A Population Pharmacokinetic Analysis to Study the Effect of Extracorporeal Membrane Oxygenation on Cefepime Disposition in Children.

OBJECTIVES: Limited data exist on the effects of extracorporeal membrane oxygenation on pharmacokinetics of cefepime in critically ill pediatric patients. The objective was to describe cefepime disposition in children treated with extracorporeal membrane oxygenation using population pharmacokinetic modeling. DESIGN: Multicenter, prospective observational study. SETTING: The pediatric and cardiac ICUs of six sites of the Collaborative Pediatric Critical Care Research Network. PATIENTS: Seventeen critically ill children (30 d to < 2 yr old) on extracorporeal membrane oxygenation who received cefepime as standard of care between January 4, 2014, and August 24, 2015, were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A pharmacokinetic model was developed to evaluate cefepime disposition differences due to extracorporeal membrane oxygenation. A two-compartment model with linear elimination, weight effects on clearance, intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data. The typical value of clearance in this study was 7.1 mL/min (1.9 mL/min/kg) for a patient weighing 5.8 kg. This value decreased by approximately 40% with the addition of renal replacement therapy. The typical value for V1 was 1,170 mL. In the setting of blood transfusions, V1 increased by over two-fold but was reduced with increasing age of the extracorporeal membrane oxygenation circuit oxygenator. CONCLUSIONS: Cefepime clearance was reduced in pediatric patients treated with extracorporeal membrane oxygenation compared with previously reported values in children not receiving extracorporeal membrane oxygenation. The model demonstrated that the age of the extracorporeal membrane oxygenation circuit oxygenator is inversely correlated to V1. For free cefepime, only 14 of the 19 doses (74%) demonstrated a fT_minimum inhibitory concentration of 16 mg/L, an appropriate target for the treatment of pseudomonal infections, for greater than 70% of the dosing interval. Pediatric patients on extracorporeal membrane oxygenation might benefit from the addition of therapeutic drug monitoring of cefepime to assure appropriate dosing.

CAR-Treg cell therapies and their future potential in treating ocular autoimmune conditions.

Ophthalmic autoimmune and autoinflammatory conditions cause significant visual morbidity and require complex medical treatment complicated by significant side effects and lack of specificity. Regulatory T cells (Tregs) have key roles in immune homeostasis and in the resolution of immune responses. Polyclonal Treg therapy has shown efficacy in treating autoimmune disease. Genetic engineering approaches to produce antigen-specific Treg therapy has the potential for enhanced treatment responses and fewer systemic side effects. Cell therapy using chimeric antigen receptor modified T cell (CAR-T) therapy, has had significant success in treating haematological malignancies. By modifying Tregs specifically, a CAR-Treg approach has been efficacious in preclinical models of autoimmune conditions leading to current phase 1-2 clinical trials. This review summarises CAR structure and design, Treg cellular biology, developments in CAR-Treg therapies, and discusses future strategies to apply CAR-Treg therapy in the treatment of ophthalmic conditions.

Intermediate uveitis associated with MS: Diagnosis, clinical features, pathogenic mechanisms, and recommendations for management.

Uveitis is a major cause of visual impairment and blindness among working-age adults, accounting for 10% of legal blindness in the United States. Among people with MS, the prevalence of uveitis is 10 times higher than among the general population, and because MS and uveitis share similar genetic risk factors and immunologic effector pathways, it is not clear whether uveitis is one of the manifestations of MS or a coincident disorder. This uncertainty raises several diagnostic and management issues for clinicians who look after these patients, particularly with regard to recognizing visual symptoms resulting from demyelination, intraocular inflammation, or the visual complications of disease modifying drugs for MS, e.g., fingolimod. Likewise, management decisions regarding patients with uveitis are influenced by the risk of precipitating or exacerbating episodes of demyelination, e.g., following anti-tumor necrosis factor biologic therapy, and other neurologic complications of immunosuppressive treatments for uveitis. In this review, we explore the similarities in the pathophysiology, clinical features, and treatment of patients with uveitis and MS. Based on the latest evidence, we make a set of recommendations to help guide neurologists and ophthalmologists to best manage patients affected by both conditions.

Novel Irrigation Protocol for Renal Pelvis Sterilization During Percutaneous Nephrolithotomy: A Pilot Study.

While percutaneous nephrolithotomy (PCNL) remains the treatment modality of choice for kidney stones larger than 2 cm, infectious complications are most common, ranging from 5% to 32%. We present here a novel technique for potentially improving collecting system sterility during PCNL and initial postoperative outcomes. Retrospective chart analysis data of our irrigation protocol were collected from our first 56 patients between February and July 2019. Traditional prone PCNL was performed in a standard manner using fluoroscopic guidance. Using a ureteral catheter that was placed cystoscopically, a renal pelvis urine culture was taken and subsequently 10 mL of betadine solution was instilled into the collecting system. Gentamicin in normal saline (80 mg/3 L) was utilized as the irrigant fluid for the first 6 L of irrigation. From this cohort, 57% patients were women and mean age was 60 ± 14 years. About 23% of patients were diabetic and 55% were hypertensive. Seventy percent of patients had stone burden >2 cm and no patients had stone burden <1 cm. Fifteen patients had positive urine cultures treated preoperatively, while four patients had contaminated cultures. All patients were treated with our antibiotic irrigation and betadine protocol regardless of preoperative cultures or antibiotics. Mean baseline creatinine level was 0.95 ± 0.41, with a mean change of 0.18 at postoperative day 1. Of the 15 (26%) of 56 patients with a systemic inflammatory response syndrome response (two of following four criteria: white blood cells <4 or >12; heart rate >90; hypothermia <96.8°F or hyperthermia >100.4°F; and respiratory rate >20), only six patients (11%) were febrile and two patients had positive blood cultures (3%). There were no adverse reactions to the betadine or antibiotic irrigation. We present here our initial experience of a new technique for renal pelvis sterilization and its safety and feasibility using intrarenal instillation of betadine and antibiotic irrigation. No Clinical Trial Registration number applicable.

The association of immediate post cardiac arrest diastolic hypertension and survival following pediatric cardiac arrest.

AIM: In-hospital cardiac arrest occurs in >5000 children each year in the US and almost half will not survive to discharge. Animal data demonstrate that an immediate post-resuscitation burst of hypertension is associated with improved survival. We aimed to determine if systolic and diastolic invasive arterial blood pressures immediately (0-20 min) after return of spontaneous circulation (ROSC) are associated with survival and neurologic outcomes at hospital discharge. METHODS: This is a secondary analysis of the Pediatric Intensive Care Quality of CPR (PICqCPR) study of invasively measured blood pressures during intensive care unit CPR. Patients were eligible if they achieved ROSC and had at least one invasively measured blood pressure within the first 20 min following ROSC. Post-ROSC blood pressures were normalized for age, sex and height. "Immediate hypertension" was defined as at least one systolic or diastolic blood pressure >90th percentile. The primary outcome was survival to hospital discharge. RESULTS: Of 102 children, 70 (68.6%) had at least one episode of immediate post-CPR diastolic hypertension. After controlling for pre-existing hypotension, duration of CPR, calcium administration, and first documented rhythm, patients with immediate post-CPR diastolic hypertension were more likely to survive to hospital discharge (79.3% vs. 54.5%; adjusted OR = 2.93; 95%CI, 1.16-7.69). CONCLUSIONS: In this post hoc secondary analysis of the PICqCPR study, 68.6% of subjects had diastolic hypertension within 20 min of ROSC. Immediate post-ROSC hypertension was associated with increased odds of survival to discharge, even after adjusting for covariates of interest.