Programs and processes for advancing pediatric acute kidney support therapy in hospitalized and critically ill children: a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference.

Pediatric acute kidney support therapy (paKST) programs aim to reliably provide safe, effective, and timely extracorporeal supportive care for acutely and critically ill pediatric patients with acute kidney injury (AKI), fluid and electrolyte derangements, and/or toxin accumulation with a goal of improving both hospital-based and lifelong outcomes. Little is known about optimal ways to configure paKST teams and programs, pediatric-specific aspects of delivering high-quality paKST, strategies for transitioning from acute continuous modes of paKST to facilitate rehabilitation, or providing effective short- and long-term follow-up. As part of the 26th Acute Disease Quality Initiative Conference, the first to focus on a pediatric population, we summarize here the current state of knowledge in paKST programs and technology, identify key knowledge gaps in the field, and propose a framework for current best practices and future research in paKST.

Continuous infusion of cefiderocol in a critically ill patient with continuous venovenous haemofiltration.

Cefiderocol is a broad-spectrum cephalosporin antibiotic and is indicated in patients with difficult-to-treat Gram-negative bacterial infections. Cefiderocol is applied as a 2-4-times daily prolonged 3-h infusion. The therapeutic target of cefiderocol suggests that continuous infusion (CI) may be advantageous, since it is more likely to achieve 100% of time of the unbound concentration above the minimal inhibitory concentration (MIC). However, limited information on cefiderocol as CI has been assessed. We present a case of a critically ill 37-year-old woman with continuous venovenous haemofiltration (CVVH) treated with a CI of cefiderocol for multidrug-resistant Pseudomonas aeruginosa. She received 4 g per 24 h, in accordance with the recommendations for the total daily dose during CVVH with an effluent flow rate of 2.1-3 L/h. We evaluated intraperitoneal, plasma arterial pre- and postfilter and ultrafiltrate (urine) total cefiderocol concentrations and discussed the pharmacokinetics in respect to the CVVH settings. The predicted unbound plasma concentrations during CI resulted in 6.8-9.5-fold higher concentrations than the adopted MIC of 2 mg/L for cefiderocol against P. aeruginosa. The optimal time of the unbound concentration >MIC target of cefiderocol was met during the sampling period, suggesting adequate exposure during the total treatment period. The obtained intraperitoneal concentration indicated adequate cefiderocol exposure at the site of infection. Continuous infusion of 4 g cefiderocol per 24 h led to sufficient plasma concentrations in our anuric critically ill patient treated with CVVH. This case is supportive to the use of cefiderocol as continuous infusion.

Negative calcium balance despite normal plasma ionized calcium concentrations during citrate anticoagulated continuous venovenous hemofiltration (CVVH) in ICU patients.

BACKGROUND: Supplementation of calcium during continuous venovenous hemofiltration (CVVH) with citrate anticoagulation is usually titrated using a target blood ionized calcium concentration. Plasma calcium concentrations may be normal despite substantial calcium loss, by mobilization of calcium from the skeleton. Aim of our study is to develop an equation to calculate CVVH calcium and to retrospectively calculate CVVH calcium balance in a cohort of ICU-patients. METHODS: This is a single-center retrospective observational cohort study. In a subcohort of patients, all calcium excretion measurements in patients treated with citrate CVVH were randomly divided into a development set (n = 324 in 42 patients) and a validation set (n = 441 in 42 different patients). Using mixed linear models, we developed an equation to calculate calcium excretion from routinely available parameters. We retrospectively calculated calcium balance in 788 patients treated with citrate CVVH between 2014 and 2021. RESULTS: Calcium excretion (mmol/24 h) was - 1.2877 + 0.646*[Ca]blood,total * ultrafiltrate (l/24 h) + 0.107*blood flow (ml/h). The mean error of the estimation was - 1.0 ± 6.7 mmol/24 h, the mean absolute error was 4.8 ± 4.8 mmol/24 h. Calculated calcium excretion was 105.8 ± 19.3 mmol/24 h. Mean daily CVVH calcium balance was - 12.0 ± 20.0 mmol/24 h. Mean cumulative calcium balance ranged from - 3687 to 448 mmol. CONCLUSION: During citrate CVVH, calcium balance was negative in most patients, despite supplementation of calcium based on plasma ionized calcium levels. This may contribute to demineralization of the skeleton. We propose that calcium supplementation should be based on both plasma ionized calcium and a simple calculation of calcium excretion by CVVH.

