TRIPASS XR تري باس

 with severe aortic stenosis.146

INTRAVENOUS PHENTOLAMINE

IV phentolamine is primarily used in the management of hypertensive emergencies induced by catecholamine excess, as seen

in pheochromocytoma or in those taking monoamine oxidase

inhibitors who ingest excessive amounts of tyramine-containing

foods. The mechanism of action is through nonselective competitive antagonist α-adrenergic receptors. Phentolamine is dosed

in 1- to 5-mg boluses. The onset of action is almost immediate,

and the duration of action is short (<15 minutes). IV infusions

are not recommended owing to unpredictable drops in BP.

Cerebrovascular spasm, cerebrovascular occlusion, and MI

have been reported after the administration of phentolamine.

These adverse events are usually associated with significant

hypotensive episodes. Tachycardia, arrhythmias, weakness, dizziness, flushing, and gastrointestinal effects have also been

reported.150

Aortic Dissection

TREATMENT

CASE 21-6

QUESTION 1: B.S., a 68-year-old Caucasian man with a

long history of hypertension and nonadherence, presents to

the local emergency department complaining of the sudden

onset of severe, sharp, diffuse chest pain that radiates to his

back between his shoulder blades. Significant findings on

physical examination include a pulse of 100 beats/minute,

BP of 200/120 mm Hg, clear lungs, and an S4 without murmurs. The laboratory data are unremarkable. The electrocardiogram results are interpreted as sinus tachycardia with left

ventricular hypertrophy, but no acute changes are noted.

The chest radiograph is significant for widening of the mediastinum. An emergency chest computed tomography scan

reveals a dissection at the arch of the aorta. What antihypertensive medication(s) would be most appropriate for B.S.,

and why?

Dissection of the aorta occurs when the innermost layer of

the aorta (the intima) is torn such that blood enters and separates

its layers. The ultimate treatment for this type of hypertensive

emergency depends on its location and severity; however, the

first principle of therapy is to control any existing hypertension

with agents that do not increase the force of cardiac contraction.

This lessens the force that the cardiac impulse transmits to the

dissecting aneurysm.

The aim of antihypertensive therapy in aortic dissection is

to lessen the pulsatile load or aortic stress by lowering the BP.

Reducing the force of left ventricular contractions, and consequently the rate of rise of aortic pressure, retards the propagation of the dissection and aortic rupture.151,152 The treatment

of choice for aortic dissection has classically been a vasodilatory

agent such as sodium nitroprusside, fenoldopam, or nicardipine

in combination with a β-blocker titrated to a heart rate of 55 to

65 beats/minute.151,153 Labetalol monotherapy has been used as

an alternative.154 These drugs decrease BP, venous return, and

cardiac contractility.

One common regimen is a combination of IV sodium nitroprusside (0.5–2 mcg/kg/minute) plus IV esmolol.20,152 This combination can be used as initial therapy for B.S. The concurrent

administration of a β-blocking agent with a vasodilator is desirable because the latter may induce reflex tachycardia in response

to vasodilation.

Direct vasodilators such as hydralazine should be avoided

because they increase stroke volume and left ventricular ejection

rate. These effects augment the pulsatile flow and accentuate the

sharpness of the pulse wave. This increases mechanical stress on

the aortic wall and may lead to further dissection.20

Depending on the location of the dissection, surgical intervention may be required.153,155 However, until a definitive diagnosis

is made, the primary goal is to reduce the BP and myocardial contractility to the lowest level compatible with the maintenance of

adequate renal, cerebral, and cardiac perfusion.20 Aggressive BP

control is warranted to minimize target organ damage and to

prevent further dissection or hemorrhage.152 For aortic dissection, it is suggested that the systolic BP should be lowered to 100

to 120 mm Hg or a mean arterial pressure of less than 80 mm Hg

within 5 to 10 minutes.20

Patients presenting with an aortic dissection should be

screened for tobacco, cocaine, and amphetamine use. Use of

these substances has been shown to increase the risk of dissection.

