Hanna Phan, Vinita B. Pai, and Milap C. Nahata
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Define different age groups within the pediatric population.
2. Explain general pharmacokinetic and pharmacodynamic differences in pediatric versus adult patients.
3. Identify factors that affect selection of safe and effective drug therapy in pediatric patients.
4. Identify strategies for appropriate medication administration to infants and young children.
5. Apply pediatric pharmacotherapy concepts to make drug therapy recommendations, assess outcomes, and effectively communicate with patients and caregivers.
KEY CONCEPTS
Pediatric patients are not just “smaller adult patients,” where doses are scaled only for their smaller size; there are multiple factors to consider when selecting and providing drug therapy for patients in this specific population.
Due to multiple differences including age-dependent development of organ function in pediatric patients, pharmacokinetics, efficacy, and safety of drugs within the pediatric population often differs from adults; thus, pediatric dosing should not be calculated based on a single factor of difference.
Medication errors among pediatric patients are possible due to differences in dose calculation and preparation; it is important to identify potential errors through careful review of calculations, dispensing and administration of drug therapy to infants and children.
Safety and efficacy data of drugs in pediatric patients may be limited to small studies and case reports, leading to frequent off-label use of drugs in this population.
Caregiver education is essential, as they are often responsible for administration and monitoring of drug therapy in infants and young children.
INTRODUCTION
Pediatric clinical practice involves the care of infants, children, and adolescents with the goal of optimizing their health, growth, and development toward adulthood. Clinicians serve as advocates for this unique and vulnerable patient population to maximize their well-being.
There is a continued need for pediatric health care resources, evidenced by the annual increase in the number of infants born in the United States.1 Ambulatory care settings, such as the pediatrician office and emergency department as well as hospitals, require the expertise of knowledgeable clinicians with pediatric experience. In fact, national data have noted the lack of appropriate services and supplies for pediatric patients at many institutions.2Pediatric care accounts for a considerable amount of total patient care annually. For example, patients less than 15 years of age accounted for 16.7% of physician office visits in the United States during 1995 to 2005, with 60% of the drugs used during the 2005 visits being new drug therapies.3 The overall inpatient hospitalization rate of patients less than 20 years of age was 10.8%, with an average length of stay between 3.8 and 4.5 days, similar to the overall U.S. national average length of stay of 4.8 days for all pediatric and adult patients.4
Despite the common misconception of pediatric patients as “smaller adults,” they significantly differ within their age groups and from adults regarding drug administration, psychosocial development, and organ function development, which affect efficacy and safety of pharmacotherapy.
FUNDAMENTALS OF PEDIATRIC PATIENTS
Classification of Pediatric Patients
Pediatric patients are those less than 18 years of age. Unlike an adult patient, whose age is commonly measured in years, a pediatric patient’s age can be expressed in days, weeks, months, and years. Patients are classified based on age and may be further described based on other factors, including birth weight and prematurity status (Table 3–1).5
Growth and Development
Children are monitored for physical, motor, cognitive, and psychosocial development through clinical recognition of timely milestones during routine well-child visits. As a newborn continues to progress to infant, child, and adolescent stages, different variables are monitored to assess growth compared to the general population of similar age and size. The Centers for Disease Control and Prevention (CDC) Growth Charts (Fig. 3–1) are used to plot head circumference, weight, length or stature, and body mass index for a graphical representation of a child’s growth compared to the general pediatric population.6These tools assess whether a child is meeting the appropriate physical growth milestones, thereby allowing identification of nutritional issues such as poor weight and height gain (e.g., failure to thrive).
Differences in Vital Signs
Normal values for heart rate and respiratory rate vary based on their age. Normal values for blood pressure vary based on gender and age for all pediatric patients, and also height percentile for patients greater than 1 year of age. Normal values for blood pressure in pediatric patients can be found in various national guidelines and other pediatric diagnostic references.7 Heart rates are highest in neonates and infants, ranging from 95 to 180 beats per minute (bpm) and decrease with age, reaching adult rates (60–100 bpm) around 10 years of age.8 Respiratory rates are also higher in neonates and infants (24–38 breaths/min), decreasing with age to adult rates around 15 years of age (12–20 breaths/min).9 Another vital sign commonly monitored in children by their caregivers is body temperature, especially when they seem “warm to the touch.” The American Academy of Pediatrics (AAP) recommends rectal temperature measurement in children 4 years of age or younger, using a digital thermometer. For children 4 years of age or older, axillary or oral temperature measurement is appropriate as the child is more able to cooperate when asked. Axillary thermometers can be used in children as young as 3 months, but may be less accurate.10Tympanic (otic) temperature readings are also safe for all ages; however, these temperatures may be less accurate and can be affected by cerumen accumulation. Generally, rectal temperature is greater than oral temperature by 0.6°C (1°F), and oral temperature is 0.6°C (1°F) higher than axillary temperatures. Also known as the fifth vital sign, pain assessment is more challenging to assess in neonate, infants, and young children due to inability to communicate symptoms. Indicators of possible pain include physiologic changes such as increased heart rate, respiratory rate, and blood pressure, decreased oxygen saturation, as well as behavior changes such as prolonged, higher pitch crying and facial expressions. Laboratory values also vary depending on age. Normal ranges are often noted by the laboratory facility on reported results.
