SECTION 3 SPECIAL POPULATIONS

e19
Pediatrics: General Topics in
Pediatric Pharmacotherapy
Milap C. Nahata and Carol Taketomo

KEY CONCEPTS
Children are not just “little adults,” and lack of data on important
pharmacokinetic and pharmacodynamic differences has led to several
disastrous situations in pediatric care.
Variations in absorption of medications from the gastrointestinal tract,
intramuscular injection sites, and skin are important in pediatric patients,
especially in premature and other newborn infants.
The rate and extent of organ function development and the distribution,
metabolism, and elimination of drugs differ not only between pediatric
versus adult patients but also among pediatric age groups.
The effectiveness and safety of drugs may vary among age groups and from
one drug to another in pediatric versus adult patients.
Concomitant diseases may influence dosage requirements to achieve a
targeted effect for a specific disease in children.
Use of weight-based dosing of medications for obese children may result in
suboptimal drug therapy.
The myth that neonates and young infants do not experience pain has led to
inadequate pain management in this pediatric population.
Special methods of drug administration are needed for infants and young
children.
Many medicines needed for pediatric patients are not available in
appropriate dosage forms; thus, the dosage forms of drugs marketed for
adults may require modification for use in infants and children,
necessitating assurance of potency and safety of drug use.
 The pediatric medication-use process is complex and error prone because of
the multiple steps required in calculating, verifying, preparing, and
administering doses.

Preclass Engaged Learning Activity

Visit the US Food and Drug Administration website and navigate to the New
Pediatric Labeling Information Database. The website provides
comprehensive up-to-date information related to pediatric drug labeling
changes. Explore available drugs, review recent labeling information for one
drug of interest, and summarize the label changes. This website is useful to
enhance student understanding of available resources for pediatric drug dosing
information.

INTRODUCTION
Remarkable progress has been made in the clinical management of diseases in
pediatric patients. This chapter highlights important principles of pediatric
pharmacotherapy that must be considered when the diseases discussed in other
chapters of this book occur in pediatric patients, defined as those younger than
18 years. Newborn infants born before 37 weeks of gestational age are termed
premature; those between 1 day and 1 month of age are neonates; 1 month to 1
year are infants; 1 to 11 years are children; and 12 to 16 years are adolescents.
This chapter covers notable examples of problems in pediatrics, pharmacokinetic
differences in pediatric patients, drug efficacy and toxicity in this patient group,
and various factors affecting pediatric pharmacotherapy. Specific examples of
problems and special considerations in pediatric patients are cited to enhance
understanding.
Infant mortality up to 1 year of age has declined from 200 per 1,000 births
in the 19th century to 75 per 1,000 births in 1925 and to 5.9 per 1,000 births in
2016.1 This success has resulted largely from improvements in identification,
prevention, and treatment of diseases once common during delivery and the
infancy period. Although most marketed drugs are used in pediatric patients, less
than one-half of the drugs approved by the US Food and Drug Administration
(FDA) are labeled for use in the pediatric population. Data on the
pharmacokinetics, pharmacodynamics, efficacy, and safety of drugs in infants
and children are scarce. Lack of this type of information led to disasters such as
gray baby syndrome from chloramphenicol, phocomelia from thalidomide, and
kernicterus from sulfonamide therapy. Gray baby syndrome was first reported in
two neonates who died after excessive doses of chloramphenicol (100-300
mg/kg/day); the serum concentrations of chloramphenicol immediately before
death were 75 and 100 mcg/mL (mg/L; 232 and 309 μmol/L). Patients with gray
baby syndrome usually have abdominal distension, vomiting, diarrhea, a
characteristic gray color, respiratory distress, hypotension, and progressive
shock.

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.
 e20
Pediatrics: Oral Nutrition and
Rehydration of Infants and Children
Katherine H. Chessman

KEY CONCEPTS
Human milk is the preferred source of nutrition for almost all neonates and
infants, including those born prematurely.
An infant formula is a nutritionally complete substitute if human milk is not
available.
All infant formulas sold in the United States are required to meet FDA
standards.
Cow milk–based formulas are used by most US non-breastfeeding infants.
Formulas for premature infants are designed to supply nutrients needed to
promote growth and body composition changes that mimic those of a
normal fetus at the same gestational age.
Some infants will require formulas with altered macronutrients, such as
extensively hydrolyzed protein (semi-elemental) formulas, due to cow milk
and soy protein sensitivities or other conditions.
Two nutrients of significant importance in infant nutrition are iron and
vitamin D.
Enteral products are available for children who need supplemental nutrition
beyond a regular toddler diet in most of the infant formula categories
discussed and used for similar indications.
Expressed human milk and infant formulas must be handled and stored
properly.
Oral rehydration therapy (ORT) is a mainstay of treatment for mild-to-
moderate dehydration; severe dehydration requires intravenous rehydration.
Preclass Engaged Learning Activity
Visit the American Family Physician website and review the article titled
“Infant Formula” at https://tinyurl.com/tpbj88a. The website is useful to
enhance student understanding of the available infant formulas and their place
in therapy.

