Stability and compatibility of an intramuscular fetal anesthetic cocktail for fetal intervention.

INTRODUCTION: To evaluate chemical stability and physical compatibility when combining fentanyl, rocuronium, and atropine in a fixed ratio to support intramuscular drug delivery during fetal intervention and surgery. METHODS: A highly concentrated combination of fentanyl, rocuronium, and atropine was created based on common prescribing practices at a maternal fetal care center. Chemical stability testing was completed using liquid chromatograph mass spectrometry-mass spectrometry (LC/MS-MS) to detect and quantitate atropine, rocuronium, and fentanyl, with fentanyl-d5 being an internal standard at 6-, 12, 24-, and 36-hours following sample preparation. Physical compatibility testing was completed using United State Pharmacopeia (USP)<788> recommended analytical technique of light obscuration (LO) in addition to novel backgrounded membrane imaging (BMI) at 6- and 24-hours following sample preparation. Physical compatibility was determined using USP<788> particle count limits for both techniques. RESULTS: Based on LC/MS-MS results, the samples retained expected medication concentrations at all time points tested. For physical compatibility testing, the particle counts met criteria to be considered compatible per USP<788> large volume particle count thresholds at 6 hours by both methods but exceeded tolerable thresholds at 24 hours. DISCUSSION/CONCLUSION: The combination of rocuronium, fentanyl, and atropine for intramuscular fetal administration are physically compatible and chemically stable for 6 hours.

Successful Management of Fetal Torsades de Pointes and Long QT Syndrome by a Cardio-Obstetrical Team.

A 32-week fetus with tachycardia and bradycardia, diagnosed with torsades de pointes, atrioventricular block, and sinus bradycardia due to a de novo KCNH2 mutation was successfully managed by a cardio-obstetrical team. Maternal/fetal pharmacogenomic testing resulted in appropriate drug dosing without toxicity and delivery of a term infant in sinus rhythm.

Physical Compatibility of Y-site Pediatric Drug Administration: A Call for Question of US Pharmacopeia Standards.

OBJECTIVE: To evaluate the physical intravenous Y-site compatibility of 29 combinations of medications at commonly used pediatric concentrations using both existing and novel techniques. METHODS: Medication combinations included were selected by a varied group of pediatric inpatient pharmacists, and then assessed by 3 independent reviewers for existing literature. For each combination, 2 different medications were mixed together in a 1:1 ratio and incubated at room temperature for 4 hours to simulate Y-site administration. Each sample was then analyzed using the US Pharmacopeia (USP) <788> recommended analytical technique of light obscuration (LO) in addition to novel flow imaging (FI) microscopy and backgrounded membrane imaging (BMI). Physical compatibility was determined using USP chapter <788> large volume particle count limits for all techniques. RESULTS: A total of 29 different medication combinations were studied. Five combinations met criteria for compatibility by all 3 techniques. The remaining 24 combinations reached the threshold to be considered incompatible by at least 1 of the 3 techniques. Light obscuration, BMI, and FI identified 14%, 59%, and 76% of combinations as incompatible, respectively. All samples deemed incompatible by LO were also incompatible by at least 1 of the other 2 techniques. Flow imaging and BMI results agreed in 69% of samples tested. CONCLUSIONS: Most combinations tested were found to be incompatible by at least 1 of the 3 instruments used. Light obscuration appears to have reduced accuracy for identifying particulate resulting in physical medication incompatibility when compared with the novel techniques of FI and BMI.

Physical compatibility of medications with concentrated neonatal and pediatric parenteral nutrition: A simulated Y-site drug compatibility study.