"CATCH" Study: Correct Antibiotic Therapy in Continuous Hemofiltration in the Critically Ill in Continuous Renal Replacement Therapy: A Prospective Observational Study.

The proper posology of antibiotics in the critically ill in CRRT is difficult to assess. We therefore performed a prospective observational cohort study to make clear hints in this topic. Our results reveal a high Sieving Coefficient for all antibiotics, equal to or higher than those described in previous papers. CVVH clearance in relation to total body clearance was significant, (i.e., >than 25% for all classes). A strong correlation between the antibiotic concentrations obtained in plasma and ultrafiltrate was found both at the peak and in the valley, with the determination of two equations that allow a new method for calculating the amount of antibiotic lost in CVVH both for trough levels and peak. Based on the results of our study and considering the limitations we believe that we can extrapolate the following final considerations: (1) it is likely to carry out a loading dose for the main antibiotics (2) subsequent administrations must take into account the daily loss identified by the linear regression equation. This angular coefficient gives the idea that the average daily loss of given antibiotic is about 25%; this implies that on the basis of the linear regression equation that correlates ultrafiltered/plasma antibiotic concentration, the dosage should be increased by 25% every day, while still ensuring a daily plasma TDM of the drug.

Pharmacokinetic of Cefiderocol in Critically Ill Patients Receiving Renal Replacement Therapy: A Case Series.

Background: Cefiderocol is a novel parenteral siderophore cephalosporin, demonstrating enhanced activity against multidrug-resistant (MDR) Gram-negative bacteria and difficult-to-treat Acinetobacter baumannii (DTR-AB). Plasma-free trough concentration (fCtrough) over the minimum inhibitory concentration (MIC) was reported as the best pharmacokinetic parameter to describe the microbiological efficacy of cefiderocol. Materials and methods: We retrospectively described the pharmacokinetic and pharmacodynamic profile of three critically ill patients admitted to the intensive care unit, receiving cefiderocol under compassionate use to treat severe DTR-AB infections while undergoing continuous venovenous haemofiltration. Cefiderocol was administrated at a dosage of 2 g every 8 h infused over 3 h. Therapeutic drug monitoring (TDM) was assessed at the steady state. Cthrough was evaluated by assuming a plasma protein binding of 58.0%. The fCmin/MIC was calculated assuming a cefiderocol MIC equal to the PK-PD breakpoint of susceptibility ≤ 2. The association between the PK/PD parameters and microbiological outcome was assessed. Results: fCtrough/MIC were >12 in 2 patients and 2.9 in the 1 who rapidly recovered from renal failure. Microbiological cure occurred in 3/3 of patients. None of the 3 patients died within 30 days. Conclusions: A cefiderocol dosage of 2 g q8 h in critically ill patients with AKI undergoing CVVH may bring about a very high plasma concentration, corresponding to essentially 100% free time over the MIC for DTR-AB.

Analysis of Leukocyte Recruitment in Continuous Veno-Venous Hemofiltration with Regional Citrate vs. Systemic Heparin Anticoagulation.

