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19 Safe Prescribing and Monitoring in Pediatrics
441
infants also have lower hepatic metabolic activity
for most metabolic enzymes, and slower renal
elimination. This sometimes results in neonates
requiring the same or higher individual dose (if
the drug is concentration dependent) administered less frequently compared to older pediatric
age-groups and adults. For example, for gentamicin or tobramycin, “traditional” intravenous dosing in children and adults ranges from 1 to
2.5mg/kg/dose every 8h. Due to larger Vd per kg
in neonates compared to older patients, the dosage in neonates needed to achieve similar peak
and trough concentrations as older patients is 4–5
mg/kg/dose every 24–48h depending on the
PMA[11]. Neonates and young infants also have
higher skin permeability and a greater skin surface area to body mass ratio [12]. This results in
greater systemic concentrations after topical
medication administration compared to older
children and adults.
The neonatal period includes a continual process of kidney and liver development. For the
rst 7days of life, serum creatinine (SCr) is typically unreliable as it is mainly reective of SCr
from the mother. Diuresis occurs over the rst
1–2weeks once renal function begins to improve.
Newborns have impaired conjugation of bilirubin
and potential protein binding alterations which
can impact highly protein-bound medications.
This can cause jaundice that in most cases is a
normal physiologic process that resolves in the
rst 1–2week of life without complications, but
in some scenarios, this process can cause complications. Hepatic drug metabolism with certain
enzymes can be compromised, although there are
some enzymes functioning early into life.
Generally, the most preterm neonates are
expected to have the slowest renal elimination
and hepatic metabolism, which increases to
infant levels once they have a PMA similar to that
of an infant born at full-term. This means some
neonatal safety considerations are relevant to
both preterm infants and neonates born at fullterm. An important concept is that renal and
hepatic function slowly mature with age during
the neonatal and infant periods, but during childhood, renal and hepatic clearance and elimination
of drugs is usually faster than that of adults.
In-depth discussion on pharmacokinetics in the
pediatric population has been described in the
published literature [12].
2.3 Impact ofPharmacokinetic
andPharmacodynamic
Dierences onDrug Safety
The pharmacokinetic differences described
above can create problematic medication safety
considerations in the pediatric population, especially in the neonatal and infant population,
resulting in unanticipated ADRs and increased
MEs. Many historical experiences, sometimes
labeled pediatric tragedies, occurred due to the
utilization of excessive doses or formulations of
medications in children due to a lack of knowledge at the time regarding pharmacokinetic differences [13, 14]. These are scenarios where
drugs were available and used because they were
needed, but information was not available to
ensure safe use of the medications. At the time
one could consider these ADRs because optimal
dosing was not established, but in practice today,
they would be considered an ME as more knowledge regarding appropriate dosing is now
available.
While uncommonly used currently, chloramphenicol resulted in “gray-baby syndrome” (e.g.,
metabolic acidosis followed by cardiorespiratory
collapse) when higher than required doses were
used in neonates leading to toxic serum concentrations [15, 16]. This occurred because neonates
and infants had slower renal elimination of the
chloramphenicol sodium succinate (prodrug)
leading to higher chloramphenicol concentrations,
and also decreased metabolism of chloramphenicol (active drug) by the liver which was not
accounted for in determining the dosage regimen.
When dosed appropriately or serum concentrations monitored, toxicity could be minimized
[17]. Neonates and young infants are also at risk
for ADEs from inert or excipient components of
medications due to pharmacokinetic differences
and higher than expected exposures when nor-
442
J. S. Stultz and M. C. Nahata
malized to body weight. Decreases in transformation of benzoic acid to hippuric acid (utilizing
a hepatic conjugation) in preterm neonates and
infants resulted in excessive benzoic acid and
progressive metabolic acidosis, respiratory and
central nervous system (CNS) depression (gasping respirations), and death with the use of benzyl alcohol as a preservative [18, 19]. This
toxicity was most associated with the frequent
use of 0.9% sodium chloride ushes which contained benzyl alcohol [20]. When neonates and
infants received numerous daily ushes possibly
in combination with other medications containing this preservative, the high mg/kg dose administered in combination with reduced clearance
resulted in higher, potentially toxic concentrations and fatal “gasping syndrome” in neonates.
