Premixed Parenteral Nutrition Solution Use in Children

Abstract

OBJECTIVES: In response to national drug shortages, our institution established criteria for the use of commercial premixed parenteral nutrition (PN) solutions in select pediatric patients. Although these solutions have been marketed for use in children, there are no data in this patient population. The objective of this study was to review our use of commercial premixed PN solutions in children.

METHODS: This was a retrospective review of patients ≤18 years of age who received a premixed PN solution from October 2010 to April 2012. All premixed PN courses were assessed for incidence of premixed PN discontinuation due to laboratory abnormalities. Estimated goal and actual protein and total caloric intake were evaluated for premixed PN courses that were continued for >48 hours.

RESULTS: Sixty-nine patients received 74 courses of premixed PN solutions for a mean duration of 5.6 ± 6.2 (range, 1–31) days. Fifteen courses (20%) required discontinuation of premixed PN as a result of mild laboratory abnormalities. No changes in clinical status were observed in patients and all abnormalities were corrected after switching to individualized PN. In patients receiving PN for >48 hours, premixed PN solutions provided goal protein in 48/49 (98%) courses and goal calories in 33/49 (67%) courses.

CONCLUSIONS: Premixed PN solutions were used in a wide range of pediatric patients and provide a potential option for PN support in pediatric patients when drug shortages limit PN product supply. Close monitoring for electrolyte abnormalities and protein and caloric intake is recommended when using premixed PN solutions in children.

INTRODUCTION

Commercial premixed parenteral nutrition (PN) solutions have been available in the US for over a decade but have received greater attention in recent years because of increased utilization of these products. The American Society of Parenteral and Enteral Nutrition (A.S.P.E.N.) recommends that practitioners consider using premixed PN solutions in select patients based on an institution's resources and patient needs.^1,2 In recent years drug shortages have created new obstacles for clinicians responsible for the provision of PN. In response to the parenteral amino acid (AA) shortage in 2010, our institution developed criteria for the use of commercial premixed PN solutions in select pediatric patients. Since that time, we have continued to use these solutions as other PN components have become more difficult to routinely obtain.

Since January 2015, premixed PN formulations available in the United States come as both 2- and 3-compartment bags. Prior to that time, only 2-compartment bags were available. With the 2-compartment solutions, the seal is broken and the 2 compartments are mixed immediately before infusion. They are marketed for use in patients who are ≥1 year of age, but their safety and effectiveness in pediatric patients have not been established by adequate and well-controlled studies. The solutions are available with or without electrolytes, and any other additives, such as multivitamins and trace elements, must be added separately. In the premixed PN solutions with electrolytes, one compartment contains dextrose and calcium and the other includes AAs and all of the other electrolytes and minerals. Lipids can be added once the 2 compartments are mixed or they can be administered by a Y-connector along with the premixed PN solution. Since premixed PN solutions are available in 1- and 2-L units, patients with maintenance fluid needs of greater than 2 L may require more than 1 unit per day or additional intravenous (IV) fluid.

Several studies^3–10 have established the use of commercial premixed PN solutions in adults, but there are no data related to the use of these solutions in children. Therefore, the objective of this study was to review our experience with these solutions in pediatric patients.

MATERIALS AND METHODS

This was a retrospective cohort study conducted at Le Bonheur Children's Hospital that was approved by the University of Tennessee Health Science Center Institutional Review Board (IRB) and Methodist/Le Bonheur Healthcare. Written informed consent was not required by the IRB for this study. All premixed PN courses in patients ≤18 years of age admitted to Le Bonheur Children's Hospital between October 2010 and April 2012 were included in this study. Criteria for patient selection for the premixed PN solutions included the following: ≥1 year of age, metabolic panel within normal limits at baseline, and no evidence of hepatic or renal insufficiency. All patients receiving PN were prospectively followed by the clinical pharmacy consult-based PN service, and patients were advanced to goal PN calories daily as tolerated. If a patient received more than 1 premixed PN course (separated by at least 28 days) during the study period, these courses were evaluated separately. For all courses, data collection included patient demographics (age, weight, and sex), PN indication, IV access at PN initiation and end, hospital location (critical care unit vs general pediatric medical ward), consulting service, premixed PN product used, duration of premixed PN use, whether transition to an individualized PN solution was required, reason for change to individualized PN (if applicable), and enteral nutrition (EN) intake.