Table 3–1 Pediatric Age Groups, Age Terminology, and Weight Classification
FIGURE 3–1 Example of CDC growth chart of boys, birth to 36 months: Head circumference-for-age and weight-for-length percentile, 2000. (From Ref. 6.)
Fluid Requirements
Fluid requirement and balance are important to monitor in pediatric patients, especially in premature neonates and infants. Maintenance fluid requirement can be calculated based on body surface area for patients greater than 10 kg with a range of 1,500 to 2,000 mL/m2/day. However, a weight-based method of determining normal maintenance fluid for children is often used (Table 3–2).
Table 3–2 Maintenance Fluid Calculations by Body Weight
Patient Encounter, Part 1
BB, a 27-week gestational age (GA) premature baby boy weighing 1,000 g, length 48.5 cm, was born to a 19-year-old female this morning. He is admitted to the neonatal intensive care unit, was found to have blood oxygen saturation of 84%, and was placed under an oxygen hood with FiO2 of 40%. His chest x-ray exhibited ground glass appearance of lung fields and right lower lobe atelectasis. He was intubated and requires maintenance IV fluids until his total parenteral nutrition can be started.
Calculate corrected age for BB 4 months from today.
How much maintenance fluid would you recommend for BB?
EFFECTS OF PHARMACOKINETIC AND PHARMACODYNAMIC DIFFERENCES ON DRUG THERAPY
Drug selection strategy may be similar or different depending on age and disease state, as a result of differences in pathophysiology of certain diseases, and pharmacokinetic and pharmacodynamic parameters among pediatric and adult patients. It is noteworthy that pediatric patients may require the use of different medications from those used in adults affected by certain diseases. For example, phenobarbital is commonly used for treatment of neonatal seizures, but not often used for treatment of seizures in adults, due to differences in seizure etiology and availability of extensive data regarding its use in neonates compared to newer antiepileptic medications. There also exist commonalties between pediatric and adult patients, such as therapeutic serum drug concentrations required to treat certain diseases. For example, gentamicin peak and trough serum concentrations needed to treat Gram-negative pneumonia are the same in children as in adults. The appropriate selection and dosing of drug therapy for a pediatric patient depends on specific factors such as age, weight, height, disease being treated, comorbidities, organ function, and available drug dosage forms. Often, pediatric drug doses are calculated as mg/kg/day or mg/kg/dose based on body weight compared to mg/day or mg/dose for adult patients. Thus, accurate weight should be available while writing or dispensing medications for this patient population. Pediatric doses may exceed adult doses for certain medications due to differences in pharmacokinetics and pharmacodynamics; hence, the use of pediatric drug dosing guides is recommended.
Equations proposed to calculate pediatric doses based on adjusted age or weight such as Clark’s, Fried’s, or Young’s Rule should not be routinely used to calculate pediatric doses, as they account for only one factor of difference, age or weight, and lack integration of the effect of growth and development on drug pharmacokinetics and pharmacodynamics in this population.
Absorption
Oral absorption may be reduced in premature infants and neonates due to differences in gastric acid secretion and pancreatic and biliary function. Full-term neonates have a gastric pH of 6 to 8 at birth and pH 1 to 3 by 48 hours of age. Gastric acid output per kilogram is lower in premature infants and increases with age to adult levels by 6 months of age.11,12 Low gastric acid secretion can result in increased serum concentrations of weak bases and acid-labile medications, such as penicillin, and decreased serum concentrations of weak acid medications, such as phenobarbital, due to increased ionization. Additionally, gastric emptying time and intestinal transit time are delayed in premature infants, increasing drug contact time with the GI mucosa and drug absorption.13 Diseases such as gastroesophageal reflux, respiratory distress syndrome, and congenital heart disease may further delay gastric emptying time. Pancreatic exocrine and biliary function are also reduced in newborns, with about 50% less secretion of amylase and lipase than adults, reaching adult values as early as the end of the first year and as late as 5 years of age. Deficiency in pancreatic secretions and bile salts results in decreased bioavailability of prodrug esters, such as erythromycin, which requires solubilization or intraluminal hydrolysis.12 Due to limited data on oral bioavailability of medications in infants and children for newer agents, some drug dosing recommendations may be extrapolated from adult safety and efficacy studies and case reports.
Topical or percutaneous absorption in neonates and infants is increased due to a thinner stratum corneum, increased cutaneous perfusion, and greater body surface-to-weight ratio. Hence, application of topical medications should be limited to the smallest amount possible. Increased percutaneous absorption can lead to high serum concentrations of topically applied drugs such as corticosteroids, lidocaine, or chlorhexidine, as well as inactive additives such as propylene glycol, potentially causing adverse effects.
Intramuscular absorption in premature and full-term infants can be erratic due to variable perfusion, poor muscle contraction, and decreased muscle mass compared to older patients.14 Intramuscular administration may be appropriate for some medications; however, use of this route of administration can be painful and is usually reserved when others (e.g., IV) are not accessible, such as initial doses of ampicillin and gentamicin for neonatal sepsis.
Rectal absorption can also be erratic and is not a commonly recommended route of administration if there are other routes available (e.g., oral). This route is useful in cases of severe nausea and vomiting or status epilepticus. For medications that undergo extensive first-pass metabolism, bioavailability increases as the blood supply bypasses the liver from the lower rectum directly to the inferior vena cava. Availability of rectal dosage forms varies, with acetaminophen suppositories and diazepam gel as examples of medications used by the rectal route in pediatric patients. Rectal use of oral medications or other dosage forms is based on limited studies and case reports.