Best practices are to avoid administration of
medications containing preservatives, especially
benzyl alcohol, in neonates or preterm infants
when possible due to this safety concern. If it is
not possible to avoid exposure, one could calculate the mg/kg/day exposure in a given patient to
determine the total exposure. In adults, approximately 5mg/kg/day has been administered without resulting toxicity. A denitive threshold has
not been described in neonates, but most toxic
doses described in neonates and preterm infants
were 99mg/kg/day or higher and administration
of multifold smaller single doses have not
resulted in toxicity [17, 20]. Older infants and
children are not at risk for this toxicity with benzyl alcohol.
The inability of certain neonates to conjugate
and eliminate bilirubin shortly after birth can
lead to high unconjugated bilirubin concentrations. Administration of the antibiotics trimethoprim/sulfamethoxazole, dicloxacillin, and
ceftriaxone can displace bilirubin attached to
albumin resulting in more free bilirubin and an
increased potential of kernicterus (e.g., acute
and/or chronic encephalopathy due to accumulation of bilirubin in the CNS) [21]. Ceftriaxone
can also chelate to calcium causing fatal deposits
in the lungs and kidneys in infants when both are
administered intravenously within 48h of each
other [22, 23]. These safety concerns are less relevant and limited to cases of drug–drug admix-
ture incompatibility in patients 1 year or older.
Best practices are to avoid using these medications in neonates and preterm infants (<41weeks
PMA) to prevent possible severe harm, and given
other broad-spectrum cephalosporins are typically available.
The increased skin permeability and absorption/distribution differences in young pediatric
patients can impact the safe use of topical or local
injectable medications in neonates, infants, and
young children. Use of apparent weight-based
dosages or formulations of topical injections or
creams/lotions can result in higher medication concentrations in the infant population (e.g., cushing
syndrome and/or impact linear growth associated
with corticosteroids) [24, 25]. This is especially of
concern when applied to the face and diaper areas
in infants where absorption is higher than other
areas. Due to this pharmacokinetic difference,
it is common practice to avoid the utilization of
topical corticosteroids (particularly medium- and
high-potency formulations) in infants and young
children on the face or diaper area, and use sparingly in other parts of the body [21]. These medications are generally avoided all together topically
in neonates and preterm infants and inappropriate
use could now be considered an ME.
In addition to pharmacokinetic differences
resulting in an ADR, some children are also more
at risk for an ADR due to differences primarily
focused on pharmacodynamics. For example,
children and adolescents are to a greater extent
predisposed to suicidal ideation upon initiation of
antidepressant therapy, resulting in an FDA black
box warning focused on the use of these medications in adolescents. While this is of concern, the
benets typically are believed to outweigh these
risks. In order to ensure clarity with families, it is
important that the practitioner, patient, and family
make a shared decision about starting these medications and are made aware of the potential risks.
Codeine is an example where a pharmacogenetic
and pharmacodynamic difference has led to a
contraindication focused on children <12years of
age and a warning in adolescents. Codeine, a prodrug, has been associated with respiratory depression and occasionally death in patients with
genetic differences resulting in faster and
19 Safe Prescribing and Monitoring in Pediatrics
443
greater conversion to the active metabolite morphine. This pharmacogenetic-derived difference
also impacts adults. Some of the pharmacogenomic data is extrapolated from adults and studies
are still lacking for some populations (e.g., children with decreased renal function). However,
since children have higher rates of tonsillectomy
and adenoidectomy procedures, they have the
highest risk for a severe ADE [21]. Importantly,
theuse of codeine could be considered a ME in
some scenarios as there are other options for pain
relief posttonsillectomy and adenoidectomy.
In everyday practice, practical application of
this information requires the collection and
assessment of additional pediatric-specic information to appropriately prescribe or verify a dosage for a pediatric patient. It is essential to know
the patient’s weight (including any conversions
between kg and pounds), age (including any history of preterm birth), indication, and available
dosage forms that can practically be used in the
pediatric population (including possible excipients). This information can then be used to identify the most appropriate dosage in medication
references. These additional details must also be
combined with other information commonly
used when assessing medication use in adults
(e.g., organ function, concomitant medications).
