Focus: Underdosing - Unerestimated and Underappreciated

One factor that plays a major role in underdosing is what literature refers to as “dead volume” or “residual volume”. These terms mean the same thing, namely, the (variable) volume of a prescribed drug that remains in the infusion system after the infusion has ended. Without taking measures to ensure that this volume is infused as well, the patient will not receive their full prescribed medication dose – with potentially adverse consequences such as inefficacy or resistance. Evidence has shown that the best way to avoid this from happening is to choose extension lines with a small diameter and the smallest syringe size possible, and to use infusion sets that can be flushed at the end of the infusion.

Be it overdosing or underdosing, one thing remains the same: In pediatrics, there simply is no room for error.

What are Dosage Errors?

A dosage error is the most frequent type of medication error in children.^{1, 2}

A medication error can occur during the prescription, dispensing, or administration of a drug. By definition, it is considered an error regardless of whether or not it leads to adverse consequences.^{3 4}

Pediatrics is seen as an area particularly prone to medication errors: Children, toddlers and babies famously come in all shapes and sizes and are, therefore, dosed on an individual basis using factors such as age, weight, and surface area, which requires repeated manipulations and dilutions. In neonates especially, significant weight changes over time necessitate frequent re-calculations⁵. In addition, healthcare staff may be unfamiliar with the treatment of this age group, and appropriate dosage forms may not always be available.⁶

Did you know?

• Children are more at risk of medication errors than adults.⁷
• 20% of children under 4 years and 13% of children between 4 and 12 years of age experience dosing errors.⁶
• Underdosing is just as frequent as overdosing (approximately 11%).⁶
• Antiepileptics are the most frequently underdosed medication.⁶

Why are Dosage and Medication Errors a Risk in Pediatrics?

In pediatrics and neonatology, most errors occur during dispensing and administration; dosing errors, i.e., overdosing or underdosing, are the most frequently reported error type.^{1, 2} 

As mentioned in the introduction, underdosing can be due to dead volume.¹¹ The volume may vary greatly depending on the type of infusion system used, the length and diameters of the infusion tubing and the application of distributors (e.g., Y-connectors). This can cause significant delays in drug administration, especially in small dosages and when using slow, concentrated infusions.¹¹ Experts have warned that the significance of dead volumes in infusion bottles and sets is not yet widely appreciated.¹²

How much of the drug is lost depends on various factors, including:

• Medication volume: Losing 20% of 100 mL is of greater significance than losing 20% of 500 mL.
• Guidelines on infusions: These do not always include adequate information on dead space, flushing, or drug incompatibilities.
• Infusion system: The biggest factors are inner diameter and length of the system: The bigger and longer a system is, the more drug can be lost. By contrast, the type of system, i.e., gravity vs. pump systems, does not affect the loss of drug.
• Fine-dosing medical devices with minimum residual volumes allow for maximum effect of the drug.
• Concentration and dosage: The higher the concentration of a drug, the more active substance is lost by residual volumes within the infusion system.
   

In addition, there is the issue of drug delivery: Slow-flowing, small infusion lines, such as in neonatal care, can considerably delay the active compound reaching the patient.¹³ In one experimental study, it took one and a half minutes for the medication to reach the simulated infant through a catheter alone; with extension tubing, it took seven minutes.¹¹

Health consequences in pediatrics and neonatology

The health consequences of underdosing not only depend on the amount of the active compound lost to the patient but also on the substance itself: In drugs with a broad therapeutic index, even the loss of around 10% of the active substance can be without consequence. But in drugs with a narrow therapeutic window, underdosing may well lead to serious adverse consequences, including insufficient treatment, therapy failure, disease progression, and the development of resistance to antibiotics and cytostatic agents.¹²

Dead volumes in IV systems may also have grave consequences if the following infusion has a higher flow rate, as this would result in the residue being administered as a bolus. If the following infusion contains a drug incompatible with the previous infusion, precipitation may occur.¹⁴ 

Financial consequences

• A 2018 analysis estimated that 66 million potentially clinically significant medication errors occur in England annually, with an associated cost of £98 million. Studies involving medication in children contributed to this estimated cost; however, it was not possible to extrapolate what proportion of this figure accounted for pediatric care specifically.¹⁵
• In a study of medical liability suits filed from January 1985 through December 2001, the Physician Insurers Association of America found medication error to be the fifth most common misadventure for pediatricians. More than 30% of these cases resulted in a paid claim, with total indemnity at US$14.7 million.¹⁶
• A US Institute of Medicine report estimated that preventable medical errors result in total costs of between US$17 billion and US$29 billion per year in US hospitals (including the expense of additional care caused by the errors, lost income, household productivity, and disability).¹⁷
• The mean cost per medication error ranges from €2.58 to €111,727.08.18
• In one hospital with 337 beds, medication errors extended total hospital stay by an additional 303 days, with total costs of nearly €76,000 (drugs, medical material, radiographs, scans). The presence of medication errors doubled the cost per patient.¹⁹
   

Studies specifically analyzing the financial consequences of underdosing are, to our best knowledge, still lacking. However, it stands to reason that the clinical sequelae mentioned above – insufficient treatment or treatment failure, development of resistances – will also increase costs by negatively impacting a patient’s need for additional or longer therapy and extending their length of hospital stay. tive substance applicable without causing a health risk).

How to Reduce the Risk of Dosage Errors in Pediatrics and Neonatology?