Volume of Distribution
In pediatric patients, apparent volume of distribution (Vd) is normalized based on body weight and expressed as L/kg. Extracellular fluid and total body water per kilogram of body weight are increased in neonates and infants, resulting in higher Vd for water-soluble drugs such as aminoglycosides and decreases with age. Therefore, neonates and infants often require higher individualized doses by weight (mg/kg) than older children and adolescents to achieve the same therapeutic serum concentrations.14–17 Neonates and infants have a lower normal range for serum albumin (2–4 g/dL, 20–40 g/L), reaching adult levels after 1 year of age. This affects highly protein-bound drugs such as phenytoin, resulting in lower total serum concentrations needed to achieve therapeutic, unbound serum concentrations.14
As premature neonates have lower body adipose composition compared to older children and adults, they have a decreased Vd for lipid-soluble drugs such as midazolam and require lower doses by body weight. Lipid-soluble drugs may also reach higher concentrations in the CNS due to an immature blood–brain barrier.18
Metabolism
Drug metabolism is slower at birth in full-term infants compared to adolescents and adults, with further delay in premature neonates. Phase I reactions and enzymes, such as oxidation and alcohol dehydrogenase, are impaired in premature neonates and infants and do not fully develop until later childhood or adolescence. Accordingly, the use of products containing ethanol or propylene glycol can result in increased toxicities, including respiratory depression, hyperosmolarity, metabolic acidosis, and seizures, and should be avoided in neonates and infants. Cytochrome P450 isoenzymes (e.g., CYP2C9, CYP1A2) develop at various ages, ranging from a few months to 3 years of age, with delayed development in premature infants.15
Among phase II reactions, sulfate conjugation by sulfotransferases is well developed at birth in term infants. Glucuronidation by the uridine diphosphate glucuronosyl transferases, on the other hand, is immature in neonates and infants, requiring at least several months to develop to adult values at approximately 4 years of age. In neonates this deficiency results in adverse effects including cyanosis, ash gray color of the skin, limp body tone, and hypotension, also known as “gray baby syndrome” with use of chloramphenicol.19 Products containing benzyl alcohol or benzoic acid should be avoided in neonates due to immature glycine conjugation, resulting in accumulation of benzoic acid. This accumulation can lead to “gasping syndrome,” which includes respiratory depression, metabolic acidosis, hypotension, seizures or convulsions, and gasping respirations.20 Acetylation via N-acetyltransferase reaches adult maturation at around 1 year of life, but its impact is not well understood regarding neonatal drug therapy.12Thus, reduced dosing of medications undergoing hepatic metabolism may be required for full-term and premature neonates. Conversely, hepatic enzyme activity increases to nearly twice as much as adults at 6 months of age and may continue to be high through puberty, around 9 to 12 years of age.14 These children may require higher doses per kilogram of body weight for hepatically metabolized medications. Common examples include antiepileptic medications such as phenytoin, carbamazepine, and valproic acid. This increase in metabolism slows to adult levels as the child goes through puberty into adulthood.14
Elimination
Renal drug clearance is reduced in infants and slowest in premature neonates, due to immature renal function, resulting in the need for longer dosing intervals for renally cleared medications, such as vancomycin, to prevent accumulation. Glomerular filtration rate (GFR) is lowest in premature neonates, increasing with age and peaking at 3 to 12 years of age, after which there is a gradual decline to approximate adult value. For example, vancomycin is often given every 18 to 24 hours in a low birth weight (LBW) premature neonate, every 6 hours in children with normal renal function, and every 8 to 12 hours in adult patients with normal renal function. Children with cystic fibrosis also present with greater renal clearance of drugs such as aminoglycosides, compared to children without the disease, requiring higher doses by weight and more frequent dosing intervals.21
Pediatric creatinine clearance (CrCl), an indicator of GFR, is normalized due to variable body size (mL/min/1.73 m2). The use of the Cockroft-Gault or Jelliffe equations for estimating CrCl in adults is not recommended for patients less than 18 years of age.22,23 Schwartz’s equation is a common method of estimating pediatric CrCl for LBW infants up to 21 years of age (Fig. 3–2). This equation utilizes patient length (cm), serum creatinine (mg/dL), and a constant, k, which is dependent on age for all patients and also gender for those greater than 2 years of age.24 Urine output is also a parameter used to assess renal function in pediatric patients, with a urine output of greater than 1 to 2 mL/kg/h considered normal.
FIGURE 3–2 Estimation of creatinine clearance (CrCl) in pediatric patients up to 21 years of age. (Redrawn from Ref. 24.)
Patient Encounter, Part 2
BB is now 3 days old and presents with body temperature fluctuations and hypotension. A workup to rule out sepsis was initiated with collection of blood cultures. He was empirically started on ampicillin 50 mg (50 mg/kg/dose) IV every 8 hours and gentamicin 4 mg (4 mg/kg/dose) IV daily.
Using the most appropriate method, calculate a creatinine clearance for BB.
The mg/kg dose of gentamicin administered to BB is high compared to a child or an adolescent; however, the dosing frequency is less often. How would you explain this difference?
