Pharmacokinetic Research in Pediatric Extracorporeal Therapies: Current State and Future Directions.

Extracorporeal life support (ECLS), including extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), are life-saving therapies for critically ill children. Despite this, these modalities carry frustratingly high mortality rates. One driver of mortality may be altered drug disposition due to a combination of underlying illness, patient-circuit interactions, and drug-circuit interactions. Children receiving ECMO and/or CRRT routinely receive 20 or more drugs, and data supporting optimal dosing is lacking for most of these medications. The Pediatric Paracorporeal and Extracorporeal Therapies Summit (PPETS) gathered an international group of experts in the fields of ECMO, CRRT, and other ECLS modalities to discuss the current state of these therapies, disseminate innovative support strategies, share clinical experiences, and foster future collaborations. Here, we summarize the conclusions of PPETS and put forward a pathway to optimize pharmacokinetic (PK) research in this population. We must prioritize specific medications for in-depth study to improve drug use in ECLS and patient outcomes. Based on frequency of use, potential for adverse outcomes if dosed inappropriately, and lack of existing PK data, a list of high priority drugs was compiled for future research. Researchers must additionally reconsider study designs, emphasizing pooling of resources through multi-center studies and the use of innovative PK modeling techniques. Finally, the integration of validated PK models into clinical practice must be streamlined to deliver optimal medication use at the bedside. Focusing on the proposed list of highlighted medications and key methodological considerations will maximize the impact of future research.

The Association Between Vasopressin and Adverse Kidney Outcomes in Children and Young Adults Requiring Vasopressors on Continuous Renal Replacement Therapy.

OBJECTIVES: Continuous renal replacement therapy (CRRT) and shock are both associated with high morbidity and mortality in the ICU. Adult data suggest renoprotective effects of vasopressin vs. catecholamines (norepinephrine and epinephrine). We aimed to determine whether vasopressin use during CRRT was associated with improved kidney outcomes in children and young adults. DESIGN: Secondary analysis of Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK), a multicenter, retrospective cohort study. SETTING: Neonatal, cardiac, PICUs at 34 centers internationally from January 1, 2015, to December 31, 2021. PATIENTS/SUBJECTS: Patients younger than 25 years receiving CRRT for acute kidney injury and/or fluid overload and requiring vasopressors. Patients receiving vasopressin were compared with patients receiving only norepinephrine/epinephrine. The impact of timing of vasopressin relative to CRRT start was assessed by categorizing patients as: early (on or before day 0), intermediate (days 1-2), and late (days 3-7). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1016 patients, 665 (65%) required vasopressors in the first week of CRRT. Of 665, 248 (37%) received vasopressin, 473 (71%) experienced Major Adverse Kidney Events at 90 days (MAKE-90) (death, renal replacement therapy dependence, and/or > 125% increase in serum creatinine from baseline 90 days from CRRT initiation), and 195 (29%) liberated from CRRT on the first attempt within 28 days. Receipt of vasopressin was associated with higher odds of MAKE-90 (adjusted odds ratio [aOR], 1.80; 95% CI, 1.20-2.71; p = 0.005) but not liberation success. In the vasopressin group, intermediate/late initiation was associated with higher odds of MAKE-90 (aOR, 2.67; 95% CI, 1.17-6.11; p = 0.02) compared with early initiation. CONCLUSIONS: Nearly two-thirds of children and young adults receiving CRRT required vasopressors, including over one-third who received vasopressin. Receipt of vasopressin was associated with more MAKE-90, although earlier initiation in those who received it appears beneficial. Prospective studies are needed to understand the appropriate timing, dose, and subpopulation for use of vasopressin.

Comparison of side-hole and step-tip catheters for patients requiring continuous renal replacement therapy in intensive care units: study protocol for a randomised controlled trial.