All premixed PN courses were also assessed for incidence of premixed PN discontinuation due to laboratory abnormalities. Laboratory parameters that were assessed during the course of therapy included serum metabolic panel and blood gas (when available). Abnormal values were defined as those that were outside of the normal range for the patient's age. Estimated goal and actual protein and total caloric intake were only recorded for premixed PN courses that were continued for >48 hours since nutritional goals may not be met within the first 2 days of PN supplementation. We used clinical dietitian estimations for goal protein and caloric intake to establish percent of goal protein and calories achieved. Since protein and calorie provision from the enteral route varied greatly between patients (clear liquid diet, regular diet, formula) and were not consistently available in the medical record, protein and calorie provision for each patient were calculated only from those provided by premixed PN solution and IV lipids.

While several different formulations are available with varying amounts of dextrose, AAs, and electrolytes, our institution uses one of 3 different solutions based on patient IV access and nutrition requirements.¹¹ For example, in patients with peripheral IV access only, a premixed PN solution with 10% dextrose, 2.75% AAs, electrolytes, and a total osmolarity of 920 mOsm/L is used. All 3 of the solutions used at our institution contain standard electrolytes and minerals. Additionally, lipids are infused separately in all patients and are not added to the premixed bags. Other than appropriate mixing of the 2 compartments, the only manipulations made to the premixed solution is the addition of multivitamins and spiking with infusion tubing. The macronutrient, electrolyte, and mineral composition of the solutions used at our institution is shown in Table 1.

Table 1.

Contents of Premixed PN Solutions

RESULTS

Sixty-nine patients received a total of 74 courses of premixed PN between October 2010 and April 2012. Five of the 69 patients received 2 separate courses of premixed PN during this time period. The mean duration of premixed PN therapy was 5.6 ± 6.1 (range, 1–31) days. Baseline characteristics and PN indication for each of the courses are shown in Table 2. The consulting services for PN therapy were general pediatric surgery (47%), pediatric intensive care (33%), and general medicine or gastrointestinal service (20%). The initial premixed PN solutions used for all PN courses were 10% dextrose/2.75% AAs (n = 37, 50%), 10% dextrose/4.25% AAs (n = 35, 47%), and 25% dextrose/4.25% AAs (n = 2, 3%). All premixed PN solutions contained standard electrolytes (Table 1).

Table 2.

Baseline Characteristics of Patients Receiving Premixed PN Solutions (n = 74 ^* )

Sixteen (22%) of the 74 courses required additional IV fluid administration with the premixed PN solution. Ten of these courses were initiated below maintenance rate to avoid excess protein administration, and 6 courses required more than 2 L of fluid per day, so additional IV fluid was given to meet daily fluid needs.

Forty-six (62%) of the 74 courses completed the full PN course with one of the premixed PN solutions. Twenty-eight (38%) courses required a change to an individualized PN solution as a result of laboratory abnormalities (n = 15), in order to meet nutritional goals (n = 7), in preparation for home PN administration (n = 5), or as a part of the standing orders for the initiation of extra-corporeal membrane oxygenation therapy (n = 1). Table 3 shows the lab abnormality that prompted the change to an individualized PN solution. The mean duration of premixed PN use prior to requiring a change due to lab abnormality was 2.9 ± 3.4 (range, 1–14) days. All of the laboratory fluctuations were transient and did not precipitate any acute changes in the clinical status of any patient. In addition, all were corrected after changing to an individualized PN solution.

Table 3.

