activity. Dopamine, as well as other agents capable of producing vasoconstriction,

should ideally be administered through central venous access rather than through a

peripheral IV. Extravasation of these drugs from an infiltration of the IV may produce

significant local tissue necrosis.

CASE 106-4, QUESTION 5: J.B.’s dopamine infusion has been steadily increased throughout the day. Her

dose is currently at 20 mcg/kg/minute, but she continues to have refractory hypotension with a systolic blood

pressure of 70 mm Hg. On physical examination, she is pale with cool, dry skin. Her hemoglobin remains at 10

g/dL. Central venous pressures are now being measured and range from 6 to 9 mm Hg. What alternative to

dopamine should be considered for J.B.?

Dopamine-resistant shock is diagnosed after titration of dopamine to 20

mcg/kg/minute with the persistence of signs and symptoms of shock. Patients with

dopamine-resistant shock should be reassessed to evaluate fluid status and

hemoglobin, with additional fluids or PRBC given as needed to improve tissue

oxygen. Measurement of CVP can be performed to assess intravascular volume status

with the goal of achieving a CVP of 8 to 12 mm Hg, and SvO2 can be used as a

marker of cardiac output (provided that the hemoglobin is within the normal range),

along with the clinical examination. Dopamine-resistant shock commonly responds to

epinephrine or norepinephrine.

Epinephrine

Epinephrine is a direct agent that is naturally produced in the adrenal gland and is the

principal stress hormone with widespread metabolic and hemodynamic effects. It

possesses both inotropic and chronotropic effects. Epinephrine is a reasonable

choice for the treatment of patients with low CO and poor peripheral perfusion

because it increases HR and myocardial contractility. Depending on the dose

administered, epinephrine may exert variable effects on SVR. At doses less than 0.3

mcg/kg/minute, epinephrine exerts greater β2

-adrenergic receptor activation, resulting

in vasodilation in skeletal muscle and cutaneous vascular beds, shunting blood flow

away from the splanchnic circulation.

17 At higher doses, α1

-adrenergic receptor

activation becomes more prominent and may increase SVR and heart rate. For

patients with markedly elevated SVR, epinephrine (0.05–0.3 mcg/kg/minute) may be

administered simultaneously with a vasodilator. Epinephrine increases glucogenesis

and glycogenolysis, resulting in elevated serum blood glucose concentrations.

Children receiving epinephrine infusions should have serum glucose monitored

closely.

Norepinephrine

Norepinephrine is a direct agent and is naturally produced in the adrenal gland. It is a

potent vasopressor that redirects blood flow away from skeletal muscle to the

splanchnic circulation even in the presence of decreased cardiac output.

Norepinephrine has been used extensively to elevate SVR in septic adults and

children. If the patient’s clinical state is characterized by low SVR (a wide pulse

pressure with diastolic blood pressure less than one-half of the systolic blood

pressure), norepinephrine (0.05–0.3 mcg/kg/minute) is recommended. Approximately

20% of children with volume-refractory SS have a low SVR. In children who are

intubated and receiving sedatives or analgesics, the incidence of low SVR may be

higher. The additional afterload imposed by norepinephrine may substantially

compromise CO in patients with impaired contractility. In patients with both

impaired or marginal CO and decreased SVR, it may be necessary to support

myocardial contractility through the addition of an agent such as dobutamine.

13,17

Vasopressin

Although not a recommendation in the 2015 Pediatric Advanced Life Support

guidelines, vasopressin has been suggested as an alternative therapy for refractory

cardiac arrest or hypotension due to a low SVR in children whose epinephrine

infusion exceeds 1 mcg/kg/minute.

3 Vasopressin exerts its hemodynamic effects via

the V1α

receptor, promoting an increase in intracellular calcium in the peripheral

vasculature, thus enhancing vasoconstriction and restoring systemic vascular tone. In

a preliminary case series, vasopressin at a dose of 0.3 to 2 milliunits/kg/minute (18–

120 milliunits/kg/hour) improved blood pressure and urine output in patients with

catecholamine-refractory vasodilatory shock and allowed weaning of catecholamines

once treatment was initiated.

30

In a more recent analysis conducted by the American

Heart Association, however, vasopressin use was associated with a lower rate of

return to spontaneous circulation.

31 At this time, the use of vasopressin in critically ill

children remains controversial.

3,13,17

Dobutamine

Dobutamine is a nonselective β2

-adrenergic agonist, which produces improved

contractility, chronotrophy, and some degree of lusitropy, or improved myocardial

relaxation. The β2 activity can lead to peripheral vasodilation, and this must be

considered before its use in a patient who may already be hypotensive. If hypotension

does exist, it should be used in combination with other vasopressor therapies.

Dobutamine should be considered in patient who has signs and symptoms or

laboratory values consistent with poor tissue perfusion, but has an adequate blood

pressure to tolerate some degree of vasodilation. It should be initiated at a rate of 2.5

mcg/kg/minute and titrated in increments of 2.5 mcg/kg/minute every 3 to 5 minutes to

a maximum infusion rate of 20 mcg/kg/minute.

3,17 Careful attention to the patient’s

blood pressure is critical. Improved perfusion, decreased lactate, and an increased

SvO2 will help determine appropriate dosing.

Vasodilators

Vasodilator medications are occasionally required in the treatment of septic pediatric

patients with markedly elevated SVR and normal or decreased CO. Vasodilators

decrease SVR and improve cardiac output by decreasing ventricular afterload.

Nitroglycerin or nitroprusside may be used for this indication. They each have a short

half-life; therefore, if hypotension occurs, it can be rapidly reversed by stopping the

infusion. Both drugs can be infused at an initial rate of 0.5 mcg/kg/minute and titrated

in increments of 0.5 mcg/kg/minute to a maximum infusion rate of 5 to 10

mcg/kg/minute.

3

If nitroprusside is used, it is necessary to observe for sodium

thiocyanate accumulation in the setting of renal failure, and cyanide toxicity with

hepatic failure or with prolonged infusions (more than 72 hours) of greater than 3

mcg/kg/minute. If a patient has tolerated short-term infusions of either of these agents,

milrinone may be considered as an alternative for long-term therapy. Milrinone is a

phosphodiesterase type III (PDE III) inhibitor that produces its hemodynamic effects

by inhibiting the degradation of cyclic AMP in smooth muscle cells and cardiac

myocytes. PDE III inhibitors work synergistically with catecholamines, which

produce their hemodynamic effects by increasing the production of cyclic AMP.

Milrinone, at a dose of 0.25 to 0.75 mcg/kg/minute, is useful in the treatment of

infants and children with diminished CO, impaired myocardial contractility, and

decreased SVR.

13,32 The primary concern with milrinone is its relatively long halflife of 2 to 6 hours, which requires several hours for the patient to reach steady state.

To achieve target serum concentrations more rapidly, a loading dose

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of 50 mcg/kg may be administered for 10 to 30 minutes before the start of the

infusion. Administration of a loading dose must be done with caution in children with

sepsis and shock because it may precipitate hypotension, requiring volume infusion

and/or vasopressor infusion. Administering the loading dose over several hours may

avoid this adverse effect.

J.B. remains hypotensive despite adequate fluid administration and a dopamine

infusion at the maximum rate. After reassessing her laboratory parameters to

determine whether additional fluid or blood products are needed, J.B. should be

started on epinephrine at 0.05 mcg/kg/minute. The dose may then be titrated upward

in 0.05 to 0.1 mcg/kg/minute increments every 3 to 5 minutes as needed to achieve

the desired clinical response or to the usual maximum of 2 mcg/kg/minute. Higher

doses have been used in some pediatric cases, but may not always provide additional

benefit.

3

CORTICOSTEROID ADMINISTRATION IN

PEDIATRIC SEPTIC SHOCK

CASE 106-4, QUESTION 6: J.B. is currently receiving epinephrine at an infusion rate of 0.35

mcg/kg/minute, but she continues to have refractory hypotension with a systolic blood pressure of 70 mm Hg. Is

there a role for hydrocortisone replacement in J.B.? What would be the appropriate method for assessing

adrenal insufficiency and the appropriate dose for replacement?

Although adjunctive corticosteroid therapy in patients in septic shock has not made

a significant difference in outcome in all studies published to date, replacement may

be of benefit in some patients.