Acute kidney injury (AKI) is a frequent complication in critically ill patients. Supportive treatment of AKI patients is based on renal-replacement therapy, including continuous veno-venous hemofiltration (CVVH). To limit clotting events on extracorporeal surfaces, anticoagulants are administered, including systemic heparin and local citrate. The differential and comparative effects of these anticoagulants on leukocyte function in acute kidney injury patients are, so far, insufficiently understood. In this bio-add-on-study, AKI patients were randomized as part of a parallel-group trial to either systemic heparin or regional citrate anticoagulation. Patient samples were collected upon inclusion, prior to CVVH initiation at day 0, day 1, day 3 and day 5, following CVVH initiation, and one day after cessation of CVVH, then immediately analyzed. Flow cytometric assessment of surface-receptor molecules was conducted. Whole-blood-perfused human microfluidic chambers were used for the analysis of neutrophil rolling and adhesion. Acute kidney injury was associated with significant changes in the surface expression of CD182 and CD16 throughout CVVH treatment, independent of the anticoagulation regime. AKI furthermore abrogated selectin-induced slow leukocyte rolling and diminished chemokine-induced leukocyte arrest. Subgroup analyses of citrate vs. heparin treatment showed no significant differences between groups, independent of the duration of CVVH treatment. CD182 and CD16 expression remained low in both groups throughout CVVH therapy. These data confirm that AKI impairs selectin-mediated leukocyte slow rolling and chemokine-induced leukocyte arrest in vitro. Systemic heparin or local citrate anticoagulation have no differential effect on the leukocyte recruitment steps examined in this study.

Successful treatment of linezolid-induced severe lactic acidosis with continuous venovenous hemodiafiltration: A case report.

Linezolid is an oxazolidinone antibiotic. Linezolid-associated lactic acidosis has been reported in 6.8% of linezolid-treated patients. Lactic acidosis is associated with poor clinical outcomes, with high blood lactate levels resulting in organ dysfunction and mortality. This case report describes the development of lactic acidosis in a 64-year-old Chinese woman who had received 33 days of treatment with antituberculosis drugs and 28 days of treatment with oral linezolid for tuberculous meningitis. Severe lactic acidosis was reversed by withdrawing antituberculosis drugs and using continuous venovenous hemodiafiltration (CVVH). When the patient's condition was stable, she was transferred to the infectious disease department, and antituberculosis drugs, with the exception of linezolid, were reintroduced. This did not result in recurrence of lactic acidosis. The causal relationship between lactic acidosis and linezolid was categorized as 'probable' on the Adverse Drug Reaction Probability Scale. This case demonstrates that CVVH has potential as an alternative to discontinuation of linezolid alone for rapid reversal of linezolid-associated severe lactic acidosis.

One-Year Survival for Adult Venoarterial Extracorporeal Membrane Oxygenation Patients Requiring Renal-Replacement Therapy.

OBJECTIVES: Acute kidney injury (AKI) and chronic kidney disease (CKD) previously have been associated with in-hospital and long-term mortality of patients undergoing support with venoarterial extracorporeal membrane oxygenation (VA-ECMO). Patient selection criteria and survival prediction scores for VA-ECMO often include AKI or CKD, but exclude patients requiring renal replacement therapy (RRT). The need for RRT in ECMO patients is associated with increased intensive unit care and in-hospital mortality. The effect RRT has on mortality beyond hospital survival is not well-reported. The authors hypothesized that the timing of initiation (pre-ECMO v during ECMO) of RRT can have a significant impact on short- and long-term mortality. DESIGN: The authors categorized patients into 3 groups: those receiving RRT before initiation of ECMO, those initiated on RRT while on ECMO, and those who did not need RRT while on ECMO. The authors compared survival to decannulation, 30 days and 1 year between the 3 groups. A multivariate survival analysis also was conducted. SETTING: This was a single center retrospective review of all patients receiving VA-ECMO. PARTICIPANTS: A total of 347 adult VA-ECMO extracorporeal membrane oxygenation patients. INTERVENTIONS: None, retrospective. MEASUREMENTS AND MAIN RESULTS: The authors' cohort included 347 total patients, 39 required RRT before ECMO, 139 while on ECMO, and 169 did not require RRT while on ECMO. If RRT was initiated before ECMO, survival to decannulation was 48.72%, 46.6% if RRT was initiated on ECMO, and 73.96% for patients who did not need RRT while on ECMO. One-year survival was 25.64%, 23.74%, and 46.75%, respectively. There was no significant difference in survival between patients initiated on RRT before ECMO and those who required RRT while on ECMO. CONCLUSIONS: The authors demonstrated that the need for RRT before or while on ECMO has reduced short- and long-term survival when compared with those who did not need RRT while on ECMO. The authors believe that RRT is a marker for severe multiorgan failure and that, despite the benefits of RRT, high mortality will occur. This lack of mortality difference between patients previously on RRT and those newly requiring RRT may help clinicians in deciding to initiate ECMO for patients previously on RRT. Further investigation into complication rates between the groups is required.

