Pharmacokinetics of Cefepime in Children on Extracorporeal Membrane Oxygenation: External Model Validation, Model Improvement and Dose Optimization.

BACKGROUND: Cefepime is a first-line therapy for Gram-negative infections in children on extracorporeal membrane oxygenation. Cefepime pharmacokinetics (PK) in children on extracorporeal membrane oxygenation still needs to be better established. METHODS: This was a prospective single-center PK study. A maximum of 12 PK samples per patient were collected in children <18 years old on extracorporeal membrane oxygenation who received clinically indicated cefepime. External validation of a previously published population PK model was performed by applying the model in a new data set. The predictive performance of the model was determined by calculating prediction errors. Because of poor predictive performance, a revised model was developed using NONMEM and a combined data set that included data from both studies. Dose-exposure simulations were performed using the final model. Optimal dosing was judged based on the ability to maintain free cefepime concentrations above the minimal inhibitory concentration (MIC) for 68% and 100% of the dosing interval. RESULTS: Seventeen children contributed 105 PK samples. The mean (95% CI) and median (interquartile range) prediction errors were 33.7% (19.8-47.7) and 17.5% (-22.6 to 74.4). A combined data set was created, which included 33 children contributing 310 PK samples. The final improved 2-compartment model included weight and serum creatinine on clearance and oxygenator day and blood transfusion on volume of the central compartment. At an MIC of 8 mg/L, 50 mg/kg/dose every 8 hours reached target concentrations. CONCLUSIONS: Dosing intervals of 8 hours were needed to reach adequate concentrations at an MIC of 8 mg/L. Longer dosing intervals were adequate with higher serum creatinine and lower MICs.

Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study.

Cefepime is a fourth-generation cephalosporin antibiotic with an extended spectrum of activity against many Gram-positive and Gram-negative bacteria. There is a growing need to develop sensitive, small volume assays, along with less invasive sample collection to facilitate pediatric pharmacokinetic clinical trials and therapeutic drug monitoring. The volumetric absorptive microsampling (VAMS™) approach provides an accurate and precise collection of a fixed volume of blood (10 µL), reducing or eliminating the volumetric blood hematocrit assay-bias associated with the dried blood spotting technique. We developed a high-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of cefepime. Sample extraction from VAMS™ devices, followed by reversed-phase chromatographic separation and selective detection using tandem mass spectrometry with a 4 min runtime per sample was employed. Standard curves were linear between 0.1-100 µg/mL for cefepime. Intra- and inter-day accuracies were within 95.4-113% and precision (CV) was < 15 % based on a 3-day validation study. Recoveries ranged from 40.8 to 62.1% and the matrix effect was within 89.5-96.7% for cefepime. Cefepime was stable in human whole blood under assay conditions (3 h at room temperature, 24 h in autosampler post-extraction). Cefepime was also stable for at least 1 week (7 days) at 4 °C, 1 month (39 days) at -20 °C and 3 months (91 days) at -78 °C as dried microsamples. This assay provides an efficient quantitation of cefepime and was successfully implemented for the analysis of whole blood microsamples in a pediatric clinical trial.

A patient-centric liquid chromatography-tandem mass spectrometry microsampling assay for analysis of cannabinoids in human whole blood: Application to pediatric pharmacokinetic study.

Medical cannabis is increasingly used for the treatment of various ailments in children and adults. Three major cannabinoids in cannabis are delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). There is a growing need to develop and utilize a patient-centric blood microsampling methodology to enable clinical trials and facilitate therapeutic drug monitoring. We have employed the volumetric absorptive microsampling (VAMS™) devices that enables accurate and precise collection of a fixed volume (20 µL) of blood, minimizing the impact of hematocriton accurate quantitation. We developed an ultra-performance liquid chromatographic method with tandem mass spectrometry detection for the quantification of three cannabinoids (THC, CBD, and CBN) employing deuterium labelled internal standards (THC-D3, CBD-D3, and CBN-D3). Sample extraction of VAMS™ devices, followed by solid phase extraction, reverse phase chromatographic separation, and selective detection using tandem mass spectrometry with a 6-minute runtime per sample was developed. Standard curves were linear between 1 and 500 ng/mL for THC and 0.5-500 ng/mL for CBD and CBN. Intra-day accuracies were within 91.3-112% while inter-day accuracies were within 94.4-107% with both having precisions (CV (%)) of <13% based on quality control samples in a three day validation study for all three cannabinoids. Analytes were stable in human whole blood under assay conditions (60 h at room temperature and 24 h in autosampler post-extraction). Dried microsamples were stable for one week at 40 °C, two weeks (15 days) under different storage conditions (room temperature, 4, -20 and -78 °C), one month (29 days) at -20 and -78 °C and three months (68 days) at -78 °C. This assay provides an efficient quantitation of THC, CBD, and CBN in VAMS™ devices and is currently being implemented for pediatric clinical trials.

