Medication patterns and dosing guidance in pediatric patients supported with intermittent hemodialysis or continuous kidney replacement therapy.

BACKGROUND: Hemodialysis is a life-saving technology used during periods of acute or chronic kidney failure to remove toxins, and maintain fluid, electrolyte and metabolic balance. While this technology plays an important role for pediatric patients with kidney dysfunction, it can alter the pharmacokinetic behavior of medications placing patients at risk for suboptimal dosing and drug toxicity. The ability to directly translate pharmacokinetic alterations into dosing recommendations has thus far been limited and dosing guidance specific to pediatric hemodialysis patients is rare. Despite differences in dialysis prescription and patient populations, intermittent (iHD) and continuous kidney replacement therapy (CKRT) patients are often pooled together. In order to develop evidence-based dosing guidelines, it is important to first prioritize drugs for study in each modality. METHODS: Here we aim to identify priority drugs in two hemodialysis modalities, through: 1) Identification of hospitalized, pediatric patients who received CKRT or intermittent hemodialysis (iHD) using a machine learning-based predictive model based on medications; 2) Identification of medication administration patterns in these patient cohorts; and 3) Identification of the most commonly prescribed drugs that lack published dosing guidance. RESULTS: Notable differences were found in the pattern of medications and drug dosing guidance between iHD and CKRT patients. Antibiotics, diuretics and sedatives were more common in CKRT patients. Out of the 50 most commonly administered medications in the two modalities, only 34% and 28% had dosing guidance present for iHD and CKRT, respectively. CONCLUSIONS: Our results add to the understanding of the differences between iHD and CKRT patient populations by identifying commonly used medications that lack dosing guidance for each hemodialysis modality, helping to pinpoint priority medications for further study. Overall, this study provides an overview of the current limitations in medication use in this at-risk population, and provides a framework for future studies by identifying commonly used medications in pediatric CKRT and iHD patients.

Meropenem extraction by ex vivo extracorporeal life support circuits.

BACKGROUND: Meropenem is a broad-spectrum carbapenem-type antibiotic commonly used to treat critically ill patients infected with extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. As many of these patients require extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapy (CRRT), it is important to understand how these extracorporeal life support circuits impact meropenem pharmacokinetics. Based on the physicochemical properties of meropenem, it is expected that ECMO circuits will minimally extract meropenem, while CRRT circuits will rapidly clear meropenem. The present study seeks to determine the extraction of meropenem from ex vivo ECMO and CRRT circuits and elucidate the contribution of different ECMO circuit components to extraction. METHODS: Standard doses of meropenem were administered to three different configurations (n = 3 per configuration) of blood-primed ex vivo ECMO circuits and serial sampling was conducted over 24 h. Similarly, standard doses of meropenem were administered to CRRT circuits (n = 4) and serial sampling was conducted over 4 h. Meropenem was administered to separate tubes primed with circuit blood to serve as controls to account for drug degradation. Meropenem concentrations were quantified, and percent recovery was calculated for each sample. RESULTS: Meropenem was cleared at a similar rate in ECMO circuits of different configurations (n = 3) and controls (n = 6), with mean (standard deviation) recovery at 24 h of 15.6% (12.9) in Complete circuits, 37.9% (8.3) in Oxygenator circuits, 47.1% (8.2) in Pump circuits, and 20.6% (20.6) in controls. In CRRT circuits (n = 4) meropenem was cleared rapidly compared with controls (n = 6) with a mean recovery at 2 h of 2.36% (1.44) in circuits and 93.0% (7.1) in controls. CONCLUSION: Meropenem is rapidly cleared by hemodiafiltration during CRRT. There is minimal adsorption of meropenem to ECMO circuit components; however, meropenem undergoes significant degradation and/or plasma metabolism at physiological conditions. These ex vivo findings will advise pharmacists and physicians on the appropriate dosing of meropenem.

Interaction of ceftazidime and clindamycin with extracorporeal life support.