COMMON PEDIATRIC ILLNESSES
There may be similarities and differences in illnesses such as infections, asthma, allergic rhinitis, attention deficient hyperactivity disorder, diabetes, and seizure disorders between children and adults. These have been discussed throughout the textbook. The incidence of previously common childhood illness such as measles, mumps, and rubella has significantly decreased as a result of en masse vaccination of infants and children. The Advisory Committee on Immunization Practices (ACIP) within the CDC release and update child and adolescent immunization schedules every year. Patients’ immunization records should be reviewed routinely for needed immunizations based on these schedules.25,26 Most of the common illnesses in children leading to missed school and/or need for clinician consultation are ambulatory in nature; however, some complications may require hospitalization.
Presentation of common childhood illnesses may vary depending on age and development. Older children and adolescents are able to communicate symptoms verbally, making assessment and treatment easier, unlike infants and younger children who are less able to do so. In such cases, changes in vital signs, such as respiratory rate, heart rate, body temperature, and changes in oral intake, feeding pattern, and urine output are used as indicators of potential illness. Parents may also note subjective items such as changes in mood (e.g., increased irritability or “fussiness”).
SPECIFIC CONSIDERATIONS IN DRUG THERAPY
In addition to differences in pharmacokinetics and pharmacodynamic parameters, other factors including dosage formulations, medication administration techniques, and parent/caregiver education should be considered when selecting drug therapy.
Routes of Administration and Drug Formulations
Depending on age, disease, and disease severity, different routes of administration may be considered. Use of rectal route of administration is reserved in cases where oral administration is not possible and IV route is not necessary. Topical administration is often used for treatment of dermatologic ailments. Transdermal routes are often not recommended, unless it is an approved indication such as the methylphenidate transdermal patch for treatment of attention deficit hyperactivity disorder. The injectable route of administration is used in patients with severe illnesses or when other routes of administration are not possible. As done with adult patients, IV compatibility and access should be evaluated when giving parenteral medications. However, dilution of parenteral medications may be necessary to measure smaller doses for neonates. On the other hand, higher concentration of parenteral medications may be necessary for patients with fluid restrictions such as premature infants, and patients with cardiac anomalies and/or renal disease. Appropriate stability and diluent selection data should be obtained from the literature.
When oral drug therapy is needed, one must also consider the type of dosage form available. Children less than 6 years of age are often not able to swallow oral tablets or capsules and may require oral liquid formulations. The child’s ability to swallow a solid dosage form should be determined before selecting a drug product. Not all oral medications, especially those unapproved for use in infants and children, have a commercially available liquid dosage form. Use of a liquid formulation compounded from a solid oral dosage form is an option, when data are available. Factors such as stability, suspendability, dose uniformity, and palatability should be considered when compounding a liquid formulation.27 Commonly used suspending agents include methylcellulose and carboxymethylcellulose (e.g., Ora-Plus). Palatability of a liquid formulation can be enhanced by using simple syrup or OraSweet. If no dietary contraindications or interactions exist, doses can be mixed with food items such as pudding, chocolate syrup, or applesauce immediately before administration of individual doses. Honey, although capable of masking unpleasant taste of medication, may contain spores of Clostridium botulinum and should not be given to infants less than 1 year of age due to increased risk for developing illness. Most hospitals caring for pediatric patients compound formulations in their inpatient pharmacy. Limited accessibility to compounded oral liquids in community pharmacies poses a greater challenge. A list of community pharmacies with compounding capabilities should be maintained and provided to the parents and caregivers before discharge from the hospital.
Common Errors in Pediatric Drug Therapy
Prevention of errors in pediatric drug therapy begins with identification of possible sources. Reports have shown that nearly 50% of medication errors in the United States in neonatal and pediatric critical care units are attributable to prescribing and transcribing errors.28 Up to 69.5% of overall calculation errors affect pediatric patients.29 As pediatric drug therapy is based on weight, body surface area, and age, it is crucial to verify accurate weight, height, and age for dosing calculations and dispensing of prescriptions. Consistent units of measurements in reporting patient weight (kg), height (cm), and age (weeks and years) should be used. Dosing units such as mg/kg, mcg/kg, mEq/kg, or units/kg should also be used accurately. Given the age-related differences in metabolism of additives such as propylene glycol and benzyl alcohol, careful consideration should be given to the active and inactive ingredients when selecting a formulation.
Decimal errors, including trailing zeroes (e.g., 1.0 mg misread as 10 mg) and missing leading zeroes (e.g., .5 mg misread as 5 mg) in drug dosing or body weight documentation are possible, resulting in several fold overdosing. Strength or concentration of drug should also be clearly communicated by the clinician in prescription orders. Similarly, labels that look alike may lead to drug therapy errors, e.g., mistaking a vial of heparin for insulin, when compounding parenteral solutions. Dosing errors of combination drug products can be prevented by using the right component for dose calculation (e.g., dose of sulfamethoxazole/trimethoprim is calculated based on the trimethoprim component).