3 Growth andDevelopment-
Based Adverse Event
Considerations
3.1 Impact ofMedications
onGrowth andDevelopment
Some growth and development parameters are
objectively assessable (e.g., increases in height,
increases in weight), while other are less so and
require standardized clinical assessments (e.g.,
neurocognition, tooth/bone development).
Importantly, growth and development are major
longer-term safety outcomes commonly associated with medication use in children. This type of
outcome is unique to children as adults are typically not developing substantially in regard to
height or cognitive function over time, and weight
gain is typically considered a negative outcome.
Importantly, growth rates are individualized to
the patient and based on trends over time in relation to the wide range of population norms versus
being in or outside of a narrowly focused constant range.
A well-known example of medications
impacting growth and development includes the
use of inhaled corticosteroids, which are a cornerstone of long-term management of asthma.
There are studies showing that limited systemic
exposure to patients during treatments may lead
to stunting of growth in children [26]. These risks
are generally not considered signicant (usually
minimal changes seen in height at adulthood),
especially in comparison to the benets of asthma
control with their use. Clinicians should be aware
of this concern and prepared to have a risk versus
benet discussion with patients and families and
it generally does not preclude use. Notably, as
described elsewhere in this chapter, corticosteroids do have more signicant risk when administered systemically in higher dosages for a
prolonged period and thus should be used in that
manner only when denitively needed.
Another well-described example of medication
impact on growth and development is tooth discoloration as an ADR of tetracycline antibiotics.
Permanent tooth discoloration has been described
with prolonged and higher dose administration of
tetracycline in children during the development of
permanent teeth, which ends around approximately 8years of age. While an important consideration, newer tetracyclines like doxycycline have
been shown to be safe to administer in short
courses (generally dened as <21days), especially
in cases of life-threatening diseases (e.g., Rocky
Mountain Spotted Fever) [27].
In addition to assessing for body/skeletal
growth, there is a concern that utilization of medications in young children can impact neurologic
development later in life. Assessment of this outcome requires potentially subjective and multifaceted neurocognitive scales used at various
time points throughout early childhood. In the
neonatal period, the use of systemicdexamethasone has controversially been associated with
adverse neurocognitive outcomes at 2years. The
444
J. S. Stultz and M. C. Nahata
use of this medication in neonates can help
improve short-term outcomes (e.g., time to extubation) but has the possible concern for longterm neurocognitive toxicities (e.g., development
delay, cerebral palsy, decreased neurocognitive
scale scores) [28, 29]. Morphine use in the preterm neonatal period has also been associated
with possible long-term neurocognitive ADEs
that may resolve over time [30]. There is not an
absolute contraindication to using these medications (and importantly they are likely a class
effect), but practitioners should reserve use only
for scenarios where there is a denite benet. If
the use is warranted, the lowest dose should be
used for the shortest duration possible to minimize potential complications.
A challenge with long-term growth and development outcome is that it is hard to differentiate if
the medication or other patient factors are impacting the development outcome that could not be
controlled for. A prospective randomized controlled trail is often used to control for factors
potentially impacting safety and efcacy outcomes.
But this study design may take numerous years to
complete in the pediatric population and prospective randomized controlled trials to evaluate
adverse outcomes are ethically questionable, particularly in pediatric populations [28]. Routinely
collected data, retrospective evaluative models, and
healthcare registries are commonly used sources
for pediatric medication safety analyses. Use of
medications potentially impacting long-term neurocognitive outcomes usually involves a risk and
benet assessment to determine if the benet to the
patient would outweigh the risks of the ADR.