INTRODUCTION
Infancy is a period of rapid growth followed by continued growth and
development throughout childhood. Healthy term infants will double their birth
weight in 4 months and triple it by 12 months. Adequate nutrient intake,
absorption, and utilization is vital to ensure that growth and development
progress normally. All practitioners providing healthcare for infants and children
should be knowledgeable about pediatric nutrition to be able to quickly identify
opportunities for intervention. Dietary Reference Intakes (DRIs)1 established by
the Food and Nutrition Board of the National Research Council for energy,
protein, fat, trace element, vitamin, electrolyte, and mineral requirements and
methods to estimate them are discussed in Chapter 158. This chapter will review
the various formulas that are available for infants and children and their
appropriate usage. Adolescents will typically use feeding formulations
appropriate for adults when needed (see Chapter 160). The use of oral
rehydration solutions will also be discussed.

INFANT NUTRITION
A term newborn’s stomach has a capacity of 20 to 90 mL. Gastric capacity
increases to 90 to 180 mL by 1 month of age. Too rapidly advancing oral or
enteral nutrition intake can lead to emesis. Frequent feedings (every 2-3 hours)
are needed early in life due to the stomach’s limited capacity and the infant’s
high-metabolic demand (see Table e20-1). Human milk empties from the
stomach at a faster rate than formula; thus, breastfed infants fed ad libitum (ad
lib) may demand feeding more often. Nutritive sucking ability develops at
approximately 34 weeks gestational age; before that time, tube feedings will be
required. The ability to coordinate sucking, swallowing, and breathing when the
respiratory rate is elevated also may necessitate tube feeding.
Human Milk
Human milk is the preferred source of nutrition for almost all neonates and
infants, including those born prematurely. However, human milk does not fully
meet the nutritional needs of all premature infants, and fortification may be
required. The American Academy of Pediatrics (AAP)2 and the World Health
Organization (WHO)3 recommend exclusive breastfeeding (or use of human
milk if tube- or bottle-fed) for 6 months, and the use of iron-fortified formula
when human milk is not available. After 6 months, complementary foods can be
introduced; however, continued breastfeeding or provision of expressed human
milk or iron-fortified formula is recommended until the infant is 12 months of
age or as long as desired.

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.
 e21
Pediatrics: Neonatal Critical Care
Kirsten H. Ohler and Jennifer T. Pham

KEY CONCEPTS
Pharmacokinetic parameters are altered across the age spectrum of the
neonatal population (ie, preterm to term) because of developmental
maturation and the effect of various disease states on these processes.
Therefore, medication selection and monitoring is of utmost importance in
this population.
Treatment guidelines for neonatal resuscitation have been extrapolated from
studies in older children and adults which may not be optimal because of
differences in the pathophysiology of cardiopulmonary arrest among these
populations.
Neonatal sepsis can be categorized as either early-onset sepsis (EOS) or
late-onset sepsis (LOS). Pathogens associated with neonatal sepsis vary
depending on the onset of sepsis (EOS vs LOS).
Empiric antibiotic therapy should be initiated in infants with suspected
sepsis and should target the most common pathogens.
Patent ductus arteriosus occurs commonly in preterm neonates and, if
hemodynamically significant, requires pharmacologic (with a
cyclooxygenase inhibitor) or surgical closure.
In certain congenital heart defects (eg, tetralogy of Fallot, hypoplastic left
heart syndrome, transposition of the great arteries), it is imperative that the
ductus arteriosus remains patent. Prostaglandin E1 (alprostadil) is the drug
of choice in these cases.
Neonatal hypotension can result in impaired cerebral perfusion and
ischemic damage if left untreated. Because there is no clear consensus on
the definition of neonatal hypotension, clinical judgment and review of the
physiological parameters of the infant are important when making
 diagnosis and treatment.
Pharmacologic therapy should be selected based on the etiology of
hemodynamic instability and may include fluid bolus, vasopressors (such
as dopamine, dobutamine, epinephrine, and norepinephrine),
hydrocortisone, and vasopressin. Dopamine is the preferred initial
vasopressor agent for hemodynamic support in neonates with hypotension.
Assessment of the degree of pain and sedation in the preverbal neonatal
population is difficult. Assessment tools should be used, but it is important
to recognize the population and pain type for which each tool has been
validated.
Opioids and benzodiazepines are commonly used to provide analgesia and
sedation for critically ill neonates; however, there are concerns about their
effects on long-term neurodevelopment.