INTRODUCTION: In addition to various techniques involved in catheter insertion, catheter placement location, lumen diameter and operation and management during continuous renal replacement therapy (CRRT), the design of the tip and side holes, as well as the position of the tip of the catheter, can also impact catheter function. Side-hole and step-tip catheters are commonly used during CRRT. However, there is insufficient evidence comparing their efficacy for CRRT in critically ill patients. And the optimal position of the tip of catheters is not well studied and remains controversial. This study was conducted to assess whether using a step-tip catheter could reduce the rate of catheter dysfunction compared with a side-hole catheter and whether inserting a longer catheter could reduce the incidence of catheter dysfunction and increase catheter survival time. METHODS AND ANALYSIS: A prospective, open-label, three-arm, parallel-group, single-centre randomised controlled trial will be conducted at West China Hospital of Sichuan University in China. An estimated sample of 378 participants receiving CRRT treatment will be recruited. Eligible patients will be randomly assigned to three groups to receive different dialysis catheters for the initiation of CRRT at a 1:1:1 ratio via a central randomisation system: group A, side-hole catheters (11Fr, 200 mm; GDHK-1120; Baxter International Inc., Deerfield, Illinois); group B, step-tip catheters (13Fr, 200 mm; GDHK-1320; Baxter International Inc.) and group C, step-tip catheters (13Fr, 250 mm; GDHK-1325; Baxter International Inc.). The femoral vein is the only vascular access. All catheters will be inserted under the guidance of ultrasound using the Seldinger method to reduce complications and trauma related to catheter insertion. The primary outcomes are the occurrence of catheter dysfunction and catheter survival time. Outcome assessors and data analysts will be blinded. All data will be analysed according to the group randomly assigned by an intention-to-treat analysis, in which catheters with missing data for the primary outcomes would be excluded. ETHICS AND DISSEMINATION: The trial protocol has been approved by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University (2023.1221). And the results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2300075107.

Physiologically Based Pharmacokinetic Modelling in Critically Ill Children Receiving Anakinra While on Extracorporeal Life Support.

BACKGROUND AND OBJECTIVE: Because of the pathophysiological changes associated with critical illness and the use of extracorporeal life support (ECLS) such as continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO), the pharmacokinetics of drugs are often altered. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for anakinra in children that accounts for the physiological changes associated with critical illness and ECLS technology to guide appropriate pharmacotherapy. METHODS: A PBPK model for anakinra was first developed in healthy individuals prior to extrapolating to critically ill children receiving ECLS. To account for the impact of anakinra clearance by the dialysis circuit, a CRRT compartment was added to the pediatric PBPK model and parameterized using data from a previously published ex-vivo study. Additionally, an ECMO compartment was added to the whole-body structure to create the final anakinra ECLS-PBPK model. The final model structure was validated by comparing predicted concentrations with observed patient data. Due to limited information in guiding anakinra dosing in this population, in-silico dose simulations were conducted to provide baseline recommendations. RESULTS: By accounting for changes in physiology and the addition of ECLS compartments, the final ECLS-PBPK model predicted the observed plasma concentrations in an adolescent receiving subcutaneous anakinra. Furthermore, dosing simulations suggest that anakinra exposure in adolescents receiving ECLS is similar to that in healthy counterparts. CONCLUSION: The anakinra ECLS-PBPK model developed in this study is the first to predict plasma concentrations in a population receiving simultaneous CRRT and ECMO. Dosing simulations provided may be used to inform anakinra use in critically ill children and guide future clinical trial planning.

How do filter types of renal replacement therapy affect survival in critically ill patients? Concerns about adsorption of nafamostat mesylate on AN69 membranes.

We are writing to you in response to the article published in BMC Nephrology titled "Dose of nafamostat mesylate during continuous kidney replacement therapy in critically ill patients: a two-centre observational study". The study provided valuable information on the use of nafamostat mesylate (NM) during continuous renal replacement therapy (CRRT) in critically ill patients. We noticed in this study that a higher dose of NM resulted in a decrease in ICU and hospital mortality. However, the underlying mechanism behind this phenomenon remains unclear. We believe exploring this further is warranted.

A hypothesis on treatment strategy of severe multicentric Castleman disease with continuous renal replacement therapy.

