Neonatal Drug Concentrations

In 2011, the Institute for Safe Medication Practices (ISMP) and Vermont Oxford Network (VON) put forth recommendations, developed by a multidisciplinary working group, to standardize neonatal drug concentrations. They reflect common practices of that time, but they predate some aspects of contemporary practice. 

Several considerations dictated review and revision of the ISMP/VON list in Table 1.     

1. Increased requirement for documented stability of compounded sterile products due to USP (United States Pharmacopeia) 797 and 800 regulations. Stability references have been located and added.    
2. Changes in patterns of antibiotic use due to withdrawal of cefotaxime from the US market. Cefepime and ceftazidime are now more frequently used agents. Cefotaxime remains in the table, and cefepime and ceftazidime have been added. 
3. Decreased emphasis on digoxin use in NICU. Digoxin has been removed. 
4. Increased early use of caffeine citrate, particularly in extremely low gestational age (ELGAN) infants. Caffeine has been added.   
5. More frequent resuscitation and ongoing care for infants weighing less than 500 grams. The 2011 ISMP/VON concentrations do not always accommodate measurable and deliverable dose volumes or rates for the smallest patients encountered in contemporary NICU practice. Dose volumes under 0.1 mL and infusion rates under 0.1 mL/hour represent the floor for dose volume or rate of infusion. Modeling the dose volume or rate for 400 g infants using usual doses and the ISMP/VON concentrations, we find several entries where dose volumes under these minimums are likely to occur. More dilute concentrations are recommended in Table 2. 

The benefits of all hospitals using the same standard concentrations for neonates are substantial and include the following:  

• Reduced medication error risk when critically ill neonates are transferred from one facility to another  
• Allows development of standardized infusion device drug libraries  
• Supplies the demand necessary for manufacturers to offer commercially prepared products when not already available.  
• Reduced risk of extemporaneous compounding errors within hospitals.  

We urge all hospitals that treat neonatal patients to consider adopting standard drug concentrations, and to anticipate and accommodate the smallest patients and the multidisciplinary team caring for them. The concentration guidance in this document was chosen based on the following criteria. We modeled dose and dose volume across the range of NICU patients, 400-5000 g. Our goals were measurable volumes and rates, and avoidance of excessive fluid from medications. Concentrations of known stability are offered. Concentrations that are a ten-fold difference are avoided. When possible, the same concentration will work for both NICU and pediatric patients who are small enough to receive drug infusions via syringe pump, rather than as minibags, which has error prevention and economic advantages for pharmacy practice. This document was reviewed by two pediatric pharmacists and one neonatologist.

The drug concentration recommendations offered below began as the result of a national effort to standardize typical neonatal drug infusions across all US hospitals. ISMP and VON collaborated with representatives from neonatal intensive care units in the US to identify and promote the standard concentrations of typical neonatal drug infusions listed in Table 1. After more assessment, some drugs now include two standard concentrations to accommodate various weights of neonates, including extremely-low-birth-weight infants. These are listed in Table 2. They are intended only for use when the usual NICU concentration results in dose volumes and rates that are too small to measure or deliver accurately. Although this will be comparatively rare, prospective anticipation allows technology build in the EHR, compounding software and tools, and smart pump libraries. All three should be carefully aligned.  

The 2011 recommendations are useful for many, but not all, NICU patients. The smallest and most rarely encountered patients are most likely to challenge the system. Contemporary practice reflects increased reliance on technology in medication ordering, drug compounding, and drug administration. Each node of the medication use process has supportive technology in many hospitals. Prescribers use the electronic health record (EHR) to choose and order drug therapy. Pharmacists use drug compounding software to achieve bar code compliant compounding safety during the sterile product compounding process. Nurses use smart pump libraries and more recently, interoperability between the EHR and infusion device platform.  

When a product that has not been anticipated is needed, the language used to communicate each of these processes reflects medication safety shortcuts. A non-standard concentration would be ordered on a “blank”, prepared from pharmacy build performed “on the fly”, and given using a “wildcard” in the smart pump. When a product is “not in the computer”, none of these processes happen quickly, all carry risk to patients, and create anxiety in the professionals involved. 

The American Society of Health System Pharmacists (ASHP) is developing a similar set of guidelines as of late 2022.  Although these will be put forth as concentration guidelines for Pediatric Intermittent Infusions, they intend for their work to guide NICU decisions, including those for the smallest infants. This work is part of the grant–supported Standardize for Safety (S4S), which has already supplied guidance related to continuously infused medications. The ASHP committee undertaking this work is multidisciplinary (nurse, pharmacist, physician). They meet quarterly and we expect their recommendations after a period of public comment. Our recommendations are intended to provide guidance in the meantime. Concentration guidance, validated against dose, dose volume, and infusion device needs, is needed now. The software each discipline is using is available now. Use of these tools requires decisions to be made now by informaticists and NICU specialists.