Importance of Pediatric Studies in SARS-CoV-2 Vaccine Development.

Vaccination efforts against COVID-19 must include the pediatric population, not only to protect children and their families from the virus, but also to support a safe return to in-person schooling. Given the novel methodologies and targets used in the COVID-19 vaccines and the potential for multisystem inflammatory syndrome-children, it is insufficient to extrapolate safety and efficacy data between different vaccine candidates or from adult studies. Adequate enrollment in pediatric studies for COVID-19 vaccines is crucial. The Pediatric Pharmacy Association supports continued research, surveillance, and transparency for COVID-19 vaccines in the pediatric population, including those younger than 12 years of age.

Standardization of Concentrations for Extemporaneously Compounded Oral Liquid Medications.

Many children require medications in oral liquid dosage forms when their dose does not conform to a manufactured tablet or capsule size. Liquid medications are also needed for children who are unable to swallow solid dosage forms. This statement from the PPAG is in support of standardizing the concentrations of extemporaneous formulations of liquid medications for the benefits of safety, accuracy, and overall communication between providers.

Avoidance of Overt Precipitation and Patient Harm Following Errant Y-Site Administration of Calcium Chloride and Parenteral Nutrition Compounded With Sodium Glycerophosphate.

Calcium phosphate precipitates present 1 of many challenges associated with parenteral nutrition (PN) compounding. Extensive research has led to the establishment of solubility curves to guide practitioners in the prescription and preparation of stable PN. Concurrent dosing of intravenous products via y-site administration with PN can alter the chemical balance of the solution and modify solubility. Medications containing calcium or phosphate should not be administered in the same line as PN, due to the high potential for precipitation. Herein a case is reported from a pediatric cardiac intensive care unit where a physician ordered the administration of calcium chloride. The bedside nurse added the calcium chloride intermittent infusion as a y-site administration with the patient's PN. The patient's PN had been compounded with sodium glycerophosphate, temporarily available in the United States during a sodium phosphate shortage. The patient did not experience any observable adverse effects from the y-site administration with PN. Following this event, the scenario was replicated to investigate any precipitation risk associated with the y-site administration. Additionally, a separate PN solution containing sodium phosphate rather than glycerophosphate was compounded and used in a laboratory setting to demonstrate the potential for harm had the patient's PN been compounded with an inorganic phosphate source. This replication of the error demonstrates the additional safety gained in relation to precipitation risk when PN solutions are compounded with sodium glycerophosphate in place of sodium phosphate.

Frequency and Severity of Parenteral Nutrition Medication Errors at a Large Children's Hospital After Implementation of Electronic Ordering and Compounding.

INTRODUCTION: The Institute for Safe Medication Practices has stated that parenteral nutrition (PN) is considered a high-risk medication and has the potential of causing harm. Three organizations--American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), American Society of Health-System Pharmacists, and National Advisory Group--have published guidelines for ordering, transcribing, compounding and administering PN. These national organizations have published data on compliance to the guidelines and the risk of errors. The purpose of this article is to compare total compliance with ordering, transcription, compounding, administration, and error rate with a large pediatric institution. METHOD: A computerized prescriber order entry (CPOE) program was developed that incorporates dosing with soft and hard stop recommendations and simultaneously eliminating the need for paper transcription. A CPOE team prioritized and identified issues, then developed solutions and integrated innovative CPOE and automated compounding device (ACD) technologies and practice changes to minimize opportunities for medication errors in PN prescription, transcription, preparation, and administration. Thirty developmental processes were identified and integrated in the CPOE program, resulting in practices that were compliant with A.S.P.E.N. safety consensus recommendations. Data from 7 years of development and implementation were analyzed and compared with published literature comparing error, harm rates, and cost reductions to determine if our process showed lower error rates compared with national outcomes. RESULTS: The CPOE program developed was in total compliance with the A.S.P.E.N. guidelines for PN. The frequency of PN medication errors at our hospital over the 7 years was 230 errors/84,503 PN prescriptions, or 0.27% compared with national data that determined that 74 of 4730 (1.6%) of prescriptions over 1.5 years were associated with a medication error. Errors were categorized by steps in the PN process: prescribing, transcription, preparation, and administration. There were no transcription errors, and most (95%) errors occurred during administration. CONCLUSION: We conclude that PN practices that conferred a meaningful cost reduction and a lower error rate (2.7/1000 PN) than reported in the literature (15.6/1000 PN) were ascribed to the development and implementation of practices that conform to national PN guidelines and recommendations. Electronic ordering and compounding programs eliminated all transcription and related opportunities for errors.

Failure of nasogastric omeprazole suspension in pediatric intensive care patients.