3.2 Impact ofGrowth
andDevelopment
onAssessment ofSafety
Outcomes
Pediatric developmental milestones can also
impact the ability to assess for certain ADR or
harm associated with an ME [31]. Table19.3 outlines select growth and development considerations and their impact on ADE for practical use
by practitioners. For subjective assessment, a
child must be able to communicate needed information regarding a possible ADR.This could be
conveyed verbally or nonverbally via sign language or gestures. The age at which speech or
other communication methods develop varies
(generally around 2–3years of age), but a noncommunicative child cannot describe an ADR in
the same way as an older child or adult. There are
visual scales that allow children to pick pictures
that suggest how they are feeling or the amount
of pain they are in if nonverbal. Simple ADRs
such as myalgias, headaches, changes in hearing,
and visual eld changes may not be clearly
described by the patient and must be assessed
during a thorough physical examination and
potentially at follow-up visits relative with comparison to the baseline assessment before starting
the medication.
Even after once a child is verbal, some children
may not be able to describe an ADR in sufcient
detail to a parent or caregiver to recognize it as
such. Accurate description of subjective ADRs
(e.g., headache, visual changes, pain) potentially
related to the drug may not occur until 8years of
age or older. Patients who are developmentally
delayed are also unable to verbalize possible
ADRs for longer periods of time or at any time
during their life. This makes assessment of subjective outcomes in the pediatric population difcult and potentially inaccurate. For example,
long-term linezolid use has been associated with
potentially severe optic and peripheral neuropathies [32]. Both of these ADRs require a patient to
describe the ADR to a practitioner, making use of
linezolid less desirable in children if another treatment option exists. Practitioners should be aware
of medications with severe ADRs requiring subjective assessment when deciding among the
available medications to use in children.
3.3 Objective Adverse Drug
Reaction Assessment
Considerations
In addition to subjective challenges with ADR
assessment in children based on communication
challenges, there are also laboratory limitations
19 Safe Prescribing and Monitoring in Pediatrics
Table 19.3 Select developmental milestones and impact on adverse drug events
Milestone Approximate age Impact on pediatric adverse drug events
Body movements/facial
expressions
Crawling 6–9months – Increased accuracy of assessment for joint/bone adverse
Fine motor control
resulting in feeding via
hands
Walking 12–18months – Further increased accuracy of assessment for joint/bone
Verbal communication – Nonspecic sounds
Multiple ne, gross
motor, and cognitive skills
Swallowing solid dosage
forms
Cognition 8years – Increased ability of patient correlating adverse effects with
Completed vertical
growth and reproductive
organs
1–2months – Cognitive outcomes like sedation or somnolence are hard
to assess when movements are minimal in the neonatal
period
– Assessment of pain is difcult and relies on grimacing and
vital signs
events
– Increased accuracy of assessment for neurologic toxicities
impacting gross motor skills
1year of age – Increased potential of unintentional overdoses
issuescompared to the crawling phase
– Further increased accuracy of assessment for neurologic
toxicity impacting gross motor skills ascompared to the
crawling phase
– Increased ability to communicate effectively regarding
<2years
– Nonspecic words
2–4years
2years of age – Increased ability to utilize multifaceted neurocognitive
4–8years (variability) – Unable to swallow pills, increased use of liquid
Fully developed in late
adolescent/early adult
(variable)
subjective adverse events (e.g., pain, vision changes)
scales to assess overall development
medications, and increased errors
– Increased use of off-label compounded products
– Increased reliance on intravenous and intramuscular
dosage forms if liquids are not available
receipt of a medication
– Increased ability to describe a subjective adverse effect
– Neurocognitive assessments as an outcome have increased
accuracy
– Puberty allows for accurate assessment of impacts on
height and reproductive organs
– Prior to nishing vertical growth, growth is assessed based
on trends over time as compared to others in the population
without a stable baseline for comparison
445
that impact the determination of appropriate
laboratory- based ADRs in children. Some laboratory values could require collection of 3mL or
more of blood to best conduct the required laboratory tests. Collection of numerous blood samples per day can impact the total uid and blood
volume of pediatric patients, especially neonates
and preterm infants, and make providers reluctant to obtain laboratory values frequently to
assess for an objective ADR. When samples are
obtained, they also tend to be hemolyzed or less
accurate due to limited volume issues with the
sample or if they were obtained via heel sticks.
Some laboratory values are also less standardized
in terms of normal values for children. For example, while formulas to estimate creatinine clearance are available in children, the denition of
acute kidney injury can vary substantially
between recommended guideline references [33].