Castleman disease (CD) is a rare lymphoproliferative disorder, with non-specific clinical manifestations, often delayed diagnosis and treatment, which pose a significant challenge in the present times. Patients diagnosed with this disease have poor prognosis due to the limited treatment options. Multicentric CD occurs at multiple lymph node stations and is associated with a proinflammatory response that leads to the development of the so-called 'B symptoms'. IL-6 seems to be a key cytokine involved in various manifestations such as lymphadenopathies, hepatosplenomegaly, and polyclonal hypergammaglobulinemia. Its levels correlate with the activity of the disease. Other consequences of MCD include increased fibrinogen levels leading to deep vein thrombosis and thromboembolic disorders, high hepcidin levels causing anaemia, elevated VEGF levels promoting angiogenesis and vascular permeability, which, along with hypoalbuminemia, induce oedema, ascites, pleural and pericardial effusions, and in severe cases, generalized anasarca. In extreme cases multiple organ failure can occur, often resulting in death. We propose the use of continuous renal replacement therapy (CRRT) in managing severe multicentric CD. Our arguments are based on the principles that CRRT is able to remove IL-6 from circulation thus attenuating the cytokine storm, can influence hepcidin levels, and reduction in oedema, and is often used in multiple organ failure to regain homeostasis control. Therefore, it could be used as a therapy or bridge therapy in severe cases. To sustain our hypothesis with evidence, we have gathered several studies from the literature confirming the successful removal of cytokines, especially IL-6 from circulation, which can be used as a starting point.

Effectiveness and feasibility of continuous renal replacement therapy for acute kidney injury in neonates weighing 3 kg or less: a two-centre, retrospective study.

BACKGROUND: Continuous renal replacement therapy (CRRT) is commonly used for the treatment of acute kidney injury (AKI) in critically ill neonates. This study investigated the effectiveness and feasibility of CRRT for AKI in neonates who weigh ≤3 kg. METHODS: Data from 19 neonates with a weight ≤3 kg and AKI who underwent CRRT at two centres between January 2015 and October 2021 were collected retrospectively. Kidney function, circulatory function, complications and clinical outcomes were recorded. Repeated-measures analyses of variance, t-tests and non-parametric tests were conducted. RESULTS: The median patient age at CRRT initiation was 3 days (IQR: 1-7 days). The median patient weight at CRRT initiation was 2.67 kg (IQR: 2.20-2.85 kg). The median CCRT duration was 46 hours (IQR: 32-72 hours). The serum creatinine and blood urea nitrogen levels decreased significantly, and the mean arterial pressure increased significantly after 12 hours of CRRT and at the end of CRRT. The urinary output was significantly increased at the end of CRRT. 11 patients had thrombocytopaenia, 6 had electrolyte disorders and 3 had blocked tubes. Five patients were discharged, six died after their parents chose to discontinue treatment and eight died after active treatment. Weight at CRRT initiation and urinary output at the end of CRRT were significantly lower among patients who died than among patients who survived. CONCLUSIONS: CRRT is feasible and effective for AKI in neonates who weigh ≤3 kg when accompanied by elaborate supportive care. Lower body weight and persistent oliguria may be correlated with an increased risk of poor clinical outcomes.

Characteristics of initiation timing and anticoagulation of continuous renal replacement therapy in patients following cardiac surgery: A retrospective analysis of 28 patients.

Continuous renal replacement therapy (CRRT) used in cardiac surgery-associated acute kidney injury (CSA-AKI) may have different characteristics from other diseases. We reviewed the medical records of patients with CSA-AKI requiring CRRT who underwent cardiac surgery from January 2020 to September 2021. Patients with AKI caused by other reasons who received CRRT during the same period were also evaluated. A total of 28 patients with CSA-AKI and 12 patients with AKI caused by other reasons were enrolled in this study. Compared with AKI patients caused by other reasons, patients with CSA-AKI were found to have lower mean arterial pressure, higher level of bilirubin, higher vasoactive-inotropic score, and larger daily diuretic dosage. The patients with CSA-AKI were prescribed CRRT earlier than the patients with AKI caused by other reasons. There was a significant difference in the CRRT anticoagulation method between patients with CSA-AKI and patients with AKI caused by other reasons. Six patients with CSA-AKI were treated with regional citrate anticoagulation (RCA), and the other 22 patients were treated with low molecular weight heparin or without anticoagulants. The timing of CRRT initiation in patients with CSA-AKI is earlier than that in patients with AKI caused by other reasons. Although RCA is recommended as the preferred anticoagulant for patients without contraindications, patients with CSA-AKI often have circulatory dysfunction and severe liver damage, so the risk of citrate accumulation is greater, whether to use RCA should be determined according to the individual condition of the patient.