A population-based case-control study, after adjustment for other

risk factors, revealed that amphetamine abuse or dependence in

those aged 18 to 49 years of age was associated with a threefold

increased risk of aortic dissection. A patient’s lipid panel should

be evaluated, and treatment should be initiated when appropriate

(see Chapter 13, Dyslipidemias, Atherosclerosis, and Coronary

Heart Disease). Long-term hypertension control is critical in this

patient population. Connective tissue disorders, hereditary vascular disorders, trauma, and Turner syndrome (a chromosomal

condition caused by a complete or partial absence of the second

sex chromosome) are also presumed risk factors.156

CASE 21-6, QUESTION 2: What dose of esmolol should be

administered to B.S.? And what adverse events can occur

with esmolol therapy?

Esmolol is a parenteral cardioselective β1-blocker with a rapid

onset and short duration of action. For the management of hypertension, esmolol should be given as a loading dose of 250 to 500

mcg/kg for 1 minute, followed by a maintenance infusion of 50

to 300 mcg/kg/minute. Irritation, inflammation, and induration

at the infusion site occur in 5% to 10% of patients.

Hypotension is the most commonly reported adverse event

and is directly related to the duration of esmolol administration.157 However, because of the short half-life, resolution

of hypotension occurs within 30 minutes of discontinuing the

infusion. Like other β-blockers, esmolol is contraindicated in

patients with asthma, advanced heart block, or severe HF.

535Hypertensive Crises Chapter 21

CASE 21-6, QUESTION 3: In which other patient populations may esmolol be indicated?

Esmolol has been used primarily in perioperative settings to

control tachycardia induced by various surgical stimuli, including

endotracheal intubation.157 Esmolol has also been used to manage supraventricular tachyarrhythmias.158–160 It has been particularly useful in treating postoperative hypertension, especially if

associated with tachycardia. In a small series of patients undergoing cardiac bypass surgery, the antihypertensive effect of esmolol

was comparable to that of nitroprusside.161

Cocaine-Induced Hypertensive Crisis

TREATMENT

CASE 21-7

QUESTION 1: B.K. is a 54-year-old Caucasian man who

presents to the emergency department complaining of 8/10

chest pain associated with diaphoresis and nausea that

began 2 hours ago. B.K. reports using cocaine about 1 hour

before his chest pain began. His medical and social histories include hypertension for which he takes hydrochlorothiazide 25 mg daily. He also admits to using cocaine five to

seven times per week for the past 21 years and smoking one

and a half packs per day for the past 35 years. An electrocardiogram reveals ST segment elevations less than 1 mm

in leads V2 and V3 and sinus tachycardia. The patient’s blood

was drawn to assess his cardiac enzymes; the first set is

negative. His cardiac examination was unremarkable. His

vital signs include a BP of 205/162 mm Hg, heart rate of

132 beats/minute, regular rate and rhythm, and respiratory

rate of 24 breaths/minute, and he is afebrile. All laboratory

values are within normal limits. Chest radiograph is unremarkable. What agents should be used to manage cocaineinduced hypertension? What agents should be avoided?

Cocaine, a sympathomimetic, can induce severe hypertension

by inhibiting the reuptake of norepinephrine and dopamine and

thereby increasing neurotransmitter concentrations in the synaptic cleft. This leads to pronounced vasoconstriction and tachycardia. This increase in heart rate or BP increases cardiac oxygen

demand, leading to coronary vasospasm, and places the patient at

risk for ischemia and acute coronary syndromes. Cocaine exerts

its onset of action within seconds to minutes and has a serum

half-life of 30 to 90 minutes.162,163

Management of cocaine-associated hypertensive emergencies should be controlled with nicardipine, verapamil, or nitroglycerin. Calcium-channel blockers and IV nitroglycerin are

preferred in patients with active myocardial ischemia because

they have both been shown to reverse cocaine-induced hypertension and vasoconstriction.164,165 Benzodiazepines can also

be used because they can attenuate the effect of cocaine on

the cardiac system, decrease chest pain, and reduce heart

rate.162,166 Fenoldopam and nitroprusside can be used as alternative agents.167,168

The use of β-blockers should be avoided in patients who

present with hypertension or myocardial ischemia or MI

with recent cocaine use. β-blockers will result in unopposed

α-adrenergic vasoconstriction, leading to further elevation in BP

and heart rate.167,168 Labetalol possesses both α- and β-blockade,

and its use has been reported in cocaine-intoxicated patients.169

Labetalol has been shown to increase seizure activity and mortality in animals with cocaine intoxication and does not alleviate

cocaine-induced coronary vasoconstriction.170,171 Labetalol has

also been shown to worsen BP when α-stimulation has been left

unopposed in patients with pheochromocytoma.108,172 Therefore, caution should be used if labetalol is used in patients with

recent cocaine use.

