Mark MacKay

The Solubility of Calcium and Phosphate in Two Specialty Amino Acid Solutions

BACKGROUND The purpose of this study was to determine precipitation limits and construct curves for calcium and phosphorus in parenteral nutrition solutions compounded with specialty amino acid solutions. METHODS The effect of temperature, concentration of amino acids, and pH on the solubility of calcium and phosphate was studied for two specialized amino acid solutions: NephrAmine and HepatAmine. Ten amino acid solutions were manufactured with NephrAmine and 12 with HepatAmine at amino acid concentrations of 0.8%, 1.5%, and 2%. The final dextrose concentration was 10%. Some of the solutions were tested with the additive cysteine hydrochloride, 40 mg cysteine/g of protein, and some were buffered with sodium bicarbonate or hydrochloric acid to model the pH of a combined fat emulsion and total parenteral nutrient (TPN) solution. Calcium gluconate and potassium phosphate were added to test samples of each TPN solution. A range of calcium concentrations of 2.5 to 40 mEq/L and phosphate concentrations of 2.5 to 40 mmol/L were tested. After storage at room temperature (25 degrees C) for 18 hours, solutions were inspected for precipitation. At the end of the 18-hour period, the solutions were held in a water bath at 37 degrees C for 30 minutes and inspected for precipitation and microcrystallization. RESULTS Solubility curves were plotted to represent Ca-PO4 solubility limits before visual or microscopic precipitation. These curves depend on the variables of time, temperature, concentration, and pH. CONCLUSIONS These data and graphs will help the clinical pharmacist estimate Ca-PO4 solubility limits and prevent precipitation of TPN solutions formulated with NephrAmine or Hepatamine.

Correlation of Cholestasis With Serum Copper and Whole-Blood Manganese Levels in Pediatric Patients

Many institutions reduce or eliminate copper (Cu) and manganese (Mn) in parenteral nutrition (PN) solutions when cholestasis develops. Little data exist to support this practice. Fifty-four subjects with known serum Cu, whole-blood Mn, and serum-conjugated bilirubin levels were evaluated in this prospective, observational study. Subjects ranged in weight from 760 g to 65.2 kg. Subjects weighing <25 kg received a daily parenteral dose of 20 microg/kg Cu and 5 microg/kg Mn. Subjects weighing > or =25 kg received a dose of 500 microg/d Cu and 150 microg/d Mn. Cholestasis was defined as a conjugated bilirubin level > or =2 mg/dL. Of the 54 subjects, 20 had cholestasis. Fifteen patients had elevated Cu levels, and 21 had high Mn levels. Seven of the subjects had both high Cu and high Mn levels. The regression model comparing cholestasis as a predictor of high, low, or normal Cu level was not significant (P = .9588). Cholestasis was not a significant predictor of high, low, or normal Mn levels (P = .6533). No correlation between Cu and Mn levels was found. The authors found no significant relationship between conjugated serum bilirubin levels > or =2.0 mg/dL, serum Cu, and whole-blood Mn levels. They found insufficient evidence to support the practice of dosing Mn from a Cu level or vice versa. They recommend obtaining Cu and Mn levels on all pediatric patients who develop cholestasis prior to adjusting parenteral doses and at regular intervals for all long-term PN patients.

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.

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.

Clostridium difficile Infection and Proton Pump Inhibitor Use in Hospitalized Pediatric Cystic Fibrosis Patients

Children with cystic fibrosis (CF) often take proton pump inhibitors (PPIs), which helps improve efficacy of fat absorption with pancreatic enzyme replacement therapy. However, PPI use is known to be associated with Clostridium difficile-(C. diff-) associated diarrhea (CDAD). We retrospectively evaluated the incidence of C. diff infection from all pediatric hospital admissions over a 5-year period at a single tertiary childrens hospital. We found significantly more C. diff-positive stool tests in hospitalized patients with CF compared to patients with no diagnosis of CF. However, use of a PPI was not associated with an increased risk of CDAD in hospitalized CF patients. In summary, C. diff infection is more common in hospitalized pediatric CF patients although PPI use may not be a risk factor for CDAD development in this patient population.