Transfer learning-enabled outcome prediction for guiding CRRT treatment of the pediatric patients with sepsis.

Continuous renal replacement therapy (CRRT) is a life-saving procedure for sepsis but the benefit of CRRT varies and prediction of clinical outcomes is valuable in efficient treatment planning. This study aimed to use machine learning (ML) models trained using MIMIC III data for identifying sepsis patients who would benefit from CRRT. We first selected patients with sepsis and CRRT in the ICU setting and their gender, and an array of routine lab results were included as features to train machine learning models using 30-day mortality as the primary outcome. A total of 4161 patients were included for analysis, among whom there were 1342 deaths within 30 days. Without data augmentation, extreme gradient boosting (XGBoost) showed an accuracy of 64.2% with AUC-ROC of 0.61. Data augmentation using a conditional generative adversarial neural network (c-GAN) resulted in a significantly improved accuracy (82%) and ROC-AUC (0.78%). To enable prediction on pediatric patients, we adopted transfer learning approaches, where the weights of all but the last hidden layer were fixed, followed by fine-tuning of the weights of the last hidden layer using pediatric data of 200 patients as the inputs. A significant improvement was observed using the transfer learning approach (AUCROC = 0.76) compared to direct training on the pediatric cohort (AUCROC = 0.62). Through this transfer-learning-facilitated patient outcome prediction, our study showed that ML can aid in clinical decision-making by predicting patient responses to CRRT for managing pediatric sepsis.

Impact of increasing post-filter ionised calcium target on regional citrate anticoagulation efficacy in ICU continuous renal replacement therapy: the non-inferiority randomised controlled Ca-CIBLE protocol.

INTRODUCTION: Continuous renal replacement therapy (CRRT) is a critical therapeutic intervention for patients with severe acute kidney injury in intensive care. However, premature filter clotting remains a significant challenge during CRRT, impacting treatment efficacy, costs and patient outcomes. Anticoagulation is essential to maintain circuit patency, with regional citrate anticoagulation (RCA) emerging as a preferred strategy due to its favourable bleeding profile. The standard target for post-filter ionised calcium (iCa) concentration during RCA-CRRT is set between 0.25 and 0.35 mmol/L, although evidence supporting this range is limited. We hypothesise that a higher post-filter iCa target (0.35-0.45 mmol/L) can provide comparable circuit patency while potentially reducing adverse effects associated with citrate administration. METHODS AND ANALYSIS: This multicentre randomised controlled non-inferiority trial will compare a low post-filter iCa target (0.25-0.35 mmol/L) with a higher post-filter iCa target (0.35-0.45 mmol/L) in patients undergoing RCA-CRRT in the intensive care unit. A total of 412 CRRT sessions will be randomised with a 1:1 ratio into these two groups. The primary outcome is the incidence of filter clotting. Secondary outcomes include filter lifespan, post-filter iCa levels, citrate infusion rates, the occurrence of metabolic adverse effects, financial costs and blood loss. ETHICS AND DISSEMINATION: The study has obtained approval from the ethics committee (Ethics Committee Est III, Nancy, France) and patients will be included after providing informed consent. The results will be disseminated at academic conferences and in peer-reviewed publications. All procedures were developed in order to assure data protection and confidentiality. TRIAL REGISTRATION NUMBER: NCT05814341.

Risk factors associated with hospital mortality in non-surgical patients receiving extracorporeal membrane oxygenation and continuous renal replacement treatment: a retrospective analysis.