KEY REFERENCES AND WEBSITES

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

http://thepoint.lww.com/AT10e. Below are the key references

for this chapter, with the corresponding reference number in this

chapter found in parentheses after the reference.

Key References

Anderson RJ et al. Oral clonidine loading in hypertensive urgencies. JAMA. 1981;246:848. (38)

Curran MP et al. Intravenous nicardipine: its use in the shortterm treatment of hypertension and various other indications.

Drugs. 2006;66:1755. (131)

Devlin JW et al. Fenoldopam versus nitroprusside for the treatment of hypertensive emergency. Ann Pharmacother. 2004;38:

755. (56)

Friederich JA, Butterworth JF 4th. Sodium nitroprusside: twenty

years and counting. Anesth Analg. 1995;81:152. (71)

Gray RJ. Managing critically ill patients with esmolol. An ultrashort acting beta-adrenergic blocker. Chest. 1988;93;398. (157)

Grossman E et al. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and

pseudoemergencies? JAMA. 1996;276:1328. (36)

Haas CE, LeBlanc JM. Acute postoperative hypertension: a

review of therapeutic options. Am J Health-Syst Pharm. 2004;61:

1661. (122)

Khoynezhad A, Plestis KA. Managing emergency hypertension

in aortic dissection and aortic aneurysm surgery. J Card Surg.

2006;21(Suppl 1):S3. (152)

Lebel M et al. Labetalol infusion in hypertensive emergencies.

Clin Pharmacol Ther. 1985;37:615. (96)

Marik PE, Varon J. Hypertensive crises: challenges and management. Chest. 2007;131:1949. (20)

Murphy MB et al. Fenoldopam—a selective peripheral

dopamine-receptor agonist for the treatment of severe hypertension. N Engl J Med. 2001;345:1548. (84)

Pollack CV et al. Clevidipine, an intravenous dihydropyridine

calcium channel blocker, is safe and effective for the treatment

of patients with acute severe hypertension. Ann Emerg Med. 2009;

53:329. (149)

22 Shock

Andrew D. Barnes and Susan H. Lee

CORE PRINCIPLES

CHAPTER CASES

1 Shock is a syndrome with multiple possible etiologies characterized by an

impairment of tissue perfusion.

2 The impairment of tissue perfusion, regardless of cause, can lead to cellular

dysfunction, organ dysfunction or failure, and death.

3 The diagnosis of shock is generally made by the findings of impaired tissue

perfusion on physical examination, and hemodynamic and laboratory changes

consistent with impaired perfusion. Hypotension may or may not be present.

Hemodynamic monitoring is vital for the determination of the type of shock and

assessment of response to interventions. Hypovolemic shock is caused by a

reduction in intravascular volume, which then results in specific changes in the

hemodynamic profile such as decreases in blood pressure, central venous pressure,

pulmonary capillary wedge pressure, and cardiac output, and a compensatory

increase in heart rate, systemic vascular resistance, and myocardial contractility.

Case 22-1 (Question 1)

4 Resuscitation is required to treat hypovolemic shock to maintain adequate tissue

perfusion and oxygenation. This can be achieved by administration of intravenous

fluids in the form of crystalloids, colloids, or blood.

Case 22-1

5 The physiologic response to fluid loss or gain is described by the Frank-Starling

curve.

Case 22-1

(Questions 10, 11)

6 Cardiogenic shock results from a decrease in the heart’s ability to maintain cardiac

output that is unrelated to hypovolemia.

Case 22-2 (Question 1)

7 Treatment of patients in cardiogenic shock involves optimization of preload,

increasing contractility, and reducing afterload if the blood pressure permits.

Case 22-2, Case 22-3

8 Septic shock is a type of distributive shock characterized by a profound vasodilatory

response and resultant decrease in blood pressure.

Case 22-4

9 Treatment of septic shock involves stabilization with fluids, vasopressors, and

inotropic agents and treatment of the underlying condition. Other therapies involve

modification of the body’s response to infection.

Case 22-4

(Questions 3, 6–8)

10 Patients with sepsis can experience disseminated intravascular coagulation, which

can lead to hemorrhagic and thrombotic complications.

