Ped3CB-A Compliance and Flexibility
Administration Route and Bag Activation
Study participants received a total of 854 days of PN through an umbilical catheter (n = 157 days; 18.4%), peripheral line (n = 88 days; 10.3%), or PICC (n = 610 days; 71.4%). Only 32 PN infusion days (3.7%) in 11 infants (11.3%) involved double-chamber bag activation as a result of delayed lipid infusion practice (n = 3), an increase in oral nutrition intake (n = 7), or persistent hypertriglyceridemia from study enrollment (n = 1).
Vitamins and Trace Elements
All of the infants received water-soluble and lipid-soluble vitamins during the study. Water-soluble vitamin supplementation occurred on 84.9% of infusion days, and lipid-soluble vitamins were infused on 91.5% of the 822 infusion days that included IV lipids. Overall, vitamin preparations were added to the activated Ped3CB-A in 65.9% of additions of water-soluble vitamins and 88.7% of additions of lipid-soluble vitamins. Trace elements were provided on 78.2% of infusion days in 93 of the 97 infants, but addition of zinc alone was provided during an additional 19.4% of infusion days.
Addition of Water for Injection
In 53 infants, water for injection was added to the bag on 221 (26.0%) infusion days by peripheral line (82 of 88), umbilical catheter (44 of 157), or PICC (95 of 610) to reduce osmolality or increase water supply.
Macronutrient (AA, Glucose, and Lipid) Supplementation
Table 3 depicts macronutrient supplementation. Ten infants received additional AA, accounting for 17 infusion days and providing 0.69 ± 0.28 g · kg−1 · day−1 AA supplementation. Glucose supplementation occurred in only 7 infants, accounting for 34 PN infusion days and providing 3.2 ± 2.0 g · kg−1 · day−1. In 4 infants, accounting for 9 infusion days, the lipid chamber was not activated and lipids (1.12 ± 0.43 g · kg−1 · day−1) were provided through a separate perfusion using a Y-line. In 1 infant, limited lipid quantities (0.23 and 0.43 g · kg−1 · day−1) were added to the triple-chamber solution during the first 2 days. In all, supplementation directly to the triple-chamber bag occurred on only 18 infusion days (2.1%) in 11 infants. In 1 infant, AA and glucose were added simultaneously.
Electrolyte and Mineral Supplementation
Table 3 depicts electrolyte and mineral supplementation. Minerals or electrolytes, mainly sodium, were added on 387 infusion days (45.3%) in 65 infants, primarily using a Y-line. In all, compared with the intakes provided by the triple-chamber bags, electrolyte and mineral supplementation was negligible except for sodium (1.63 mmol · kg−1 · day−1). Chloride supplementation was the result of NaCl or KCl supplementation (1.85 mmol · kg−1 · day−1) and was also in the range of the amounts provided by Ped3CB-A. Additions directly to Ped3CB-A occurred on 185 (21.7%) infusion days in 36 infants (37.1%).
Use of Ped3CB-A for Macronutrient, Electrolyte, and Mineral Supplementation
Macronutrient, electrolyte, and mineral supplements were administered primarily through a Y-line. A total of 199 additions were made to the Ped3CB-A bags on 197 infusion days (23.1%) in 43 infants (44.3%). Multiple additions to the bag accounted for only 1 perfusion day.
As shown in Table 3, mean intakes of administered parenteral nutrients from the triple-chamber bag solution and from supplements were AA 2.8 g · kg−1 · day−1 and 81 kcal · kg−1 · day−1. The mean maximum intakes from Ped3CB-A were AA 3.6 g · kg−1 · day−1 and 104 kcal · kg−1 · day−1, within the actual recommended ranges for this population (2,4).
Enteral nutrition increased progressively during the study. Combined with enteral nutrition, mean protein and energy intakes represented AA 3.6 g · kg−1 · day−1 and 115 kcal · kg−1 · day−1, respectively (Table 4). Enteral protein and energy intakes accounted for 17.8% to 25.4% of total protein equivalent and 24.9% to 34.4% of total energy, respectively.
Weight gain and nutrient intakes were evaluated based on postnatal age at study enrollment (Table 4). In preterm infants included during the first 3 days of life, weight gain represented 10.0 ± 9.5 g · kg−1 · day−1. In infants included between 4 and 7 days of life or thereafter, weight gain was higher and reached 21.5 and 22.6 g · kg−1 · day−1, respectively.
Practical Handling and Ease of Use
VAS scores for Ped3CB-A were significantly higher for ease of bag manipulation and prescription-to-infusion time than were the scores for bags compounded in the ward, RTU compounded bags, and tailored premixes. The highest scores were for manipulation when Ped3CB-A was compared with the use of ward-compounded bags (Fig. 3).