BACKGROUND: Ceftazidime and clindamycin are commonly prescribed to critically ill patients who require extracorporeal life support such as ECMO and CRRT. The effect of ECMO and CRRT on the disposition of ceftazidime and clindamycin is currently unknown. METHODS: Ceftazidime and clindamycin extraction were studied with ex vivo ECMO and CRRT circuits primed with human blood. The percent recovery of these drugs over time was calculated to determine the degree of interaction between these drugs and circuit components. RESULTS: Neither ceftazidime nor clindamycin exhibited measurable interactions with the ECMO circuit. In contrast, CRRT cleared 100% of ceftazidime from the experimental circuit within the first 2 h. Clearance of clindamycin from the CRRT circuit was slower, with about 20% removed after 6 h. CONCLUSION: Clindamycin and ceftazidime dosing adjustments are likely required in patients who are supported with CRRT, and future studies to quantify these adjustments should consider the pathophysiology of the patient in combination with the clearance due to CRRT. Dosing adjustments to account for adsorption to ECMO circuit components are likely unnecessary and should focus instead on the pathophysiology of the patient and changes in volume of distribution. These results will help improve the safety and efficacy of ceftazidime and clindamycin in patients requiring ECMO and CRRT.

Timing of Pediatric Palliative Care Consults in Hospitalized Patients with Heart Disease.

Pediatric palliative care (PPC) provides an extra layer of support for families caring for a child with complex heart disease as these patients often experience lifelong morbidities with frequent hospitalizations and risk of early mortality. PPC referral at the time of heart disease diagnosis provides early involvement in the disease trajectory, allowing PPC teams to longitudinally support patients and families with symptom management, complex medical decision-making, and advanced care planning. We analyzed 113 hospitalized pediatric patients with a primary diagnosis of heart disease and a PPC consult to identify timing of first PPC consultation in relation to diagnosis, complex chronic conditions (CCC), and death. The median age of heart disease diagnosis was 0 days with a median of two CCCs while PPC consultation did not occur until a median age of 77 days with a median of four CCCs. Median time between PPC consult and death was 33 days (interquartile range: 7-128). Death often occurred in the intensive care unit ( n = 36, 67%), and the most common mode was withdrawal of life-sustaining therapies ( n = 31, 57%). PPC referral often occurred in the context of medical complexity and prolonged hospitalization. Referral close to the time of heart disease diagnosis would allow patients and families to fully utilize PPC benefits that exist outside of end-of-life care and may influence the mode and location of death. PPC consultation should be considered at the time of heart disease diagnosis, especially in neonates and infants with CCCs.

Remdesivir and GS-441524 Extraction by Ex Vivo Extracorporeal Life Support Circuits.

Patients with severe, COVID-related multi-organ failure often require extracorporeal life support (ECLS) such as extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT). An ECLS can alter drug exposure via multiple mechanisms. Remdesivir (RDV) and its active metabolite GS-441524 are likely to interact with ECLS circuits, resulting in lower than expected exposures. We evaluated circuit-drug interactions in closed loop, ex vivo ECMO and CRRT circuits. We found that mean (standard deviation) recovery of RDV at 6 hours after dosing was low in both the ECMO (33.3% [2.0]) and CRRT (3.5% [0.4]) circuits. This drug loss appears to be due primarily to drug adsorption by the circuit materials and potentially due to metabolism in the blood. GS-441524 recovery at 6 hours was high in the ECMO circuit 75.8% (16.5); however, was not detectable at 6 hours in the CRRT circuit. Loss in the CRRT circuit appears to be due primarily to efficient hemodiafiltration. The extent of loss for both molecules, especially in CRRT, suggests that in patients supported with ECMO and CRRT, RDV dosing adjustments are needed.

Cefepime Extraction by Extracorporeal Life Support Circuits.