33–35

In a recent study, 77% of children with septic

shock admitted to two PICUs for a 6-month period exhibited adrenal insufficiency.

35

Due to the limited evidence of their efficacy and safety in children, corticosteroids

should be reserved for those with catecholamine-resistant shock, severe septic shock

and purpura, children who have previously received steroid therapies for chronic

illness, children with pituitary or adrenal abnormalities, and those who previously

received etomidate.

5–7,13,33–35 Assessment of serum cortisol should be used to guide

treatment. There are no strict definitions, but adrenal insufficiency in adults with

catecholamine-resistant shock has been defined as a random cortisol level of less

than 18 mcg/dL or an increase in cortisol of less than or equal to 9 mcg/dL at 30 or

60 minutes after an adrenocorticotropic hormone stimulation test.

33 Similar values

have been recommended for assessment of serum cortisol in children with SS.

13

If J.B. has a random cortisol of 10 mcg/dL in the face of catecholamine-resistant

hypotension, a trial of hydrocortisone is warranted. Published guidelines for

hemodynamic support of pediatric and neonatal patients in septic shock recommend

0.5 to 1 mg/kg IV every 6 hours (with a maximum dose of 50 mg).

16 Using this

regimen, J.B. should be treated with 10 to 20 mg IV every 6 hours. As an alternative,

some clinicians use a regimen of a single 50-mg/m2

loading dose, followed by the

same dose (50 mg/m2

) divided into four doses and given every 6 hours.

13

ADJUNCTIVE THERAPIES

Stress-Related Mucosal Bleeding

The use of prophylaxis to prevent stress-related mucosal bleeding, although common

in adult ICU patients, is not as widely used in PICUs. Studies conducted to date have

provided a wide range of gastrointestinal tract bleeding rates in children, ranging

from 10% to 50%, with rates of clinically significant bleeding of approximately 1%

to 4%.

36,37 Several investigators have identified thrombocytopenia, coagulopathy,

organ failure, and mechanical ventilation as important risk factors for gastrointestinal

bleeding, similar to studies conducted in adults. A recent systematic review

suggested that critically ill pediatric patients may benefit from prophylaxis; however,

the results were limited by the small number of controlled studies available.

37

Thrombosis Prophylaxis

Patients admitted to the PICU can range from newborns to young adults. Unlike

adults, there are no data on the use of subcutaneous heparin or low-molecular-weight

heparins as prophylaxis to prevent deep venous thrombosis (DVT) in children.

However, when children reach puberty, the hormone changes that take place appear

to increase their risk of thrombosis to that of adults. Although no published guidelines

or consensus papers exist to guide therapy at this time, all pubescent adolescents

should be considered for DVT prophylaxis. Most cases of thrombosis in infants and

young children are associated with long-term use of central venous catheters.

Unfortunately, a study evaluating low-dose heparin infused at 10 units/kg/hour did not

prevent catheter-related thrombosis in infants after cardiac surgery.

38

It is important

to note that the dose of heparin used in this study was less than the anticoagulant dose

recommended for infants and children (15–25 units/kg/hour). At this time, the routine

use of DVT prophylaxis in children remains controversial.

CONGENITAL HEART DISEASE

CASE 106-5

QUESTION 1: J.F. is a 3-week-old, 3.5-kg male infant who was seen by his physician with a history of poor

feeding and increased work of breathing. On admission, he was mottled, and grunting, and had severe

retractions. The physician referred him to the emergency department of the local children’s hospital where his

temperature was 40.8°C, heart rate was 200 beats/minute, respiratory rate was 80 breaths/minute, and oximetry

saturation was between 60% and 70%; he had very poor peripheral perfusion. Blood gas analysis results were

as follows:

pH, 6.96

PCO2

, 35 mm Hg

Base deficit, 29 mmol/L

Chest radiography showed cardiomegaly and pulmonary edema. J.F. has presented with symptoms of both

respiratory failure and shock. Based on his age, the severity of his hypoxemia, and evidence of cardiomegaly,

congenital heart disease (CHD) is suspected. Echocardiography reveals coarctation of the aorta. What initial

therapies are needed to stabilize J.F.?

With the neonate’s first breath, changes in oxygen tension and a reduction in

endogenous prostaglandin E2 production stimulate closure of the ductus arteriosus

(DA), the connection between the pulmonary artery and aorta that allows shunting of

blood to the aorta during fetal circulation. Functional closure of the DA typically

occurs within the first 10 to 14 hours of life, but complete anatomic closure may not

occur until 2 to 3 weeks of age. Prematurity, acidosis, and hypoxia prolong the time

to closure. In infants with ductal-dependent CHD, closure of the DA results in

inadequate delivery of oxygenated blood to the systemic circulation (Table 106-11).

These infants will present just as any other patient in shock. The immediate goal in

evaluating a cyanotic neonate is to differentiate between cardiac and noncardiac

causes. The classic hyperoxia test is carried out by obtaining an ABG, then placing

the patient on 100% oxygen for 10 minutes and then repeating the ABG. If the cause

of cyanosis is pulmonary, the Pao2 should increase by 30 mm Hg, but if the cause is

cardiac, there should be minimal improvement in the Pao2

. If the patient is too

unstable, one could place a pulse oximeter and place the patient on 100% FIO2

. With

administration of oxygenation, there will typically be at least a 10% increase in

oxygen saturation in neonates with pulmonary disease, but those with ductaldependent CHD will have minimal or no improvement.

p. 2209

p. 2210

Table 106-11

Ductal-Dependent Congenital Heart Lesions

Lesions That Depend on Flow Via the Ductus Arteriosus to Maintain Systemic Circulation

Hypoplastic left heart syndrome (HLHS)

Coarctation of the aorta

Critical aortic stenosis

Interrupted aortic arch

Total anomalous pulmonary venous return (TAPVR) with obstruction

Lesions that Depend on Flow Via the Ductus Arteriosus to Maintain Pulmonary Circulation

Pulmonary atresia with intact ventricular septum

Critical pulmonic stenosis

Tricuspid atresia

Tetralogy of Fallot (TOF)

Epstein anomaly

Lesions that Depend on Flow Via the Ductus Arteriosus to Maintain Adequate Mixing of the

Pulmonary and Systemic Circulations

Truncus arteriosus

Transposition of the great vessels (TGV)

Total anomalous pulmonary venous return (TAPVR) without obstruction

If the neonate’s oxygen saturation or Pao2

fails to improve and CHD is suspected,

an infusion of alprostadil, prostaglandin E1

(PGE1

), should be initiated at a rate of

0.05 to 0.1 mcg/kg/minute.

39

Infusion of PGE1 maintains patency of the DA and

allows blood to reach the descending aorta, bypassing the cardiac defect. Apnea is a

common adverse effect of PGE1

, occurring in 10% to 20% of patients, so ageappropriate equipment for intubation and mechanical ventilation should be

immediately available before starting treatment and throughout therapy.

40 Within 10

to 15 minutes after starting an alprostadil infusion, there should be an improvement in

the patient’s oxygen saturation. The dose may then be titrated to optimize ductal flow

and minimize dose-related adverse effects. The infusion is typically continued until

corrective cardiac surgery can be performed. J.F. should receive fluid boluses as

needed to correct his dehydration and will require intubation. In addition, he should

be started on PGE1 at a rate of 0.05 mcg/kg/minute, with subsequent titration of the

dose to open and maintain the DA until the time of surgery.

PEDIATRIC TRAUMATIC BRAIN INJURY

Among children, traumatic brain injury (TBI) is the leading cause of mortality and

leads to significant morbidity among survivors. Each year more than 400,000

children in the United States suffer a TBI requiring an emergency department visit,

resulting in 30,000 hospitalizations and 3,000 deaths.

41 The most common

mechanisms of injury differ by patient age. Children less than 4 years old most often

suffer injuries due to child abuse, falls, and motor vehicle collisions (MVC). Child

abuse, or nonaccidental trauma (NAT), sadly represents up to two-thirds of severe

TBI in some series. Although it is difficult to obtain accurate data, in a populationbased study from North Carolina, the incidence of TBI due to NAT in the first 2 years

of life was 17 per 100,000 person-years.

42 According to the National Center on

Shaken Baby Syndrome, this translates to approximately 1,300 children per year in

the United States who experience severe head trauma from child abuse. In schoolaged children, those 5 to 12 years of age, pedestrian–motor vehicle collision and

bicycle-related injuries are among the more common causes of severe injuries. For

adolescents, MVC replace falls as the leading cause of all injuries, followed by

assault and sports-related injuries.