These practical differences make laboratory
assessment of ADRs in pediatric patients more
challenging than among adults.
446
J. S. Stultz and M. C. Nahata
3.4 Medications withFewer
Adverse Drug Reactions
inChildren
Much of pharmacovigilance in the pediatric population is focused on a higher risk of ADR in children, although it is important to highlight that
some ADRs may be less common in the pediatric
population due to physiologic differences. For
example, Clostridioides difcile-associated acute
colitis is less prevalent in children, especially
infants <1year of age due to possible favorable
microbiota [34]. Amphotericin B conventional
has been associated with less nephrotoxicity in
neonates compared to adults and is considered
the rst-line treatment in this population [35].
3.5 Safety Data Limitations
inChildren andPossible
Solutions
The ADR determination and assessment challenges described above impact not only daily
practice but also the availability of high-quality
data regarding ADRs in children. Many ADRs
take years of well-designed studies and adequate
sample sizes to make denite attributions.
Prospective pediatric studies are commonly small
in size, in part due to difculty in recruiting sufcient patients and ethical considerations regarding undertaking clinical trials in children [36].
Because of these limitations, many prospective
randomized studies are stopped early due to slow
recruitment and safety analyses are based on a
relatively small number of patients who received
the medication. Retrospective studies after widespread utilization of a given medication are commonly performed to provide needed medication
safety data.
With the enhancement of health information
technology (HIT) in clinical practice around the
world, there have been automated systems implemented to detect ADRs (e.g., trigger tools), electronic tracking systems developed, and large
databases created in an attempt to more easily
identify and quantify ADRs, including infrequent
ones [23, 37, 38]. The manufacturers of new
drugs without robust safety analyses done during
clinical trials may be required to report additional
ADR assessments longitudinally. These mechanisms have increased our knowledge regarding
ADRs with the use of medications; however, a
reactive approach after an occurrence of an ADR
still continues due to limited knowledge of ADRs
prior to widescale use of medications in the pediatric population.
4 Medication Prescribing
andSafe Utilization
Considerations
Pediatric medication prescribing is considered
more complicated than prescribing of medications in the adult patient, with ME reported in
13% of pediatric prescriptions in the inpatient
setting [39]. Major causes of prescribing errors
were due to fundamental differences within pediatric age-groups and the required dosages, calculations based on age or body weight, and off-label
prescribing [40]. The disparate complexity compared to adults was highlighted in a landmark
study suggesting that children were at three-fold
higher risk for potential ADEs compared to adults
[41].
The prescription and administration phases
have been reported as the two most error-prone
steps in the medication use process for pediatric
patients. It has been reported that 27–74% of
MEs often originate at the prescription phase of
the medication use process, with errors during
administration comprising 13–55% [38, 41, 42].
Differences between proportional error origination are typically due to the inclusion of actual
ADE vs. possible ADE (e.g., those not reaching
the patient or not causing harm) and the introduction of medication safety initiatives focused
on reducing errors originating at a specic phase
of the medication use process (e.g., prescribing
error reduction with computerized provider
order entry). Importantly, MEs are often multifactorial and many errors originating at the
beginning of the medication use process are
propagated by other phases of the medication
use process.
19 Safe Prescribing and Monitoring in Pediatrics
447
At institutions caring for children, it is prudent
to ensure that practitioners have the needed mathematical calculation skills to safely prescribe medications for children. If an institution cares for a
signicant proportion of adult and pediatric
patients, it is important to have a pediatric- specic
medication safety ofcer who is well trained about
pediatric-specic safety issues. Numerous studies
have repeatedly illustrated reduced prescribing
errors with unit-based clinical pharmacists available to assist with the prescription process at the
time of prescribing [43, 44]. Thus, it is recommended that institutions caring for pediatric
patients have clinical pharmacists focused on optimizing drug use in pediatric patients. The sections
below and Table 19.4 outline the primary phases
of the medication use process and error-prone
aspects of those phases specic to the pediatric
population. This information can be used to devise
target educational initiatives and best utilize pharmacist and other practitioner’s efforts to most
effectively prevent MEs.