Preclass Engaged Learning Activity

Watch the video titled “Healthcare Heroes – NICU episode.”
https://tinyurl.com/t2d2noh. This 8-minute video provides a brief overview of
the initial assessment and treatment of a critically ill neonate admitted to the
neonatal intensive care unit. The video will enhance the student’s
understanding of the role of a multidisciplinary team in the complex care of an
NICU patient. After watching the video, the student’s reflection should
include identification of the roles a pharmacist can play in the management of
an unstable neonate. The ASSESS and PLAN steps of the patient care process
will be developed through this exercise.

INTRODUCTION
Healthcare providers working in the neonatal intensive care unit (NICU) care for
a wide range of patients—from those born prematurely to term newborns, newly
born infants to infants who have spent months to years in the NICU, those with
acute illnesses to those with chronic morbidities associated with prematurity. A
large proportion of NICU patients are born prematurely. In the United States,
almost 1 in 10 births is premature.1 Preterm birth occurs when a neonate is born
before 37 completed weeks of gestation.2 Prematurity can be further categorized
as late preterm (ie, 34-37 weeks), moderate preterm (ie, 32-34 weeks), very
preterm (ie, 28-32 weeks), and extremely preterm (ie, less than 28 weeks).2
Neonates born prematurely can have multiple complications including
respiratory distress syndrome, intraventricular hemorrhage (IVH), seizures,
necrotizing enterocolitis (NEC), and sepsis, among others. Survivors of preterm
birth often have morbidities such as bronchopulmonary dysplasia (BPD),
neurodevelopmental delay, and cerebral palsy.1,3 Despite medical advances,
mortality in this population, especially those born extremely premature, remains
high (30%-50%).3

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.
 e22
Geriatrics: The Aging Process in
Humans and Its Effects on Physiology
Krista L. Donohoe, Elvin T. Price, Tracey L. Gendron, and Patricia
W. Slattum

KEY CONCEPTS
The population of people 65 years and older is increasing.
Age-related changes in physiology affect the functions of various organ
systems and contribute to the onset of diseases.
Age-related changes in physiology can affect the pharmacokinetics and
pharmacodynamics of numerous medications.
Successful aging is determined by individually defined measures of well-
being that include maximizing health span and socio-environmental
engagement.

Preclass Engaged Learning Activity

Brainstorm a list of age-related changes that occur in the human physiology
and the effects they may have on pharmacokinetics/pharmacodynamics of
medications in older adults.

INTRODUCTION
Medications can cure or palliate medical conditions in older adults, however,
they can also cause a number of drug-related problems. Prevention of drug-
related problems requires that health professionals be knowledgeable about the
changes that occur with aging and the implications this has on prescribing,
monitoring, and evaluating medication regimens in older adults. This chapter
will focus on the epidemiology of aging, mechanisms of aging, physiologic
changes due to aging with an emphasis on the age-related changes in
pharmacokinetics and pharmacodynamics of medications, and successful aging
to maximize health span and quality of life.

EPIDEMIOLOGY OF AGING
The proportion of persons 65 years and older is increasing worldwide. In
2015, the percentage of people 65 years and older in the world was 8.5% and is
projected to increase to 16.7% in 2050. In the United States, the population of
older adults has changed from a pyramidal shape to a pillar. The rectangular
shape will be top heavy in 2050 due to the baby boomer population. In 2015,
14.9% of the population was considered geriatric in the United States, and in
2050 it is projected to be 22.1%.1 In 2035, the older adult population will
outnumber children under 18 years old for the first time in US history.2
The population is aging due to people having fewer children and living
longer. In the United States, the life expectancy in 2014 at birth for men is 76.4
years and 81.2 years for women. At age 65 and 85 years old, respectively, men
are projected to live an additional 18 and 5.9 years, compared to 20.5 and 7 years
for women.3 The US life expectancy is down for the second year in a row from
78.7 in 2015 to 78.6 years in 2016. This may be attributed to an increase in drug
overdose deaths and suicide rates in younger adults.4
Older adults often have multiple chronic conditions and thus need to see a
number of specialists and healthcare providers. In 2013 to 2014, the highest
reported chronic health conditions in the United States for adults 65 and older
were hypertension (55.9%), arthritis (49%), heart disease (29.4%), cancer
(23.4%), diabetes (20.8%), asthma (10.6%), chronic bronchitis or emphysema
(8.1%), and stroke (7.9%). Women have a higher prevalence of arthritis and
asthma, while men have higher rates of heart disease, cancer, and diabetes.3 Data
from the 2014 National Health Interview Survey (NHIS) revealed that 62% of
adults above the age of 65 had at least two chronic conditions.5 The six leading
causes of death among persons 65 years and older were: heart disease, cancer,
chronic lower respiratory diseases, stroke, Alzheimer’s disease, unintentional
injuries, and influenza and pneumonia. Heart disease and cancer were the top
two leading causes of death.3
Older adults have a high prevalence of chronic diseases along with
polypharmacy. The increased number of medications can lead to potential drug-
related problems, such as drug-drug interactions.6–8 To provide the best
pharmacotherapy for this diverse and heterogeneous population of older adults it
will be important to understand the mechanisms, pharmacokinetic, and
pharmacodynamic changes that occur with aging, especially with respect to the
common chronic conditions and medications that are used to treat them.