CASE 106-6

QUESTION 1: K.B. is an 8-week-old, 4-kg male infant who was brought to an urgent care clinic by his 17-

year-old mother. She stated that he would not wake up for his usual 7:00 PM feeding that evening. He had been

in his usual state of health that morning. She fed him his usual bottle, changed his diaper, and laid him down for

a nap. She left him in the care of her 19-year-old boyfriend and went to work. At the clinic, the infant was

floppy and unarousable. There were no bruises or other signs of injury, but the anterior fontanel was bulging.

His pupils were 3 mm and responded sluggishly to light. When prompted, the boyfriend stated that K.B. fell off

the couch early in the morning but only cried for a few minutes. After some comforting, he went back to

playing. He fed well the remainder of the day and was taking his evening nap when the mother returned from

work. The urgent care clinic suspected NAT and transferred K.B. to the closest hospital with pediatric critical

care services. What physiologic differences place K.B. at greater risk for severe TBI than an older child?

What risk factors or associations for NAT can you identify in this case?

The anatomic differences of the infant’s brain render it more susceptible to certain

types of injuries after head trauma.

43

Infants such as K.B. and young children have

large, heavy heads. The head is unstable because of its relative size to the rest of the

body. If an infant or young child falls a significant distance, is ejected during an

MVC, or is thrown from a bicycle after colliding with an automobile, the head will

tend to lead (i.e., the infant or child will fly head first) and severe head injuries will

occur when the head ultimately strikes the ground or another object. The infant’s

weak neck muscles also allow for greater movement when the head is acted on by

acceleration/deceleration forces. The skull is thinner during infancy and early

childhood, providing less protection for the brain and allowing forces to transfer

more effectively across the shallow subarachnoid space. The base of the infant’s

skull is relatively flat, which also contributes to greater brain movement in response

to acceleration/deceleration forces. In addition, the infant’s brain has a higher water

content (approximately 88% vs. 77% in an adult), which makes the brain softer and

more prone to acceleration/deceleration injury. The water content is also inversely

related to the myelination process, and the higher percentage of unmyelinated brain

makes it more susceptible to sheer injuries. The infant brain is typically fully

myelinated by 1 year of age. As the result of these physiologic differences, there are

differences in the pathology after pediatric TBI by age group. In infants and young

children, diffuse injury, such as diffuse cerebral swelling, and subdural hematomas

are more common than focal injury, such as contusions, that are typically seen in

older children and adults. The typical pattern of hypoxic-ischemic injury in infants

and young children after NAT is rarely seen in older children and adults who are

victims of abuse.

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p. 2211

Table 106-12

Modified Glasgow Coma Scale

Eye Opening

Score ≥1 year 0–1 year

4 Opens eyes spontaneously Opens eyes spontaneously

3 Opens eyes to verbal command Opens eyes to shout

2 Opens eyes in response to pain Opens eyes in response to pain

1 No response No response

Best Motor Response

Score ≥1 year 0–1 year

6 Obeys command N/A

5 Localizes pain Localizes pain

4 Flexion withdrawal Flexion withdrawal

3 Flexion abnormal (decorticate) Flexion abnormal (decorticate)

2 Extension (decerebrate) Extension (decerebrate)

1 No response No response

Best Verbal Response

Score >5 years 2–5 years 0–2 years

5 Oriented and able to converse Uses appropriate words Cries appropriately

4 Disoriented and able to

converse

Uses inappropriate words Cries

3 Uses inappropriate words Cries and/or screams Cries and/or screams

inappropriately

2 Makes incomprehensible sounds Grunts Grunts

1 No response No response No response

Source: Chung CY et al. Critical score of Glasgow Coma Scale for pediatric traumatic brain injury. Pediatr

Neurol. 2006;34:379.

Goldstein et al.

44 have published risk factors for NAT based on data gathered from

several earlier reports. They found that victims of inflicted head injury tended to be

younger, more often from families of poorer socioeconomic backgrounds, and were

more likely to have parents who were younger than 18 years of age and who had

never been married. In addition, a history inconsistent with physical findings was

strongly associated with the presence of inflicted head injury. Additional risk factors

reported as associated with NAT are alcohol or drug abuse, previous social service

intervention, or a past history of child abuse, in combination with either retinal

hemorrhages or an inconsistent history or physical examination. These investigators

found this combination was 100% predictive of child abuse in children admitted to a

PICU. K.B. met many of these risk factors: He is young, has an unmarried parent who

is younger than 18, and is from a low socioeconomic background. In addition, his

injuries appear inconsistent with the history of falling from a couch. A fall of

approximately 3 feet is required to cause significant head injury to an infant or child;

a standard couch is 18 inches from the floor.

45

CASE 106-6, QUESTION 2: K.B. was transferred immediately to the emergency department at a local

hospital. The O2

saturation on room air was 100%, blood pressure 90/63 mm Hg, and HR 120 beats/minute.

The initial Glasgow Coma Scale (GCS) score on presentation was 7, with 2 for eye opening in response to pain,

4 for withdrawing to pain, and 1 for no verbal response. What test or assessment tools are useful for evaluating

the extent of K.B.’s injuries? Which are best for predicting his outcome?

The ability to evaluate the severity of TBI is essential to appropriately direct care,

predict outcomes, and compare results to evaluate and improve patient care. Initial

symptoms on presentation have been found to have little or no correlation with injury

severity after TBI. The GCS is a widely accepted method in initially evaluating and

characterizing trauma patients with head injuries (Table 106-12). The scale is

composed of visual, motor, and verbal components, with lower scores representing

more serious injuries. The severity of TBI may be characterized as mild (GCS 13–

15), moderate (GCS 9–12), or severe (GCS 3–8) on presentation; however,

continued evaluation of GCS scores is the best way to track the patient’s clinical

progress. K.B.’s GCS of 7 on admission puts him in the category of severe TBI.

The radiologic examination of choice for immediate assessment of a child with

severe TBI is a noncontrast cerebral-computed tomography (CT) scan. Most children

with severe TBI undergo immediate CT imaging to delineate their injuries as soon as

they have been fully assessed and sufficiently stabilized to permit safe transport to

the radiology suite. If the brain injury does not need

p. 2211

p. 2212

immediate surgical intervention, the patient’s care is continued in the PICU with

the implementation of therapies designed to minimize secondary brain injury. In a

retrospective review of 309 children presenting with TBI, Chung et al.

46

found that

GCS was more useful in predicting survival among pediatric victims of TBI than CT

findings and the presence of injuries to other organ systems. In addition, they

identified that a GCS score of less than 5, rather than a score of less than 8 as used in

adults, was the threshold at which the patient was more likely to have a poor

outcome. The authors also found that head CT findings of swelling or edema and

subdural and intracerebral hemorrhage were associated with worse outcomes than

subarachnoid or epidural hemorrhage.

Retinal hemorrhages are frequently, although not always, observed in inflicted

head injury in infants and young children. These hemorrhages are the result of sheer

forces disrupting vulnerable tissue interfaces. The vitreous body is adherent to the

retina in early childhood; shaking can cause retinal hemorrhaging throughout multiple

tissue layers, extending to the periphery of the retina. This pattern is unique to

“shaken baby syndrome.” Although useful for diagnosis, the ocular examination is

often deferred initially when evaluating an infant or child for TBI, because the

medications used to facilitate funduscopy will preclude the use of pupillary reactivity

as a tool to monitor evolving intracranial events.

According to the American Academy of Pediatrics guidelines on imaging for NAT,

a skeletal survey is strongly recommended in all cases of suspected physical abuse in

children under the age of 24 months.

47 A skeletal survey consists of films of the

extremities, skull, and axial skeletal images. Follow-up radiographs of the ribs to

assess for healing fractures not seen in the acute phase may be helpful 2 to 3 weeks

after the skeletal survey. As with the eye examination, the skeletal survey is often

delayed until the child is more stable.

CASE 106-6, QUESTION 3: After assessment by the emergency room physician, K.B. was intubated using

rocuronium and pentobarbital, placed on an FIO2

of 100% and sent for a CT scan. The CT reveals a subdural

hematoma and cerebralswelling. On arrival to the PICU, K.B.’s vitalsigns are as follows:

Blood pressure, 85/58 mm Hg

HR, 125 beats/minute

Respiratory rate on the ventilator, 20 breaths/minute

Temperature was 36.9°C. What are the next goals for stabilization of K.B.?

