Impact of cumulative fluid balance on the pharmacokinetics of extended infusion meropenem in critically ill patients with sepsis.

BACKGROUND: Meropenem dosing for septic critically patients is difficult due to pathophysiological changes associated with sepsis as well as supportive symptomatic therapies. A prospective single-center study assessed whether fluid retention alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy. METHODS: Twenty-five septic ICU patients (19 m, 6f) aged 32-86 years with the mean APACHE II score of 20.2 (range 11-33), suffering mainly from perioperative intra-abdominal or respiratory infections and septic shock (n = 18), were investigated over three days after the start of extended 3-h i.v. infusions of meropenem q8h. Urinary creatinine clearance (CLcr) and cumulative fluid balance (CFB) were measured daily. Plasma meropenem was measured, and Bayesian estimates of PK parameters were calculated. RESULTS: Eleven patients (9 with peritonitis) were classified as fluid overload (FO) based on a positive day 1 CFB of more than 10% body weight. Compared to NoFO patients (n = 14, 11 with pneumonia), the FO patients had a lower meropenem clearance (CLme 8.5 ± 3.2 vs 11.5 ± 3.5 L/h), higher volume of distribution (V1 14.9 ± 3.5 vs 13.5 ± 4.1 L) and longer half-life (t1/2 1.4 ± 0.63 vs 0.92 ± 0.54 h) (p < 0.05). Over three days, the CFB of the FO patients decreased (11.7 ± 3.3 vs 6.7 ± 4.3 L, p < 0.05) and the PK parameters reached the values comparable with NoFO patients (CLme 12.4 ± 3.8 vs 11.5 ± 2.0 L/h, V1 13.7 ± 2.0 vs 14.0 ± 5.1 L, t1/2 0.81 ± 0.23 vs 0.87 ± 0.40 h). The CLcr and Cockroft-Gault CLcr were stable in time and comparable. The correlation with CLme was weak to moderate (CLcr, day 3 CGCLcr) or absent (day 1 and 2 CGCLcr). Dosing with 2 g meropenem q8h ensured adequate concentrations to treat infections with sensitive pathogens (MIC 2 mg/L). The proportion of pre-dose concentrations exceeding the MIC 8 mg/L and the fraction time with a target-exceeding concentration were higher in the FO group (day 1-3 f Cmin > MIC: 67 vs 27%, p < 0.001; day 1%f T > MIC: 79 ± 17 vs 58 ± 17, p < 0.05). CONCLUSIONS: These findings emphasize the importance of TDM and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens, if guided by population covariate relationships between CLme and creatinine clearance.

Can early postoperative parenteral nutrition have some impact on postoperative inflammatory response intensity?

BACKGROUND AND AIMS: Enhanced recovery after surgery (ERAS) is currently the modern perioperative method of care for improvement of post-surgery patient condition and for minimising various postoperative complications. A question of some negative impact of early postoperative parenteral nutrition on postoperative inflammatory response intensity has not clear-cut answer yet. This pilot project was focused on the possible influence of early parenteral nutrition on the intensity of inflammatory postoperative response to operating trauma in surgical patients. Elected as a model of these conditions were patients with colorectal cancer undergoing major surgery. PATIENTS AND METHODS: 45 patients (of whom 39 were analysed finally) operated for cancer of the large bowel were enrolled into the clinical, prospective, randomized, blinded, and monocentric trial - reference number 201811 S09P of the Ethics committee, University Hospital Hradec Kralove, Czech Republic. Patients were divided into two subgroups according to the type of nutrition: subgroup A - supplemented only with 10% glucose for supported mineral carrier; and subgroup B - supplemented with total parenteral nutrition. Samples of blood and urine were examined immediately after surgery, and on the first, second, and fourth days postoperatively. The inflammatory reaction was monitored by the serum or/and urine concentration of neopterin, tryptophan, and kynurenine, and their urinary ratios with creatinine. The results were analysed by multivariate analysis, and p-values ≤ 0.05 were considered statistically significant. RESULTS: The final total of 39 patients comprised 20 from subgroup A and 19 from subgroup B. The intensity of the inflammatory response detected by the selected inflammatory markers (serum and urine concentrations of neopterin, kynurenine, tryptophan, their serum ratios, and their urinary ratios to creatinine) did not demonstrate statistically significant differences after early administration of the two alternative types of parenteral nutrition. CONCLUSIONS: The results of the study demonstrated the same or a very similar impact on the intensity of postoperative inflammatory response, regardless of whether the patient received intravenous administration of a small simple sugar infusion or total parenteral nutrition during early postoperative care.