Primary Electrolyte Imbalance that Necessitated the Change to an Individualized PN Solution (n = 15)

Parenteral nutrition courses of >48 hours in length (n = 49, 66%) were assessed for nutrition goals. Forty-eight of the 49 courses (98%) met protein needs using the premixed PN solution. In one patient the premixed PN solution was not advanced to provide goal protein because this patient was receiving supplemental EN that provided the remainder of protein requirements. Thirty-three courses (67%) met total caloric goals from the premixed PN solution alone. Of the 16 courses that did not meet full caloric goals from the premixed PN solution, 7 (44%) were initiated on EN within the first 24 to 48 hours of PN therapy, and thus PN calories were not advanced. Table 4 lists all of the reasons for failure to meet total caloric goals from the premixed PN solution alone.

Table 4.

Reasons Total Caloric Goals Unmet by Premixed PN Alone (n = 16)

Our estimated pharmacy cost for a compounded PN solution is approximately $70.40 per unit. The cost for dispensing a 2-L bag of premixed PN plus pediatric multivitamin ranges from $34.70 to $43.70 at our institution. Based on these estimates, use of a premixed PN solution results in a cost savings of approximately $26–$35 per patient per day. If a compounded IV fluid is administered along with the premixed PN solution, the estimated cost savings is $19–$28 per patient per day. These cost savings are specific to our institution; other institutions may see different savings based on their PN process. See Table 5 for a summary of the cost analysis at our institution.

Table 5.

Cost Analysis of Premixed PN and Compounded PN ^*

DISCUSSION

There have been several adult studies^3–10 comparing the use of commercial premixed PN solutions to the use of compounded PN solutions. Potential benefits of premixed PN solutions include decreased risk of IV compounding errors^12,13 and decreased risk for bloodstream infections.^8,9 In addition, several studies^3,4,6,9 assessing overall cost favor the use of premixed PN solutions in select patients. Another potential advantage is the convenience and ease of use during both the prescribing and dispensing process. In addition, these solutions can help provide a more complete PN formulation when product shortages limit the individual components necessary for compounded PN solutions. By using these premixed solutions in select patients, institutions can conserve PN product supply for more vulnerable patients and those with more complex nutrition requirements.

When initiating a premixed PN order at our institution, the specific solution and rate are chosen to approximate protein needs. If possible, the rate chosen is an appropriate volume to provide maintenance fluid requirements based on the Holliday-Segar equation.¹⁴ In some patients, infusion of the higher AA premixed PN at maintenance rate would provide a protein dose significantly above estimated needs, while infusion of the lower AA premixed PN at maintenance rate would underdose protein. Thus, the higher AA premixed PN is ordered to infuse at a rate below maintenance volume, and additional IV fluid is ordered to be administered through a Y-connector to provide the remainder of the maintenance fluid requirements. The additional IV fluid used at our institution is either a standard IV fluid or a compounded IV fluid depending on the patient's laboratory values and caloric requirements.

A disadvantage of premixed PN solutions that could limit their use in some patients is the fixed amount of electrolytes and minerals they contain. As seen in our study, some patients may require individualized dosing of certain electrolytes and minerals based on clinical status, age-specific requirements, organ function, concurrent disease states, or concomitant medications. Premixed PN solutions may not contain the long-term electrolyte and mineral requirements needed for some children, especially younger patients. As a result of the need for larger calcium dosing and different calcium:phosphorus dosing ratios, these solutions are not ideal for neonates and infants, young PN-dependent patients, or any child who is actively making bone. Also, as seen in our study, some patients may experience metabolic alkalosis as a result of the amount of acetate in these solutions. In addition, premixed PN solutions contain 30 mEq/L of potassium, which is more than the potassium content of many standard IV fluids given to pediatric patients (20 mEq/L). One of the methods that can be used in patients who are receiving additional IV fluid along with the premixed PN solution is to remove or manipulate the amount of potassium in the additional IV fluid based on the patient's serum potassium concentration. Of note, only 3 patients developed hyperkalemia, and 2 actually developed hypokalemia. Finally, the amount of sodium in premixed PN solutions (35 mEq/L) is lower than that typically provided to older children, adolescents, and adults (51–77 mEq/L), so hyponatremia may occur. This was not a common cause for change to an individualized solution in our patients; however, this may have been the result of using a higher sodium content in the additional IV fluid (if used). For example, in order to balance the lower sodium and higher potassium content of the premixed PN solutions, D10% + NS (no potassium) is often used in conjunction with premixed PN. In addition, the dextrose content in compounded IV fluid may be increased as tolerated to advance calories. This method has been particularly important when IV lipids have been in short supply.