The initial management of a child with a head injury should focus on the basics of

resuscitation: assessing and securing the airway, ensuring adequate ventilation, and

supporting circulation.

48

In addition, the goals of treatment of TBI are directed

toward protecting against secondary brain insults (SBI) which can exacerbate

neuronal damage and brain injury. SBI are often the result of systemic hypotension,

hypoxia, hypercarbia, anemia, and hyperglycemia. Aggressive treatment strategies

are needed to prevent and/or treat these conditions to decrease morbidity and

improve neurologic outcome after TBI in children. The criteria for tracheal

intubation include hypoxemia not resolved with supplemental oxygen, apnea,

hypercarbia (Paco2 >45 mm Hg), a GCS score less than or equal to 8, a decrease in

GCS greater than 3 compared with the initial score, cervical spine injury, loss of

pharyngeal reflex, or any clinical evidence of herniation. K.B. was intubated in the

emergency room based on his presenting GCS of 7. All patients should be assumed to

have a full stomach and cervical spine injury, so the intubation should be carried out

using a rapid sequence intubation using appropriate short-acting sedatives and

muscle relaxants (Tables 106-3 and 106-4).

After intubation, K.B.’s ventilatory goals include 100% oxygen saturation,

normocarbia (35–39 mm Hg), and no hyperventilation, as confirmed by ABGs, endtidal CO2 monitoring, and chest radiographs showing tracheal tube in good position.

Unless he has signs or symptoms of herniation, prophylactic hyperventilation (Paco2

<35 mm Hg) should be avoided.

48 Hyperventilation causes cerebral vasoconstriction,

which decreases cerebral blood flow and subsequent blood volume. Although it will

lower ICP, hyperventilation may result in ischemia. Furthermore, respiratory

alkalosis caused by hyperventilation makes it more difficult to release oxygen to the

brain, shifting the oxygen–hemoglobin curve to the left. Short-term use of

hyperventilation, however, may be useful in preventing herniation while other

medical therapies are implemented. In addition to mechanical ventilation, the head of

the bed should be kept in the neutral position and jugular venous obstruction should

be avoided to prevent ICP elevation. Elevation of the head of the bed to thirty

degrees usually decreases ICP.

Assessment and reassessment of the patient’s circulatory status, including central

and peripheral pulse quality, capillary refill, heart rate, and blood pressure, is

critical. Hypotension after pediatric TBI is associated with increased morbidity and

mortality.

48

Initial treatment of hypotension in the head-injured child is similar to that

described earlier for pediatric shock; however, the goal systolic blood pressure in

the TBI patient is typically higher: equal to or greater than the 50th to 75th percentile

for age, sex, and height. Systolic blood pressure less than the 75th percentile has

been associated with a fourfold increase in the risk for poor outcome after severe

TBI, even when values were 90 mm Hg or greater.

49 This suggests a possible benefit

of a higher blood pressure target until ICP or cerebral perfusion pressure (CPP)

monitoring is in place to guide therapy. As a result of the need for higher SBP,

norepinephrine and phenylephrine, agents with greater vasopressor effects, are more

frequently used in this patient population.

50

The solution of choice for IV maintenance fluids in children with TBI is normal

saline for children older than 1 year of age and 5% dextrose with normal saline for

infants. Because hyperglycemia is known to worsen SBI, initial IV fluids for children

should not contain dextrose. Infants are an exception, because their low glycogen

stores make them prone to hypoglycemia, especially with poor oral intake.

Hypoglycemia can also worsen neurologic outcome and should be avoided. Frequent

assessment of blood glucose either by point-of-care testing or on an ABG is

recommended.

Fever increases metabolic demands and is associated with worse outcomes after

TBI. Treatment for K.B. should include 60 mg of acetaminophen (15 mg/kg) orally or

rectally every 6 hours as needed and a cooling blanket when necessary. Ibuprofen

should be avoided because it may increase the risk of bleeding. Patients who are

hypothermic on arrival should only be actively rewarmed if there is hemodynamic

instability or bleeding thought to be exacerbated by hypothermia. Serum electrolytes

and osmolarity should be monitored regularly in K.B., along with accurate

assessment of urine output. This is important to identify the development of either

syndrome of inappropriate antidiuretic hormone or diabetes insipidus. Both have

been reported to occur after pediatric TBI.

48

CASE 106-6, QUESTION 4: K.B. has been intubated and placed on mechanical ventilation with an ABG

showing that he is maintaining goal parameters. He is receiving fentanyl at 1 mcg/kg/hour and a midazolam

infusion at 0.05 mg/kg/hour. The head of the bed is raised 30 degrees and his head is midline, supported by a

head roll. K.B. has both a pulse oximeter and an end-tidal CO2 monitor for continuous evaluation of his

oxygenation and CO2

. Blood pressure is being maintained at the 75th percentile for age, height, and sex. What

is the next step in monitoring head injury in K.B.?

p. 2212

p. 2213

One of the most significant consequences of TBI is the development of intracranial

hypertension. The presence of an open fontanel or sutures in an infant with severe

TBI does not preclude the development of intracranial hypertension or negate the

utility of ICP monitoring. ICP monitoring is recommended for any child presenting

with a GCS of 8 or less.

51 When possible, placement of a ventriculostomy catheter

provides accurate pressure monitoring and allows for acute drainage of

cerebrospinal fluid (CSF) for treatment of elevated ICP and assessment of CPP. The

CPP value is calculated by subtracting the ICP from the mean arterial pressure

(MAP):

This value is important as an indication of blood flow and oxygen that reach the

brain. Maintaining CPP requires optimization of MAP with fluid therapy, and if

necessary, vasoactive drugs. In the case of ICP elevation, inotropic or vasopressor

agents may be used to optimize CPP by increasing MAP, even to the point of relative

systemic hypertension. In adults, a CPP of 60 to 70 mm Hg is usually targeted.

There are no data that correlate CPP in infants to outcome. There are, however,

pediatric TBI studies showing that CPP values ranging from 40 to 70 mm Hg are

associated with a favorable outcome and that a CPP less than 40 mm Hg is

associated with poor outcomes.

51 Because infants and children normally have a

lower MAP and ICP, the SCCM Pediatric Fundamental Critical Care Support course

recommends the following CPP ranges: 40 to 50 mm Hg in infants, 50 to 60 mm Hg

in children, and 60 to 70 mm Hg in adolescents.

52 This is more specific than the 2003

pediatric recommendations that recommend a CPP greater than 40 mm Hg and an

“age-related continuum” of CPP from 40 to 65 mm Hg in infants and adolescents be

maintained.

48

CASE 106-6, QUESTION 5: The neurosurgeon has placed a ventriculostomy in K.B., and his initial ICP is

25 mm Hg. His other vitals are as follows:

Blood pressure, 83/50 mm Hg

HR, 140 beats/minute

Temperature, 38.5°C

His pulse oximeter still reads 100% and the ETCO2 monitor reads 35 mm Hg. Sedative infusions are

unchanged: fentanyl 1 mcg/kg/hour and midazolam 0.05 mg/kg/hour. The pediatric intensivist has placed a

central line, and the CVP is 10 mm Hg. What is K.B.’s calculated CPP? What interventions are recommended

to treat this ICP elevation?

Uncontrolled increased ICP is very deleterious and must be aggressively treated as

soon as possible to reduce cerebral ischemia. In this setting, the goal of any therapy

is to lower ICP enough to increase CPP and improve cerebral oxygenation. All initial

treatments should be reassessed for efficacy, including treatment of fever, avoidance

of jugular venous outflow tract obstruction, maintenance of normovolemia and

normocarbia, and provision of sedation and analgesia. The latter is of considerable

importance, because anxiety and pain have been shown to increase ICP. K.B. appears

to be euvolemic by CVP measurement, is normocapnic, and his O2 saturation is

100%. He is febrile; however, measures should be taken to treat the elevated

temperature. Although he is receiving continuous sedation, additional bolus doses of

sedatives should be given whenever needed. Because K.B. has an elevated CPP in

spite of these initial therapies, the best option would be to drain CSF. This will

provide an immediate, but transient, decrease in ICP. K.B. may have CSF drained

until an ICP value of 15 mm Hg is reached; it should never be drained to 0 mm Hg

because edema and diffuse brain swelling could cause an obstruction in the lateral

ventricles. When a ventriculostomy is in place and CSF is frequently drained, it is

important to replace the CSF drained with an equal amount of normal saline.