4.1 Prescribing Errors: Medication
Selection
Prescribing of an ideal medication for a pediatric
patient for a given indication can be difcult, primarily due to age-related warnings or complications, some of which were described previously
in this chapter. Another example is the use of
sodium phosphate rectal enema solutions which
are commonly used in the adult population but
can cause severe electrolyte abnormalities and
acute kidney injury (even death) in infants. Thus,
this medication is typically avoided in this population. Salicylate products are also not ideal for
use in children when they have inuenza or varicella due to the risk of Reye’s syndrome. A more
complete list of medications and common warnings/contraindications is provided elsewhere
[21]. It is important for practitioners to know that
some medications should be avoided whenever
possible in certain pediatric age-groups.
In addition to many known safety concerns
about medications approved by a regulatory
agency for use, other complications may be rela-
tively unknown due to the lack of data at the time
of approval. Approximately 50% of FDAapproved medications in the United States with
possible pediatric utilization did not have appropriate pediatric labeling, although recent initiatives have increased the number of products with
pediatric labeling [45, 46]. In Europe, off-label
prescribing (generally considered prescribing
outside of recommendations by national or international drug regulatoryagencies for drug dosing
based on age and indication) can range widely
from 13% to 69% in the inpatient setting and has
been reported up to 100% in the outpatient setting in some countries [47]. These off-label uses
can even be found in professional societyendorsed practice guidelines. For example, metronidazole remains a rst-line treatment option
and has been used for decades in the treatment of
Clostridioides difcile infections in children in
the United States, but it still does not have an
FDA-labeled indication for use in children for
this indication [48].
Medication utilization could be consideredoff-label due solely to the patient’s age, the
indication being used for, dose or regimen being
used, or other reasons. Labeling requirements
vary among countries. In some scenarios, medications have to be used out of clinical necessity in
the pediatric population in the absence of other
options. Optimal prescribing and safety considerations in the pediatric population are often
unknown at the time of a new medication
approval and are typically not required in most
countries, although some countries have offered
incentives for submitting pediatric data [45].
While many countries will have different laws
regarding off-label prescribing, prescribers may
need to in some scenarios inform patients that
they are prescribing a medication that is not
labeled by a regulatory agency for use in the specic patient for the desired indication. This may
be considered compassionate use depending on
the medication being prescribed. Institutions may
also consider obtaining consent and assent as is
commonly done when enrolling cognitively
capable children in clinical trials for certain highrisk medications that have minimal data related
to use in the pediatric population [49].
448
Table 19.4 Select medication use process stage and pediatric safety considerations
Medication process
stage
Prescription and
order verication
Dispensing 1. Excipient age-/weight-specic
Administration 1. Lack of intravenous access
Monitoring 1. Communication primarily with family
ADE Adverse drug event, IM Intramuscular, ME Medication error,SQ Subcutaneous
Additional steps needed in the pediatric
population Resulting medication error (ME) concerns
1. Age-/weight-related contraindications
2. Inclusion of weight and age in
addition to other factors considered in
adults
3. Less reliable renal function equations
4. Decreased well-designed studies in
children
warnings and contraindications
2. Measurement errors
3. Concentration selection errors
2. Possible division of IM/SQ injections
3. Inability to swallow tablets/pills
4. Patient refusal/agitation upon
administration
2. Inability to express subjective adverse
events
3. Possible inability to tolerate signicant
volume loss needed for laboratory values
1. Possibly severe preventable ADE if
alternatives exist
2. Increased potential of calculation errors or
drug selection errors resulting inpreventable
ME
3. Less precise dosing in renal dysfunction
4. Increased chance of unknown event
occurrence
1. Possible selection errors resulting in harm
2. Incorrect dosage errors
3. Incorrect dosage errors
1. Required IM/SQ administration
2. Increased injection site reactions and error
potential
3. Increased risk of error due to liquid/
compounded products
4. Inaccurate receipt of medication
1. Missed adverse events due to nonspecic
symptoms
2. Missed adverse events due to nonspecic
symptoms
3. Inability to accurately assess for adverse
events
J. S. Stultz and M. C. Nahata
4.2 Prescribing Errors:
Appropriate Dosing
Once an appropriate medication is decided upon,
there is also a process of prescribing a safe dose
for infants and children when the appropriate
dose is known. Most medications are prescribed
based on a patient’s weight and this calculation
step can prove to be difcult. As previously
described, incorrect dose determination is a large
contributor to medication prescribing errors [39,
40]. This dose determination also may include
converting a mg dose to an appropriate volume
due to product availability and administration
considerations described later in this chapter.