OBJECTIVES: The prognosis-predicting factors for non-surgical patients receiving continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) remains limited. In this study, we aim to analyze prognosis-predicting factors in the non-surgical patients receiving these two therapies. METHODS: We retrospectively analyzed data from non-surgical patients with ECMO treatment from December 2013 until April 2023. Hospital mortality was primary endpoint of this study. The area under the curve and receiver operating characteristic curves were used to assess the sensitivity and specificity of mortality. The independent risk factors were identified by multivariate logistic regression. The prediction model was a nomogram, and decision curve analysis and the calibration plot were used to assess it. Using restricted cubic spline curves and Spearman correlation, the correlation analysis was performed. RESULTS: The model that incorporated CRRT duration and age surpassed the two variables alone in predicting hospital mortality in non-surgical patients with ECMO therapy (AUC value = 0.868, 95% CI = 0.779-0.956). Older age, CRRT implantation, and duration were independent risk factors for hospital mortality (all p < 0.05). The nomogram predicting outcomes model containing on CRRT implantation and duration was developed, and the consistency between the predicted probability and observed probability and clinical utility of the models were good. CRRT duration was negatively associated with hemoglobin concentration and positively associated with urea nitrogen and serum creatinine levels. CONCLUSION: Hospital mortality in non-surgical ECMO patients was found to be independently associated with older age, longer CRRT duration, and CRRT implantation.

Estimation of renal function immediately after cessation of continuous renal replacement therapy at the ICU.

Estimating glomerular filtration (eGFR) after Continuous Renal Replacement Therapy (CRRT) is important to guide drug dosing and to assess the need to re-initiate CRRT. Standard eGFR equations cannot be applied as these patients neither have steady-state serum creatinine concentration nor average muscle mass. In this study we evaluate the combination of dynamic renal function with CT-scan based correction for aberrant muscle mass to estimate renal function immediately after CRRT cessation. We prospectively included 31 patients admitted to an academic intensive care unit (ICU) with a total of 37 CRRT cessations and measured serum creatinine before cessation (T1), directly (T2) and 5 h (T3) after cessation and the following two days when eGFR stabilized (T4, T5). We used the dynamic creatinine clearance calculation (D3C) equation to calculate eGFR (D3CGFR) and creatinine clearance (D3Ccreat) between T2-T3. D3Ccreat was corrected for aberrant muscle mass when a CT-scan was available using the CRAFT equation. We compared D3CGFR to stabilized CKD-EPI at T5 and D3CCreat to 4-h urinary creatinine clearance (4-h uCrCl) between T2-T3. We retrospectively validated these results in a larger retrospective cohort (NICE database; 1856 patients, 2064 cessations). The D3CGFR was comparable to observed stabilized CKD-EPI at T5 in the prospective cohort (MPE = - 1.6 ml/min/1.73 m2, p30 = 76%) and in the retrospective NICE-database (MPE = 3.2 ml/min/1.73 m2, p30 = 80%). In the prospective cohort, the D3CCreat had poor accuracy compared to 4-h uCrCl (MPE = 17 ml/min/1.73 m2, p30 = 24%). In a subset of patients (n = 13) where CT-scans were available, combination of CRAFT and D3CCreat improved bias and accuracy (MPE = 8 ml/min/1.73 m2, RMSE = 18 ml/min/1.73 m2) versus D3CCreat alone (MPE = 18 ml/min/1.73 m2, RMSE = 32 ml/min/1.73 m2). The D3CGFR improves assessment of eGFR in ICU patients immediately after CRRT cessation. Although the D3CCreat had poor association with underlying creatinine clearance, inclusion of CT derived biometric parameters in the dynamic renal function algorithm further improved the performance, stressing the role of muscle mass integration into renal function equations in critically ill patients.

COMPARISON OF OXIRIS AND CONVENTIONAL CONTINUOUS RENAL REPLACEMENT THERAPY IN MANAGING SEVERE ABDOMINAL INFECTIONS: IMPACT ON SEPTIC SHOCK MORTALITY.