Citrate dose for continuous hemofiltration: effect on calcium and magnesium balance, parathormone and vitamin D status, a randomized controlled trial.

BACKGROUND: Regional citrate anticoagulation may cause a negative calcium balance, systemic hypocalcemia and parathormone (PTH) activation but randomzed studies are not available. Aim was to determine the effect of citrate dose on calcium (Ca) and magnesium (Mg) balance, PTH and Vitamin D. METHODS: Single center prospective randomized study. Patients, requiring continuous venovenous hemofiltration (CVVH) with citrate, randomized to low dose citrate (2.5 mmol/L) vs. high dose (4.5 mmol/L) for 24 h, targeting post-filter ionized calcium (pfiCa) of 0.325-0.4 mmol/L vs. 0.2-0.275 mmol/L, using the Prismaflex® algorithm with 100% postfilter calcium replacement. Extra physician-ordered Ca and Mg supplementation was performed aiming at systemic iCa > 1.0 mmol/L. Arterial blood, effluent and post-filter aliquots were taken for balance calculations (area under the curve), intact (i), oxidized (ox) and non-oxidized (nox) PTH, 25-hydroxy-Vitamin D (25D) and 1,25-dihydroxy-Vitamin D (1,25D). RESULTS: 35 patients were analyzed, 17 to high, 18 to low citrate. Mean 24-h Ca balance was - 9.72 mmol/d (standard error 1.70) in the high vs - 1.18 mmol/d (se 1.70)) (p = 0.002) in the low citrate group and 24-h Mg-balance was - 25.99 (se 2.10) mmol/d vs. -17.63 (se 2.10) mmol/d (p = 0.008) respectively. Physician-ordered Ca supplementation, higher in the high citrate group, resulted in a positive Ca-balance in both groups. iPTH, oxPTH or noxPTH were not different between groups. Over 24 h, median PTH decreased from 222 (25th-75th percentile 140-384) to 162 (111-265) pg/ml (p = 0.002); oxPTH from 192 (124-353) to 154 pg/ml (87-231), p = 0.002. NoxPTH did not change significantly. Mean 25 D (standard deviation), decreased from 36.5 (11.8) to 33.3 (11.2) nmol/l (p = 0.003), 1,25D rose from 40.9 pg/ml (30.7) to 43.2 (30.7) pg/ml (p = 0.046), without differences between groups. CONCLUSIONS: A higher citrate dose caused a more negative CVVH Ca balance than a lower dose, due to a higher effluent Calcium loss. Physician-ordered Ca supplementation, targeting a systemic iCa > 1.0 mmol/L, higher in the high citrate group, resulted in a positive Ca-balance in both groups. iPTH and oxPTH declined, suggesting decreased oxidative stress, while noxPTH did not change. 25D decreased while 1,25-D rose. Mg balance was negative in both groups, more so in the high citrate group. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02194569. Registered 18 July 2014.

Dose Optimization of Vancomycin for Critically Ill Patients Undergoing CVVH: A Prospective Population PK/PD Analysis.