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.
 e23
Prescribing in the Older Adult
Emily R. Hajjar, Lauren R. Hersh, and Shelly L. Gray

KEY CONCEPTS
Improving and maintaining functional status is a cornerstone of care for
older adults.
Adverse drug reactions in older adults are common and cause considerable
morbidity.
Inappropriate prescribing is a major concern and is guided by the Beer’s
criteria.
Polypharmacy can be defined in various ways and is a common occurrence
in older adults.
Underutilization of medications also occurs and can be improved by using
the START criteria.
Pharmacists can play a major role in optimizing drug therapy and
preventing adverse consequences of medications in older adults.
Deprescribing should be considered to reduce medications in older adults.
Practitioners may consider targeting high-risk older adults to implement
comprehensive management strategies.

Preclass Engaged Learning Activity

Read the current American Geriatrics Society Beers Criteria®16 and discuss
the impact of the recommendations on medication use in older adults.

INTRODUCTION
 Pharmacotherapy for older adults can cure or palliate disease as well as
enhance health-related quality of life (HRQOL). HRQOL considerations for
older adults include focusing on improvements in physical functioning (eg,
activities of daily living), psychological functioning (eg, cognition, depression),
social functioning (eg, social activities, support systems), and overall health (eg,
general health perception).1 Despite the benefits of pharmacotherapy, HRQOL
can be compromised by drug-related problems. The clinical response to a
medication in an older adult is the result of the interaction of a number of
complex processes, including pharmacokinetics, pharmacodynamics, concurrent
medications, comorbidities, and frailty. Age-related changes in physiology can
affect drug pharmacokinetics and pharmacodynamics.2 When applying general
knowledge of pharmacokinetic and pharmacodynamic alterations in an older
adult in the clinical setting, it is necessary to consider the patient’s overall
condition, age, diseases, frailty status, and concurrent medications. Prevention of
drug-related problems in older adults requires that health professionals become
knowledgeable about a number of age-specific issues. To address these
knowledge needs, this chapter discusses the epidemiology of adverse
consequences of medications in older adults and an approach to optimizing
medication use through the provision of a comprehensive geriatric assessment.

ADVERSE CONSEQUENCES OF MEDICATION

USE
Although medications used by older adults can lead to improvement in HRQOL,
adverse outcomes caused by drug-related problems are considerable.3 Adverse
drug reactions (ADRs) and negative consequences of drug therapy are major
threats to the HRQOL of outpatient older adults and account for a significant
portion of healthcare expenditures.4 Estimates are that more than $520 billion
was spent in 2016 for prescription-associated morbidity and mortality from
nonoptimized medications.4

ADVERSE DRUG REACTIONS

ADRs are a major public health problem for older adults in all settings.5
ADRs are defined as “a response to a drug that is noxious and unintended and
occurs at doses normally used in man for the prophylaxis, diagnosis or therapy
of disease, or for modification of physiological function” and excludes
therapeutic failure and adverse drug withdrawal events.6 Approximately 9% of
hospitalizations in older adults are caused by ADRs.7 Moreover, ADRs occur
frequently in community-dwelling older adults (10%-35% yearly). Transitions of
care are often high-risk times for ADRs.8 For example, one study found that
19% of older adults experienced an adverse drug event within 45 days of
hospital discharge. Some medication classes, such as anticoagulants, antidiabetic
agents, and opioids, are especially problematic for causing serious ADRs in
older adults.9 Interestingly, use of potentially inappropriate medications (eg,
Beers criteria drugs) only cause a small proportion of ADRs.7–9 Number of
medications is a consistent risk factor for ADRs.7,10

Inappropriate Prescribing
Inappropriate prescribing is defined broadly as prescribing medications
outside the bounds of accepted medical standards. However, inappropriate
prescribing is challenging to define and operationalize. Furthermore,
“appropriateness” of prescribing is viewed differently in people with multiple
chronic conditions or in those who are frail.11 Inappropriate prescribing is
associated with adverse drug events, falls, hospitalizations, and increased
healthcare costs.12–14