ABSTRACT: Objective: The objective of this study is to assess and compare the efficacy of oXiris with conventional continuous renal replacement therapy (CRRT) in managing severe abdominal infections. Methods: A retrospective analysis encompassing cases from 2017 to 2023 was conducted at the Department of Critical Care Medicine within the First Affiliated Hospital of Fujian Medical University. Parameters including heart rate (HR), mean arterial pressure (MAP), oxygenation index, lactate (Lac), platelet count, neutrophil ratio, procalcitonin, C-reactive protein (CRP), interleukin 6 (IL-6), norepinephrine dosage, Acute Physiology and Chronic Health Evaluation II (APACHE II), and Sequential Organ Failure Assessment (SOFA) were recorded prior to treatment initiation, at 24 h, and 72 h after treatment for both the oXiris and conventional CRRT groups. In addition, the duration of respiratory support, CRRT treatment, length of stay in the intensive care unit (ICU), total hospitalization period, and mortality rates at 14 and 28 days for both groups were recorded. Results: 1) Within the conventional CRRT group, notable enhancement was observed solely in Lac levels at 24 h after treatment compared with pretreatment levels. In addition, at 72 h after treatment, improvements were evident in HR, Lac, CRP, and IL-6 levels. 2) Conversely, the oXiris group exhibited improvements in HR, MAP, Lac, oxygenation index, neutrophil ratio, and IL-6 at 24 h after treatment when compared with baseline values. In addition, reductions were observed in APACHE II and SOFA scores. At 72 h after treatment, all parameters demonstrated enhancement except for platelet count. 3) Analysis of the changes in the indexes (Δ) between the two groups at 24 h after treatment revealed variances in HR, MAP, Lac, norepinephrine dosage, CRP levels, IL-6 levels, APACHE II scores, and SOFA scores. 4) The Δ indexes at 72 h after treatment indicated more significant improvements following oXiris treatment for both groups, except for procalcitonin. 5) The 14-day mortality rate (24.4%) exhibited a significant reduction in the oXiris group when compared with the conventional group (43.6%). However, no significant difference was observed in the 28-day mortality rate between the two groups. 6) Subsequent to multifactorial logistic regression analysis, the results indicated that oXiris treatment correlated with a noteworthy decrease in the 14-day and 28-day mortality rates associated with severe abdominal infections, by 71.3% and 67.6%, respectively. Conclusion: oXiris demonstrates clear advantages over conventional CRRT in the management of severe abdominal infections. Notably, it reduces the fatality rates, thereby establishing itself as a promising and potent therapeutic option.

Analysis of metabolic alterations as 30 days intensive care mortality predictors for patients undergoing continuous renal replacement therapy.

BACKGROUND: Acute kidney injury patients on continuous renal replacement therapy are subjected to alterations in metabolism, which in turn are associated with worse clinical outcome and mortality. The aim of this study is to determine which metabolism indicators can be used as independent predictors of 30 days intensive care unit (ICU) mortality. METHODS: This was a prospective observational study on critical care patients on renal replacement therapy. Integrated approach of metabolism evaluation was used, combining the energy expenditure measured by indirect calorimetry, bioelectrical impedance provided fat free mass index (FFMI), amino acid and glucose concentrations. ICU mortality was defined as all cause 30 days mortality. Regression analysis was conducted to determine the conventional and metabolism associated predictors of mortality. RESULTS: The study was conducted between the 2021 March and 2022 October. 60 high mortality risk patients (APACHE II of 22.98 ± 7.87, 97% on vasopressors, 100% on mechanical ventilation) were included during the period of the study. The rate of 30 days ICU mortality was 50% (n = 30). Differences across survivors and non-survivors in metabolic predictors were noted in energy expenditure (kcal/kg/day) (19.79 ± 5.55 vs 10.04 ± 3.97 p = 0.013), amino acid concentrations (mmol/L) (2.40 ± 1.06 vs 1.87 ± 0.90 p = 0.040) and glucose concentrations (mmol/L) (7.89 ± 1.90 vs 10.04 ± 3.97 p = 0.010). No differences were noted in FFMI (23.38 ± 4.25 vs 21.95 ± 3.08 p = 0.158). In the final linear regression analysis model, lower energy expenditure (exp(B) = 0.852 CI95%: 0.741-0.979 p = 0.024) and higher glucose (exp(B) = 1.360 CI95%: 1.013-1.824 p = 0.041) remained as independent predictors of the higher mortality. CONCLUSION: The results of the study imply strong association between the metabolic alterations and ICU outcome. Our findings suggest that lower systemic amino acid concentration, lower energy expenditure and higher systemic glucose concentration are predictive of 30 days ICU mortality.