The optimal dose of vancomycin in critically ill patients receiving continuous venovenous hemofiltration (CVVH) remains unclear. The objective of this study was to identify factors that significantly affect pharmacokinetic profiles and to further investigate the optimal dosage regimens for critically ill patients undergoing CVVH based on population pharmacokinetics and pharmacodynamic analysis. A prospective population pharmacokinetic analysis was performed at the surgical intensive care unit in a level A tertiary hospital. We included 11 critically ill patients undergoing CVVH and receiving intravenous vancomycin. Serial blood samples were collected from each patient, with a total of 131 vancomycin concentrations analyzed. Nonlinear mixed effects models were developed using NONMEM software. Monte Carlo Simulation was used to optimize vancomycin dosage regimens. A two-compartment model with first-order elimination was sufficient to characterize vancomycin pharmacokinetics for CVVH patients. The population typical vancomycin clearance (CL) was 1.15 L/h and the central volume of distribution was 16.9 L. CL was significantly correlated with ultrafiltration rate (UFR) and albumin level. For patients with normal albumin and UFR between 20 and 35 mL/kg/h, the recommended dosage regimen was 10 mg/kg qd. When UFR was between 35 and 40 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. For patients with hypoalbuminemia and UFR between 20 and 25 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. When UFR was between 25 and 40 mL/kg/h, the recommended dosage regimen was 10 mg/kg q12h. We recommend clinicians choosing the optimal initial vancomycin dosage regimens for critically ill patients undergoing CVVH based on these two covariates.

Prognostic Performance of Existing Scoring Systems among Critically Ill Patients Requiring Continuous Renal Replacement Therapy: An Observational Study.

BACKGROUND: Among critical patients, few studies have evaluated the discrimination of current illness scoring systems in predicting outcomes after continuous renal replacement therapy (CRRT) initiation. METHODS: Patients receiving CRRT in the ICU between 2005 and 2018 from the Chang Gung Research Database were extracted. All the components of the Acute Physiology Assessment and Chronic Health Evaluation (APACHE) III, Sequential Organ Failure Assessment (SOFA), qSOFA, and MOSAIC scoring systems on days 1, 3, and 7 of CRRT were recorded. Patients older than 80 years were identified and analyzed separately. RESULTS: We identified 3370 adult patients for analysis. The discrimination ability of the scoring systems was acceptable at day 7 after CRRT initiation, including SOFA (area under the receiver operating characteristic curve, 74.1% (95% confidence interval, 71.7-76.5%)), APACHEIII (74.7% (72.3-77.1%)), and MOSAIC (71.3% (68.8%-73.9%)). These systems were not ideal on days 1 and 3, and that of qSOFA was poor at any time point. The discrimination performance was slightly better among patients ≥80 years. CONCLUSIONS: APACHE III, MOSAIC, and SOFA can be intensivists and families' reference to make their decision of withdrawing or withholding CRRT after a short period of treatment, especially in adults ≥80 years old.

Evaluation of dosing strategies and trough concentrations of vancomycin in patients undergoing continuous venovenous hemofiltration.

STUDY OBJECTIVE: Recommendations regarding vancomycin dosing in critically ill patients on continuous venovenous hemofiltration (CVVH) are limited. The purpose of this study was to evaluate current dosing practices of pharmacists for patients treated with CVVH, develop guidelines for optimal dosing and monitoring of vancomycin to improve target trough attainment, and reduce pharmacist workload. DESIGN: A retrospective cohort study. was performed of critically ill adult patients from January 2015 to December 2018. Patients were included if they received vancomycin during CVVH for at least 48 h. Patients with significant residual kidney function, defined as daily urine output >400 ml or significant fluctuations (≥1000 ml/h in a 24-h period) in their hemofiltration rates, were excluded. Interruptions in CVVH up to 6 h/day were permitted. Dosing strategies with two dosing categories were defined: (1) dosing based on random serum levels (dosing by level, DBL) or (2) scheduled vancomycin dosing (SD). SETTING: Academic medical center in Detroit, Michigan. PATIENTS: Critically ill adult patients. MEASUREMENTS AND MAIN RESULTS: During the study period, 942 patients were evaluated and 200 met inclusion criteria, for a total of 586 serum vancomycin levels. There were 141 patients with 443 random vancomycin serum levels in the DBL group and 59 patients with143 vancomycin trough levels in the SD group. Mean vancomycin trough levels were similar between groups (17.1 ± 6 vs. 16.5 ± 4 mcg/ml) for the DBL and SD groups, respectively. For the primary end point of overall target trough achievement of 15-20 mcg/ml, significantly more trough levels in the SD group were in the 15-20 mcg/ml range compared with the DBL group, 50% vs. 38%; p < 0.001, respectively. When target trough range was extended to 10-20 mcg/ml, success rates were similar between groups (74% DBL vs. 82% SD, p = 0.021). The number of interventions required by the pharmacist, including notes per day and orders per day, were reduced by approximately 50% when the SD strategy was utilized. Scheduled vancomycin dosing regimens of 15-22 mg/kg every 12-24 h were required to yield trough levels in the 15-20 mcg/ml range. CONCLUSIONS: Target vancomycin trough achievement of 15-20 mcg/ml occurred more frequently when vancomycin was scheduled at a dose of 15-22 mg/kg every 12-24 h based on ultrafiltration rate and may alleviate the time and cost associated with frequent vancomycin serum monitoring.