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.
 e24
Assessing Health and Delivering
Healthcare to Older Adults
Leigh Ann Mike, Zachary A. Marcum, and Shelly L. Gray

KEY CONCEPTS
The population of older adults in the United States is increasing and is
expected to become more racially and ethnically diverse.
The primary goal of care for older adults is to maximize the amount of time
they can live independently.
Living arrangements of older adults are tied to health and functional status,
presence of disabilities, and caregiver ability, rather than chronological age.
Geriatric assessment is a multidisciplinary, multifaceted approach to
promote wellness and prolong independence.
Geriatric syndromes are multifactorial clinical conditions that are linked
with poor health outcomes.
Pharmacists can play an important role in identifying medications that may
be contributing to geriatric syndromes.
Transitions of care are common and risky for older adults.
Optimal care transitions require teamwork, and the pharmacist’s primary
role on the care transitions team is to identify and address current and
potential medication-related problems.

INTRODUCTION
The population of older adults age 65 years or older is growing both globally and
in the United States. This is due to increased life expectancy associated with
advances in science and technology in early detection of diseases, therapeutic
interventions that increase survival, and overall improved healthcare delivery to
the general public such as vaccinations, access to care, and multiple treatment
options.1
As people are living longer, they are likely to experience multiple chronic
medical conditions. The fraction of older adults using healthcare resources will
increase, primarily due to the aging of the “Baby Boomer” generation. Despite
the development of chronic medical conditions, many older adults lead full,
active lives with functional abilities largely preserved. This is contrary to the
myth that older age is linked with sickness and disability or poor functional
status. Many of these older adults either have few chronic conditions or have
them well-controlled. The healthcare needs for an active 65-year-old person are
very different from an octogenarian living in a skilled-nursing facility.
Additionally, with the advances in cancer treatment, and the emergence of new
therapies that have transformed diseases such as hepatitis C and acquired
immunodeficiency syndrome into chronic conditions, it is likely that the
healthcare resources used by older adults will include treatment of advanced
diseases, life-prolonging measures, and general health maintenance.
The goal of providing optimal healthcare to older adults is to promote and
maintain independence, which has a direct effect on quality of life. To achieve
and maintain independence, healthcare providers can target interventions and
approaches to promote and maintain functional status. The functional status of
older adults is impacted by disease, accidents, age-related changes (eg,
decreased muscle mass or bone density), and frailty; it is independent of
chronological age. Because of this, there has been a shift in focus in older adults
from managing health conditions alone to incorporating functional status into the
assessment of health and wellness. This requires a holistic, multidisciplinary
approach.
In addition to the anticipated growth in numbers, the older American
population is also expected to become more racially and ethnically diverse. An
increasingly large body of literature describes differences across various ethnic
groups and patient populations with regard to body composition, risk for
developing certain diseases, assessment approaches, threshold for interventions,
and treatment goals. From the pharmacotherapeutics standpoint, it is also
important to understand the predictors of efficacy and adverse drug reactions in
different patient populations. Some of these factors may include diet, lifestyle,
and genetics. Equally important is the understanding of the patient’s values and
believes in their acceptance of interventions. Collectively, these factors help
clinicians develop and implement a personalized health management plan that is
more likely to reach the mutually defined goals established by both the older
adults and their healthcare providers.
This chapter will discuss the epidemiology of aging as well as various threads
of wellness and illness, independence, functional status, and disability that are
relevant for clinical practice. In addition, housing options for older adults,
geriatric syndromes, and some of the most common models of care delivery will
be introduced. This chapter concludes with a summary of transitions of care for
older adults.

EPIDEMIOLOGY OF AGING
In 2050, 21.3% of the global population will be at least 60 years old.2 The US
population will experience similar trends. By 2030, as the “Baby Boomers” age,
approximately 20% of the US population will be 65 years old. Those aged ≥85
years will reach 4.3% of the total population by 2050.3 Nearly half of older
adults in the 50- to 54-year-old age range self-report their health as “excellent”
or “very good.” This decreases with age to 28% of those aged 85 and older.4
Many older adults report that they receive assistance with Instrumental Activities
of Daily Living (IADLs) or Activities of Daily Living (ADLs); more than half of
those who have reached 85 years of age report receiving no assistance or
supervision with functionally-related activities.4

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.
 e25
Critical Care: General Topics in
Critical Care
Adrian Wong and Sandra L. Kane-Gill