Draining of large amounts of CSF without IV normal saline replacement is associated

with the development of hypochloremic metabolic alkalosis. Drainage of CSF in

K.B. will provide a CPP in the 40- to 50-mm Hg range. If the ICP increases again,

two interventions are recommended, either the addition of a vasopressor to increase

SBP or institution of hyperosmolar therapy.

Hyperosmolar therapy may be useful in preventing the ICP from exceeding 20 mm

Hg and in maintaining normal CPP. Mannitol has long been the standard of care for

management of elevated ICP.

48 Although extensively used since 1961 to control

elevated ICP, mannitol has never been compared with placebo. Mannitol reduces

ICP by reducing blood viscosity, which promotes reflex vasoconstriction of the

arterioles by autoregulation, thus decreasing cerebral blood volume and ICP. This

mechanism is rapid, but transient, lasting about 75 minutes and requiring an intact

autoregulation. It also produces an osmotic effect by increasing serum osmolarity,

causing the shift of water from the brain cell to the intravascular space. Although this

effect is slower in onset (15–30 minutes), the osmotic effect lasts up to 6 hours.

Mannitol is a potent osmotic diuretic; osmotic diuresis should be anticipated and

fluid resuscitation is available to avoid hemodynamic compromise. A Foley catheter

is recommended in these patients for accurate measurement of urine output. Mannitol

is excreted unchanged in the urine; serum osmolarity should be maintained lower than

320 mOsm/L to avoid the development of mannitol-induced acute tubular necrosis.

Although mannitol has traditionally been the drug of choice for reducing elevated

ICP, hypertonic saline (3% sodium chloride) is gaining favor. The main mechanism

of action of hypertonic saline is an osmotic effect similar to mannitol. Hypertonic

saline exhibits several other theoretic benefits such as restoration of normal cellular

resting membrane potential and cell volume, inhibition of inflammation, stimulation

of atrial natriuretic peptide release, and enhancement of cardiac output.

48 The

theoretic advantage over mannitol is that hypertonic saline can be administered in a

hemodynamically unstable patient without the risk of a subsequent osmotic diuresis.

Continuous infusions of 0.1 to 1 mL/kg/hour of hypertonic saline titrated to maintain

an ICP less than 20 mm Hg have been used successfully in children.

53 Bolus doses of

5-10 mL/kg of 3% sodium chloride have been administered over 20 to 30 minutes.

Serum osmolarity and serum sodium increase when this regimen is used, but

sustained hypernatremia and hyperosmolarity appear to be generally well tolerated.

Hypertonic saline has been administered with a serum osmolarity reaching 360

mOsm/L without adverse effects in pediatric patients. Another potential concern with

the use of hypertonic saline is central pontine myelinolysis that has been reported

with rapid changes in serum sodium. Currently, clinical trials have shown no

evidence of demyelinating disorders.

To bring his ICP values down to the normal range (<20 mm Hg), K.B. may be

given mannitol at an IV dose of 2 to 4 g (0.5– 1 g/kg) administered over 20 to 30

minutes. The effects of mannitol on ICP should be evident within 15 minutes. This

dose may be repeated every 4 to 6 hours as needed. If intermittent mannitol fails to

bring his ICP down adequately, K.B. may be given hypertonic saline 3%, beginning

at 0.1 mL/kg/hour or as a bolus dose of 5-10 mL/kg administered over 20 minutes.

Dosing of either agent should be guided by regular assessment of serum electrolytes

and osmolarity.

CASE 106-6, QUESTION 6: K.B. has been in the PICU for 24 hours. Initial treatment allowed K.B. to

maintain a CPP of 50 mm Hg and an ICP less than 20 mm Hg the majority of the day.

p. 2213

p. 2214

He is receiving 3% sodium chloride combined with maintenance IV fluids, giving him a serum sodium of 166

mEq/L. Intermittent ICP spikes have responded to intermittent 4 g doses of mannitol; however, the most recent

serum osmolarity is 330 mOs/L. What options remain to treat increased ICP in K.B.?

Two nonsurgical options are included in the TBI guideline: barbiturate coma and

therapeutic hypothermia.

48 Barbiturates exert neuroprotective effects by reducing

cerebral metabolism, lowering oxygen extraction and demand, and alternating

vascular tone. Barbiturate serum levels poorly correlate with clinical efficacy;

therefore, monitoring of electroencephalographic (EEG) patterns for burst

suppression is recommended. Burst suppression also represents near-maximum

reduction in cerebral metabolism and cerebral blood flow. A pentobarbital loading

dose of 10 mg/kg/dose may be administered over 30 minutes, followed by a

continuous infusion of 1 mg/kg/hour. Additional loading doses, in 5 mg/kg/dose

increments, may be necessary to achieve burst suppression. The primary

disadvantage of barbiturate coma is the risk for myocardial depression and

hypotension. In addition, the long-term effect on neurologic outcome is unknown. The

TBI guideline states that high-dose barbiturate therapy may be considered in

hemodynamically stable patients with salvageable severe head injury and refractory

intracranial hypertension.

48

Post-traumatic hyperthermia is defined as a core body temperature greater than

38.5°C, and hypothermia is defined as a temperature of less than 35°C. Although

most clinicians agree that hyperthermia should be avoided in children with TBI, the

role of hypothermia is unclear. Potential complications associated with hypothermia

are increased bleeding risk, arrhythmias, and increased susceptibility to infection. A

multicenter, international study of children with severe TBI randomly assigned to

hypothermia therapy initiated within 8 hours after injury (32.5°C for 24 hours) or to

normothermia (37°C) was recently published.

52 The study reported a worsening trend

with hypothermia therapy: 31% of the patients in the hypothermia group had an

unfavorable outcome, compared with 22% of the normothermia group. There were

several methodological problems with this study. Although the investigators screened

patients within 8 hours, the mean time to initiation of cooling was 6.3 hours, with a

range of 1.6 to 19.7 hours. In addition, the protocol included a rapid rewarming of

0.5°C every 2 hours so that the patients were normothermic by a mean of 19 or 48

hours postinjury. They found that the ICP was significantly lower in the hypothermia

group during the cooling period, but that it was significantly higher than the

normothermic group during rewarming. Another trial conducted in Australia and New

Zealand evaluated strict normothermia (temperature 36°C–37°C) versus therapeutic

hypothermia (temperature 32°C–33°C).

54 Patients were enrolled within 6 hours of

injury and therapeutic hypothermia or strict normothermia was maintained for 72

hours. The rewarming rate was at a maximum of 0.5°C every 3 hours or slower if

needed to maintain normal CPP or ICP <20 mmHg. Rewarming took a median of 21.5

hours (16–35 hours) and was without complications. However, there was no

difference in pediatric cerebral performance category (PCPC) scores between the 2

groups at 12 months.

54

It is unclear whether therapeutic hypothermia is not efficacious

because patients are not cooled soon enough (median time to target temperature = 9.3

hours) or due to the heterogeneous nature of TBI. The pediatric TBI guideline states

that despite the lack of clinical data, hypothermia may be considered in the setting of

refractory hypertension.

48

Decompressive craniectomy, removal of a section of skull to allow room for brain

swelling without herniation, is another option for managing pediatric TBI patients

who fail to respond to standard therapies. A randomized trial of early decompressive

craniectomy in children with TBI and sustained intracranial hypertension revealed

that 54% of the surgically treated patients had a favorable outcome compared with

only 14% of the medically treated group.

55 Additional case series have confirmed

that patients who receive a decompressive craniectomy have improved survival and

neurologic outcomes compared with those undergoing medical management alone.

56

As with barbiturate coma and therapeutic hypothermia, decompressive craniectomy

is not without risk. A recent study reported an increased risk of post-traumatic

hydrocephalus, wound complications, and epilepsy in children with severe TBI.

57

Further studies are needed to establish the timing, efficacy, and safety of this

management strategy. The pediatric TBI guideline states that decompressive

craniectomy should be considered in pediatric patients with severe TBI, diffuse

cerebral swelling, and intracranial hypertension refractory to intensive medical

management.