Physical Compatibility of Sodium Glycerophosphate and Calcium Gluconate in Pediatric Parenteral Nutrition Solutions

BACKGROUND The solubility of inorganic calcium and phosphate in parenteral solutions can be complicated in pediatrics due to the dosing of calcium and phosphorus at the saturation point. The purpose of this study was to test the solubility of sodium glycerophosphate (NaGP) with calcium gluconate in pediatric parenteral nutrition (PN) solutions. METHODS Five PN solutions were compounded by adding calcium gluconate at 10, 20, 30, 40, and 50 mEq/L and corresponding concentrations of NaGP at 10, 20, 30, 40, and 50 mmol/L. Each of the 5 solutions was compounded using 1.5% and 4% amino acids, cysteines, and lipids. Compatibility was evaluated by visual inspection (precipitation, haze, and color change). Solutions were evaluated microscopically for any microcrystals and measured by a turbidimeter for changes in turbidity. Solutions were further analyzed using United States Pharmacopeia 788 standards. Six hundred seventy-one PN solutions were compounded at various concentrations and evaluated for visual stability. RESULTS Compatibility testing showed no changes in the PN solution in any of the concentrations tested. Microscopically, no microcrystals were detected. The turbidimeter measurements had changes of ≤ 0.14 nephelometric turbidity units for all test solutions. There were no visual changes in any of the 671 PN solutions. CONCLUSION It is recommended that NaGP replace sodium phosphate in PN solutions. This would eliminate the concern of calcium and phosphorus precipitation and the need of any saturation curves.

Physical and Chemical Stability of Iron Sucrose in Parenteral Nutrition

INTRODUCTION Current literature supports iron dextran as the only iron preparation compatible with parenteral nutrition (PN). Iron sucrose has been used for iron replacement therapy because of its lower rate of adverse events. The purpose of this study is to determine the physical and chemical stability of iron sucrose in PN. METHODS Physical and chemical stability of iron sucrose in nonlipid PN solutions (PN 1 for neonates and PN 2 for patients weighing >20 kg) is tested over time in triplicate. Physical stability is determined by visually inspecting each PN solution for particulate matter and by filtering and analyzing each aliquot quantitatively for crystal precipitates. Chemical stability is confirmed if the iron concentrations by mass spectrometry remain within United States Pharmacopeia (USP) standards. RESULTS Visual clarity is maintained in all PN solutions at hours 0 through 4. PN solution 1 remains clear for hours 8 through 24, whereas PN solution 2 shows an increase in particulate matter by 8 hours. All PN solutions 2 are considered visually incompatible by hour 24. Physical stability of iron sucrose for PN solutions 1 and 2 from hours 0 to 4 is within the USP guidelines for crystalline particulate matter. At hour 24, only solution 1 remains within USP guidelines. Chemical stability data indicate that iron concentrations are maintained throughout the 24-hour time period. CONCLUSION The physical stability of iron sucrose in PN is time and concentration dependent. Concentrations >0.25 mg/dL showed increasing particulate and should not be added to PN. However, iron sucrose is chemically stable in PN solutions.

Dose Standardization of Oral Liquid Medications in a Pediatric Hospital

Standardizing oral liquid medications in a pediatric hospital reduces errors and costs by reducing the number of different doses and preparation time required to compound medications. The Institute of Medicine recommends that hospitals implement standard processes for medication doses, timing, and scales in a given patient care unit.12 Using a standardized dose, based on therapeutic ranges within the weight-based dosing, allows for a reduction in the number of doses compounded. In this study, data from the daily usage of oral medications were evaluated. The top 20% of the oral liquid medications were evaluated to determine the medications with the most doses (assuming that 80% of the doses are controlled by 20% of the medications). The dosage range for each medication was determined and a spreadsheet was used to calculate and predict a standard dose. The standard doses reduced the number of similar doses ordered from 329 to 59. Standardizing doses reduced wastage by 90% and resulted in departmental saving of

Improving Pediatric Outcomes through Intravenous and Oral Medication Standardization

15,000.

Physical Compatibility of Calcium Chloride and Sodium Glycerophosphate in Pediatric Parenteral Nutrition Solutions

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