KEY CONCEPTS
Pharmacists are one member of the interdisciplinary patient care team;
other members include physicians, nurses, advanced providers, physical
therapists, and respiratory therapists.
There are numerous types of ICUs that pharmacists can work in such as
burn, cardiovascular, medical, neurology, surgical, trauma, and tele-ICU.
Patients in each of these units will have specific care needs.
Fundamental activities of a critical care pharmacist include evaluation of
medications for appropriate indication, dose, and general appropriateness;
monitoring of medications and identification of ADEs.
The management of ICU patients may lead to long-term cognitive effects in
survivors.
Medication errors and ADEs are more common in the ICU than general
care units. Medication errors can lead to ADEs, which are often
preventable.
Management of renally-excreted and nephrotoxic drugs is important to
avert unwanted adverse effects and possibly prevent disease progression.
Critical care pharmacists’ participation in patient care rounds decreases the
rate of ADEs.
One-third of total hospital drug costs are attributed to drug use in the ICU,
so pharmacoeconomic analyses are important to make informed decisions
about drug selection.
Preclass Engaged Learning Activity
Watch the video “ICU episode 1, season 1” at https://tinyurl.com/stcvm9b.
This short video provides insight into the complexity of care provided in a
contemporary intensive care setting, as well as the differences in the care
required of critically ill patients compared to patients in general care units.
The video is useful to enhance student understanding regarding the
COLLECT and ASSESS steps in the patient care process.

INTRODUCTION
A clinician’s initial exposure to critically ill patients within the intensive care
unit (ICU) is challenging. Critically ill patients commonly have multiple lines in
place and are attached to life-support machines (eg, mechanical ventilation,
continuous renal replacement therapy), which may appear foreign and/or
difficult to manage. This chapter provides a brief overview of the complexity of
care and the role of a pharmacist in the care provided in a contemporary
intensive care setting.

HISTORY OF CRITICAL CARE PHARMACY

Clinical pharmacy services began in the 1970s and are currently considered an
essential resource for ICU patient care.1,2 This is unique as few disciplines have
documented the positive value of pharmacists as clearly as critical care
medicine. Despite this, a survey in 2006 found that only 62.2% of respondents
(n=382) in the United States had a dedicated ICU pharmacist.3 Similarly, only
74.4% of respondents (n=168) to an international survey indicated a dedicated
pharmacist attended daily rounds.4
Over the past three decades, critical care pharmacy has evolved considerably.
Select examples of notable advances include the following:

• Creation of the Clinical Pharmacy and Pharmacology section within the

Society of Critical Care Medicine (SCCM; 1989)
• Creation of the Critical Care Practice and Research Network within the
American College of Clinical Pharmacy (1992)
• Critical care pharmacists recognized as integral member of the
 interdisciplinary team (2001)
• Appointment of the first pharmacist to serve as the president of SCCM
(2010)
• Appointment of the first pharmacist to serve as the president of the
Neurocritical Care Society (2017)
• Numerous pharmacists being awarded the designation of the Fellow or
Master of the American College of Critical Care Medicine
• Pharmacist serving on critical care medicine guideline committees,
including as first and senior authors

Additional advances have been made in the areas of training and certification.
Critical care pharmacy residencies have increased dramatically. In 2005, there
were 39 American Society of Health-System Pharmacists-accredited residencies,
which increased to 145 as of this edition.5 Moreover, board certification in
critical care pharmacy became available in 2015 through the Board of Pharmacy
Specialties. Since that time, over 2,100 pharmacists have been board certified.

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.
 e26
Critical Care: Pain, Agitation, and
Delirium
Gilles L. Fraser and Richard R. Riker

KEY CONCEPTS
The primary goal of pain, agitation, and delirium (PAD) management is to
provide patient comfort and safety with secondary goals to prevent
immediate and long-term adverse physical and psychological outcomes.
PAD are interrelated and can confound efforts to provide intensive care
including mobility, sleep, participation in care and in shared
patient/caregiver decisions about appropriate levels of care.
It is important to systematically evaluate PAD with validated tools for
timely identification and correction of inciting clinical issues.
Preventative measures and nonpharmacologic strategies for PAD
management should be initiated as early as possible.
A multifaceted, multidisciplinary approach to PAD management impacts
care and clinical outcomes.
Pain is an important cause of agitation in the intensive care unit (ICU) and
should be assessed and treated before administration of sedatives.
No proven pharmacologic strategies limit the severity and duration of ICU
delirium.
Sedative choice (dexmedetomidine or propofol) and depth of sedation may
have an important impact on patient assessments and outcomes.

Preclass Engaged Learning Activity

Watch the video entitled “CAM-ICU Delirium Test”
 https://tinyurl.com/ubl8br2. This brief 3-minute video is useful to enhance
student understanding of a common and valid method of screening for
delirium in critically ill adults who are unable to verbalize.