Case 22-4 (Questions 9–12)

INTRODUCTION

Shock is defined in simple terms as a syndrome of impaired tissue

perfusion usually, but not always, accompanied by hypotension.

This impairment of tissue perfusion eventually leads to cellular

dysfunction, followed by organ damage and death if untreated.

The most common causes of shock are situations that result

in a reduction of intravascular volume (hypovolemic shock),

myocardial pump failure (cardiogenic shock), or increased vascular capacitance (distributive shock, sepsis). The type of treatment

required depends on the etiology.

In recent years, medical support of patients with shock

has improved because of better technologies for hemodynamic

536

537Shock Chapter 22

TABLE 22-1

Classification of Shock and Precipitating Events

Hypovolemic Shock

Hemorrhagic

Gastrointestinal bleeding

Trauma

Internal bleeding: ruptured aortic aneurysm, retroperitoneal

bleeding

Nonhemorrhagic

Dehydration: vomiting, diarrhea, diabetes mellitus, diabetes

insipidus, overuse of diuretics

Sequestration: ascites, third-space accumulation

Cutaneous: burns, nonreplaced perspiration and insensible water

losses

Cardiogenic Shock

Nonmechanical causes

Acute myocardial infarction

Low cardiac output syndrome

Right ventricular infarction

End-stage cardiomyopathy

Mechanical causes

Rupture of septum or free wall

Mitral or aortic insufficiency

Papillary muscle rupture or dysfunction

Critical aortic stenosis

Pericardial tamponade

Distributive Shock

Septic shock

Anaphylaxis

Neurogenic

Spinal injury, cerebral damage, severe dysautonomia

Drug-induced

Anesthesia, ganglionic and adrenergic blockers, overdoses of

barbiturates and narcotics

Acute adrenal insufficiency

monitoring, recognition of the value of vigorous volume replacement, appropriate use of inotropic and vasoconstrictive agents,

and the development of better ways to treat the underlying cause

of the shock syndrome. Understanding the principles of shock

should further enhance prompt recognition of patients at risk,

rapid initiation of corrective measures, and development of innovative treatment regimens.

CAUSES

Table 22-1 outlines the classification of shock and precipitating

events.1 Recognition of the etiology and underlying pathology

of the various forms of shock is essential for managing this condition. The distinctions among subtypes of shock only apply,

however, in the relatively early stages. As the syndrome evolves

and compensatory mechanisms are overwhelmed, it becomes

increasingly difficult to determine the subtypes because the clinical and pathophysiologic features of advanced shock are the

same for all. Also, different types of shock can occur at the same

time (e.g., a patient with septic shock who is also hypovolemic).

PATHOPHYSIOLOGY

Tissue perfusion is a complex process of oxygen and nutrient

delivery as well as waste removal. When perfusion is impaired,

it sets up a cascade of events that can eventually end in death.

Although the etiology of shock is varied, the eventual progression (if untreated) to cell death and subsequent organ dysfunction results from a common pathway of ischemia, endogenous

inflammatory cytokine release, and the generation of oxygen radicals. When cells are subjected to a prolonged period of ischemia,

anaerobic metabolism begins. This inefficient process results in a

decrease of adenosine triphosphate stores and causes the buildup

of lactic acid and other toxic substances that can alter mitochondrial function and eventually result in cell death. In the advanced

stages of shock, irreversible cellular damage leads to multiple

organ system failure, also known as multiple organ dysfunction

syndrome.

Inflammatory cytokines are produced by the body in response

to ischemia, injury, or infection. The phrase systemic inflammatory

response syndrome (SIRS) is the recommended umbrella term to

describe any acute, overwhelming inflammatory response, independent of the cause.2 This syndrome has best been described

in the sepsis literature; however, it can occur after a wide variety of insults, including hemorrhagic shock, infection (septic

shock), pancreatitis, ischemia, multitrauma and tissue injury,

and immune-mediated organ injury. SIRS is usually a late manifestation of hypovolemic forms of shock. It is uncommon in

cardiogenic shock, but is the hallmark of septic shock. SIRS is

clinically characterized by profound vasodilation, which impairs

perfusion, and increased capillary permeability, which can lead

to reduced intravascular volume.