CASE 106-7

QUESTION 1: L.B. is an 18-kg, 6-year-old child hit by a car while riding her bicycle. When emergency

medical services arrived, they witnessed a 2-minute tonic-clonic seizure. GCS at the scene was 11. Should L.B.

receive anticonvulsant medication after her TBI?

Post-traumatic seizures (PTS) are classified as early (occurring within 7 days after

injury) or late (occurring after 7 days). In the immediate period after severe TBI,

seizures increase the brain metabolic demands, increase ICP, and are associated with

TBI. Therefore, it would be prudent to prevent PTS in the period when the patient is

at highest risk of SBI. Infants and children are reported to have a greater risk of early

PTS compared with adults. Children younger than 2 years of age have almost a

threefold greater risk of early PTS after TBI than children between 2 and 12 years of

age. In addition to age, a low GCS (8–11) has been linked to an increased risk of

early PTS. The pediatric TBI guideline states that prophylactic antiseizure therapy

may be considered as a treatment to prevent early PTS. No prophylactic

anticonvulsant therapy is recommended to prevent late PTS.

48

The majority of the published studies in children have used phenytoin for PTS

prophylaxis. Both phenytoin and carbamazepine have been reported to reduce the

incidence of PTS in adults. A large (n = 813) prospective multicenter trial evaluated

the effectiveness of levetiracetam for seizure prophylaxis in severe TBI in adults.

58

Although the trial demonstrated that levetiracetam was equally effective to phenytoin

in preventing PTS after TBI, the authors concluded that the significant cost difference

between the 2 treatments makes phenytoin the preferred therapy. There are currently

no studies of levetiracetam for PTS prophylaxis in children. Due to the seizure

witnessed at the scene, her young age, and her initial GSC score of 11, L.B. meets the

criteria for prophylaxis. An appropriate regimen for L.B. would be phenytoin 45 mg

given orally 3 times daily (7.5 mg/kg/day) for 7 days.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Adelson PD et al. Guidelines for the acute medical management of severe traumatic brain injury in infants,

children, and adolescents. Pediatr Crit Care Med. 2003;4(3, Suppl):S1. (48)

p. 2214

p. 2215

Brierley J et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007

update from the American College of Critical Care Medicine [published correction appears in Crit Care Med.

2009;37:1536]. Crit Care Med. 2009;37:666. (17)

Dellinger RP et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic

shock 2012. Crit Care Med. 2013;41:580. (13)

de Oliveria CR et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcome

comparison with and without monitoring central venous oxygen saturation. Intensive Care Med. 2008;34:1065.

(18)

de Caen AR et al. Part 12: Pediatric advanced life support. 2015 American Heart Association Guidelines for

Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(Suppl 2):S526. (3)

Namachivayam P et al. Three decades of pediatric intensive care: who was admitted, what happened in intensive

care, and what happened afterward. Pediatr Crit Care Med. 2010;11:549. (2)

Key Websites

International Liaison Committee on Resuscitation (ILCOR). Consensus 2015 Documents. www.ilcor.org.

Accessed November 9, 2015.

The Surviving Sepsis Campaign. Guidelines for Management of Severe Sepsis and Septic Shock.

www.survivingsepsis.com. Accessed November 9, 2015.

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Namachivayam P et al. Three decades of pediatric intensive care: who was admitted, what happened in intensive

care, and what happened afterward. Pediatr Crit Care Med. 2010;11:549.

De Caen AR et al. Part 12: Pediatric advanced life support. 2015 American Heart Association Guidelines for

Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(Suppl 2):S526.

Shott SR. The nose and paranasalsinuses. In: Ruldoph CD et al., eds. Rudolph’s Pediatrics. 21st ed. New York,

NY: McGraw-Hill Professional; 2003:1258.

Perkett EA. Lung growth in infancy and childhood. In: Ruldoph CD et al., eds. Rudolph’s Pediatrics. 21st ed. New

York, NY: McGraw-Hill Professional; 2003:1905.

Dawson-Caswell M, Muncie HL, Jr. Respiratory syncytial virus infection in children. Am Fam Physician.

2011;83:141.

Kumar P et al. Premedication for nonemergency endotracheal intubation in the neonate. Pediatrics. 2010;125:608.

den Brinker M et al. One single dose of etomidate negatively influences adrenocortical performance for at least 24

h in children with meningococcalsepsis. Intensive Care Med. 2008;34:163.

Cuthbertson BH et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic

shock. Intensive Care Med. 2009;35:1868.

Jackson WL Jr. Should we use etomidate as an induction agent for endotracheal intubation in patients with septic

shock? A critical appraisal. Chest. 2005;127:1031.

Zelicof-Paul A et al. Controversies in rapid sequence intubation in children. Curr Opin Pediatr. 2005;17:355.

Johansson M, Kokinsky E. The COMFORT behavioural scale and the modified FLACC scale in paediatric

intensive care. Nurs Crit Care. 2009;14:122.

Dellinger RP et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and

septic shock. Crit Care Med. 2013;41:580.

Hartman ME et al. Trends in the epidemiology of severe sepsis. Pediatr Crit Care Med. 2013;14:686.

Rivers E et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med.

2001;345:1368.

Carcillo JA et al. Clinical practice variables for hemodynamic support of pediatric and neonatal patients in septic

shock. Crit Care Med. 2002;30:1365.

Brierley J et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock:

2007 update from the American College of Critical Care Medicine [published correction appears in Crit Care

Med. 2009;37:1536]. Crit Care Med. 2009;37:666.

de Oliveria CR et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcome

comparison with and without monitoring central venous oxygen saturation. Intensive Care Med. 2008;34:1065.

de Oliveira CF. Early goal-directed therapy in treatment of pediatric septic shock. Shock. 2010;34(Suppl 1):44.

Wynn JL, Wong HR. Pathophysiology and treatment of septic shock in neonates. Clin Perinatol. 2010;37:439.

Carcillo JA. Pediatric septic shock and multiple organ failure. Crit Care Clin. 2003;19:413.

Bone RC et al. Definitions for sepsis and organ failure. Crit Care Med. 1992;20:724.

Bone RC et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.

The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of

Critical Care Medicine. Chest. 1992;101:1644.

Goldstein B et al. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction

in pediatrics. Pediatr Crit Care Med. 2005;6:2.

Ceneviva G et al. Hemodynamic support in fluid refractory pediatric septic shock. Pediatrics. 1998;102:e19.

Akech S et al. Choice of fluids for resuscitation in children with severe infection and shock: systematic review.

BMJ. 2010;341:c4416.

Zimmerman JL. Use of blood products in sepsis: an evidence based review. Crit Care Med. 2004;32(11,

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Finfer S et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N EnglJ Med.

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Mann K et al. Beneficial effects of vasopressin in prolonged pediatric cardiac arrest: a case series. Resuscitation.

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Duncan JM et al. Vasopressin for in-hospital pediatric cardiac arrest: results from the American Heart

Association National Registry of Cardiopulmonary Resuscitation. Pediatr Crit Care Med. 2009;10:191.

Hoffman TM et al. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and

children after corrective surgery for congenital heart disease. Circulation. 2003;107:996.

de Kleijn ED et al. Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are

associated with poor outcome in children with very severe meningococcal disease. Pediatr Infect Dis J.

2002;21:330.

Casartelli CH et al. Adrenal response in children with septic shock. Intensive Care Med. 2007;33:1609.

Zimmerman JJ, Williams MD. Adjunctive corticosteroid therapy in pediatric severe sepsis: observations from the

RESOLVE study. Pediatr Crit Care Med. 2011;12:2.

Deerojanawong J et al. Incidence and risk factors of upper gastrointestinal bleeding in mechanically ventilated

children. Pediatr Crit Care Med. 2009;10:91.

Reveiz L et al. Stress ulcer, gastritis, and gastrointestinal bleeding prophylaxis in critically ill pediatric patients: a

systematic review. Pediatr Crit Care Med. 2010;11:124.

Schroeder AR et al. A continuous heparin infusion does not prevent catheter related thrombosis in infants after

cardiac surgery. Pediatr Crit Care Med. 2010;11:489.

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Perinat Med. 2004;32:368.

Meckler GD, Lowe C. To intubate or not to intubate? Transporting infants on prostaglandin E1. Pediatrics.

2009;123:e25.

