The population pharmacokinetics and dose optimization of polymyxin B in critically ill patients with or without extracorporeal membrane oxygenation.

WHAT IS KNOWN AND OBJECTIVE: The presence of extracorporeal membrane oxygenation (ECMO) is suggested to further exacerbate the pharmacokinetics (PK) alterations that occur during critical illness. The objectives of this study were to determine the population PK model of polymyxin B in critically ill patients with or without ECMO support investigated the influence of ECMO on PK variability and to identify an optimal dosing strategy. METHODS: Forty-four critically ill patients were enrolled, including eight patients with ECMO support. Eight serial serum samples were collected from each patient at steady state. The population PK was determined using NONMEM and Monte Carlo simulation was performed to evaluate the exposures of different dosing regimens. RESULTS: The PK analyses included 342 steady-state concentrations and a two-compartment model was optimal for polymyxin B PK data modelling. In the final model, creatinine clearance (CLCR ) was the significant covariate on CL (typical value 1.27 L/h; between-subject variability 15.1%) and ECMO did not show a significant impact on the polymyxin B PK. Additionally, we found that the PK parameter estimates of patients with and without ECMO support were mostly similar. Based on Monte Carlo simulations, the dose escalation of polymyxin B in patients with increased CLCR improved the probability of achieving required exposure. For patients with CLCR ≤ 120 ml/min, a dosage regimen of 100 mg every 12 h may represent the optimal regimen at an MIC of 1 mg/L. WHAT IS NEW AND CONCLUSION: The impact of ECMO on the polymyxin B PK is likely to be minimal. Our study showed a potential relationship between CLCR and polymyxin B CL, and the dose of polymyxin B should be adjusted in patients with increased CLCR .

Estimation of the area under concentration-time curve of polymyxin B based on limited sampling concentrations in Chinese patients with severe pneumonia.

AIMS: The efficacy and toxicity of polymyxin B (PB) are closely related to its pharmacokinetic/pharmacodynamic (PK/PD) index area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratio. The purpose of this study was to obtain PK data for PB in Chinese severe pneumonia patients and establish appropriate blood sampling time points for the PB therapeutic drug monitoring (TDM). SUBJECT AND METHOD: After treatment with at least four doses of PB (50 IU, q12h), the blood samples were collected immediately after the end of infusion (C0) and 1.5, 2, 4, 6, 8, and 12 h (C1.5, C2, C4, C6, C8, C12) after PB administration. The PB blood plasma concentrations were determined using an ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). All 42 patients were randomly divided into modeling (n = 24) and validation (n = 18) groups. The relationship between AUCss,24h and PB plasma concentration at each time point in modeling group was analyzed using limited sampling strategy and a PK method based on one-compartment with correction model. RESULTS: C6 scheme was found to provide the most accurate prediction of AUCss,24h values (r2 = 0.984) with the target value of 1.9-4.2 µg/ml at steady state to reach the 50-100 µg h/ml criteria of AUCss,24h. C0 with target value of 1.0-2.8 µg/ml can be considered an alternative sampling scheme (r2 = 0.900) but prediction deviation may exist. C0 and Cmax sampling scheme also demonstrated good predicting ability of AUC values using PK model. CONCLUSION: This study provides a clear plan for the implementation of TDM of PB, which is useful for optimizing the dosing regimen and individualizing treatment in severe pneumonia patients.

Population Pharmacokinetics of Caspofungin among Extracorporeal Membrane Oxygenation Patients during the Postoperative Period of Lung Transplantation.

Little is known about the influence of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of caspofungin. The aim of this study was to describe population PK of caspofungin in patients with and without ECMO during the postoperative period of lung transplantation (LTx) and to investigate covariates influencing caspofungin PK. We compared ECMO patients with non-ECMO patients, and patients before and after ECMO weaning as self-controls, to analyzed changes in caspofungin PK. Eight serial blood samples were collected from each patient for PK analysis. The population PK of caspofungin was described using nonlinear mixed-effects modeling. Twelve ECMO and 7 non-ECMO lung transplant recipients were enrolled in this study. None of the patients received renal replacement therapy during any part of the study period. The PK of caspofungin was best described by a two-compartment model. There were no significant differences in the PK parameters and concentrations of caspofungin among the ECMO, non-ECMO, and self-control group. In the final covariate model, we found that there was a significant association between the male gender and increased distribution volume, that a higher sequential organ failure assessment score was related to an increase in intercompartmental clearance, and that a longer operative time was related to an increase in clearance and the volume of distribution. ECMO did not have a significant impact on the PK of caspofungin in patients after LTx. Some factors were identified as statistically significant covariates related to the PK of caspofungin; however, their impact on clinical practice of caspofungin needs to be investigated further in more studies. (This study has been registered at ClinicalTrials.gov under identifier NCT03766282.).