INTRODUCTION
The ICU is an inhumane environment where pain, agitation, and delirium are
considered the most common clinical conditions confronting patients and their
caregivers on a daily basis. These issues are stressful for patients as well as
families and are often precipitated by factors that are frequently seen in the
critically ill; hemodynamic instability, inadequate oxygenation, metabolic
derangements, pain, the inability to communicate, immobility, sleep deprivation,
the need for invasive instrumentation, and loss of autonomy all occurring in an
unfamiliar and threatening environment.
Short-term patient goals for PAD management include the provision of
comfort and safety. It is also important to consider newly recognized long-term
outcomes in critical care survivors that affect their quality of life such as the
inability to return to baseline physiologic and cognitive function and a high
frequency (50%) of unemployment for a year or longer after discharge from the
hospital.1,2 In addition, postdischarge posttraumatic stress disorder (PTSD) and
depression are experienced by 7% and 30% of ICU survivors respectively at one
year.3
All of these outcomes are impacted by our choice of therapeutics for PAD
management. For example, the provision of inadequate pain relief can be
regarded as inhumane, but conversely, overaggressive opioid therapy continued
in the outpatient setting represents an obvious and avoidable risk factor in this
era of opioid abuse.4 The complexity of the pharmacologic and
nonpharmacologic management of pain, agitation, and delirium requires
knowledge of the risks and benefits of each option and necessitates a
standardized, but flexible evidence-based approach5 (Table e26-1).
Although we will be discussing pain, agitation, and delirium in this chapter as
discrete clinical issues, the reader should appreciate that they are inter-related.6
The interwoven nature of PAD is well demonstrated by a patient with unrelieved
pain (a risk factor for delirium) who develops agitation. This agitation can result
in patient harm or injury, but attempts to control these dangerous behaviors with
sedatives can in turn precipitate delirium all the while without controlling the
inciting problem of pain.
DEFINITIONS AND CONSEQUENCES OF PAD
Pain
Pain is defined as “an unpleasant sensory and emotional experience associated
with actual or potential tissue damage or described in terms of such damage.”5
Healthcare providers readily accept and anticipate that ICU patients will have
pain associated with surgery, trauma, pancreatitis, or with invasive procedures,
but less frequently recognize that pain is provoked by routine ICU care such as
repositioning, endotracheal suctioning, and arterial gas determinations.7,8

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.
 e27
Critical Care: Considerations in Drug
Selection, Dosing, Monitoring, and
Safety
Erin F. Barreto and Amy L. Dzierba

KEY CONCEPTS
Intensive care units are designed to support the complex needs of critically
ill patients with acute organ dysfunction in need of a higher level of
monitoring and treatment.
The four phases of critical illness include rescue, optimization, stabilization,
and de-escalation, each of which can affect drug selection, dosing, and
monitoring.
Ideal medications for use in the ICU have predictable bioavailability, fast
onset, rapid titratability, and a wide therapeutic window.
Critically ill patients exhibit a uniquely complex pharmacokinetic profile
and response to therapies that needs to be considered when individualizing
drug regimens.
Acute changes to end-organ function occur more commonly in the ICU and
affect drugs in a dynamic way.
Perfusion deficits and iatrogenic exposures can decrease enteral,
subcutaneous, and intramuscular drug bioavailability which makes the
intravenous route preferred in acutely ill unstable patients in the ICU.
The use of advanced organ support devices is common in the ICU and each
device differentially affects the pharmacokinetics and pharmacodynamics
of medications.
Key properties of drugs susceptible to sequestration in the ECMO circuit
include high percentage of protein binding and high degree of lipophilicity.
 Highly protein bound drugs are readily cleared by MARS and TPE, but not
efficiently cleared by renal replacement therapies.
Many patient, provider, and environmental factors increase an ICU patient’s
vulnerability to medical errors, adverse drug events, and their related
consequences, relative to their noncritically ill counterparts.

Preclass Engaged Learning Activity

Watch the first 12-minutes of the video “Right dose, right now: customizing
drug dosing for the critically ill patient”. This video briefly overviews some of
the key pharmacokinetic and pharmacodynamic changes present in critically
ill patients and the potential impact on anti-infective effectiveness and safety
in the ICU.