PMMA-Based Continuous Hemofiltration Modulated Complement Activation and Renal Dysfunction in LPS-Induced Acute Kidney Injury.

Sepsis-induced acute kidney injury (AKI) is a frequent complication in critically ill patients, refractory to conventional treatments. Aberrant activation of innate immune system may affect organ damage with poor prognosis for septic patients. Here, we investigated the efficacy of polymethyl methacrylate membrane (PMMA)-based continuous hemofiltration (CVVH) in modulating systemic and tissue immune activation in a swine model of LPS-induced AKI. After 3 h from LPS infusion, animals underwent to PMMA-CVVH or polysulfone (PS)-CVVH. Renal deposition of terminal complement mediator C5b-9 and of Pentraxin-3 (PTX3) deposits were evaluated on biopsies whereas systemic Complement activation was assessed by ELISA assay. Gene expression profile was performed from isolated peripheral blood mononuclear cells (PBMC) by microarrays and the results validated by Real-time PCR. Endotoxemic pigs presented oliguric AKI with increased tubulo-interstitial infiltrate, extensive collagen deposition, and glomerular thrombi; local PTX-3 and C5b-9 renal deposits and increased serum activation of classical and alternative Complement pathways were found in endotoxemic animals. PMMA-CVVH treatment significantly reduced tissue and systemic Complement activation limiting renal damage and fibrosis. By microarray analysis, we identified 711 and 913 differentially expressed genes with a fold change >2 and a false discovery rate <0.05 in endotoxemic pigs and PMMA-CVVH treated-animals, respectively. The most modulated genes were Granzyme B, Complement Factor B, Complement Component 4 Binding Protein Alpha, IL-12, and SERPINB-1 that were closely related to sepsis-induced immunological process. Our data suggest that PMMA-based CVVH can efficiently modulate immunological dysfunction in LPS-induced AKI.

Feasibility and efficacy of modified fixed citrate concentration protocol using only commercial preparations in critically ill patients: a prospective cohort study with a historical control group.

BACKGROUND: The cumbersome program and the shortage of commercial solution hindered the regular application of regional citrate anticoagulation (RCA). It is urgent to simplify the protocol using only commercial preparations. The aim of this study was to explore the feasibility and efficacy of the modified protocol for continuous veno-venous hemofiltration (CVVH) in unselected critically ill patients. METHODS: A prospective cohort study was conducted in 66 patients who received a new protocol combining fixed citrate concentration with modified algorithm for supplements (i.e., fixed protocol), and compared the efficacy, safety and convenience for this group to a historical control group with a traditional protocol (n = 64), where citrate was titrated according to the circuit ionized calcium concentration (i.e., titrated protocol). The convenience was defined as the demand for monitoring test and dose adjustment of any supplement. RESULTS: The filter lifespan was 63.2 ± 16.1 h in the fixed group and 51.9 ± 17.7 h in the titrated group, respectively. Kaplan-Meier survival analysis demonstrated longer circuit lifetime for fixed group (log-rank, p = 0.026). The incidence of circuit clotting was lower in the fixed protocol (15.2% vs. 29.7% in the titrated protocol, p = 0.047). Moreover, compared with the titrated group, patients with fixed protocol had less demand for monitoring test and dose adjustment of any supplement (the number of times per person per day) (3.3 [IQR 2.3-4.5] vs. 5.7 [IQR 3.3-6.9], p = 0.001 and 1.9 [IQR 0.5-2.7] vs. 6.3 [IQR 4.2-7.9], p < 0.001; respectively). No new onset bleeding complications occurred in all patients. The overall incidence of suspected citrate accumulation was 4.6% and there was no difference between the two groups (p = 0.969), yet a lower rate of metabolic alkalosis was found in the fixed group (3.0% vs. 14.1%, p = 0.024). CONCLUSIONS: Our modified fixed citrate concentration protocol is feasible, safe and effective to enhance the circuit lifespan and the convenience of implementation while maintaining a similar safety when compared to the traditional protocol. Using only commercial preparations may be helpful for widespread application of RCA. TRIAL REGISTRATION: Clinicaltrials.gov. NCT02663960 . Registered 26 January 2016.