The use of the “rule of six” was previously used to calculate infusions of medication such as inotropes for critically ill patients in hospitals.30 However, the Institute for Safe Medication Practice (ISMP) has found a relationship between medication errors and use of nonstandard injectable concentrations, such as those resulting from use of the “rule of six.” The Joint Commission on Accreditation of Healthcare Organizations determined that “the rule of six” did not meet its goals of standardizing and limiting the number of drug concentrations. Use of standardized concentrations and programmable infusion pumps, such as smart pumps with built-in libraries, is encouraged to minimize errors with parenteral medications. Some hospitals have also adopted the use of enhanced photoemission spectroscopy to scan small samples of compounded IV solution in verification of high-risk IV solutions.31 Introduction of technological advances such as computer physician order entry (CPOE) systems with ability for dose range checks by weight for pediatric medication orders and the use of bar code technology for dispensing of medications have decreased medication errors.32,33
Prevention of medication errors is a joint effort between health care professionals and parents/caregivers. Obtaining a complete medication history including over-the-counter (OTC) and complementary and alternative medicines (CAMs), simplification of medication regimen, clinician awareness for potential errors, and appropriate patient/parent/caregiver education on measurement and administration of medications are essential in preventing medication errors.
CAM and OTC Medication Use
An estimated 31% to 84% of children with cancer, 74% with autism spectrum disorder, 71% with asthma, and 15% seen in the emergency department utilize CAM or other OTC products.34–37 Over 50% of parents/caregivers do not disclose this use to the physicians.35 CAM can include mind-body therapy (e.g., imagery, hypnosis), energy field therapies (e.g., acupuncture, acupressure), massage, antioxidants (e.g., vitamins C and E), herbs (e.g., St. John’s wort, kava, ginger, valerian), prayer, immune modulators (e.g., echinacea), or other folk/home remedies.
It is critical to realize that there are limited data establishing efficacy of various CAM therapies in children. For example, colic is a condition of unclear etiology in which an infant cries inconsolably for over a few hours in a 24-hour period, usually during the same time of day. Symptoms of excessive crying usually improve by the third month of life and often resolve by 9 months of age. No medication has been approved by the FDA for this condition. This condition is self-limiting and infants will outgrow it as they age. Some parents are advised by family and friends to use alternative treatments, such as gripe water, to treat colic. Gripe water is an oral solution containing a combination of ingredients such as chamomile, peppermint, fennel, ginger, aloe, sodium bicarbonate, and lemon balm. Combinations of ingredients vary among manufacturers as there is no defined formulation. These options have not been proven safe or effective in the treatment of colic in infants and are not regulated by the FDA. Further, some of these therapies (e.g., St. John’s wort) can interact with prescription drugs and produce toxicities. St. John’s wort can increase adverse effects of selective serotonin receptor antagonists and 5-HT1 serotonin receptor agonists due to serotonergic syndrome and decrease effectiveness of anticonvulsants, warfarin, cyclosporine, digoxin, and protease inhibitors due to their increased metabolism and reduced serum concentration.38
It is important to assess OTC product use in pediatric patients. For example, treatment of the common cold in children is similar to adults, including symptom control with adequate fluid intake, rest, use of saline nasal spray, and acetaminophen (15 mg/kg/dose every 6–8 hours) or ibuprofen (4–10 mg/kg/dose every 8 hours) for relief of discomfort and fever. Unlike adults, symptomatic relief through the use of pharmacologic agents, such as OTC combination cold remedies, is not recommended for pediatric patients younger than 4 years of age. Currently, the FDA does not recommend the use of OTC cough and cold medications (e.g., diphenhydramine and dextromethorphan) in children less than 2 years of age; however, the Consumer Healthcare Products Association, with the support of the FDA, has voluntarily changed product labeling of OTC cough and cold medications to state “do not use in children under 4 years of age.” This is due to increased risk for adverse effects (e.g., excessive sedation, respiratory depression) and no docu-mented benefit in relieving symptoms. It has also been noted that these medications may also be less effective in children under 6 years of age compared with older children and adults.39,40 Also noteworthy is the potential for medication error with use of OTC products in older children, such as cold medications containing diphenhydramine and acetaminophen. A parent/caregiver may inadvertently overdose a child on one active ingredient, such as acetaminophen, by administering acetaminophen suspension for fever and an acetaminophen-containing combination product for cold symptoms. The use of aspirin in patients less than 18 years of age with viral infections is not recommended due to risk of Reye’s syndrome. While making an appropriate recommendation for an OTC product for a pediatric patient, the parent/caregiver should always be referred to their pediatrician for further advice and evaluation, especially in the care of a neonate.
Clinicians should respect parents’/caregivers’ beliefs in use of CAM and OTC products and encourage a discussion with the intention of providing information regarding their risks and benefits to achieve desired health outcomes as well as optimize medication safety.
Off-Label Medication Use
Pharmacotherapy in pediatric patients often includes use of approved and unapproved (off-label) drugs. Off-label use of medication is the use of a drug outside of its approved labeled indication. This includes the use of a medication in the treatment of illnesses not listed on the manufacturer’s package insert, use outside the licensed age range, dosing outside those recommended, or use of a different route of administration.41 Such off-label use in infants and children is frequently based on limited data.
Patient Encounter, Part 3
BB is now older (6 months corrected age) and his mother calls the clinic and tells you that her son is “just miserable” with a runny nose, cough, and a fever (axillary temperature) of 38.3°C (101°F). She wanted to know if she could use baby aspirin instead of the acetaminophen, which doesn’t seem to help. She also wanted to know which cough and cold preparation would be most appropriate for BB.
