Donor-Recipient Chimeric Cell Transplantation as the Bridging Therapy for Mitigating Total Body Irradiation-Induced Injury.

In recent years, cell-based therapies have emerged as a promising approach for mitigating radiation-induced injury. Acute radiation syndrome (ARS) results from exposure to high doses of radiation over a short time period. This study aimed to compare the efficacy of donor-recipient chimeric cell (DRCC) therapy in mitigating ARS induced by a total body irradiation (TBI) dose of 10 gray (Gy). Thirty irradiated Lewis rats were employed as ARS models to assess the efficacy of systemic-intraosseous transplantation of different cellular therapies in five experimental groups (n = 6/group): saline control, isogenic bone marrow transplantation (isoBMT), allogeneic BMT (alloBMT), DRCC, and alloBMT+DRCC. DRCC were created by polyethylene glycol-mediated fusion of bone marrow cells from 24 ACI (RT1a) and 24 Lewis (RT11) rat donors. The creation of DRCC and chimeric state was confirmed by flow cytometry (FC) and confocal microscopy (CM). Recovery of blood parameters was evaluated through complete blood count analysis. Graft-versus-host disease (GvHD) signs were assessed clinically and histopathologically using kidney, skin, and small intestine biopsies. FC and CM confirmed the fusion feasibility and the chimeric state of DRCC. A 100% mortality rate was observed in the saline control group, whereas a 100% survival was recorded following DRCC transplantation, correlating with significant recovery of peripheral blood parameters. In addition, no clinical or histopathological signs of GvHD were observed after DRCC and alloBMT+DRCC transplantation. These findings confirm efficacy of DRCC in mitigating GvHD, promoting hematopoietic recovery, and increasing animal survival following TBI-induced ARS. Moreover, tolerogenic and immunomodulatory properties of DRCC therapy support its feasibility for clinical applications. Therefore, this study introduces DRCC as an innovative bridging therapy for alleviating the acute effects of TBI, with broad implications for stem cell research and regenerative medicine.

Population Pharmacokinetic Model of Dexmedetomidine in a Heterogeneous Group of Patients.

Dexmedetomidine is a hepatically eliminated drug with sedative, anxiolytic, sympatholytic, and analgesic properties that has been increasingly used for various indications in the form of a short or continuous intravenous infusion. This study aimed to propose a population pharmacokinetic (PK) model of dexmedetomidine in a heterogeneous group of intensive care unit patients, incorporating 29 covariates potentially linked with dexmedetomidine PK. Data were collected from 70 patients aged between 0.25 and 88 years and treated with dexmedetomidine infusion for various durations at 1 of 4 medical centers. Statistical analysis was performed using a nonlinear mixed-effect model. Categorical and continuous covariates including demographic data, hemodynamic parameters, biochemical markers, and 11 single-nucleotide polymorphisms were tested. A 2-compartment model was used to describe dexmedetomidine PK. An allometric/isometric scaling was used to account for body weight difference in PK parameters, and the Hill equation was used to describe the maturation of clearance. Typical values of the central and peripheral volume of distribution and the systemic and distribution clearance for a theoretical adult patient were central volume of distribution = 22.50 L, peripheral volume of distribution = 86.1 L, systemic clearance = 34.7 L/h, and distribution clearance = 40.8 L/h. The CYP1A2 genetic polymorphism and noradrenaline administration were identified as significant covariates for clearance. A population PK model of dexmedetomidine was successfully developed. The proposed model is well calibrated to the observed data. The identified covariates account for <5% of interindividual variability and consequently are of low clinical significance for the purpose of dose adjustment.

Pharmacokinetics and pharmacodynamics of propofol and fentanyl in patients undergoing abdominal aortic surgery - a study of pharmacodynamic drug-drug interactions.

Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target-controlled infusion system. Fentanyl 2-3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non-linear mixed-effect model (NONMEM 7.2 software) was conducted. Two-compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect-site concentrations through an additive Emax model. Context-sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol-fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two-fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John Wiley & Sons, Ltd.

Pharmacokinetics and pharmacodynamics of propofol in patients undergoing abdominal aortic surgery.