Influence of venovenous extracorporeal membrane oxygenation on pharmacokinetics of vancomycin in lung transplant recipients.

WHAT IS KNOWN AND OBJECTIVE: The influence of venovenous extracorporeal membrane oxygenation (VV-ECMO) on the population pharmacokinetics (PPK) of vancomycin in recipients after lung transplantation (LTx) is unknown. We investigated whether VV-ECMO influences vancomycin PPK and determined optimal recommended dosage for patients after LTx. METHODS: We tested vancomycin serum concentration and calculated PPK parameters using NONMEM. To check for any potential influence of ECMO on vancomycin PK, we compared ECMO patients with a non-ECMO patient control group, and patients before and after ECMO weaning as self-control to analysed changes in vancomycin PK. Monte Carlo dosing simulation was conducted to explore vancomycin dosing regimens. RESULTS: Nineteen ECMO and 6 non-ECMO lung transplant recipients were enrolled. Vancomycin serum concentrations did not significantly differ between patients with and without ECMO support. Comparison of separate vancomycin population pharmacokinetic models showed that ECMO patients had smaller peripheral compartment volume of distribution (V2 ) [Estimate (relative standard error, RSE, %) 19.7 (12) vs. 22 (17) L, P = .003] than non-ECMO patients. For treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections with MIC ≤ 0.5 µg/mL, venous infusion of 400 mg vancomycin every 8 hours was recommended. For MRSA infection with MIC ≤ 1 µg/mL, the proposed dosage was 600 mg every 8 hours. WHAT IS NEW AND CONCLUSION: Venovenous extracorporeal membrane oxygenation slightly alters vancomycin PK but does not significantly impact vancomycin serum concentration in patients after LTx. Dose adjustment is not necessary for VV-ECMO support. Specific vancomycin dosing regimens with lower nephrotoxicity may benefit LTx recipients with VV-ECMO.

Early bedside detection of pulmonary perfusion defect by electrical impedance tomography after pulmonary endarterectomy.

Pulmonary endarterectomy (PEA) is the standard treatment for chronic thromboembolic pulmonary hypertension. However, it poses risks of perioperative vascular complications, which can lead to serious clinical outcomes. This study introduces a novel noninvasive and radiation-free clinical imaging tool, electrical impedance tomography (EIT), for real-time bedside assessment of lung perfusion after PEA. It identifies ventilation-perfusion mismatches arising from postoperative complications, particularly valuable for patients with hemodynamic instability, thus eliminating risks tied to CT room transfers. The article reports a case where EIT was used to identify an in-situ thrombosis post-PEA, marking the first such application. The emphasis is on early detection using EIT, which offers a promising approach for therapeutic interventions and improved postoperative evaluations.

Micafungin exerts antitumor effect on breast cancer and osteosarcoma through preventing EMT in tumor cells in an USP7/AKT/GSK-3ß pathway-dependent manner.

Breast cancer and osteosarcoma are common cancers in women and children, respectively, but ideal drugs for treating patients with breast cancer or osteosarcoma remain to be found. Micafungin is an antifungal drug with antitumor activity on leukemia. Based on the notion of drug repurposing, this study aims to evaluate the antitumor effects of micafungin on breast cancer and osteosarcoma in vitro and in vivo, and to elucidate the underlying mechanisms. Five breast cancer cell lines (MDA-MB-231, BT-549, SK-BR-3, MCF-7, and 4T1) and one osteosarcoma cell line (143B) were chosen for the in vitro studies. Micafungin exerted an inhibitory effect on the viability of all cell lines, and MCF-7 cells were most sensitive to micafungin among the breast cancer cell lines. In addition, micafungin showed an inhibitory effect on the proliferation, clone formation, and migration in MCF7 and 143B cells. The inhibitory effect of micafungin on the growth of breast cancer and osteosarcoma was further confirmed with xenograft tumor mouse models. To explore the underlying mechanisms, the effect of micafungin on epithelial-mesenchymal transition (EMT) was examined. As expected, the levels of matrix metalloproteinase 9 and vimentin in MCF-7 and 143B cells were notably reduced in the presence of micafungin, concomitant with the decreased levels of ubiquitin-specific protease 7 (USP7), p-AKT, and p-GSK-3ß. Based on these observations, we conclude that micafungin exerts antitumor effect on breast cancer and osteosarcoma through preventing EMT in an USP7/AKT/GSK-3ß pathway-dependent manner.