The impact of extracorporeal support on antimicrobial pharmacokinetics in critically ill neonatal and paediatric patients: A systematic review.

OBJECTIVES: Infections represent a major risk for critically ill neonatal and paediatric patients requiring extracorporeal life-saving support such as extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapies (CRRT). Patient outcomes rely on achieving target antimicrobial concentrations. In critically ill adults on extracorporeal support, suboptimal antimicrobial concentrations have been shown to be common. Our objective was to systematically review antimicrobial pharmacokinetic studies in critically ill term neonatal and paediatric patients receiving ECMO and/or CRRT and compare them to similar cohorts of patients not receiving ECMO or CRRT. METHODS: Studies published between 1990 and 2022 were identified through systematic searches in PUBMED, Embase, Web of Science, Medline, Google Scholar and CINAHL. Studies were included which provided antimicrobial pharmacokinetic parameters (volume of distribution and clearance) in the neonatal and paediatric patients receiving ECMO and/or CRRT. Studies were excluded if no antimicrobial pharmacokinetic parameters were described or could be calculated. RESULTS: Forty-four pharmacokinetic studies were identified describing 737 patients, with neonatal patients recruited in 70% of the ECMO studies and <1% of the CRRT studies. Of all the studies, 50% were case reports or case series. The pharmacokinetics were altered for gentamicin, daptomycin, ceftolozane, micafungin, voriconazole, cefepime, fluconazole, piperacillin, and vancomycin, although considerable patient variability was described. CONCLUSION: Significant gaps remain in our understanding of the pharmacokinetic alterations in neonatal and paediatric patients receiving ECMO and CRRT support.

Pink urine syndrome in an anuric patient during continuous renal replacement therapy: A case report.

INTRODUCTION: Pink urine syndrome is a rare, poorly understood condition, often prompted by obesity, insulin resistance, and the drug propofol. It is characterized by pink urine or urine sediment and occurs in the absence of a heme or food-based pigment. The pathophysiology of this syndrome is not yet fully understood but is linked to a uric acid metabolism disorder. Pink urine syndrome is less familiar to anesthesiologists than other propofol infusion complications. Our case report aims to highlight this rarely encountered syndrome, whose both diagnosis and therapeutic may be challenging. We have reported the first case of this syndrome evidenced by the change in color of the effluent bag during continuous veno-venous hemofiltration (CVVHF). CASE PRESENTATION: A 61-year-old woman was admitted to the intensive care unit following a recovered cardiorespiratory arrest due to ventricular arrhythmia. She was placed in hypothermia, sedated with propofol (300 mg/h), and started on CVVHF for oligo-anuric acute kidney injury associated with severe metabolic acidosis. A few hours after initiation of CVVHF, the effluent bag turned bright pink. Given the pink color of the effluent bag and the hypothesis of propofol-induced pink urine syndrome, propofol was replaced by midazolam. After stopping propofol, the color of effluent bag lightened. Unfortunately, the patient died on the third day of hospitalization due to diffuse cerebral edema. CONCLUSIONS: We report here the first case of pink urine syndrome as revealed by the change in color of the contents of the CVVHF effluent bag in an anuric patient. This syndrome is rare but significant in anesthesia/intensive care settings, where propofol is a frequently used sedative. Knowledge of this syndrome appears to be important to avoid irrelevant additional investigations and to optimize the therapeutic strategy.