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.

Use of Intravenous Acetaminophen in Children for Analgesia After Spinal Fusion Surgery: A Randomized Clinical Trial.

OBJECTIVES: Opioid pharmacotherapy is the cornerstone of postoperative analgesia. Despite its effectiveness, it has a variety of potential adverse effects. Therefore, a multimodal approach with non-opioid analgesics would be optimal. The aim of this study was to determine if intravenous (IV) acetaminophen would reduce opioid requirements and improve clinical outcomes in children after surgery. METHODS: A single-center, randomized, double-blind study was conducted in 57 children (10-18 years old) undergoing posterior spine fusion surgery between July 2011 to May 2014. All subjects received either acetaminophen or placebo at the end of surgery, followed by repeated doses every 6 hours for a total of 8 doses. RESULTS: In the first 24 postoperative hours, the average opioid consumption was lower for the active group compared with the placebo group (p = 0.02). The total unadjusted time to patient controlled analgesia (PCA) discontinuation was also longer in the placebo group than the active group (90 hours vs. 73 hours, p = 0.02); however, this was not statistically significant after normalizing for body weight. Additionally, time to first solid intake was longer without the use of acetaminophen (69 hours vs. 49 hours, p = 0.01). CONCLUSIONS: Postoperative use of IV acetaminophen was associated with earlier time to diet advancement and discontinuation of IV analgesics and may result in lower opioid consumption.

Nurses' Attitudes Toward Clinical Research: Experience of the Therapeutic Hypothermia After Pediatric Cardiac Arrest Trials.

OBJECTIVES: To understand factors affecting nurses' attitudes toward the Therapeutic Hypothermia After Pediatric Cardiac Arrest trials and association with approach/consent rates. DESIGN: Cross-sectional survey of pediatric/cardiac intensive care nurses' perceptions of the trials. SETTING: Study was conducted at 16 of 38 self-selected study sites. SUBJECTS: Pediatric and cardiac intensive care nurses. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion of nurses with positive perceptions, as defined by agree or strongly agree with the statement "I am happy to take care of a Therapeutic Hypothermia after Pediatric Cardiac Arrest patient". Associations between perceptions and study approach/consent rates were also explored. Of 2,241 nurses invited, 1,387 (62%) completed the survey and 77% reported positive perceptions of the trials. Nurses, who felt positively about the scientific question, the study team, and training received, were more likely to have positive perceptions of the trials (p < 0.001). Nurses who had previously cared for a research patient had significantly more positive perceptions of Therapeutic Hypothermia After Pediatric Cardiac Arrest compared with those who had not (79% vs 54%; p < 0.001). Of the 754 nurses who cared for a Therapeutic Hypothermia After Pediatric Cardiac Arrest patient, 82% had positive perceptions, despite 86% reporting it required more work. Sixty-nine percent believed that hypothermia reduces brain injury and mortality; sites had lower consent rates when their nurses believed that hypothermia was beneficial. Institution-specific approach rates were positively correlated with nurses' perceptions of institutional support for the trial (r = 0.54; p = 0.04), ICU support (r = 0.61; p = 0.02), and the importance of conducting the trial in children (r = 0.61; p = 0.01). CONCLUSIONS: The majority of nurses had positive perceptions of the Therapeutic Hypothermia After Pediatric Cardiac Arrest trials. Institutional, colleague, and study team support and training were contributing factors. Despite increased work, nurses remained enthusiastic demonstrating that studies with intensive bedside nursing procedures are feasible. Institutions whose nurses believed hypothermia was beneficial had lower consent rates, suggesting that educating nurses on study rationale and equipoise may enhance study participation.