OBJECTIVES: To determine the efficacy of nasogastric administration of omeprazole suspension in raising the gastric pH >4 in critically ill pediatric patients and to determine the most appropriate dosing regimen for this indication. DESIGN: Open-label pharmacodynamic study. SETTING: Twenty-six bed tertiary-care pediatric intensive care unit. PATIENTS: Mechanically ventilated children aged 1-18 yrs with an additional risk factor for stress ulcer formation. INTERVENTIONS: Continuous gastric pH monitoring was performed during administration and dose titration of omeprazole suspension to achieve the goal of gastric pH >4 for greater than 75% of the dosing interval. MEASUREMENTS AND MAIN RESULTS: Data were collected from 18 patients. Subjects were categorized based on the pharmacologic response to nasogastric administration of 1 mg/kg omeprazole suspension (maximum 20 mg) as rapid (n = 9), late (n = 5), and nonresponders (n = 4). Rapid responders required 0.72 mg/kg per day omeprazole suspension to achieve adequate gastric pH elevation for stress ulcer prophylaxis. Late responders required 1.58 mg/kg per day. Nonresponders did not achieve adequate elevation of gastric pH for stress ulcer prophylaxis. CONCLUSIONS: Nasogastric administration of omeprazole suspension has variable efficacy in critically ill pediatric patients. Half of the studied subjects either required significant dose titrations to achieve gastric acid suppression or did not respond to nasogastric administration of omeprazole suspension.

Drug shortages and implications for pediatric patients.

Drug shortages in the United States continue to be a significant problem that negatively impacts pediatric patients of all ages. These shortages have been associated with a higher rate of relapse among children with cancer, substitution of less effective agents, and greater risk for short- and long-term toxicity. Effective prevention and management of any drug shortage must include considerations for issues specific to pediatric patients; hence, the Pediatric Pharmacy Advocacy Group (PPAG) strongly supports the effective management of shortages by institutions caring for pediatric patients. Recommendations published by groups such as the American Society of Health-System Pharmacists and the American Society for Parenteral and Enteral Nutrition should be incorporated into drug shortage management policies. PPAG also supports the efforts of the Food and Drug Administration (FDA) to not only address but prevent drug shortages caused by manufacturing and quality problems, delays in production, and discontinuations. Prevention, mitigation, and effective management of drug shortages pose significant challenges that require effective communication; hence, PPAG encourages enhanced and early dialogue between the FDA, pharmaceutical manufacturers, professional organizations, and health care institutions.

Standard dose development for medications commonly used in the neonatal intensive care unit.

OBJECTIVES: To establish standardized, rounded doses of medications for neonates in the neonatal intensive care unit (NICU) through a multi-institutional peer-reviewed process. METHODS: Pediatric faculty and pediatric pharmacy residents from the Ernest Mario School of Pharmacy (Piscataway, NJ) conducted a systematic review of rounded, weight-based medication information for neonatal patients from September 2010 to April 2011. After initial review, an expanded workgroup of expert neonatal pharmacy clinicians from academic institutions throughout the United States were invited to conduct a final review. The workgroup identified 74 medications or indications in the NICU. Recommended standardized doses were established for discrete weight categories at workgroup consensus web meetings conducted from June to December 2011. Workgroup recommendations were cross-referenced with published neonatal pharmacology resources. Consensus was obtained when references provided insufficient information on medication information. RESULTS: Seventeen weight categories of increasing ranges were used, from 40 g for the lowest weights (e.g., 410-450 g) to 840 g for the highest weights (e.g., 3660-4500 g). Medications were divided into 3 categories of administration routes: oral (n = 4), intermittent intravenous (n = 64), and other (e.g., intramuscular; n=6). A significant majority of standardized doses (84%) were within 15% of their corresponding weight-calculated dose. CONCLUSIONS: Establishment of a portfolio of standardized, rounded doses of medications commonly used in the NICU was feasibly established by a multi-institutional peer review process, with the great majority of standardized doses being within clinically acceptable ranges of administration. Use of standardized, rounded doses for reduction in dosing errors may be feasible on a systematic level.

Practice-based validation of calcium and phosphorus solubility limits for pediatric parenteral nutrition solutions.