BACKGROUND: The physical intravenous Y-site compatibility of 15 different medications with highly concentrated neonatal and pediatric parenteral nutrition (PN) compounds is described, using existing and novel methods. METHODS: PN formulations were developed based on common prescribing practices in a 400+-bed freestanding children's hospital. Medications at commonly used pediatric concentrations were mixed in a 1:1 ratio with both pediatric and neonatal PN formulations and incubated at room temperature for 4 h to simulate Y-site administration. Samples were then analyzed using the light obscuration (LO) technique, as recommended by United States Pharmacopeia (USP) chapter 788, in addition to novel flow imaging (FI) microscopy and backgrounded membrane imaging (BMI). Physical compatibility was determined using USP 788 particle count limits for all techniques. RESULTS: Most combinations were found to be compatible per USP 788 thresholds. Pediatric PN was incompatible by at least two methods with cisatracurium 2 mg/ml, sildenafil 0.8 mg/ml, furosemide 10 mg/ml, and ketamine 10 mg/ml. Neonatal PN was incompatible by at least two methods with cisatracurium 2 mg/ml and furosemide 10 mg/ml. Overall, results for 20 of the 30 combinations (66%) agreed across all three methods. FI and BMI results agreed for 22 of 30 combinations. LO agreed with FI in 25 of 30 combinations, and BMI and LO results agreed in 23 of 30 combinations. CONCLUSION: Most combinations tested were found to be compatible across all methods. Novel methods of FI and BMI seem useful to further evaluate LO findings and improve accuracy of particle counts when assessing PN-medication combinations.

Effects of Transportation of IV Bags Containing Protein Formulations Via Hospital Pneumatic Tube System: Particle Characterization by Multiple Methods.

In hospitals, often drug products in intravenous (IV) bags are transported via pneumatic tube systems (PTS). The goal of this study was to evaluate the effects of such transportation of protein products on particle formation in polyvinyl chloride (PVC) and polyolefin (PO) IV bags, containing either IV saline or dextrose. We studied intravenous immunoglobulin (IVIG) and a monoclonal antibody (mAb). Particles were quantified with flow imaging, light obscuration and nanoparticle tracking analysis. PTS transportation of IVIG caused large increases in protein particle concentrations, with much greater increases observed in saline than in dextrose. The increases were greater in IV solutions in PO than those in PVC bags. With the mAb, PTS transportation in saline caused increases in protein particle levels in PO bags, but not in PVC bags. Transportation in dextrose did not result in significant increases in mAb particle concentrations in IV bags made of either material. Overall, the results document that the PTS transportation can result in large increases in protein particles and that magnitude of these increases depends the protein itself, the bag material and the IV solution. The main conclusion is that protein products in IV solutions should not be transported in hospital PTS.

Compatibility of medications with intravenous lipid emulsions: Effects of simulated Y-site mixing.

PURPOSE: To determine the physical intravenous Y-site compatibility of 19 commonly used medications at pediatric concentrations with 3 different types of lipid emulsion. METHODS: Medications at commonly used pediatric concentrations were mixed in a 1:1 ratio with lipid emulsions (Intralipid, Nutrilipid, and Smoflipid) and incubated at room temperature for 4 hours to simulate Y-site administration. Each sample was then diluted with particle-free water and analyzed using the analytical technique of light obscuration recommended in United States Pharmacopeia (USP) general information chapter 729 (USP <729>). Physical compatibility was determined by measuring the percentage of fat residing in globules larger than 5 µm (PFAT5) per USP <729> recommendations. RESULTS: Most combinations tested were physically compatible based on USP <729> regulations. Incompatibilities differed for the different brands of lipid emulsion. The two combinations that met USP <729> criteria for physical incompatibility were cisatracurium 2 mg/mL with Intralipid and gentamicin 2 mg/mL with Smoflipid. CONCLUSION: Three different lipid emulsions were physically compatible at the Y site with the majority of medications tested. Data regarding Y-site compatibility for one lipid emulsion product cannot be safely extrapolated to another without additional testing.

Diuretic Use and Subsequent Electrolyte Supplementation in a Level IV Neonatal Intensive Care Unit.

