This study aimed to develop a population pharmacokinetic model for cefepime in critically ill pediatric and young adult patients to inform dosing recommendations and to evaluate the model’s predictive performance for model-informed precision dosing. Patients in the pediatric intensive care unit receiving cefepime were prospectively enrolled for clinical data collection and opportunistic plasma sampling for cefepime concentrations. Nonlinear mixed effects modeling was conducted using NONMEM. Allometric body weight scaling was included as a covariate with fixed exponents. Monte Carlo simulations determined optimal initial dosing regimens against susceptible pathogens. The model’s predictions were evaluated with an external dataset. Data from 510 samples across 100 patients were best fit with a two-compartment model with first-order elimination. Estimated glomerular filtration rate and cumulative percentage of fluid balance were identified as significant covariates on clearance and central volume of distribution, respectively. Internal validation showed no model misspecification. External validation confirmed that bias and precision for both population and individual predictions were within commonly accepted ranges. Monte Carlo simulations suggested that the usual dose of 50 mg/kg may require a 3-h infusion or a 6-h dosing interval to keep concentrations above the Pseudomonas aeruginosa minimum inhibitory concentration (≤ 8 mg/L) throughout the dosing interval for patients with normal or augmented renal clearance. A cefepime population pharmacokinetic model for critically ill pediatric patients was successfully developed, accounting for patient renal function, fluid status, and body size, using real-world data. The model was internally and externally validated for use in optimal dosing simulations and model-informed precision dosing.

Continuous kidney replacement therapy (CKRT) is often used for acute kidney injury (AKI) or fluid overload (FO) in children ≤ 10 kg. Intensive care unit (ICU) mortality in children ≤ 10 kg reported by the prospective pediatric CRRT (ppCRRT, 2001–2003) registry was 57

Introduction: Critically ill admitted patients are at high risk of acute kidney injury (AKI). The renal angina index (RAI) and urinary biomarker neutrophil gelatinase-associated lipocalin (uNGAL) can aid in AKI risk assessment. We implemented the Trial in AKI using NGAL and Fluid Overload to optimize CRRT Use (TAKING FOCUS 2; TF2) to personalize fluid management and continuous renal replacement therapy (CRRT) initiation based on AKI risk and patient fluid accumulation. We compared outcomes pre-TF2 and post-TF2 initiation. Methods: Patients admitted from July 2017 were followed-up prospectively with the following: (i) an automated RAI result at 12 hours of admission, (ii) a conditional uNGAL order for RAI ≥8, and (iii) a CRRT initiation goal at 10% to 15% weight-based fluid accumulation. Results: A total of 286 patients comprised 304 intensive care unit (ICU) RAI+ admissions; 178 patients received CRRT over the observation period (2014–2021). Median time from ICU admission to CRRT initiation was 2 days shorter (P < 0.002), and ≥15% pre-CRRT fluid accumulation rate was lower in the TF2 era (P < 0.02). TF2 ICU length of stay (LOS) after CRRT discontinuation and total ICU LOS were 6 and 11 days shorter for CRRT survivors (both P < 0.02). Survival rates to ICU discharge after CRRT discontinuation were higher in the TF2 era (P = 0.001). These associations persisted in each TF2 year; we estimate a conservative $12,500 health care cost savings per CRRT patient treated after TF2 implementation. Conclusion: We suggest that automated clinical decision support (CDS) combining risk stratification and AKI biomarker assessment can produce durable reductions in pediatric CRRT patient morbidity.

OBJECTIVE:Several human studies have associated nitric oxide administration via the cardiopulmonary bypass circuit with decreased incidence of cardiopulmonary bypass-associated acute kidney injury, but histopathologic and serologic evidence of nitric oxide efficacy for acute kidney injury attenuation are lacking. METHODS:By using a survival ovine model (72 hours), acute kidney injury was induced by implementing low-flow cardiopulmonary bypass for 2 hours, followed by full-flow cardiopulmonary bypass for 2 hours. The nitric oxide cohort (n = 6) received exogenous nitric oxide through the cardiopulmonary bypass circuit via the oxygenator, and the control group (n = 5) received no nitric oxide. Serial serologic biomarkers and renal histopathology were obtained. RESULTS:Baseline characteristics (age, weight) and intraoperative parameters (cardiopulmonary bypass time, urine output, heart rate, arterial pH, and lactate) were equivalent (P > .10) between groups. Postoperatively, urine output, heart rate, respiratory rate, and peripheral arterial saturation were equivalent (P > .10) between groups. Post-cardiopulmonary bypass creatinine elevations from baseline were significantly greater in the control group versus the nitric oxide group at 16, 24, and 48 hours (all P < .05). Histopathologic evidence of moderate/severe acute kidney injury (epithelial necrosis, tubular slough, cast formation, glomerular edema) occurred in 60% (3/5) of the control group versus 0% (0/6) of the nitric oxide group. Cortical tubular epithelial cilia lengthening (a sensitive sign of cellular injury) was significantly greater in the control group than in the nitric oxide group (P = .012). CONCLUSIONS:In a survival ovine cardiopulmonary bypass model, nitric oxide administered with cardiopulmonary bypass demonstrated serologic and histologic evidence of renal protection from acute kidney injury. These results provide insight into 1 potential mechanism for cardiopulmonary bypass-associated acute kidney injury and supports continued study of nitric oxide via cardiopulmonary bypass circuit for prevention of acute kidney injury.