Clinical outcomes and safety of intravenous polymyxin B-based treatment in critically ill patients with carbapenem-resistant Acinetobacter baumannii nosocomial pneumonia.

OBJECTIVES: Polymyxin B (PMB)-based therapy is one of the most important treatments for patients with nosocomial pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB). However, the optimal PMB-based combination regimen has not been well documented. METHODS: In this retrospective study, 111 critically ill patients in the intensive care unit with CRAB nosocomial pneumonia who received intravenous PMB-based therapy between 1 January 2018 and 1 June 2022 were included. The primary outcome was all-cause mortality within 28 days. Cox proportional hazards regression was used to explore risk factors for mortality in the enrolled patients treated with PMB-based regimens and the three most frequent combination regimens. RESULTS: PMB + sulbactam (SB) regimen was significantly associated with a decreased risk of mortality (aHR = 0.10, 95% CI 0.03-0.39; P = 0.001). The proportion of low-dose PMB in PMB + SB regimen (79.2%) was higher than in PMB + carbapenem (61.9%) or tigecycline (50.0%) regimens. In contrast, PMB + carbapenem regimen significantly increased mortality (aHR = 3.27, 95% CI 1.47-7.27; P = 0.004). Although the proportion of high-dose PMB in PMB + tigecycline (17.9%) was higher than in the other two regimens, mortality remained highest (42.9%) and serum creatinine increased significantly. CONCLUSIONS: PMB in combination with SB may be a promising treatment option for patients with CRAB-induced nosocomial pneumonia, as mortality was significantly reduced with low-dose PMB and no increased risk of nephrotoxicity was observed.

Effectiveness, nephrotoxicity, and therapeutic drug monitoring of polymyxin B in nosocomial pneumonia among critically ill patients.

OBJECTIVES: We aimed to assess the effectiveness and nephrotoxicity of polymyxin B in critically ill patients with nosocomial pneumonia and to evaluate the utility of its therapeutic drug monitoring (TDM). METHODS: We retrospectively analyzed patients who received polymyxin B treatment for ≥48 h since the establishment of polymyxin B TDM in a 26-bed tertiary referral intensive care unit. Univariate and multivariate analyses were conducted to assess the variables associated with polymyxin B effectiveness and nephrotoxicity. RESULTS: A total of 62 patients were enrolled. Most (56.5%) of the patients performed TDM, 54.3% of them reached the therapeutic target of area under curve across 24 h at steady state (AUCss,24h ) of 50-100 mg h L-1 , and 10 patients had an AUCss,24h value of <50 mg h L-1 . Thirty-six (58.1) and 31 (50.0%) patients had favorable clinical and microbiological responses, respectively. Reaching the therapeutic target of AUCss,24h (odds ratio [OR] = 13.15, p = 0.015), a favorable microbiological response (OR = 40.80, p = 0.00), and complicated with septic shock (OR = 0.12, p = 0.021) were independently associated with favorable clinical outcomes of polymyxin B treatment. The incidence of acute kidney injury (AKI) was 45.2%. A lower creatinine clearance (OR = 0.96, p = 0.008) and concomitant treatment with loop diuretics (OR = 5.93, p = 0.046) were predictive of nephrotoxicity. CONCLUSION: Our findings show that TDM of polymyxin B is a valuable intervention, and the achievement of its optimal pharmacodynamic target can improve treatment outcome. Renal insufficiency and concomitant treatment with loop diuretics were found to be associated with the risk of nephrotoxicity.

[Risk factors and diagnostic methods of intensive care unit-acquired weakness].

