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.

Could we predict asymptomatic cardiovascular autonomic neuropathy in type 1 diabetic patients attending out-patients clinics?

BACKGROUND AND AIMS: Diabetic cardiovascular autonomic neuropathy (CAN) is associated with increased morbidity and mortality. This complication may be asymptomatic for a long time. The aim of this study was to assess the prevalence, severity and predictors of asymptomatic CAN in patients with type 1 diabetes mellitus (DM1). PATIENTS AND METHODS: 107 patients with DM1 were enrolled: 52 men and 55 women aged 39.8 +/- 12.4 years (18-72), duration of DM 16.6 +/- 9.5 years (0.5-43), age at DM manifestation 23.5 +/- 12.8 years (1-54) and BMI 25.1 +/- 3.2 (18.9-33.91). CAN was assessed using standard cardiovascular reflex tests (Ewing battery) and the patients were divided into three groups according to the results: Group 0, without CAN; Group I, 1(st) degree CAN; Group II, 2(nd) degree CAN. We assessed the most frequent relationships between CAN and chronic complications, episodes of severe hypoglycemia, time-related parameters (age of patients, duration of diabetes, age at manifestation), glycosylated hemoglobin (HbA(1)c), BMI, cardiovascular diseases and blood pressure, and determined the predictability of CAN on the basis of these relationships. RESULTS: Only 50 of the 107 patients (46%) showed no CAN. We found 1(st) degree CAN in 38 patients (36%) and 2(nd) degree CAN in 19 (18%). CAN correlated more significantly with the duration of diabetes (p < 0.001) than with age (p < 0.05). The relationship between CAN and HbA(1)c was on the borderline of statistical significance (p = 0.053). We found a positive correlation between CAN and the presence of chronic complications [peripheral neuropathy (p < 0.001), retinopathy (p < 0.001), and some markers of nephropathy: creatinine (p < 0.03), albuminuria (p < 0.01)]. Although blood pressure was within the physiological range (124.2/74.5 +/- 11.5/7.8 mmHg) in all patients, a positive correlation with CAN was confirmed (p < 0.05). No relationship with occurrence of severe hypoglycemia was found. CONCLUSIONS: According to our results, asymptomatic CAN is very frequent in patients with DM1. By using multifactorial logistic regression (step-wise) analysis we demonstrated that if albuminuria, peripheral neuropathy and elevated systolic BP are present simultaneously, there is a high probability that the patient also has CAN (84.9% of initial group correctly predicted, p < 0.001).

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.

Czech multicenter research database of severe COPD.

PURPOSE: Chronic obstructive pulmonary disease (COPD) has been recognized as a heterogeneous, multiple organ system-affecting disorder. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) places emphasis on symptom and exacerbation management. The aim of this study is examine the course of COPD and its impact on morbidity and all-cause mortality of patients, with respect to individual phenotypes and GOLD categories. This study will also evaluate COPD real-life patient care in the Czech Republic. PATIENTS AND METHODS: The Czech Multicentre Research Database of COPD is projected to last for 5 years, with the aim of enrolling 1,000 patients. This is a multicenter, observational, and prospective study of patients with severe COPD (post-bronchodilator forced expiratory volume in 1 second ≤ 60%). Every consecutive patient, who fulfils the inclusion criteria, is asked to participate in the study. Patient recruitment is done on the basis of signed informed consent. The study was approved by the Multicentre Ethical Committee in Brno, Czech Republic. RESULTS: The objective of this paper was to outline the methodology of this study. CONCLUSION: The establishment of the database is a useful step in improving care for COPD subjects. Additionally, it will serve as a source of data elucidating the natural course of COPD, comorbidities, and overall impact on the patients. Moreover, it will provide information on the diverse course of the COPD syndrome in the Czech Republic.