OBJECTIVES: To evaluate the relationship between diuretic use, serum electrolyte concentrations, and supplementation requirements in infants admitted to the neonatal intensive care unit. METHODS: This was a single-center retrospective cohort study conducted in a freestanding children's hospital Level IV NICU. Data were collected for all infants younger than 6 months, admitted to the NICU between January 2015 and May 2017, who received 2 or more consecutive doses of furosemide, chlorothiazide, hydrochlorothiazide, and/or hydrochlorothiazide/spironolactone. The primary outcome was the composite of the incidence of electrolyte abnormalities and/or electrolyte supplementation requirement within 30 days of diuretic exposure. RESULTS: A total of 72 patients met inclusion criteria, with a median gestational age of 30 weeks. Overall, 92% of patients exposed to diuretics experienced derangement in at least 1 serum electrolyte and/or required electrolyte supplementation during diuretic therapy. Patients born at 36 to 41 weeks' gestational age, receiving thiazide diuretics, experienced a significantly lower rate of the primary outcome (37%, p ≤ 0.001). The most common electrolytes affected by diuretic use were potassium and bicarbonate, with the highest incidence of the primary outcome for potassium occurring in patients receiving furosemide (p = 0.0196). Last, the median total daily dose of chlorothiazide in patients with an adverse event was 15 mg/kg/day, compared with 10 mg/kg/day in patients without an adverse event (p = 0.0041). CONCLUSIONS: Use of diuretics in young infants is likely to cause electrolyte derangements and/or require electrolyte supplementation. Patients born at earlier gestational ages may be at higher risk for developing such adverse effects.

DEHP Nanodroplets Leached From Polyvinyl Chloride IV Bags Promote Aggregation of IVIG and Activate Complement in Human Serum.

Concerns regarding the impact of subvisible particulate impurities on the safety and efficacy of therapeutic protein products have led manufacturers to implement strategies to minimize protein aggregation and particle formation during manufacturing, storage, and shipping. However, once these products are released, manufacturers have limited control over product handling. In this work, we investigated the effect of di(2-ethylhexyl) phthalate (DEHP) nanodroplets generated in polyvinyl chloride (PVC) bags of intravenous (IV) saline on the stability and immunogenicity of IV immunoglobulin (IVIG) formulations. We showed that PVC IV bags containing saline can release DEHP droplets into the solution when agitated or transported using a pneumatic tube transportation system in a clinical setting. We next investigated the effects of emulsified DEHP nanodroplets on IVIG stability and immunogenicity. IVIG adsorbed strongly to DEHP nanodroplets, forming a monolayer. In addition, DEHP nanodroplets accelerated IVIG aggregation in agitated samples. The immunogenicity of DEHP nanodroplets and IVIG aggregates generated in these formulations were evaluated using an in vitro assay of complement activation in human serum. The results suggested DEHP nanodroplets shed from PVC IV bags could reduce protein stability and induce activation of the complement system, potentially contributing to adverse immune responses during the administration of therapeutic proteins.

Evaluation of prolonged epidural chloroprocaine for postoperative analgesia in infants.

STUDY OBJECTIVE: To describe the use and adverse effects of chloroprocaine for epidural analgesia in young infants for infusion durations greater than 3.5 hours. DESIGN: A retrospective cohort review of the electronic medical record over a 14-month period. SETTING: The level IV neonatal intensive care unit of a 414-bed free-standing children's hospital. PATIENTS: Eighteen infants (mean age, 1.7 ± 1.8 months [0.03-6.3]; mean weight, 3.8 ± 1.3 kg [1.56-6.9]; n = 10 [55%] males) received 1% chloroprocaine for epidural analgesia postoperatively for up to 96-hour duration and met criteria for inclusion. MEASUREMENTS: Dosing requirements, placement of epidural catheter, supplementary analgesic therapy, respiratory support, vital signs, and incidence of adverse events associated with local anesthetics were collected. MAIN RESULTS: Epidural catheter placement was caudal (n = 8), lumbar (n = 6), or thoracic (n = 4). Mean operative time was 2.48 ± 1 hour (1-5). Initial chloroprocaine dose was 1.3 ± 0.5 mL/h (0.4-2.5) (3.5 ± 1 mg/kg per hour [1.4-5]) with a maximum dose of 1.5 ± 0.6 mL/h (0.4-3) (4.2 ± 1.1 mg/kg per hour [2.2-6.1]). Duration of epidural analgesia was 48.3 ± 21.5 hours (10-96). Duration of epidural infusion did not influence dosing requirement, suggesting the absence of drug tachyphylaxis. All patients received intermittent doses of opioid and nonopioid pain medications while receiving chloroprocaine. Two mechanically ventilated patients required continuous infusion of opioids. No adverse events were directly attributed to chloroprocaine use. CONCLUSION: Epidural 1% chloroprocaine, in doses of 0.4-3 mL/h (1.5-6.1 mg/kg per hour), was well tolerated in both mechanically ventilated and spontaneously breathing infants for up to 96 hours with no identified adverse effects or tachyphylaxis.

Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.

PURPOSE: The development and use of a decision support tool to help formulate recommendations for dosing of commonly prescribed medications in critically ill obese children are described. METHODS: Medications prescribed in 2010 to critically ill infants and children (younger than 18 years) were identified from the Pediatric Health Information System. The most commonly prescribed and therapeutically monitored medications were extracted. Supportive evidence for obesity dosing was identified through a standardized computerized search involving medical subject heading terminology and age filters using PubMed and Ovid. A usefulness scoring system was developed to rate the strength and applicability of the literature to critically ill obese children. A decision supporttool was then created to aid in the formulation of a dosing weight for each medication based on the usefulness score, published pharmacokinetic properties, clinical studies available in the primary literature, and consideration of clinical consequences of underdosing or overdosing. RESULTS: A total of 113 medications were evaluated, and 122 discrete citations, supporting 66 medications, were reviewed. Seventy-two percent of citations had general obesity dosing information, and 13% had pediatric-specific information. The overall mean usefulness score was 5.1±4.7 (median, 7). The decision support tool was incorporated to make final dosing weight recommendations for obese children. Ultimately, total body weight was recommended for 52 medications, adjusted weight for 43 medications, and ideal body weight for 18 medications. CONCLUSION: The inadequacy of obesity dosing information for most medications commonly ordered for children admitted to a pediatric intensive care unit led to the development of a decision support tool to aid in formulating dosing recommendations.

Comparison of 3 body size descriptors in critically ill obese children and adolescents: implications for medication dosing.

OBJECTIVE: To compare 3 methods of weight determination for medication dose calculations in obese children and to discuss feasibility for use in routine care. METHODS: This was a patient safety and quality improvement study evaluating patients (2-19 years old) admitted to the pediatric intensive care unit during a 13-month period (July 2010-July 2011). Patients identified as obese (≥95th percentile body mass index [BMI] for age), including severely obese (≥99th percentile BMI for age), were included in the weight method comparison portion of this study. Lean body mass estimations, using equations derived by the Peters and Foster methods, were compared to ideal body weight estimates by using the BMI method. Absolute differences between values generated by the 3 methods, intraclass correlation (ICC), and Bland-Altman plots were calculated. RESULTS: A total of 1369 patients met initial criteria; 176 met criteria for the dosing weight comparison (age ± SD = 9.28 ± 5 years; actual weight ± SD = 55.5 ± 33.9 kg; 46% female). Sixty were severely obese and 116 were obese. Mean ICC between methods was 0.968 (95% Confidence interval (CI): 0.959, 0.975). The Peters method estimated higher weights than the Foster or BMI method. Bland-Altman plots illustrated good agreement between methods in children with weight below 50 kg, but decreased agreement above 50 kg, which was influenced by sex. CONCLUSIONS: All methods demonstrated strong correlation and acceptable agreement in children below 50 kg. Systematic biases were identified in children above 50 kg where variance was higher. The BMI method was least complex to calculate and the most feasible method for daily use.