Hemophagocytic lymphohistiocytosis (HLH) is a dysregulated immune disorder in children, associated with Epstein–Barr virus (EBV) infection or malignancies. In severe forms, HLH presents with signs and symptoms of hyperinflammation that progress to life-threatening multiorgan failure. Intervention with an extracorporeal immunomodulatory treatment utilizing a selective cytopheretic device (SCD) could be beneficial. The SCD with regional citrate anticoagulation selectively binds the most highly activated circulating neutrophils and monocytes and deactivates them before release to the systemic circulation. Multiple clinical studies, including a multicenter study in children, demonstrate SCD therapy attenuates hyperinflammation, resolves ongoing tissue injury and allows progression to functional organ recovery. We report the first case of SCD therapy in a patient with HLH and multi-organ failure. A previously healthy 22-month-old toddler presented with fever, abdominal distension, organomegaly, pancytopenia, and signs of hyperinflammation. EBV PCR returned at > 25 million copies. The clinical and laboratory pictures were consistent with systemic EBV-positive T-cell lymphoma with symptoms secondary to HLH. The patient met inclusion criteria for an ongoing study of integration of the SCD with a continuous kidney replacement therapy (CKRT) as part of standard of care. The patient received CKRT-SCD for 4 days with normalization of serum markers of sepsis and inflammation. The patient underwent hematopoietic stem cell transplantation 52 days after presentation and has engrafted with normal kidney function 8 months later. SCD treatment resulted in improvement of poor tissue perfusion reflected by rapid decline in serum lactate levels, lessened systemic capillary leak with discontinuation of vasoactive agents, and repair and recovery of lung and kidney function with extubation and removal of hemodialysis support.

Introduction: Acute kidney injury (AKI) occurs in one-fourth of children and young adults admitted to pediatric intensive care unit (PICU). Severe AKI (sAKI; Kidney Disease: Improving Global Outcomes stage 2 or 3) is associated with morbidity and mortality. An AKI risk stratification system, the Renal Angina Index (RAI) calculated at 12 hours of admission, exhibits excellent performance to rule out sAKI at 72 hours of admission. We found that integration of urine neutrophil gelatinase-associated lipocalin (NGAL) with RAI improves prediction of sAKI. We now report the first-year results after implementation of our prospective automated RAI-NGAL clinical decision support (CDS) program.Methods: Patients 3 months to 25 years of age were eligible. Admission order sets have a conditional order for urine NGAL released when a 12-hour RAI >= 8. The primary outcome was sAKI any time at days 2 to 4 of admission. We assessed performance of the RAI and RAI+/NGAL to predict the primary outcome.Results: A total of 1427 unique patients accounted for 1575 admissions. In 147 admissions, RAI was >= 8. RAI <8 had negative predictive value (NPV) of 0.98 (95% CI 0.97-0.99); RAI >= 8 had positive predictive value (PPV) of 0.37 (95% CI 0.30-0.46) to predict days 2 to 4 sAKI (area under the receiver operating characteristic curve [AUC-ROC] 0.88 [95% CI 0.84-0.92]). Of 147 RAI+ patients, 89 had NGAL available. RAI/NGAL combination improved PPV (0.64, 95% CI 0.50-0.79) without decrement in NPV (0.98, 95% CI 0.97-0.98).Conclusion: AKI biomarker assessment directed by risk stratification improves prediction of sAKI in criti-cally ill children and young adults. This CDS process has potential to enrich the population for interven-tional study, although improvement to adherence to CDS is needed.