In an effort to maximize the precipitation-free delivery of calcium and phosphorus to neonates, Fitzgerald and MacKay published in 1986 the results of empirical determination of calcium-phosphate saturation curves for a number of parenteral nutrition (PN) solutions. The saturation curves generated from these investigations have been used to formulate thousands of PN solutions. The curves were developed testing only calcium and phosphate without other components added to PN solutions. The authors reviewed 38,019 PN orders from 2007-2010 and plotted the calcium and phosphate concentrations for each solution in relation to the published curves to assess the practical validity of the curves. The solutions reviewed were compounded using standard weight ranges for electrolytes, trace minerals, and vitamins. The solutions were evaluated for precipitation using standards for visual compatibility against a black and white background. There were no visual precipitates found in the 38,019 PN solutions. All calcium and phosphorus concentrations plotted below the precipitation limits predicted by the published curves despite a large range of concentrations of electrolytes and minerals. There has always been concern about extrapolating data from solubility curves that were developed empirically from a limited number of test solutions based on the few variables of calcium, phosphorus, amino acid concentration, and presence of cysteine HCl and/or fat emulsion. This experience validates the calcium and phosphorus solubility limits represented by published curves. Moreover, the findings support the concept that principal variables governing calcium and phosphorus precipitation in PN solutions are calcium, phosphorus, amino acid concentrations, temperature, and pH.

A survey of the utilization of anti-pseudomonal beta-lactam therapy in cystic fibrosis patients.

The purpose of this study was to characterize the utilization of anti-pseudomonal beta-lactam antibiotics in the treatment of acute pulmonary exacerbations (APE) among Cystic Fibrosis Foundation (CFF)-accredited care centers. An anonymous national cross-sectional survey of CFF-accredited care centers was performed using an electronic survey tool (SurveyMonkey.com®). One hundred and twenty-one of 261 centers completed the survey (46%) representing 56% (14,856/26,740) of patients in the CFF Patient Registry. One hundred and nineteen of 121 (98%) respondents reported using beta-lactams for the treatment of APE. Intermittent dosing regimens constituted 155/167 (93%) reported regimens, while extended infusions were 12/167 (7%). Ceftazidime was the most commonly utilized beta-lactam comprising 74/167 (44%) of all infusions (intermittent and extended) of which 70/74 (95%) were intermittent infusions. The majority of intermittent ceftazidime regimens (56/70; 80%) were at doses lower than CFF and European guidelines recommended doses. In conclusion, a great majority of respondents use intermittent anti-pseudomonal beta-lactam antibiotics, with over half of respondents utilizing lower than guidelines recommended doses. While this is of concern, it is not known if optimization of dosing strategies according to guidelines recommendations will result in clinical benefit.

Population pharmacokinetic and pharmacodynamic modeling of high-dose intermittent ticarcillin-clavulanate administration in pediatric cystic fibrosis patients.

BACKGROUND: The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)-approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen. OBJECTIVES: The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF). METHODS: This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included ≥30% for bacteriostasis and ≥50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses. RESULTS: A total of 127 patients (age, 0-19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 µg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 µg/mL. CONCLUSIONS: The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs <16 µg/mL. Bacteriostatic and bactericidal effects were not frequently achieved among P. aeruginosa isolates with MICs >32 µg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen.

High dose intermittent ticarcillin-clavulanate administration in pediatric cystic fibrosis patients.

BACKGROUND: The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400mg/kg/day divided every 6h, (maximum 24 g/day). This dosing strategy is higher than the Cystic Fibrosis Foundation (CFF) recommendations and the Food and Drug Administration (FDA) approved package labeling. The purpose is to determine the safety of this dosing regimen. METHODS: A retrospective study of pediatric cystic fibrosis (CF) patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Baseline and follow-up laboratory parameters were recorded. Statistical analysis was performed. RESULTS: 127 patients met inclusion criteria. The mean (+ or - SD) ticarcillin dose was 3.5 g (+ or - 2.16) every 6 h; while the mean (+ or - SD) total ticarcillin dose was 13.5 g (+ or - 6.5) per day. No significant differences occurred in liver function tests, white blood count, and platelet count from baseline. Serum creatinine showed a statistically significant decrease from baseline. CONCLUSIONS: Higher than FDA approved doses of ticarcillin-clavulanate may be safely used in the treatment of exacerbations in pediatric cystic fibrosis patients.

Improving Pediatric Outcomes through Intravenous and Oral Medication Standardization.