What additional information would you need to help BB and his mom?
What is your recommendation regarding use of aspirin for BB?
What cough and cold preparation would you recommend for BB?
Currently, there is a lack of pediatric dosing, safety, and efficacy information for over 75% of drugs approved in adults. Off-label use occurs in both outpatient and inpatient settings. About 80% of hospitalized pediatric patients receive at least one off-label medication.42 It is appropriate to use a drug off-label when no alternatives are available; however, clinicians should refer to published studies and case reports for available safety, efficacy, and dosing information. FDA regulatory changes, such as patent exclusivity, provide incentives for a pharmaceutical manufacturer to market drugs for pediatric patients.
Medication Administration to Pediatric Patients and Caregiver Education
Considering the challenges in cooperation from infants and younger children, medication administration can become a difficult task for any parent or caregiver. Clinicians should consider ease of measurement and administration when selecting and dosing pediatric drug therapy. Clinicians should check concentrations of available products and round doses to a measurable amount. For example, if a patient were to receive an oral formulation, such as amoxicillin 400 mg/5 mL suspension, and the dose was calculated to be 4.9 mL, the dose should be rounded to 5 mL for ease of administration. Rounding the dose by 10% to the closest easily measureable amount is commonly practiced for most medications; however, drugs with narrow therapeutic indices are exceptions to this guideline.
The means or devices for measuring and administering medications by the caregivers should also be closely considered. Special measuring devices as well as clear and complete education about their use are essential. Oral syringes are accurate and offered at most community pharmacies for measurement of oral liquid medications. Oral droppers that are included specifically with a medication may be appropriate for use in infants and young children. Medicine cups are not recommended for measuring doses for infants and young children due to possible inaccuracy of measuring smaller doses. Household dining or measuring spoons are not accurate or consistent and should not be used for administration of oral liquids.
Comprehensive and clear parent/caregiver education improves medication adherences, safety, and therapeutic outcomes. Information about the drug including appropriate and safe storage from children, possible drug interactions, duration of therapy and importance of adherence, adverse effects, and expected therapeutic outcomes should be provided. Parent/caregiver education is important in both inpatient and outpatient care settings and should be reviewed at each point of care.
As parents/caregivers are often sole providers of home care for ill children, it is important to demonstrate appropriate dose preparation and administration techniques to the caregivers before medication dispensing. First, a child should be calm for successful dose administration. Yet, calming a child is often a challenge during many methods of administration (e.g., otic, ophthalmic, rectal). Parents/caregivers should explain the process in a simple and understandable form to the child as this may decrease child’s potential anxiety. In addition, it is also recommended to distract younger children using a favorite item such as toy, or reward cooperative or “good” behavior during medication administration. Administration of ophthalmic drops or ointment is best when the child is calm and laying in a supine position, with similar instructions of washing hands before administration, avoiding contact of the applicator tip to the eye or other surfaces as noted in adult administration. Otic drop administration should begin with the child lying in a prone position with head tilted to expose the treated ear followed by gentle pulling of the outer ear outward, followed by pulling downward and upward for patients less than and greater than 3 years of age, respectively, due to the change in angle of the eustachian tube with age. Another challenging route of administration for caregivers is use of nasal drops, which should be administered when the child is in a supine position with the head slightly tilted back, remaining in position for a few minutes for appropriate distribution of medication. Rectal administration, also a difficult route to achieve patient cooperation, is similar to adults regarding preparation of dose; however, for patients under 3 years of age, a smaller finger (e.g., pinky finger) should be used to insert the suppository, whereas the index finger can be used in older children for administration.43
Accidental Ingestion in Pediatric Patients
Over 1.2 million accidental ingestions occurred in children less than 6 years of age in 2001; these often occur in the home.44 Ingested substances can vary, from household cleaning solutions to prescription and nonprescription medications. Management of accidental ingestions varies depending on the ingested substance, the amount, and the age and size of the child. Clinicians receiving calls regarding management of accidental ingestions should direct them to the local or regional poison control center for specific recommendations, which can be located through the American Association of Poison Control Centers (www.aapcc.org).
Inducing emesis is not recommended for suspected ingestions of acidic or alkaline substances. The American Academy of Clinical Toxicology and the AAP do not recommend the use of ipecac syrup as it can decrease effectiveness of activated charcoal treatment administered in the emergency department and compromise patient outcomes.45 Activated charcoal use is preferred for treatment of ingestion in the emergency department at a dose of 1 g/kg for infants less than 1 year of age, 1 to 2 g/kg orally for children greater than 1 year of age and adults, as a single dose.46 Monitor symptoms of toxicities from the substance ingested during hospitalization. Parents/caregivers should continue monitoring at home following discharge.
Patient Encounter, Part 4
BB is now 23 months old, brought by his father to the pediatrician. He has a 4-day history of left ear pain, excessive crying, decreased appetite, and difficulty sleeping over the past 2 days. The child’s temperature last night was 39°C (102.2°F) by electronic axial thermometer. The father gave the child several doses of acetaminophen drops (80 mg/0.8 mL), but the pain or temperature did not improve and none was given this morning. His immunizations are up to date. He was last treated for acute otitis media 4 months ago using oral amoxicillin 40 mg/kg/day divided every 12 hours. He has no known drug allergies.