Mean values of the biological parameters evaluated during the study are shown in Table 5 and Figures 4 and 5. Plasma triglyceride concentrations remained mainly in the normal range (<250 mg/dL; Fig. 4). Hypertriglyceridemia was observed in 8 infants at inclusion, 7 infants at day 5, and 2 infants at the end of the study. Blood urea nitrogen (BUN) levels decreased during the study. Only 4 infants had a BUN level >25 mmol/L at the end of the study. Plasma glucose concentrations remained satisfactory during the study. Four infants had plasma glucose concentrations >10 mmol/L at day 5. Insulin was required in 13 infants on 34 infusion days. During the study, a moderate but significant increase in plasma bicarbonate was observed. Sodium, potassium, and calcium variability decreased during the study and remained in the normal range (Fig. 5). By contrast, relative hypophosphoremia was frequent during the study, occurring in 27.5% of infants at baseline and in 30.7% of infants at the end of the study. Phosphorus supplements were administered to 11 infants, providing a mean 0.79 mmol/kg and increasing mean serum inorganic phosphorus concentrations by 0.45 mmol/L.
In addition, a few abnormal biological parameters were reported as adverse events, including hyperglycemia (n = 13), hypernatremia (n = 2), hyponatremia (n = 9), hyperkalemia (n = 4), hyperphosphoremia (n = 4), hypophosphoremia (n = 4), hypercalcemia (n = 3), and hypertriglyceridemia (n = 5).
Four patients experienced 6 treatment-emergent serious adverse events consisting of herpes simplex infection, staphylococcal sepsis, severe emphysema, pneumothorax, septic shock, or catheter sepsis. One 9-day-old infant (27 weeks’ gestational age) died during the study after septic shock. These serious adverse events were not believed to be related to the infusion of PN. Additional adverse events included patent ductus arteriosus (7 events), sepsis (18 events), anemia (12 events), and constipation (8 events). The majority of adverse events were thought not to be related to the infusion of PN.
The present study shows that the Ped3CB-A system, the first standardized industrially prepared RTU triple-chamber PN system designed for commercial use in preterm infants, is easy to use, has the flexibility required to meet the varied and changing nutritional needs of preterm infants, provides levels of nutrients within the ranges of recent recommendations (2,4), produces appropriate weight gain rates, and is safe.
Prescriptions of RTU, all-in-one–tailored PN solutions specially designed to satisfy the daily nutritional requirements of individual preterm infants appear to be the criterion standard to provide PN in the NICU, but they require optimal hospital pharmaceutical structures with day and night availability to safely provide, with minimal delay, PN to meet medical prescriptions and reformulations. Therefore, compounded RTU parenteral solutions prepared inside or outside the hospital pharmacy are frequently used in NICUs as “starter bags” or as standardized formulations immediately available after birth. In some units, 3 to 7 different RTU compounded PN solutions are available according to postnatal age and requirements (8–11). To improve stability and reduce peroxidation, trace elements and vitamins need to be added extemporaneously on a daily basis in the pharmacy or in the neonatal unit. In addition, to fulfill the nutritional requirements of an increasing population of preterm infants, supplementation with electrolytes and minerals is frequently requested. Thus, those standardized compounded parenteral solutions are not truly all-in-one solutions. Nevertheless, standardized PN, in general, is associated with fewer risks than tailored PN (21). Unlike individualized PN, standardized PN reduces the chance for potential errors with ordering and compounding; the risk of PN-associated infections; or adverse outcomes from the infusion of incompatible mixtures (21). In infants, standardized PN improves nutritional support and weight gain, and reduces electrolyte disturbances compared with individualized PN (8,9,12). Recently, it has been suggested that RTU compounded parenteral solutions are safe and that optimal nutritional intakes and adequate early growth rate can be achieved in preterm infants fed a RTU compounded parenteral solution with high nutritional density (12,18).
The use of multichamber PN bags has been suggested in adults (19,20); they are associated with few risks for virtually any indication or application (19). The industrially prepared PN MCBs offer the advantage of being designed in separate chambers, which reduces the interactions among the various components and allows storage at room temperature. Additionally, they are submitted to rigorous stability studies and checked according to good manufacturing practices before batches are released. The quality of the checks performed by the pharmaceutical industry is largely superior to that of the checks performed by hospital pharmacies. In hospital pharmacies, although all of the components of compounded or manually prepared PN admixtures undergo routine sterility and stability testing during the manufacturing process, subsequent extensive routine testing of the final admixtures is not performed. By contrast, during the manufacturing process for Ped3CB-A, the individual components and activated (mixed) bags are thoroughly tested for sterility, stability, free fatty acid levels, endotoxin levels, fat globule size, and degradation products. The testing of both the individual components and activated (mixed) bags provides an additional layer of safety that is not available from admixtures prepared from individual components. After reconstitution, the pediatric MCBs can be infused as is or can be specifically supplemented with adequate small, manufacturer-pretested volumes of micronutrients to deliver ready-to-infuse admixtures, whose final stability would be further ensured by manufacturer testing.
