glucose concentrations of laboratory mice by exogenous glucose and insulin administration. The sensors experienced an 8-30 min initialization period after implantation and then closely tracked commercial capillary glucose meter readings with time lags ranging from 0-15 min during rapid glucose concentration changes. Clarke error grid plots obtained from sensor calibration suggest that, for the viscometric and dielectric sensors, respectively, approximately 95% (in the hyperglycemic range) and 84% (ranging from hypoglycemic to hyperglycemic glucose concentrations) of measurement points were clinically accurate, while 5% and 16% of the points were clinically acceptable. The miniaturized MEMS sensors explore differential measurements of affinity glucose recognition. In vivo testing demonstrated excellent accuracy and stability, suggesting that the devices hold the potential to enable long-term and reliable CGM in clinical applications.

Interstitial fluid volume, plasma volume and transcapillary colloid osmotic gradient in patients with hepatic cirrhosis and fluid retention.

Colloid osmotic pressure in plasma (IIp) and in subcutaneous interstitial fluid (IIi) (wick technique), plasma volume (PV) and interstitial fluid volume (IFV) were measured in 12 patients with hepatic cirrhosis and fluid retention. The value of IIp (mean +/- SD) was 21.4 +/- 4.2 mmHg (28.6 +/- 3.4 mmHg in normal subjects (p less than 0.01)), mean IIi was 8.6 +/- 2.2 mmHg (15.8 +/- 2.7 mmHg in normal subjects (p less than 0.01)) and mean transcapillary colloid osmotic gradient (IIp-IIi) was 12.7 +/- 3.8 mmHg compared to 12.8 +/- 2.7 mmHg in normal subjects (p greater than 0.1). Mean PV was increased by 21% compared to normal values (p less than 0.01) and IFV increased by 43% (p less than 0.01). The study demonstrates that reduction in IIp in hepatic cirrhosis is accompanied by a decrease of IIi in subcutaneous tissue resulting in unchanged transcapillary colloid osmotic gradient. The reduction in IIi can partly be explained by simple dilution and partly by a decrease in interstitial protein mass. The wash-down of interstitial proteins in non-splanchnic tissues reduces the tendency to oedema and hypovolaemia.