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2003;290:621.

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Goldstein B et al. Inflicted versus accidental head injury in critically injured children. Crit Care Med.

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Management. 3rd ed. Elk Grove Village, IL: American Academy of Pediatrics. 2009:54.

Chung CY et al. Critical score of Glasgow Coma Scale for pediatric traumatic brain injury. Pediatr Neurol.

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Adelson PD et al. Guidelines for the acute medical management of severe traumatic brain injury in infants,

children, and adolescents. Pediatr Crit Care Med. 2003;4(3, Suppl):S72.

Vavilala MS et al. Blood pressure and outcome after severe traumatic brain injury. J Trauma. 2003;55:1039.

Di Gennaro JL et al. Use and effect of vasopressors after pediatric traumatic brain injury. Dev Neurosci.

2010;32:420.

Catala-Temprano A et al. Intracranial pressure and cerebral perfusion pressure as risk factors in children with

traumatic brain injuries. J Neurosurg. 2007;106(6, Suppl):463.

Hutchison JS et al. Hypothermia therapy after traumatic brain injury in children. N EnglJ Med. 2008;358:2447.

Beca J et al. Hypothermia for traumatic brain injury in children—a phase II randomized controlled trial. Crit Care

Med. 2015;43:1458.

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of Critical Care Medicine; 2008.

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injury. Childs Nerv Syst. 2001;17:154.

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a 10 year single-center experience with long term follow up. J Neurosurg. 2007;106(4, Suppl):268.

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p. 2215

AGE-RELATED PHYSIOLOGIC, PHARMACOKINETIC, AND

PHARMACODYNAMIC CHANGES

Age-associated physiologic changes are associated with

pharmacokinetic and pharmacodynamic alterations of drugs in older

adults. Decline in drug metabolism and excretion and exaggerated

response to drugs are important considerations in drug therapy of the

elderly.

Case 107-1 (Questions 1–4)

Adverse drug events are one of the most important problems associated

with drug

use in older adults.

Case 107-2 (Question 1)

DISEASE-SPECIFIC GERIATRIC DRUG THERAPY

Elderly patients have multiple chronic conditions and take numerous

medications. Disease state education, awareness of potential adverse

effects and drug interactions, consultation with healthcare providers, and

behavioral modification are important steps to ensure medication safety.

Case 107-3 (Questions 1, 2)

Pharmacologic treatments of heart failure in the elderly include a

diuretic, β-blocker, an angiotensin-converting enzyme (ACE) inhibitor or

angiotensin receptor blocker (ARB), with or without digoxin and

spironolactone. Benefits should be weighed against risks based on the

patient’s concurrent conditions.

Case 107-3 (Questions 3–6)

Statins are the drug of choice for treating hyperlipidemia in the elderly.

Combination

with other agents is considered only if necessary and is based on

concurrent disease states, potential adverse effects, and drug

interactions.

Case 107-3 (Questions 7, 8)

First-line therapy for prevention of coronary artery disease (CAD)

includes acetylsalicylic acid (ASA) and β-blockers. Other agents are

considered based on concomitant diseases and relative indications.

Case 107-3 (Question 9)

Hypertension should be treated in the elderly according to the guidelines,

and monitoring is essential to prevent excessively low blood pressure,

Case 107-3 (Question 10)

bradycardia, and orthostatic hypotension.

The glycosylated hemoglobin (Hgb A1c

) goal may be higher for elderly

patients who have hypoglycemia. Pharmacologic therapies for diabetes

are recommended based on level of hyperglycemia and relative

contraindications.

Case 107-3 (Question 11)

Depression is the most common psychiatric disorder in the elderly, often

presenting with atypicalsymptoms. Selective serotonin reuptake

inhibitors are generally better tolerated than other agents and are

considered first-line therapy for older adults.

Case 107-4 (Questions 1, 2)

Asthma is a significant source of morbidity in the elderly. The

management of asthma in older adults does not differ significantly from

that for younger individuals. However, coexisting chronic medical

conditions, exaggerated systemic adverse drug reactions, and dexterity

concerns must be considered when managing drug therapy for asthma

in the elderly.

Case 107-5 (Questions 1, 2)

p. 2216

p. 2217

Pneumonia is the leading infectious cause of mortality in the elderly, who

typically present with atypicalsymptoms of lower respiratory infection.

Influenza and pneumococcal vaccinations are beneficial in the

prevention of pneumonia in the older population.

Case 107-5 (Questions 3–5)

Urinary tract infection is the most common bacterial infection in the

elderly. Oral antibiotics are appropriate for most older patients with

symptomatic infection.

Case 107-6 (Question 1, 2)

Arthritis is the most common cause of disability in the elderly, and there

are several analgesic agents available for the management of

osteoarthritis. Safe and appropriate use of these analgesic medications

is important because older adults are at increased risk of adverse drug

reactions.

Case 107-7 (Questions 1, 2)

LONG-TERM CARE FACILITIES

Federally mandated responsibilities of pharmacists in long-term care

facilities include monthly medication regimen review for appropriateness

of drug therapy. Provision of pharmaceutical care in long-term care

facilities helps to minimize medication errors, adverse drug reactions,

and inappropriate prescribing.

Case 107-8 (Questions 1, 2)

DEMOGRAPHIC AND ECONOMIC

CONSIDERATIONS

Demographic changes and medical progress in the United States (U.S.) over the last

half of the 20th century have created the need for imperatives to improve our

knowledge about the health care and drug therapy of older adults. The Federal

Interagency Forum on Aging-Related Statistics, is made up of multiple Federal

agencies which came together in 1996 to provide information on the health, finances,

and well-being of older Americans in the United States.

1 The latest report compiles

information from over 16 national data sources and separates data into 41 indicators

in the areas of population, economics, health status, health risks and behaviors, and

health care and environment, of the older population. The U.S. Department of Health

& Human Services published “A Profile in Older Americans”, updated in 2016.

2

Both reports include valuable information that describe the older population (Table

107-1).

The oldest-old category (i.e. those older than 85 years of age) will have the

greatest impact on the healthcare system because the number of people in this group

has increased faster than any other age category. This group will triple its size by

2040.

2

Older adults often have multiple chronic conditions, higher prescription drug

costs, and higher out of pocket healthcare expenditures, and account for more

overnight hospital stays than younger adults. Many older adults live at home and may

receive personal assistances with one or more activities of daily living (ADLs)

including bathing, eating, and dressing; or instrumental activities of daily living

(IADLs), which include preparing meals, washing clothes, shopping, paying bills,

and taking medication. Often, informal care from children and other relatives is a

large reason disabled older adults can continue to live in the community. Thus, it is

important to include the caregiver in the counseling and monitoring of daily activities

when feasible. An increase in this informal assistance and the reliance on others to

perform ADLs and IADLs leads to a loss of independence and the inability of older

adults to remain living at home or alone in the community. Approximately 1.2 million

U.S. residents 65 years of age or older reside in long-term care facilities (LTCFs).

The percentage of those living in nursing homes increases greatly with age (1% age

65–74; 3% age 75–84; 9% age 85 and greater).

Health care for older adults in an institutional setting is largely based on a

prospective reimbursement system, where payment for services is based on a fixed

amount. Managed-care practices aim to minimize high-cost hospitalizations by

shifting care to lower-cost alternatives, such as home health care, assisted living, and

hospice care. The escalating costs and affordability of medications are a national

concern, especially in the Medicare population. The Medicare Prescription Drug

Improvement and Modernization Act of 2003 provided voluntary prescription drug

insurance benefits, known as Medicare Part D, to improve older adults’ access to

prescription drugs. Medicare Part D implementation is associated with up to a 13%

increase in drug use in older adults and up to an 18% decrease in patient out-ofpocket costs.

3

Table 107-1

Profile of Older Americans

Current Facts About Older Americans

1,2

The older population, persons aged 65 years and older, numbered 47.8 million in 2015, representing 14.9% of

the U.S. population. This is a 30% increase from 2005.

Approximately 1 in every 7 of the U.S. population is considered an older American.

The older population is predominantly female. There are 126.5 women for every 100 men aged 65 and older,

and this increases to 189.2 women to 100 men at age 85 and older.

The older population is getting even older. The 85 and older age group grew from just over 100,000 in 1900 to

0.3 million in 2015.