In the present study, the AA and energy intakes during the first week of life were in the range of “aggressive” nutrition recommendations for VLBW infants. In addition, the maximum parenteral AA and energy intakes coming from the bag and the total combined parenteral and enteral intakes recorded during the study were in the range of the most recent recommendations (2,4), demonstrating that clinicians were able to use and easily adapt the standardized Ped3CB-A system to meet the nutritional needs of preterm infants. These results suggest that the use of the Ped3CB-A in NICUs could be an important factor in helping to reduce the cumulative protein and energy deficit during the first few weeks of life.
The daily weight gain of approximately 22 g · kg−1 · day−1 observed in infants included after the first week of life is at the high end of the expected weight gain rate of 10 to 20 g · kg−1 · day−1 expected with PN (2). Early weight gain (10.0 g · kg−1 · day−1) was observed in the early inclusion group, suggesting that the use of the Ped3CB-A could reduce postnatal growth deficits (6,13,18) and improve long-term neurological development and growth outcomes (6,7).
The majority of prescription days were successfully fulfilled using Ped3CB-A as is, with the addition of vitamins and trace elements as usually performed in adult patients. Few additional supplementations into the bag, mainly sodium, were performed, representing only 23.1% of the perfusion days in 44.3% of the infants. Sodium supplementation was requested as sodium requirements in preterm infants range between 3 and 5 or 7 mmol · kg−1 · day−1, whereas the sodium content of the Ped3CB-A was specifically limited to be provided to preterm infants even during the first few days of life. In the future, the availability of 2 different MCBs, 1 designed for the first few days of life with low sodium and potassium content, as is the Ped3CB-A, and another with higher sodium content for VLBW infants after the third to the fourth day of life, could reduce the need for extra micronutrient supplementation. An increase in the sodium content of the Ped3CB-A, allowing an increase in the phosphorus and the calcium content, could also reduce the need for extra micronutrient supplementation without limiting its use during the first days of life. Indeed, it has been suggested that the use of early PN with high AA content in preterm infants increases the need for electrolyte supplies during the first 3 days of life (22). The results of our recent study in VLBW infants (18) support this hypothesis. Nevertheless, the question is still open and requires further investigation.
Mean values of the biological parameters evaluated during the study remained mainly in the normal range for preterm infants during the first weeks of life. Relative hypophosphoremia was observed at baseline and during the study, but it appears that adult reference levels were frequently used instead of preterm reference values. The rapid increase in fat intakes during the study provided by the Ped3CB-A was well tolerated, and the nonactivation of the lipid chamber was mainly the result of an increasing oral nutrition intake.
Adverse events were limited during the study, and none were directly attributable to the design of the Ped3CB system; all of the adverse events were consistent with the known clinical status and the invasive treatments required by clinical condition. Most of the adverse events were mild, and patient vital signs remained relatively stable throughout the study.
The main limitation of this prospective multicenter study is its noncomparative design. Nevertheless, this study confirms the results of our recent study (18) demonstrating that, in preterm infants with a BW <1250 g, the early use of an appropriate RTU compounded solution can provide nutritional intakes in the range of the more recent recommendations (ESPGHAN/ESPEN 2005 and ESPGHAN 2010). It enables the avoidance of both postnatal cumulative protein and energy deficits as well as postnatal growth restriction in ELBW and VLBW infants.
In conclusion, Ped3CB-A is the first standardized, industrially manufactured, triple-chamber bag developed to provide well-balanced and safe nutritional support in premature infants. This study demonstrated the ease of use of the Ped3CB system. Clinicians and staff were able to configure the system, including selective activation (triple- or double-chamber bag), and to provide additions and supplements to meet the nutritional needs of preterm infants. Early nutritional support, maximal nutrient intakes, and body weight gain were favorable, meeting the requirements and expectations in the more recent recommendations for preterm infants. The new design of the Ped3CB system provides well-balanced PN with the benefits of multiple manufacturing process controls, improving the safety of PN in preterm infants.
We thank Debby Berlyne, PhD, of ACCESS Medical, LLC, for editorial assistance. ACCESS Medical obtained funding from Baxter Healthcare for editorial assistance with this manuscript.
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Keywords:Copyright 2012 by ESPGHAN and NASPGHAN
multichamber bags; parenteral nutrition administration; Ped3CB; pediatric parenteral nutrition; premature infants; standard parenteral nutrition