INTRODUCTION
Epidemiology of Critical Illness
Since the poliomyelitis epidemic of the 1950s when mechanical ventilation was
first introduced, significant advancements have been made in our understanding
of the pathophysiology of syndromes of critical illness and the interventions
needed to improve patient outcomes.1 Only recently, however, have we begun to
quantify the true global burden of critical illness. In the United States, 27% of all
hospitalizations or 4.6 million stays annually include an intensive care unit
(ICU) admission.2 Short-term mortality for ICU patients is 8% to 22%, but can
be much higher in patients with sepsis, acute respiratory distress syndrome,
shock, or those in the developing world, where mortality still reaches 50% to
60% in some studies.3 Although surviving critical illness is a short-term goal,
survivors can experience long-term physical, psychological, and cognitive
consequences, collectively termed “post-intensive care syndrome.” When
considering these sequelae, care of critically ill patients is estimated to cost $121
to $263 billion annually in the United States, on par with the financial burden of
cancer care or cardiovascular disease.4 It is essential that clinicians and scientists
seek new ways to more effectively prevent and treat critical illness to improve
patient outcomes and limit the global health burden.
The Dynamic Trajectory of Critical Illness
Critical care medicine is a diverse discipline that integrates aspects of medicine,
surgery, and anesthesia. Broadly, contemporary ICU patients include those with
acute organ dysfunction in need of resuscitation or organ support and those in
need of monitoring after a major event or intervention who are at high risk for
complications (eg, surgical procedure, trauma, bleed).5

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.
 e28
Palliative Care
Nina M. Bemben and Mary Lynn McPherson

KEY CONCEPTS
Palliative care may be provided to any patient with a serious illness, at any
point in the course of the illness, including while a patient receives curative
or disease-focused therapy.
Hospice is a form of palliative care, which has been defined by Medicare to
encompass care solely focused on comfort and quality of life during the last
6 months of a patient’s life.
Pain is a common symptom among patients receiving palliative care and
may be managed safely and effectively using nonopioid, adjuvant, and/or
opioid therapies.
Opioids are the drug of choice for the management of dyspnea.
Constipation, nausea, vomiting, anxiety, and delirium are common
symptoms among patients receiving palliative care and may be managed
effectively with drug and nondrug therapies.
End-of-life care can be provided to patients in the last days of their lives
through palliative or hospice care, and provides management of common
terminal symptoms.
Identifying a patient’s goals and structuring care to achieve those goals is a
key component of palliative care. Identifying a patient’s goals of care
involves communication with patients, their families and/or caregivers, as
well as other healthcare professionals.
Addressing nonphysical needs, such as spirituality and faith, are key
components of providing quality palliative care.
Preclass Engaged Learning Activity
Navigate to the website http://www.graduate.umaryland.edu/palliative, then
click on “Palliative Care Chat Podcast” on the left hand side. Scroll down to
Episode 15: “Ten Tips Palliative Care Pharmacists Want the Palliative Care
Team to Know When Caring for Patients.” Select any two tips discussed in the
podcast and critically think through why the tip is an important one for the rest
of the hospice or palliative care team. This podcast is useful to enhance your
understanding regarding the PLAN and MONITORING and FOLLOW-UP
steps in the patient care process.

INTRODUCTION
Palliative care, or palliative medicine, is specialized care provided to patients
with serious illness with a goal of managing symptoms and helping patients to
cope with their illnesses.1 It is provided by an interdisciplinary team of
healthcare professionals, including physicians, pharmacists, nurses, nurse
practitioners, social workers, chaplains, and others.2 Palliative care is appropriate
for any patient with a serious or potentially life-limiting illness, at any point
during the time course of that illness. Common diseases for which palliative care
is appropriate include cancer, heart failure, advanced lung disease such as
chronic obstructive pulmonary disease (COPD), organ failure such as liver or
renal failure, and neurologic diseases such as dementia and Parkinson disease.2
Patients may receive palliative care throughout the course of a serious illness,
including while the patient receives treatment aimed at managing or curing the
disease. If or when the serious illness progresses and disease-focused therapies
are no longer helpful or desired, palliative care continues to be provided to
manage symptoms and maximize quality of life.
Provision of palliative and hospice care to patients with limited prognoses has
been shown to improve patient and caregiver satisfaction,3–5 reduce healthcare
utilization,3,4 and decrease healthcare costs.3,4,6 In addition to providing
symptom management, improving patient and caregiver satisfaction, and
reducing healthcare costs, early integration of palliative care has been shown to
increase survival among patients with advanced cancer.7,8
Because of the evidence supporting the benefits of palliative care, clinical
practice guidelines for serious illnesses incorporate palliative care into treatment
recommendations. The American Society of Clinical Oncology and National
Comprehensive Cancer Network both recommend palliative care as a component
of oncology management.9,10 In addition, the American College of Cardiology
Foundation/American Heart Association practice guideline for the management
of heart failure supports the incorporation of palliative care into the management
of patients with advanced heart failure due to its effectiveness in increasing
quality of life.11

The complete chapter, learning objectives, and other resources can be found
at www.pharmacotherapyonline.com.