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients.

AIMS: Critically ill patients undergoing aggressive fluid resuscitation and treated empirically with hydrosoluble time-dependent beta-lactam antibiotics are at risk for sub-therapeutic plasma concentrations. The aim of this study was to assess the impact of two covariates - creatinine clearance (Clcr) and cumulative fluid balance (CFB) on pharmacokinetics/pharmacodynamics (PK/PD) target attainment within a week of treatment with meropenem (ME) or piperacillin/tazobactam (PIP/TZB). METHODS: In this prospective observational pharmacokinetic (PK) study, 18 critically ill patients admitted to a surgical Intensive Care Unit (ICU) were enrolled. The primary PK/PD target was free antibiotic concentrations above MIC at 100% of the dosing interval (100%fT>MIC) to obtain maximum bactericidal activity. Drug concentration was measured using liquid chromatography-tandem mass spectrometry. RESULTS: The treatment of both 8 septic patients with IV extended ME dosing 2 g/3 h q8 h and 10 polytraumatized patients with IV intermittent PIP/TZB dosing 4.0/0.5 g q8 h was monitored. 8/18 patients (44%) manifested augmented renal clearence (ARC) where Clcr ≥130 mL/min/1.73 m2. Maximum changes were reported on days 2-3: the median positive CFB followed by the large median volume of distribution: Vdme=70.3 L (41.9-101.5), Vdpip = 46.8 L (39.7-60.0). 100%fTme>MIC was achieved in all patients on ME (aged ≥60 years), and only in two patients (non-ARC, aged ≥65 years) out of 10 on PIP/TZB. A mixed model analysis revealed positive relationship of CFBpip with Vdpip (P=0.021). CONCLUSION: Assuming that the positive correlation between CFB and Vd exists for piperacillin in the setting of the pathological state, then CFB should predict Vdpip across subjects at each and every time point.

The effect of three different surgical techniques for colon anastomosis on regional postoperative microperfusion: Laser Doppler Flowmetry study in pigs.

BACKGROUND: The optimal surgical approach to reconnecting bowel ends safely after resection is of great importance. OBJECTIVES: This project is focused on assessment of the perianastomotic microcirculation quality in the short postoperative period when using three different anastomosis techniques in experimental animal. METHODS: The experimental study involved 27 young female domestic pigs divided into three subgroups of 9 animals according to each surgical method of anastomosis construction in the sigmoid colon region: by manual suture, by stapler, or by gluing. Blood microcirculation in the anastomosis region was monitored using Laser Doppler Flowmetry (LDF). Anastomosis healing was evaluated by macroscopic and histological examination. RESULTS: Evaluation of the microcirculation in the anastomosis region showed the smallest decrease in perfusion values in animals reconstructed by suturing (Δ= -38.01%). A significantly more profound drop was observed postoperatively after stapling or gluing (Δ= -52.42% and Δ= -59.53%, respectively). All performed anastomoses healed without any signs of tissue and function pathology. CONCLUSIONS: Sewing, stapling, and gluing techniques for bowel anastomosis each have a different effect on regional microcirculation during 120 min. postoperatively. Nevertheless, the final results of anastomosis healing were found without of any pathology in all experimental animals managed by above mentioned anastomotic techniques.

Plasmafiltration as a possible contributor to kinetic targeting of pegylated liposomal doxorubicin (PLD) in order to prevent organ toxicity and immunosuppression.