Effects of continuous venovenous hemofiltration on vancomycin trough concentrations in critically ill children.

BACKGROUND: Vancomycin trough concentrations are associated with clinical outcomes and drug adverse effects. This study investigates the effects of continuous venovenous hemofiltration (CVVH) on vancomycin trough concentrations in critically ill children with a vancomycin dosage of 40-60 mg/kg/day. METHODS: Children with steady-state vancomycin trough concentrations admitted to the pediatric intensive care unit (PICU) between January 2016 and December 2019 were retrospectively enrolled. Patients were divided into CVVH and non-CVVH groups according to treatment differences and renal function. Vancomycin trough concentrations were then compared between the groups, and risk factors for supratherapeutic trough concentrations (>20 mg/L) were analyzed with logistic regression. RESULTS: Of the 119 patients included, 35 were enrolled in the CVVH group and 84 in the non-CVVH group. Median vancomycin trough concentrations were significantly higher in the CVVH group than those in the non-CVVH group [14.9 (IQR =9.6-19.6) vs. 9.3 (IQR =7.0-13.4), P<0.001] and the proportion of therapeutic trough concentrations (10-20 mg/L) was similar between CVVH and non-CVVH groups (54.3% vs. 39.3%, P=0.133). However, CVVH therapy patients had a significantly higher proportion of supratherapeutic trough concentrations (20.0% vs. 1.2%, P=0.001) compared to the non-CVVH group. Multivariate analysis demonstrated that the Pediatric Risk of Mortality (PRISM) III score ≥28 (OR =13.7; 95% CI, 1.4-137.0; P=0.026] was an independent risk factor for supratherapeutic trough concentrations in critically ill patients. CONCLUSIONS: CVVH therapy affects vancomycin trough concentrations and is associated with supratherapeutic concentrations with a 40-60 mg/kg/day vancomycin dosage. PRISM III scores ≥28 may serve as an independent risk factor for supratherapeutic trough concentrations in children receiving CVVH therapy.

Pharmacokinetics and dialytic clearance of apixaban during in vitro continuous renal replacement therapy.

BACKGROUND: To evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations. METHODS: Apixaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types, flow rates, and point of CVVH replacement fluid dilution. Concentrations of apixaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for apixaban were estimated via noncompartmental analysis. CLTM was calculated via the estimated area under the curve (AUC) and by the product of the sieving/saturation coefficient (SC/SA) and flow rate. Two and three-way analysis of variance (ANOVA) models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLTM by each method. Optimal doses were suggested by matching the AUC observed in vitro to the systemic exposure demonstrated in Phase 2/3 studies of apixaban. Linear regression was utilized to provide dosing estimations for flow rates from 0.5-5 L/h. RESULTS: Mean adsorption to the HF1400 and M150 filters differed significantly at 38 and 13%, respectively, while mean (± standard deviation, SD) percent protein binding was 70.81 ± 0.01%. Effect of CVVH point of dilution did not differ across filter types, although CLTM was consistently significantly higher during CRRT with the HF1400 filter compared to the M150. The three-way ANOVA demonstrated improved fit when CLTM values calculated by AUC were used (adjusted R2 0.87 vs. 0.52), and therefore, these values were used to generate optimal dosing recommendations. Linear regression revealed significant effects of filter type and flow rate on CLTM by AUC, suggesting doses of 2.5-7.5 mg twice daily (BID) may be needed for flow rates ranging from 0.5-5 L/h, respectively. CONCLUSION: For CRRT flow rates most commonly employed in clinical practice, the standard labeled 5 mg BID dose of apixaban is predicted to achieve target systemic exposure thresholds. The safety and efficacy of these proposed dosing regimens warrants further investigation in clinical studies.