The average life expectancy for someone born in 2015 is 78.8 years, an increase by about 30 years as

compared to 1900.

The centenarian population or those aged 100 and greater accounted for 0.2% of the age 65 and older

population in 2015.

The most common and costly health conditions among all persons aged 65 and older are heart disease, heart

disease, stroke, cancer, diabetes and arthritis.

Among all persons aged 65 and older, the leading causes of death are heart disease, cancer, chronic lower

respiratory diseases, stroke, Alzheimer’s disease, diabetes, unintentional injuries, and influenza and

pneumonia.

Future Expected Growth

A rapid increase in the older population is expected between the baby boomer generation reaches age 65.

The population of those age 65 and older is expected to double to 98 million by 2060.

The very old, those age 85 and greater are expected to double from 6.3 million in 2015 to 14.6 million in 2040.

Adapted from Federal Interagency Forum on Aging-Related Statistics. Federal Interagency Forum on AgingRelated Statistics. Older Americans 2016 and Department of Health & Human Services USA. A Profile of Older

Americans: 2016.

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p. 2218

AGE-RELATED PHYSIOLOGIC,

PHARMACOKINETIC, AND

PHARMACODYNAMIC CHANGES

Physiologic changes that are seen with aging are progressive and occur gradually

over a lifetime, rather than abruptly at any given age.

4 These changes may lead to

decreases in the function of tissues and organs and the ability for each organ system

to maintain homeostasis: a phenomenon often called “homeostenosis.”

5,6 The

impaired ability to recover from drug-induced insults may increase the risk of drugrelated problems in older adults. Homeostatic mechanisms in the cardiovascular and

nervous systems are less efficient, drug metabolism and excretion decrease, and body

tissue composition and drug volume of distribution change and drug receptor

sensitivity may be altered. Age-related physiologic changes may result in

pharmacokinetic and pharmacodynamic changes and should be considered when

selecting and evaluating drug therapy.

Absorption

The absorption of some drugs administered by the extravascular route may be altered

by age-related physiologic changes, unlike drugs administered by the intravascular

route which are considered to have 100% bioavailability.

7

In the gastrointestinal (GI)

tract, a decrease in intestinal blood flow, increase in gastric pH, delayed gastric

emptying, and decreased gastrointestinal motility occur with aging. Increased gastric

pH due to aging alone is thought to have a minimal effect on absorption and be rarely

clinically significant.

8 However, the use of H2-receptor antagonists and proton pump

inhibitors combined with gastric pH changes may affect drugs that require an acidic

environment for absorption such as iron and ketoconazole.

9

In general, the rate of

absorption is slower or unaltered in older patients, and the extent of absorption by

the oral route is similar as compared to young adults.

The transdermal administration of drugs is becoming increasingly common and

used for several medications prescribed to older adults. Changes in skin seen with

aging such as decreased elasticity, thinning of the epidermis, dryness, and decreased

sebaceous gland activity may affect drug absorption.

10

Lipophilic drugs (e.g., estradiol) appear to be less affected by aging skin and are

easily dissolved, whereas hydrophilic compounds may not dissolve as readily on

aging skin.

CASE 107-1

QUESTION 1: M.G. is a 75-year-old female, 5

′4

″

, 120 pounds, with a serum creatinine concentration of 1.9

mg/dL. She has an acute exacerbation of heart failure (HF). She is given furosemide 40 mg orally, but this

produces little increase in urine output or resolution of her symptoms.

What would explain M.G’s lack of response to furosemide and how might the desired response to furosemide

be achieved?

The extent of furosemide absorption is not changed in older patients, but the rate of

absorption is slowed. This results in a diminished efficacy of the drug because active

secretion into the urine (rate of entry) must reach the steep portion of the sigmoid

dose–response curve for maximal effect of the drug.

11

M.G. should be given a 40 mg dose of furosemide intravenously to bypass the

problem of decreased rate of absorption. High sodium intake or concurrent use of

nonsteroidal anti-inflammatory drugs (NSAIDs) may also decrease the effectiveness

of furosemide. Further increases in dose of furosemide may be necessary, with

consideration of a continuous infusion in patients with severe chronic renal

insufficiency (see Chapter 28, Chronic Kidney Disease).

Distribution

There are a number of age-related changes that may affect the distribution of drugs in

the body.

12 Total body water and lean body mass both decline with age by 10% to

15%, and total fat content increases by 20% to 40%. Thus, the volume of distribution

(Vd) of drugs that are distributed primarily in body water or lean body mass (e.g.,

lithium, digoxin) is decreased in older adults, and unadjusted dosing may result in

higher blood levels. Conversely, the Vd of highly lipid-soluble drugs, such as longacting benzodiazepines (e.g., diazepam), may be increased, thereby delaying maximal

effects or leading to accumulation with continued use.

Serum albumin concentrations were found to progressively decrease for each

decade beyond 40 years of age, reaching a mean of 3.58 g/dL in those older than 80

years of age, and this may reduce protein binding.

13 Changes in protein binding due to

aging alone are thought to be only clinically significant with highly extracted drugs,

drugs that are highly protein bound, that have a narrow therapeutic index, those with a

small volume of distribution, and those given intravenously.

7,9,14 Other factors in

older patients that may also affect binding include protein concentration, disease

states, coadministration of other drugs, and nutritional status.

Altered Protein Binding

CASE 107-1, QUESTION 2: M.G. is brought to the emergency department (ED) for evaluation of a

“shaking spell”. In the ED, another “spell” is observed, starting with shaking of the left arm and progressing into

a generalized tonic–clonic seizure. A loading dose of phenytoin 1,000 mg is given intravenously (IV) over 30

minutes. M.G. is admitted to the neurology unit for further evaluation and given phenytoin 300 mg by mouth

(PO) at bedtime. Is the phenytoin regimen appropriate for M.G.? What laboratory tests should be ordered, and

how often should these be monitored?

M.G. received a phenytoin loading dose of 17 mg/kg (adult dose 15–20 mg/kg) and

is receiving the usual oral daily maintenance dose.

15 Monitoring parameters include a

serum sodium concentration to rule out a hyponatremia-induced seizure. Because

phenytoin is 90% protein bound, a serum albumin concentration should be drawn. In

patients with hypoalbuminemia or renal impairment, free (unbound) phenytoin levels

should be monitored. A serum phenytoin concentration at discharge to determine

whether the desired therapeutic serum concentration has been achieved is also

recommended. A follow-up, steady state serum phenytoin concentration should be

obtained in 10 to 14 days to evaluate the current dose and to determine whether dose

adjustments are needed. The serum phenytoin concentration should be monitored

periodically thereafter and whenever an adverse drug reaction or seizure occurs.

CASE 107-1, QUESTION 3: M.G. returns for a follow-up appointment 2 weeks later after having labs

drawn. Serum albumin concentration is 2.2 g/dL, sodium 140 mEq/L, and serum phenytoin 15 mcg/mL. M.G.

complains of drowsiness and has a wide-based, unsteady gait. What is the most likely cause of her symptoms?

Although the serum phenytoin is within the therapeutic range (10–20 mcg/mL),

phenytoin is highly protein bound, and in the presence of low albumin, free phenytoin

concentrations could be higher. A corrected phenytoin level can be calculated using

an equation:

p. 2218

p. 2219

This would produce an equivalent phenytoin concentration of 27 mcg/mL,

explaining M.G.’s symptoms (assuming her serum phenytoin concentration is at

steady state). In M.G.’s case, free phenytoin (unbound phenytoin) concentration

monitoring would be appropriate, if available, and her dosage should be adjusted

accordingly.

15,16

Metabolism

M.G.’s phenytoin metabolism may be affected by factors known to influence hepatic

drug metabolism, which include disease states, concurrent drug use, nutritional status,

environmental compounds, genetic differences, sex, liver mass, and blood flow.

Liver mass decreases by approximately 20% to 30% with age, and hepatic blood

flow decreases by approximately 20% to 50%.

7,12 Compounds undergoing phase I

metabolism (reduction, oxidation, hydroxylation, demethylation) have a decreased or

unchanged clearance, whereas compounds metabolized by phase II processes

(conjugation, acetylation, sulfonation, glucuronidation) have no change in clearance

with age.

7 Drugs with high hepatic-extraction ratios, such as the nitrates, barbiturates,

lidocaine, and propranolol, may have reduced hepatic metabolism in older adults.

17