BACKGROUND: Standardization is an invaluable tool to promote safety, improve care, and decrease costs, which ultimately improves outcomes. However, a pediatric setting presents unique challenges with its wide variety of weights, medications, and needs that are distinctly different. Our goal was to develop and implement standards in complex high risk areas that show improved outcomes and safety. PROGRAM DESCRIPTION: A computerized prescriber order entry program with decision support for pediatrics was developed for parenteral nutrition prescribing. The program included dosing, calculations, calcium phosphate compatibility checks, automated IV compounder interface, osmolarity route calculation, end product testing verification, aluminum exposure and many other quality improvements. This same electronic order program, interface to sterile compounders, and end product testing was used to standardize and make common non-manufactured intravenous solutions. The drip compounding process was reengineered to include standard concentrations, label changes, and beta-testing of a smart syringe pump with dosing ranges for pediatrics. Common standard oral doses were developed along with standard oral formulations. CONCLUSIONS: Total parenteral nutrition (TPN) error rates decreased from 7% to less than 1% and compatibility issues decreased from 36 to 1 per year. Neonatal osteopenia rates decreased from 15% to 2%. Results from end product testing of TPN solutions were within USP standards showing statistical correlation (p<0.001). Intravenous standardization decreased error rates by 15% and compounding time decreased by 12 minutes (64%). Drip standardization allowed for drug concentration and smart pump standardization and decreased drip errors by 73% from 3.1 to 0.8 per 1000 doses. Compounding errors decreased from 0.66 to 0.16 per 1000 doses and ten-fold errors decreased from 0.41 to 0.08 per 1000 doses. Eleven oral liquids, including 329 different doses, were standardized, decreasing the number of doses to 59 (83% change). This decreased workload 15%, wastage 90%, improved turnaround time 32%, and saved $15,000/year. One hundred evidence-based standard oral formulations were developed and used in 22 different hospitals.

Standard drug concentrations and smart-pump technology reduce continuous-medication-infusion errors in pediatric patients.

OBJECTIVE: To determine if combining standard drug concentrations with "smart-pump" technology reduces reported medication-infusion errors. DESIGN: Preintervention and postintervention comparison of reported medication errors related to infusion therapies during the calendar years 2002 and 2003. SETTING: A 242-bed university-affiliated tertiary pediatric hospital. INTERVENTION: Change in continuous-medication-infusion process, comprising the adoption of (1) standard drug concentrations, (2) "smart" syringe pumps, and (3) human-engineered medication labels. MAIN OUTCOME MEASURES: Comparison of reported continuous-medication-infusion errors before and after the intervention. RESULTS: The number of reported errors dropped by 73% for an absolute risk reduction of 3.1 to 0.8 per 1000 doses. Preparation errors that occurred in the pharmacy decreased from 0.66 to 0.16 per 1000 doses; the number of 10-fold errors in dosage decreased from 0.41 to 0.08 per 1000 doses. CONCLUSIONS: The use of standard drug concentrations, smart syringe pumps, and user-friendly labels reduces reported errors associated with continuous medication infusions. Standard drug concentrations can be chosen to allow most neonates to receive needed medications without concerns related to excess fluid administration.

The accuracy and precision of measuring Lorazepam from three liquid preparations.

OBJECTIVES: Commercially available lorazepam solution contains both polyethylene glycol (PEG) and propylene glycol. When large doses are administered for deep sedation in the pediatric intensive care unit (PICU), PEG may cause diarrhea, and the accumulation of propylene glycol may result in toxicity. These adverse effects may be avoided by preparing a slurry from crushed lorazepam tablets suspended in water immediately prior to administration. This slurry, which is extemporaneously prepared at bedside by nurses, lacks a suspending agent, and, therefore, the rapid settling of drug particles may produce suspensions that are not homogeneous. Thus, there may be significant inaccuracy and imprecision in dosage measurement. The objective of this study was to compare the accuracy and precision of lorazepam dosage measurement from three liquid preparations: 1) tablet slurry prepared at bedside by a nurse; 2) lorazepam suspension extemporaneously prepared by a pharmacist; and 3) the commercially available lorazepam solution. METHODS: Sixteen PICU nurses measured three doses of lorazepam (0.5 mg, 1.5 mg, 3.5 mg) in triplicate from each of the three liquid preparations using oral syringes. PICU nurses prepared the slurry by mixing crushed lorazepam tablet(s) with water and drawing up the appropriate dose in an oral syringe. Additionally, nurses drew up the appropriate dose from a pharmacist-prepared lorazepam suspension (1 mg/mL) and the commercially available lorazepam solution (2 mg/mL). All samples were analyzed by HPLC and the groups were compared using two-way ANOVA. RESULTS: Dosage accuracy for the slurry (91.2 ± 7.8%) and suspension (109.2 ± 4.9%) were significantly different from the commercially available solution (101.5 ± 3.1%) (P < .05). Imprecision in dosage measurement, as determined by the relative standard deviation, was greatest for the slurry (8.6%) as compared to the suspension (4.5%) and commercially available solution (3.0%). CONCLUSIONS: Dosage measurement from lorazepam slurry and suspension led to significant deviation from the intended dose. Dosage measurement using the slurry was the least precise among the three preparations.