CLINICAL PRESENTATION

AND DIAGNOSIS

Independent of the pathophysiologic cause, the clinical syndrome of shock progresses through several stages. During each

step, the body uses and exhausts various compensatory mechanisms to balance oxygen delivery (D˙ o2) and oxygen consumption

(V˙ o2) in an effort to maintain perfusion of vital organs. Oxygen

delivery is determined by the arterial concentration of oxygen

multiplied by the blood flow (cardiac output [CO]) (Fig. 22-1 and

Table 22-2). Normally, consumption is independent of supply,

except at low rates of D˙ o2. In some critically ill patients, however, consumption can depend on supply even in what would be

considered “normal”D˙ o2 ranges. WhenV˙ o2 becomes dependent

on the supply, it indicates an impairment of adequate perfusion.

For a more detailed discussion of

hemodynamic principles, go to

http://thepoint.lww.com/AT10e.

Although hypotension is often described as the hallmark of shock,

it is not necessarily present in all patients.

The diagnosis of shock is based on the finding of impaired

tissue perfusion on examination.3 These findings may include

the following:

 Systolic blood pressure (SBP) less than 90 mm Hg, or a

greater than 40 mm Hg decrease from baseline in a hypertensive patient, or a mean arterial pressure (MAP) less than

65 mm Hg

 Tachycardia (heart rate [HR] >90 beats/minute)  Tachypnea (respiratory rate [RR] >20 breaths/minute)  Cutaneous vasoconstriction: cold, clammy, mottled skin

(although not typical of distributive shock)

 Mental confusion (agitation, stupor, or coma)

 Oliguria: urine output less than 20 mL/hour

6Section 3 Pulmonary Disorders

ASTHMA

According to the National Institutes of Health (NIH) Expert Panel

Report 3 (EPR-3), Guidelines for the Diagnosis and Management

of Asthma,1 asthma is defined as a chronic inflammatory disorder

of the airways in which many cells and cellular elements play a

role, in particular, mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells. In susceptible persons, this inflammation causes recurrent episodes of wheezing, breathlessness,

chest tightness, and cough, particularly at night and in the early

morning. These episodes are usually associated with widespread

but variable airflow obstruction that is often reversible either

spontaneously or with treatment. The inflammation also causes

an increase in the existing bronchial hyperresponsiveness to a

variety of stimuli.2 This definition of asthma is the same as the

1997 NIH guidelines2 and has evolved from earlier national and

international guidelines.3–6

At least 22 million Americans have asthma.1 It is an underdiagnosed and undertreated condition that is estimated to have

overall costs exceeding $12 billion annually in the United States.7

Asthma is the leading cause of lost school days in children and is

a common cause of lost workdays among adults.

Mortality from asthma has decreased in the 21st century, from

4,657 deaths in 1999 to 3,447 deaths in 2007 in the United States

according to the Centers for Disease Control and Prevention,8,9

but morbidity and mortality are still unacceptably high, especially

in inner-city minority populations. This chapter emphasizes the

2007 NIH EPR-3 guidelines.1 Application of the principles of

these recent guidelines by clinicians and patients is vital to further

reducing asthma morbidity and mortality.

Etiology

Childhood-onset asthma is usually associated with atopy, which is

the genetic predisposition for the development of immunoglobulin E (IgE)–mediated response to common aeroallergens. Atopy is

the strongest predisposing factor in the development of asthma.1

A very common presentation of asthma is a child with a positive

family history of asthma and allergy to tree and grass pollen,

house dust mites, household pets, and molds.

Adult-onset asthma may also be associated with atopy, but

many adults with asthma have a negative family history and negative skin tests to common aeroallergens. Some of these patients

may have nasal polyps, aspirin sensitivity, and sinusitis. In the

British 1958 birth cohort study, participants were monitored

for wheezing and asthma at periodic intervals from birth into

their mid-forties.10 In the subset of patients who were seemingly

asymptomatic during late adolescence and early adulthood, the

presence of asthma at 42 years of age was significantly higher

in those patients who had a history of wheezing in childhood.

Exposure to factors (e.g., wood dust, chemicals) at the workplace that may cause airway inflammation is also important in

many adults. Inflammatory mechanisms are similar, but not the

same, as in atopic asthma. Some clinicians may still refer to intrinsic asthma when referring to these patients and extrinsic asthma

when discussing atopic asthma.