Extracorporeal life support (ECLS) devices are lifesaving for critically ill patients with multi-organ dysfunction. Despite this, patients supported with ECLS are at high risk for ECLS-related complications, including nosocomial infections, and mortality rates are high in this patient population. The high mortality rates are suspected to be, in part, a result of significantly altered drug disposition by the ECLS circuit, resulting in suboptimal antimicrobial dosing. Cefepime is commonly used in critically ill patients with serious infections. Cefepime dosing is not routinely guided by therapeutic drug monitoring and treatment success is dependent upon the percentage of time of the dosing interval that the drug concentration remains above the minimum inhibitory concentration of the organism. This ex vivo study measured the extraction of cefepime by continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) circuits. Cefepime was studied in four closed-loop CRRT circuit configurations and a single closed-loop ECMO circuit configuration. Circuits were primed with a physiologic human blood-plasma mixture and the drug was dosed to achieve therapeutic concentrations. Serial blood samples were collected over time and concentrations were quantified using validated assays. In ex vivo CRRT experiments, cefepime was rapidly cleared by dialysis, hemofiltration, and hemodiafiltration, with greater than 96% cefepime eliminated from the circuit by 2 hours. In the ECMO circuits, the mean recovery of cefepime was similar in both circuit and standard control. Mean (standard deviation) recovery of cefepime in the ECMO circuits (n = 6) was 39.2% (8.0) at 24 hours. Mean recovery in the standard control (n = 3) at 24 hours was 52.2% (1.5). Cefepime is rapidly cleared by dialysis, hemofiltration, and hemodiafiltration in the CRRT circuit but minimally adsorbed by either the CRRT or ECMO circuits. Dosing adjustments are needed for patients supported with CRRT.

Embodied valuation: Directional action is associated with item values.

We have a lifetime of experience interacting with objects we value. Although many economic theories represent valuation as a purely cognitive process independent of the sensorimotor system, embodied cognitive theory suggests that our memories for items' value should be linked to actions we use to obtain them. Here, we investigated whether the value of real items was associated with specific directional movements toward or away from the body. Participants priced a set of food items to determine their values; they then used directional actions to classify each item as high- or low-value. To determine if value is linked to specific action mappings, movements were referenced either with respect to the object (push toward high-value items; pull away from low-value items) or the self (pull high-value items toward self; push low-value items away). Participants who were assigned (Experiment 1) or chose (Experiment 2) to use an object-referenced action mapping were faster than those using a self-referenced mapping. A control experiment (Experiment 3) using left/right movements found no such difference when action mappings were not toward/away from the body. These results indicate that directional actions toward items are associated with the representation of their value, suggesting an embodied component to economic choice.

Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury.

Recent work reveals that the innate immune system is able to recognize self-targets and initiate an inflammatory response similar to that of pathogens. One novel example of this innate autoimmunity is ischemia/reperfusion (I/R) injury, in which reperfusion of the ischemic tissues elicits an acute inflammatory response activated by natural IgM (nIgM) binding to ischemia-specific self-antigens, which are non-muscle myosin heavy chains type II (NMHC-II) subtype A and C. Subsequently, the complement lectin pathway is activated and eventually tissue injury occurs. Although earlier studies in the intestinal model showed that the classical complement pathway did not initiate I/R injury, C1q deposition was still observed in the local injured tissues by imaging analysis. Moreover, the involvement of the alternative complement pathway became unclear due to conflicting reports using different knockout mice. To explore the immediate downstream pathway following nIgM-ischemic antigen interaction, we isolated the nIgM-ischemic antigen immunocomplexes from the local tissue of animals treated in the intestinal I/R injury model, and examined the presence of initial molecules of three complement pathways. Our results showed that mannan-binding lectin (MBL), the early molecule of the lectin pathway, was present in the nIgM-ischemic Ag immunocomplex. In addition, C1q, the initial molecule of the classical pathway was also detected on the immunocomplex. However, Factor B, the early molecule in the alternative pathway, was not detected in the immunocomplex. To further examine the role of the alternative pathway in I/R injury, we utilized Factor B knockout mice in the intestinal model. Our results showed that Factor B knockout mice were not protected from local tissue injury, and their complement system was activated in the local tissues by nIgM during I/R. These results indicated that the lectin complement pathway operates immediately downstream of the nIgM-ischemic antigen interaction during intestinal I/R. Furthermore, the classical complement pathway also appears to interact with the of nIgM-ischemic antigen immunocomplex. Finally, the alternative complement pathway is not involved in I/R injury induction in the current intestinal model.