Risk factors for unplanned weaning of continuous renal replacement therapy in ICU patients: a meta-analysis.

OBJECTIVE: To systematically review the risk factors for unplanned weaning during continuous renal replacement therapy in ICU patients. METHODS: A combination of subject words + free words was used to search the relevant literature published in CNKI, Wanfang, VIP, CBM, PubMed, EMbase, Web of Science, Cochrane Library, Mediline and other databases. The search period was from the establishment of the databases to June 25, 2024. Revman 5.4 software and Stata15.0 software was used to meta-analyze the risk factors for unplanned weaning during continuous renal replacement therapy in ICU patients. RESULTS: A total of 23 studies were included in this meta-analysis, describing 15 variables, 3793 patients, and using 7197 filters. Meta-analysis results showed that risk factors for unplanned weaning during continuous renal replacement therapy in ICU patients were as follows: Low mean arterial pressure [OR = 1.02, 95%CI (1.00, 1.03), p < 0.05], hypothermia [OR = 3.40, 95%CI (1.78, 6.47), p < 0.05], age (≥60 years) [OR = 4.45, 95%CI (3.18, 6.22), p < 0.05], comorbid underlying disease [OR = 3.63, 95%CI (2.70, 4.88), p < 0.05], agitation [OR = 4.97, 95%CI (3.20, 7.74), p < 0.05], no anticoagulant use [OR = 1.65, 95%CI (1.25, 2.17), p < 0.05], short activated partial prothrombin time [OR = 1.23, 95%CI (1.13, 1.34), p < 0.05], hyper-hematocrit [OR = 1.73, 95%CI (1.13, 2.66), p = 0.01], low ionized calcium concentration [OR = 1.48, 95% CI (1.08, 2.02), p = 0.01], CRRT that was treated at a high dose [OR = 1.42, 95%CI (1.14, 1.76), p < 0.05], mechanical ventilation [OR = 4.25, 95%CI (2.67, 6.77), p < 0.05], and lack of dedicated care [OR = 5.08, 95%CI (2.51, 10.28), p < 0.05]. However, it is unclear whether platelet count, prothrombin activity, and blood flow velocity are risk factors for unplanned weaning during CRRT in ICU patients, and more studies are needed for further validation. CONCLUSION: Available evidence suggests that a variety of factors contribute to unplanned weaning of CRRT in ICU patients. Early detection of these risk factors is essential for healthcare professionals to develop preventive and curative strategies. REGISTRATION: This study is registered on the PROSERO website under registration number CRD42024543554.

Risk factors for mortality in patients receiving extracorporeal membrane oxygenation.

OBJECTIVE: Patients on extracorporeal membrane oxygenation (ECMO) are often complex and have a high mortality rate. Currently, risk assessment and treatment decisions for patients receiving ECMO are controversial. Therefore, we sought to identify risk factors for mortality in patients receiving ECMO and provide a reference for patient management. METHODS: We retrospectively analyzed the clinical data of 199 patients who received ECMO support from December 2013 to April 2023. Univariate and multivariable logistic regression analyses were used to identify risk factors. The cutoff value was determined by receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 199 patients were selected for this study, and the mortality rate was 76.38%. More than half of the patients underwent surgery during hospitalization. Multivariable logistic regression analysis revealed that continuous renal replacement therapy (CRRT) implantation (OR = 2.994; 95% CI, 1.405-6.167; p = 0.004) and age (OR = 1.021; 95% CI, 1.002-1.040; p = 0.032) were the independent risk factors for mortality. In the ROC curve analysis, age had the best predictive effect (AUC 0.646, 95% CI 0.559-0.732, p = 0.003) for death when the cutoff value was 48.5 years. Furthermore, in patients receiving combined CRRT and ECMO, lack of congenital heart disease and previous surgical history were the independent risk factors for mortality. CONCLUSIONS: CRRT implantation and age were independent risk factors for patients with ECMO implantation in a predominantly surgical cohort. In patients receiving a combination of CRRT and ECMO, lack of congenital heart disease and previous surgical history were independent risk factors for mortality.