Available propofol pharmacokinetic protocols for target-controlled infusion (TCI) were obtained from healthy individuals. However, the disposition as well as the response to a given drug may be altered in clinical conditions. The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol during total intravenous anesthesia (propofol/fentanyl) monitored by bispectral index (BIS) in patients scheduled for abdominal aortic surgery. Population nonlinear mixed-effect modeling was done with Nonmem. Data were obtained from ten male patients. The TCI system (Diprifusor) was used to administer propofol. The BIS index served to monitor the depth of anesthesia. The propofol dosing was adjusted to keep BIS level between 40 and 60. A two-compartment model was used to describe propofol PK. The typical values of the central and peripheral volume of distribution, and the metabolic and inter-compartmental clearance were V(C) = 24.7 l, V(T) = 112 l, Cl = 2.64 l/min and Q = 0.989 l/min. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment with the rate constant for the distribution to the effector compartment equal to 0.240 min(-1). The BIS index was linked to the effect site concentrations through a sigmoidal E(max) model with EC(50) = 2.19 mg/l. The body weight, age, blood pressure and gender were not identified as statistically significant covariates for all PK/PD parameters. The population PK/PD model was successfully developed to describe the time course and variability of propofol concentration and BIS index in patients undergoing surgery.

Utility of measurements of abdominal perfusion pressure as a measure of isovolemic status and intestinal perfusion in patients with ruptured aortic aneurysm.

UNLABELLED: Ruptured abdominal aorta aneurysm of ten results in intraabdominal hypertension (IAH). When IAH exceeds 20 mm Hg, intestinal ischemia can result that is a common cause of severe postoperative complications, including death. THE AIM OF THE STUDY: was to evaluate utility of measurement of abdominal perfusion pressure (APP) to estimate intestinal perfusion and isovolemic status in patients undergoing surgical treatment for ruptured abdominal aorta aneurysm. MATERIAL AND METHODS: A group of 40 patients of either sex, aged 47-93 years (average age 70 ± 10) was treated at an Intensive Care Unit after surgical reconstruction of abdominal aorta due to ruptured aortic aneurysm. The study was prospective. The following were measured: parameters of intraabdominal pressure (intraabdominal pressure - IAP, abdominal perfusion pressure - APP); parameters of intestinal perfusion - tonometric (intramucosal gastric carbon dioxide partial pressure PgCO(2), intramucosal-arterial difference in carbon dioxide partial pressure - Pg-aCO(2)); hemodynamic parameters (mean arterial pressure - MAP, central venous pressure - CVP). RESULTS: A statistically significant correlation was demonstrated between parameters of visceral perfusion and abdominal perfusion pressure. Pearson correlation coefficient for APP/PgCO(2) and APP/Pg-aCO(2) was negative and was -0.4664 and -0.3498, respectively. CONCLUSIONS: Abdominal perfusion pressure is an useful parameter in the evaluation of intestinal perfusion in IAH patients after surgical treatment of ruptured aortic aneurysm. MAP reflects current physiological body reserves at a critical stage of the disease, informing about possibility to provide visceral perfusion and indirectly, about adequacy of fluid replacement therapy. In intraabdominal hypertension, CVP is falsely elevated, making it of low utility in the evaluation of volemic status and intestinal perfusion.

Improved outcome after rupture of abdominal aortic aneurysm over an 18-year period.

The purpose of the study was to analyze changes in in-hospital mortality of patients with ruptured abdominal aortic aneurysm (RAAA) during an 18-year period. A retrospective analysis of 246 patients with RAAA in the years 1987-2005 was performed. The patients were divided into groups that consisted of 111 patients treated in the years 1987-2000 (group I) and 135 patients treated in the years 2001-2005 (group II). The in-hospital mortality rates of all patients and of operated patients in both groups were analyzed. Preoperative variables such as age, gender, size of the aneurysm, duration of symptoms, distance to the vascular surgery department, full blood count, serum creatinine and urea concentrations, and systolic and diastolic blood pressures, as well as the number of all AAAs and RAAAs treated per year, were compared between the groups. The Mann-Whitney U-test and Fisher exact test were used to analyze differences in continuous and categorical variables, respectively. The in-hospital mortality of all patients was significantly lower in group II (p = 0.006) The difference in in-hospital mortality of operated patients was of borderline statistical significance (p = 0.07). The proportion of nonoperated patients decreased from 21% to 6% (p = 0.0008). The patients from group II had significantly higher preoperative levels of hemoglobin, hematocrit, erythrocytes, and platelets, as well as higher systolic and diastolic blood pressure and smaller diameter of aneurysm. The number of both all aneurysms and RAAAs per year was significantly higher in group II. The improved preoperative status of the patients and more aggressive surgical approach are associated with reduction in in-hospital mortality of patients with RAAA. The increased experience of the center may also improve outcome of RAAA.