Medications prior to admission: Acetaminophen drops as needed for pain and fever.
PE:
General: Crying, tugging on his left ear
VS: T 39°C (102.2°F), BP 104/58 mm Hg (90th percentile), HR 133 bpm, RR 36 bpm, wt 14 kg (30.8 lb) (75th percentile), ht 89 cm (75th percentile)
HEENT: Tympanic membranes erythematosus (L>R); left ear is bulging and nonmobile. Throat erythematous; nares patent.
Diagnosis: Acute otitis media, left ear
You and the pediatrician decide to start BB on high-dose oral amoxicillin (90 mg/kg/day divided every 12 hours, using a 400 mg/5 mL suspension) for a total of 10 days and continue acetaminophen drops (10 mg/kg/dose every 6 hours as needed for fever or pain).
Based on the information available, create a care plan for BB. The plan should include:
(a) Statement of the drug-related needs and/or problems,
(b) Patient-specific detailed therapeutic plan with specific dosing, and
(c) Parent/caregiver education points.
Abbreviations Introduced in This Chapter
Patient Care and Monitoring
For all pediatric patients, review and consider the following when selecting and monitoring drug therapy:
• Gestational age, postnatal age, and corrected age if the patient is a neonate
• Patient’s demographic information including age, weight (and birth weight if a neonate), and gender
• Disease or illness for which treatment is needed
• Past medical history, including comorbidities
• Medication history current and past (including OTC and complementary and alternative products)
• History of medication adherence
• Other concurrent medications
• Previous therapy failures
• Available routes of administration
• Can the patient take medications orally?
• If IV medication is needed what types of IV accesses are available? For example, does the patient have a central or peripheral line?
• Is intramuscular administration needed?
• Fluid status—Is the patient dehydrated, balanced, or edematous?
• Available data regarding safe and effective dosing of selected drug
• Verification of accurate dose calculation
• Verify weight and dosing units (e.g., mg/kg/day, mg/kg/dose)
• Is the dosing interval appropriate?
• Is the dose an easily measurable amount for the caregiver?
• Will the drug be administered at home and/or a daycare facility or school?
• Does the parent/caregiver need additional documentation for medication administration at other locations?
• Are additional supplies for medication administration at other locations needed?
• Educate parent/caregiver/patient, regarding selected drug therapy
• Regular assessment of weight
• Premature neonates and infants can change frequently, check weight daily
• Depending on illness in older children, daily weight check may be necessary
• Organ function
• For drugs that undergo extensive hepatic metabolism and clearance, assess liver function at baseline and periodically (depending on severity of illness)
• For drugs that undergo extensive renal elimination
• Note changes in serum creatinine and urine output
• Calculate serum creatinine clearance using Schwartz’s or Traub–Johnson’s equations
• Measure drug serum concentrations when appropriate
• Monitor clinical outcomes of pharmacotherapy
• Monitor, manage, and prevent adverse drug events
• Monitor for drug–drug or drug–food interactions
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
REFERENCES
1. Hamilton BE, Martin JA, Ventura SJ. Births: Preliminary data for 2006. National vital statistics reports; vol 56 no 7. Hyattsville, MD: National Center for Health Statistics. 2007.
2. Committee on the Future of Emergency Care in the United States Health System. Emergency Care for Children, Growing Pains. Executive Summary. The Institute of Medicine, 2007, http://books.nap.edu/catalog/11655.html.
3. Cherry DK, Woodwell DA, Rechtsteiner EA. National Ambulatory Medical Care Survey: 2005 Summary. Advance data from vital and health statistics; no. 387. Hyattsville, MD: National Center for Health Statistics. 2007.
4. Kozak LJ, DeFrances CJ, Hall MJ. National Hospital Discharge Survey: 2004 annual summary with detailed diagnosis and procedure data. National Center for Health Statistics. Vital Health Stat 13(162). 2006.
5. American Academy of Pediatrics, Committee on Fetus and Newborn. Age terminology during the perinatal period. Pediatrics 2004;114: 1362–1364.
6. Center for Disease Control Growth Charts, 2000. Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion. http://www.cdc.gov/growthcharts.
7. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. NIH Publication No. 05-5268. Bethesda, MD: National Heart, Lung, and Blood Institute. Pediatrics 2004;114:555–576.
8. Gajewski KK. Cardiology. In: Robertson J, Shilkofski N, eds. The Harriet Lane Handbook: A Manual for Pediatric House Officers, 17th ed. Philadelphia: Mosby, 2005.
9. Loughlin CE. Pulmonology. In: Robertson J, Shilkofski N, eds. The Harriet Lane Handbook: A Manual for Pediatric House Officers, 17th ed. Philadelphia: Mosby. 2005.
10. American Academy of Pediatrics. Fever and Your Child. 2007.
11. Boyle JT. Acid secretion from birth to adulthood. J Pediatr Gastroenterol Nutr 2003;37:S12–S16.
12. Alcorn J, Nakamura PJ. Pharmacokinetics in the newborn. Adv Drug Deliv Rev 2003;55:667–686.
13. Ramirez A, Wong WW, Shulman RJ. Factors regulating gastric emptying in preterm infants. J Pediatr 2006;149:475–479.
14. Soldin OP, Soldin SJ. Therapeutic drug monitoring in pediatric patients. Ther Drug Monit 2002;24:1–8.
15. Strolin Benedetti M, Baltes EL. Drug metabolism and disposition in children. Fundam Clin Pharmacol 2003;17:281–299.
16. Semchuk W, Shevchuk YM, Sankaran K, Wallace SM. Prospective, randomized, controlled evaluation of a gentamicin loading dose in neonates. Biol Neonate 1995;67(1):13–20.