PURPOSE: To examine the removal of pegylated liposomal doxorubicin (PLD) during plasmafiltration (PF) and determine whether the drug could be withheld prior to its organ distribution responsible for mucocutaneous toxicity. METHODS: Six patients suffering from platinum-resistant ovarian cancer were treated with a 1-h IV infusion 50 mg/m(2) of PLD/cycle-for three cycles q4w. Over 44 (46)-47(49) h postinfusion, five patients (14 cycles in total) underwent PF using a cascade PF method consisted of plasma separation by centrifugation and plasma treatment using filtration based one volume of plasma treatment, i.e., 3.18 L (±0.6 L) and plasma flow 1.0 L/h (0.91-1.48 L/h). Doxorubicin concentration in blood was monitored by a high-performance liquid chromatography method for 116 h postinfusion. Pharmacokinetic parameters determined from plasma concentration included volume of distribution, total body clearance, half-life of elimination, and area under the plasma concentration versus time. The amount of doxorubicin in the body eliminated by the patient and via extracorporeal treatment was evaluated. Toxicity was tested using CTCAE v4.0. RESULTS: The efficacy of PF and early responses to PLD/PF combination strategy were as follows: over 44(46) h postinfusion considered necessary for target distribution of PLD to tumor, patients eliminated 46 % (35-56 %) of the dose administered. Over 44(46)-47(49) h postinfusion, a single one-volume plasma filtration removed 40 % (22-45 %) (Mi5) of the remaining doxorubicin amount in the body. Total fraction eliminated attained 81 % (75-86 %). The most common treatment-related adverse events (grade 1-2) such as nausea (4/14 cycles-28 %) and vomiting (3/14 cycles-21 %) appeared during 44 h postinfusion. Hematological toxicity-anemia (5/14 cycles-35 %) was reported after cycle II termination. Symptoms of PPE-like syndrome (grade 1-2) appeared in one patient concomitantly with thrombophlebitis and malignant effusion. In this study, only one adverse reaction (1/14-7 %) as short-term malaise and nausea was reported by the investigator as probably related to PF. CONCLUSION: A single one-volume PF does remove a clinically important amount of doxorubicin in a kinetic targeting approach. There were no serious signs of drug toxicity and/or PF-related adverse events. Kinetically guided therapy with pegylated liposomal doxorubicin combined with PF may be a useful tool to the higher efficacy and tolerability of therapy with PLD.

A pilot study on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving piperacillin/tazobactam.

BACKGROUND: In critically ill patients, multi-trauma and intensive therapy can influence the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics with time-dependent bacterial killing. Consequently, PK/PD targets (%fT>MIC) - crucial for antimicrobial effects -may not be attained. METHODS: Two patients admitted to the surgical ICU of the University Hospital in Hradec Králove for multiple-trauma were given piperacillin/tazobactam by 1-hour IV infusion 4/0.5 g every 8h. PK variables: total and renal clearance (CLtot, CLR), volume of distribution (Vd), and elimination half-life (T1/2) were calculated, followed by glomerular filtration rate (MDRD) and cumulative fluid balance (CFB-total fluid volume based on 24-h registered fluid intake minus output). The PK/PD target attainment (100%fT>MIC) was defined as free (f) piperacillin plasma concentrations that remain, during the entire dosing interval (T), above the minimum inhibitory concentration (100%fT>MIC) within days 4-8 (when CFB culminates and disappears). Piperacillin concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and corrected for unbound fraction (22%). RESULTS: CFB culminated over days 2-5 reaching 15-30 L and was associated with a large Vd (29-42 L). While MDRD in patient 1 was low (0.3-0.4 mL s⁻¹ 1.7 m⁻²), that of patient 2 was increasing (> 3.1 mL s⁻¹ 1.7 m⁻²), which was associated with augmented CLR. In patient 2, the fT reached only 62, 52, and 44% on days 4, 6, and 8, respectively. In patient 1, the %fT was much higher, attaining values four to fivefold greater than that targeted. CONCLUSIONS: Critically ill patients are at risk of drug under- or overdosing without dose up-titration with regard to covariate effects and individual drug pharmacokinetics.