Another consideration for the use of premixed PN is the total volume required since solutions are only available as 1- or 2-L bags. At our institution, patients needing greater than 2 L per day are given an additional IV fluid since we do not send more than 1 PN solution per patient per day, thus limiting the long-term utility of premixed PN solutions. In this study, premixed PN volume limitations did not directly result in any patient requiring a change to an individualized solution since these solutions are mostly used short-term. As reported in our results, only 1 patient did not meet goal protein requirements from the premixed PN solution, and this was not due to the size of the premixed bag. However, this may still be a consideration in children with greater protein requirements that cannot be achieved with the higher AA premixed PN solution.

In approximately one-third of the courses in our study, PN was given for <48 hours, which may suggest inappropriate use of PN in those patients. At our institution, PN is managed by a clinical pharmacy consult-based service. It is routine practice for this service to assess the appropriateness of PN in all patients prior to initiation. This includes assessment of a patient's age and weight, underlying nutrition status, disease state, duration of NPO status, and ability to access the gastrointestinal tract. Occasionally, the anticipated length of PN support can be difficult to predict. A prolonged NPO period prior to the consult or a more rapid achievement of enteral nutrition may ultimately result in shorter courses of PN support than were initially expected. However, the use of premixed PN solutions in select children who are not likely to require long-term PN therapy may actually be advantageous since the use of these solutions has resulted in a cost benefit and also conserves overall PN product supply.^3,4,6,9 Our cost analysis was consistent with these findings and revealed a cost benefit associated with the use of premixed PN solutions with and without an additional compounded IV fluid.

There are some limitations to this study. Since protein and calorie provision was calculated only from premixed PN and IV lipids, we were not able to assess whether patients who received a combination of parenteral and enteral nutrition were able to meet their total caloric goal. Therefore, the number of patients who did not meet their caloric goal after receiving >48 hours of PN may have been falsely elevated. In addition, the retrospective study design makes it difficult to control for bias and other confounders and limits the ability to predict which pediatric patients may respond best to a premixed PN solution. A larger prospective study comparing the use of premixed PN solutions with individualized PN solutions would be beneficial to help establish optimal use of these solutions in children.

The results of this study summarize our practice of using premixed PN solutions in pediatric patients at our institution. We have found that premixed solutions work well for short-term PN therapy in pediatrics patients outside of infancy without underlying electrolyte abnormalities or end-organ function at baseline. Our results are specific to 2-compartment premixed PN formulations. Our findings cannot be extrapolated to the newly available 3-compartment premixed PN formulations as these solutions are not recommended for use in pediatric patients <2 years of age and have considerable differences with respect to macronutrient and electrolyte content. Institutions using premixed PN solutions should develop guidelines for use to include patient criteria and dosing and monitoring guidelines.

CONCLUSIONS

In this study, premixed PN solutions appeared to be safe and effective in a wide range of pediatric patients receiving PN for a short period of time. Close monitoring of electrolytes and minerals and continual assessment of protein and calorie provision are recommended in children receiving these solutions. Although there are some limitations to the use of premixed PN solutions, they provide a potential option in pediatric patients when drug shortages limit the product supply required for compounded PN.

ABBREVIATIONS

AAs

amino acids

A.S.P.E.N.

American Society of Parenteral and Enteral Nutrition

EN

enteral nutrition

GI

gastrointestinal

IRB

institutional review board

IV

intravenous

MVI

multivitamin

PN

parenteral nutrition