A pragmatic checklist to identify pediatric ICU patients at risk for cardiac arrest or code bell activation.

BACKGROUND: In-hospital cardiac arrest is a rare event associated with significant morbidity and mortality. The ability to identify the ICU patients at risk for cardiac arrest could allow the clinical team to prepare staff and equipment in anticipation. METHODS: This pilot study was completed at a large tertiary care pediatric intensive care unit to determine the feasibility of a simple checklist of clinical variables to predict deterioration. The daily checklist assessed patient risk for critical deterioration defined as cardiac arrest or code bell activation within 24h of the checklist screen. The Phase I checklist was developed by expert consensus and evaluated to determine standard diagnostic test performance. A modified Phase II checklist was developed to prospectively test the feasibility and bedside provider "number needed to train". RESULTS: For identifying patients requiring code bell activation, both checklists demonstrated a sensitivity of 100% with specificity of 76.0% during Phase I and 97.7% during Phase II. The positive likelihood ratio improved from 4.2 to 43.7. For identifying patients that had a cardiac arrest within 24h, the Phase I and II checklists demonstrated a sensitivity of 100% with specificity again improving from 75.7% to 97.6%. There was an improved positive likelihood ratio from 4.1 in Phase I to 41.9 in Phase II, with improvement of "number needed to train" from 149 to 7.4 providers. CONCLUSIONS: A novel high-risk clinical indicators checklist is feasible and provides timely and accurate identification of the ICU patients at risk for cardiac arrest or code bell activation.

Induction and maintenance of therapeutic hypothermia after pediatric cardiac arrest: efficacy of a surface cooling protocol.

OBJECTIVE: To assess the feasibility, effectiveness, side effects, and adverse events associated with a standardized surface cooling protocol. Induced therapeutic hypothermia after pediatric cardiac arrest is an important intervention. DESIGN: Prospective intervention trial. SETTING: Urban, tertiary care children's hospital. PATIENTS: Twelve pediatric cardiac arrest survivors. INTERVENTIONS: Standardized surface cooling protocol. MEASUREMENTS AND MAIN RESULTS: Patients (age: median, 1.5 yrs; interquartile range, 0.5-6.25; cardiopulmonary resuscitation duration: median, 18 mins; interquartile range, 10-45) were cooled by a standard surface cooling protocol for rapid induction and maintenance of goal rectal temperature (T) 32°C-34°C for 24 hrs, with prospectively defined rescue protocols. Side effects and clinical interventions were recorded. Median time to rectal T ≤34°C was 1.5 (1, 1.5) hrs from cooling initiation and 6 (5, 6.5) hrs from arrest. T was documented every 30 mins. Maintenance target T 32°C-34°C was attained in 78% (414 of 531) of measurements, overshoot hypothermia <32°C in 15% (81 of 531), and overshoot hyperthermia >34°C in 7% (36 of 531). Mean bias between rectal vs. esophageal T was -0.42°C (95% confidence interval, -0.49 to -0.35), and between rectal and bladder T was 0.16°C (95% confidence interval, 0.11-0.22). Side effects observed included: hypokalemia <3.0 mEq/L in 67% of patients and bradycardia <2% for age in 58%. There were no episodes of bleeding or ventricular tachyarrhythmia that required treatment. Six (50%) of 12 patients survived to discharge. CONCLUSIONS: A standard surface cooling protocol achieved rapid induction of hypothermia after pediatric cardiac arrest. During maintenance of hypothermia, 78% of measures were within target T 32°C-34°C. Commonly employed temperature sites (esophageal, rectal, and bladder) were similar. Overshoot hypothermia and associated side effects were common, but there were no serious adverse events attributable to induced therapeutic hypothermia in this case series. Surface cooling protocols to induce and maintain therapeutic hypothermia after pediatric cardiac arrest are potentially feasible.