OBJECTIVE: To explore the risk factors of intensive care unit-acquired weakness (ICU-AW) and the characteristics of Medical Research Council (MRC) score and electromyogram. METHODS: A case control study was conducted. Patients with mechanical ventilation ≥ 7 days and MRC score admitted to department of respiratory and critical care medicine of China-Japan Friendship Hospital from September 2018 to January 2020 were enrolled, and they were divided into ICU-AW group (MRC score < 48) and non-ICU-AW group (MRC score ≥ 48) according to MRC score. The general situation, past medical history, related risk factors, MRC score, respiratory support mode, laboratory examination results, electromyogram examination results, ICU-AW related treatment, outcome and length of ICU stay were collected, and the differences between the two groups were compared. The risk factors of ICU-AW were analyzed by binary multivariate Logistic regression, and the characteristics of MRC score and electromyogram were analyzed. RESULTS: A total of 60 patients were enrolled in the analysis, including 17 patients in ICU-AW group and 43 patients in non-ICU-AW group. Univariate analysis showed that there were significant differences in acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, brain natriuretic peptide (BNP), blood urea nitrogen (BUN) on the first day of ICU admission and the ratio of invasive mechanical ventilation between ICU-AW group and non-ICU-AW group [APACHE II score: 21 (18, 25) vs. 18 (15, 22), SOFA score: 7 (5, 12) vs. 5 (3, 8), BNP (ng/L): 364.3 (210.1, 551.2) vs. 160.1 (66.8, 357.8), BUN (mmol/L): 9.9 (6.2, 17.0) vs. 6.0 (4.8, 9.8), invasive mechanical ventilation ratio: 88.2% vs. 46.5%, all P < 0.05]. Binary multivariate Logistic regression analysis showed no independent risk factor for ICU-AW. The average MRC score of 17 ICU-AW patients was 33±11. The limb weakness was symmetrical, and the proximal limb weakness was the main manifestation. Electromyography examination showed that the results of nerve conduction examination in ICU-AW patients mainly revealed that the amplitude of compound muscle action potential (CMAP) and sensory nerve action potentials (SNAP) were decreased, and the conduction velocity was slowed down; needle electromyography showed increased area of motor unit potential (MUP), prolonged time limit and a large number of spontaneous potentials. Prognosis evaluation showed that compared with non-ICU-AW group, patients in ICU-AW group underwent more tracheotomy (70.6% vs. 11.6%), longer length of ICU stay (days: 57±52 vs. 16±8), and more rehabilitation treatment (58.8% vs. 14.0%), and the differences were statistically significant (all P < 0.01). CONCLUSIONS: The occurrence of ICU-AW may be related to high APACHE II score and SOFA score, high levels of BNP and BUN on the first day of ICU admission and the proportion of invasive mechanical ventilation, but the above factors are not independent risk factors for ICU-AW. The MRC score of ICU-AW patients was characterized by symmetrical limb weakness, mainly proximal limb weakness; in electromyography examination, the nerve conduction examination results mainly showed that CMAP and SNAP amplitude were decreased, and conduction velocity was slowed down; needle electromyography examination showed increased MUP area, prolonged duration and a large number of spontaneous potentials.

The Availability and Safety Study of Remimazolam Besylate for Injection on Sedation of ERAS Patients Under Mechanical Ventilation in ICU: Protocol for a Randomized, Open-Label, Controlled Trial.

Introduction: The most common physiological and psychological disorders associated with critical care patients are pain and anxiety. Sedatives and analgesics are commonly used to relieve these symptoms. However, the adverse effects of sedatives and analgesics are common and inevitable. As a new type of sedative drug, limited number of trials are available to evaluate Remimazolam Besylate's availability and safety compared with propofol. Methods: This study is a single center, randomized, open-label, controlled trial. A total of 84 patients who meet ERAS criteria and receive mechanical ventilation in ICU, aged ≥18 years old will be included. Patients will be randomized (1:1) into two groups: Remimazolam Besylate group and Propofol group. The Primary outcomes includes satisfaction rate of sedation and incidence rate of major clinical events. Secondary outcomes including incidence of delirium, time to weaning and extubation, Difficulty of nursing RASS, BIS and PI, 28-days survival, side-effect and vital signs during medications, total dose and dose per kilogram body weight of analgesic and sedatives and incidence of rescue therapy in experimental group. Ethics and Dissemination: This trial has been approved by the ethics boards of Peking Union Medical College Hospital. Recruitment began in January 2022 and will continue until June 2022. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04947345.

[Pharmacokinetics changes of antimicrobial agents in adult patients receiving extracorporeal membrane oxygenation: an updated literature review].

Extracorporeal membrane oxygenation (ECMO) is a viable ultimate support therapy for patients with severe cardiorespiratory failure. Antimicrobial agents are commonly prescribed in critically ill patients with ECMO. However, an increasing number of studies have shown that ECMO circuit is associated with significant pharmacokinetic (PK) alterations, including the increased volume of distribution and reduced the clearance. In addition, the critical illness pathophysiology can also influence PK of antimicrobial, such as systemic inflammation, excessive fluid resuscitation, hypo-albuminemia, worsening hepatic or renal function. These PK alterations may increase the possibility of therapeutic failure or toxicity. Therefore, this study reviews published studies of the effects of ECMO on PK of antimicrobial agents in adults and makes preliminary recommendations on possible dosing regimen.