This multiple step process can lead to signicant
decimal point and unit errors when prescribing a
dosage (possible 10- to 100-fold over- or underdoses). Sometimes these errors can lead to disastrous outcomes for the patient [50].
In addition to manual dosing calculation
errors, as in other populations, a pediatric prescriber still needs to take into account the
appropriate dose based on indication, which can
vary multifold between indications (e.g., pneumonia vs. meningitis) and renal function-based
dose estimates [51]. Some indication-based dosing recommendations, however, may not be
based on well-controlled studies in children and
thus may not provide optimal outcomes.
4.3 Dispensing
andPreparationErrors:
Product Selection
andPreparation
Many children are unable to swallow tablets or
capsules, and thus, liquid formulations are commonly utilized to administer medications. Some
liquid formulations may be commercially available and others may need to be compounded by
pharmacists after crushing or manipulating formulations designed for use in adults [52]. Once a
dose is decided upon, there can be errors during
compounding and/or when calculating a measur-
19 Safe Prescribing and Monitoring in Pediatrics
449
able volume for the desired dose in a pediatric
patient. If liquid formulations are commercially
available, they also often come in multiple concentrations, which can increase the potential for
errors. For example, liquid iron products in children can come as an elixir containing alcohol
(potentially unsafe for use in neonates and young
infants) or nonalcohol-based formulations (solutions and syrups). These dosage forms can have
1.25- to 10-fold different concentrations among
products available within a given country [53,
54]. Additionally, the products are labeled based
on the amount of ferrous sulfate versus elemental
iron (a 5 times difference), but most dosage recommendations are based on the amount of elemental iron [54]. A common error is prescribing
based on the wrong concentration on the bottle in
addition to inadvertently selecting the wrong
dosage form. Consistent and clearly labeled
descriptions (in the electronic ordering system
and in storage areas) of concentrations based on
different quantitative measurements of a given
drug are important ways to prevent these concentration errors from occurring.
Medications administrated intravenously or
intramuscularly may also be associated with
complications. Many intravenous products do not
have available premade strengths that provide the
dosage required for many younger children.
Thus, medications are often manipulated from
their original packaging or compounded into a
new formulation before administration. For
example, enoxaparin premade dosages for pediatric weight ranges are not available in the outpatient setting and require utilization of a multidose
vial to get appropriate doses for younger children
and even the use of concentrated dosage forms to
administer to young neonates [50, 55]. These
adaptations have been hallmarks of pediatric care
for decades, but can increase the risk of a dosing
error due to inappropriate product selection and
dispensing. A common strategy to prevent this
type of error is to use standardized concentrations, and some societies have suggested to use
national or international standardized concentrations to avoid errors during transitions in care.
Some products containing previously
described excipients (e.g., benzyl alcohol) may
be administered at unsafe dosages to extremely
low birth weight infants [19, 20]. Depending on
the practice setting, some of the dosage form
selection may be done by pharmacists, along
with nurses who may administer medications
from storage areas. Other settings may have specic products selected by prescribers. Appropriate
labeling on the product and potentially in electronic ordering systems stating that it should not
be used in neonates is an important prevention
strategy.
4.4 Administration Errors:
Considerations
Administration of medications also differs in the
pediatric population and has been reported to
cause similar or more errors than at the prescribing phase. As previously discussed, medications
for oral use are often administered as liquids versus tablets due to the need to measure accurate
doses based on body weight or difculty in swallowing tablets among infants and young children.