Continuous Renal Replacement Therapy in the Critically Ill Patient: From Garage Technology to Artificial Intelligence.

The history of continuous renal replacement therapy (CRRT) is marked by technological advances linked to improvements in the knowledge of the mechanisms and kinetics of extracorporeal removal of solutes, and the pathophysiology of acute kidney injury (AKI) and other critical illnesses. In the present article, we review the main steps in the history of CRRT, from the discovery of continuous arteriovenous hemofiltration to its evolution into the current treatments and its early use in the treatment of AKI, to the novel sequential extracorporeal therapy. Beyond the technological advances, we describe the development of new medical specialties and a shared nomenclature to support clinicians and researchers in the broad and still evolving field of CRRT.

Filter clotting with continuous renal replacement therapy in COVID-19.

Coronavirus disease 2019 (COVID-19) appears to be associated with increased arterial and venous thromboembolic disease. These presumed abnormalities in hemostasis have been associated with filter clotting during continuous renal replacement therapy (CRRT). We aimed to characterize the burden of CRRT filter clotting in COVID-19 infection and to describe a CRRT anticoagulation protocol that used anti-factor Xa levels for systemic heparin dosing. Multi-center study of consecutive patients with COVID-19 receiving CRRT. Primary outcome was CRRT filter loss. Sixty-five patients were analyzed, including 17 using an anti-factor Xa protocol to guide systemic heparin dosing. Fifty-four out of 65 patients (83%) lost at least one filter. Median first filter survival time was 6.5 [2.5, 33.5] h. There was no difference in first or second filter loss between the anti-Xa protocol and standard of care anticoagulation groups, however fewer patients lost their third filter in the protocolized group (55% vs. 93%) resulting in a longer median third filter survival time (24 [15.1, 54.2] vs. 17.3 [9.5, 35.1] h, p = 0.04). The rate of CRRT filter loss is high in COVID-19 infection. An anticoagulation protocol using systemic unfractionated heparin, dosed by anti-factor Xa levels is reasonable approach to anticoagulation in this population.

Determinants of Total/ionized Calcium in patients undergoing citrate CVVH: A retrospective observational study.

PURPOSE: To identify potential determinants of the Total/ionized Ca ratio (T/iCa), a marker of citrate accumulation. MATERIALS AND METHODS: Single-center retrospective observational study evaluating citrate dose, citrate target, albumin, phosphate, pH, lactate, and APACHE II score as potential determinants. Linear mixed models (LMM) using citrate dose and citrate target were developed describing associations with T/iCa. RESULTS: From a dataset of 471 samples in 103 patients, an LMM in 379 complete samples (95 patients) sets revealed that citrate dose, pH, phosphate, albumin and APACHE were interactively related to T/iCa. A rising citrate dose was associated with a higher increase in T/iCa when phosphate was high, and less when phosphate was low. A rising albumin was associated with a higher increase in T/iCa when APACHE was high and phosphate was low and less when APACHE was low and phosphate high. In case of acidosis, a rising lactate was associated with a higher increase in T/iCa. In the LMM using citrate target, citrate target and pH were the main independent predictors of T/iCa with albumin, phosphate and APACHE score as modifiers. CONCLUSIONS: Besides citrate dose, a high pH and high phosphate, albumin and APACHE are also associated with a rising T/iCa.