17. Shevchuk YM, Taylor DM. Aminoglycoside volume of distribution in pediatric patients. DICP Ann Pharmacother 1990 Mar;24(3):273–276.
18. Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinet 1998;35(1):37–47.
19. Mulhall A, de Louvois J, Hurley R. Chloramphenicol toxicity in neonates: Its incidence and prevention. Br Med J (Clin Res Ed) 1983 Nov 12;287(6403):1424–1427.
20. Menon PA, Thach BT, Smith CH, et al. Benzyl alcohol toxicity in a neonatal intensive care unit. Incidence, symptomatology, and mortality. Am J Perinatol 1984;1(4):288–292.
21. Rey E, Tréluyer JM, Pons G. Drug disposition in cystic fibrosis. Clin Pharmacokinet 1998 Oct;35(4):313–329.
22. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.
23. Jelliffe RW. Creatinine clearance: Bedside estimate. Ann Intern Med 1973;79:604–605.
24. Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin N Am 1987;34:571–590.
25. General Recommendations on Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention. MMWR 2006:55(RR15); 1–48.
26. Department of Health and Human Services, Center for Disease Control and Prevention. Recommended immunization schedules for persons aged 0–18 years, United States, 2008.
27. Nahata MC, Hipple TF, Pai VB. Pediatric Drug Formulations, 5th ed. Cincinnati, OH: Harvey Whitney Books Co., 2003:1–293.
28. Swanson A. Nix the six: Raise the bar on medication delivery. Newborn Infant Nursing Rev 2006;6:230–236.
29. Lesar TS. Errors in the use of medication dosage equations. Arch Pediatr Adolesc Med 1998;152(4):340–344.
30. McLeroy PA. The rule of six: Calculating intravenous infusions in a pediatric crisis situation. Hosp Pharm 1994;29:939–940, 943.
31. Kaakeh Y, Phan H, DeSmet BD, et al. Enhanced photoemission spectroscopy for verification of high-risk i.v. medications. Am J Health Syst Pharm 2008;65:49–54.
32. Cordero L, Kuehn L, Kumar RR, Mekhjian HS. Impact of computerized physician order entry on clinical practice in a newborn intensive care unit. J Perinatol 2004;24(2):88–93.
33. Potts AL, Barr FE, Gregory DF, et al. Computerized physician order entry and medication errors in a pediatric critical care unit. Pediatrics 2004;113(1 Pt 1):59–63.
34. Sencer SF, Kelly KM. Complementary and alternative therapies in pediatric oncology. Pediatr Clin N Am 2007;54:1043–1060.
35. Hanson E, Kalish LA, Bunce E, et al. Use of complementary and alternative medicine among children diagnosed with autism spectrum disorder. J Autism Dev Disord 2007;37:627–636.
36. Sidora-Arcoleo K, Yoos HL, Kitzman H, McMullen A, Anson E. Don’t ask, don’t tell: Parental nondisclosure of complementary and alternative medicine and over-the-counter medication use in children’s asthma management. J Pediatr Health Care 2008;22:221–229.
37. Sawni A, Ragothaman R, Thomas RL, Mahajan P. The Use of complementary/alternative therapies among children attending an urban pediatric emergency department. Clin Pediatr 2007;46:36–41.
38. Rey JM, Walter G, Soh N. Complementary and alternative medicine (CAM) treatments and pediatric psychopharmacology. J Am Acad Child Adoles Psych 2008;47:4:364–368.
39. US Food and Drug Administration. Public Health Advisory: Nonprescription Cough and Cold Medicine Use in Children. January 17, 2008, http://www.fda.gov/Cder/drug/advisory/cough_cold_2008.htm.
40. MedWatch Safety Summary, October 8, 2008. FDA Statement Following CHPA’s Announcement on Nonprescription Over-the-Counter Cough and Cold Medicines in Children, http://www.fda.gov/bbs/topics/NEWS/2008/NEW01899.html.
41. Conroy S. Unlicensed and off-label drug use: Issues and recommendations. Pediatr Drugs 2002;4:363–369.
42. Shah SS, Hall M, Goodman DM, et al. Off-label drug use in hospitalized children. Arch Pediatr Adolesc Med 2007;161:282–290.
43. Pediatric Medication Administration. In: Taketomo CK, Hodding JH, Kraus DM, eds. Pediatric Dosage Handbook, 14th ed, Hudson, OH: Lexi-Comp, Inc., 2007: Miscellaneous Appendix.
44. American Academy of Pediatrics Committee on Injury, Violence, and Poison Prevention. Poison treatment in the home. Pediatrics 2006;112:1182–1185.
45. Manoguerra AS, Cobaugh DJ. Guideline on the use of ipecac syrup in the out-of-hospital management of ingested poisons. Clin Toxicol (Phila) 2005;43(1):1–10.
46. Burns MM. Activated charcoal as the sole intervention for treatment after childhood poisoning. Curr Opin Pediatr 2000;12:166–171.