It is important for practitioners to know the volume (e.g., mL) as well as strength (e.g., mg) for
appropriate administration and double check the
dosage calculation. However, if a caregiver is
administering the medication, the volume is
likely the most relevant to focus on during
patient/caregiver counseling. Administering liquids to infants and children can be challenging
due to poor palatability or other unfavorable features, leading to difculty in ensuring administration of the desired entire doses over time.
Flavoring or administration with a palatable food
such as apple sauce is one strategy used to help
mask the taste, but the impact of avoring or food
on drug potency is often unknown.
Intramuscular and subcutaneous medications
also create unique challenges in the pediatric
population. Due to altered muscle/tissue size in
infants and young children, gluteal and vastus
lateralis muscles are often preferred for administration compared to the deltoid in adults due to
increased potential of local ADRs when administered into the deltoid. Additionally, the amount of
volume that can be administered via this route to
450
J. S. Stultz and M. C. Nahata
an infant and young child without causing excessive pain or local tissue damage is often less and
changes based on their weight. This results in the
need to divide a dose into multiple injections
administered at different sites, and introduces
multiple additional error-prone steps during dispensing and administration.
Administration of intravenous medications
can also be problematic in children. While use of
infusion pumps can increase safety of administering intravenous medications, errors may occur
with infusion pump programming. Ideally the
infusion pumps should be integrated with an
electronic medical record and institutional standards should be set for common concentrations
utilized [56]. The infusion pumps used may also
have variability in ow rates which can delay
administration of desired dose volumes at low
rates and attainment of desired peak concentration of medications with short half-lives, leading
to unintentional outcomes [57]. The strategy to
avoid infusion pump issues is to dilute the medication from the initial concentration. While this
prevents pump administration issues, it also
could lead to mathematical errors or errors related
to utilizing the incorrect product or programming
the intravenous pump incorrectly. Some organizations (e.g., the Institute for Safe Medical
Practices) have recommended ow rates to try
and systemically combat this issue, but institutions may still have rate limits for use at their specic institutions. These issues illustrate examples
of medication administration being more complex among infants and children compared to
adults. Focused training for practitioners related
to common mathematical calculations with
respect to drug administration is necessary to
avoid calculation errors during administration.
4.5 Health Information
Technology andPediatric
Medication Use
Health information technology (HIT) adoption
has greatly improved the safe use of medications
in the pediatric population, although errors still
persist and new types of errors occur possibly
related to the HIT [58, 59]. The major innovations with prescribing have been with electronic
medication administration records, computerized
provider order entry (CPOE or electronic prescribing in the outpatient setting), and clinical
decision support (CDS) functionalities [60–62].
While these were at times implemented together,
they can be considered separate medication
safety-related HIT advancements.
The transition to CPOE or electronic prescribing has been shown to make an impact primarily
on preventing errors of manual transcription during prescribing (e.g., omitting information
needed or handwriting misinterpretations) [61].
While implementation success has varied, CPOE
is considered to have improved patient care and
reduced ADEs [58, 63]. Importantly, implementation and modications of CPOE systems
require a large, multidisciplinary team-based
approach to ensure all involved in the medication
use process have input on the design and implementation. Inclusion of specic pediatric needs
within the system is important. Some important
aspects include common pediatric drug
concentrations, pediatric-specic prescription
order sentences, and other pediatric-centric HIT
functionalities. This is especially important when
the institution cares for adult and pediatric
patients. It is highly recommended that pediatric
practitioners are involved directly in building and
customization of a system to ensure the system
ts specic institutional needs and practices.
After implementation, updates and continual
practitioner educational efforts related to the
appropriate use of the HIT are vital to ensure safe
and effective use and prevent MEs using HIT.
CDS functionalities are meant to target errors
in decision-making such as dosing calculation
errors, drug interaction errors, unsafe drug selection errors, or prescribing of suboptimal treatments. A CDS functionality can include dosage
calculators, order sets, interruptive and noninterruptive alerts to practitioners, drug-interaction
alerts, and duplicate therapy alerts, to name a few
[62]. In many systems, some of the CDS functionalities are capable of only alerting certain
practitioners (e.g., prescribers, pharmacists,
nurses). Many successful CDS implementations
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