In addition to atopy and exposure to occupational chemical sensitizers being major risk factors for the development of

asthma, several contributing factors may increase the susceptibility to the development of the disease in predisposed individuals.1,5

These factors include viral infections, small size at birth, diet,

exposure to tobacco smoke, and environmental pollutants.1,5

Recent literature has focused on the “hygiene hypothesis,” an

imbalance of TH2 and TH1 type T lymphocytes, to explain the

marked increase in asthma in westernized countries.1,5,8 Infants

who have older siblings, early exposure to day care, and typical

childhood infections are more likely to activate TH1 responses

(protective immunity), resulting in an appropriate balance of TH1

to TH2 cells and the cytokines that they produce. On the other

hand, if the immune response is predominately from TH2 cells

(which produce cytokines that mediate allergic inflammation),

development of diseases such as asthma is more likely. Examples

of factors favoring this imbalance include the common use of

antimicrobial agents, urban environment, and Western lifestyle.

Further insights into the pathogenesis of asthma continue to be

discovered.1,7,11,12

Pathophysiology

Asthma is caused by a complex interaction between inflammatory cells and mediators. As noted in the definition of asthma,

mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells are of central importance. The bronchial epithelium in

asthmatic patients has been described as fragile, with various

abnormalities including destruction of ciliated cells and overexpression of epidermal growth factors.13 Figure 23-1 depicts the

complex interaction of cells and mediators associated with airway inflammation.

After exposure to an asthma-precipitating factor (e.g., aeroallergen), inflammatory mediators are released from bronchial

mast cells, macrophages, T lymphocytes, and epithelial cells.

These mediators direct the migration and activation of other inflammatory cells, most notably eosinophils, to the airways.1,11,12

Eosinophils release biochemicals (e.g., major basic protein and

eosinophil cationic protein) that cause airway injury, including

epithelial damage, mucus hypersecretion, and increased reactivity of smooth muscle.1,7,11

Research continues to determine the role of a subpopulation

of T lymphocytes (TH2) in asthmatic airway inflammation.1,11

TH2 lymphocytes release cytokines (e.g., interleukin [IL] 4 and

IL-5) that at least partially control the activation and enhanced

survival of eosinophils.1,4,11 The complexity of airway inflammation is indicated by the fact that at least 27 cytokines may have a

role in the pathophysiology of asthma.11 In addition, at least 18

chemokines (e.g., eotaxins) have been identified that are important in delivery of eosinophils to the airways.11 One biomarker

of airway inflammation is exhaled nitric oxide (NO), which has

been used as a treatment guide in chronic asthma.1 Bronchial

NO has been found to be elevated during periods of exacerbations and is measurably decreased with administration of inhaled

steroids but not β2-agonists.1,14 Failure to adequately minimize

severe and long-term airway inflammation in asthma may result

in airway remodeling in some patients. Airway remodeling refers

to structural changes, including an alteration in the amount and

composition of the extracellular matrix in the airway wall, leading

to airflow obstruction that eventually may become only partially

reversible.1,15

Hyperreactivity (defined as an exaggerated response of

bronchial smooth muscles to trigger stimuli) of the airways to

physical, chemical, immunologic, and pharmacologic stimuli is

pathognomonic of asthma.2 Examples of these stimuli include

inhaled allergens; respiratory viral infection; cold, dry air; smoke;

other pollutants; and methacholine. Endogenous stimuli that

can worsen asthma include poorly controlled rhinitis, sinusitis,

and gastroesophageal reflux disease.1 In addition, premenstrual

asthma has been reported, but the exact hormonal mechanism

is not known.16

Although patients with allergic rhinitis, chronic bronchitis,

and cystic fibrosis also experience bronchial hyperreactivity,

these patients do not experience bronchiolar constriction as

severely as do patients with asthma. The degree of bronchial

567Asthma Chapter 23

Airway

Antigen

Mast cell

Histamine

Leukotrienes

Interleukin 4

GM-CSF

Interleukin 5

Endothelium

Chemokines

(RANTES, eotaxin,

MCP-1, MIP-1α)

Cytokine

activation

Selectin

VCAM-1

ICAM-1

Prolonged survival

Airway

injury

Transmigration

TH2 cell

Granule proteins

Leukotrienes

Eosinophil

Bone marrow

Adhesion

Blood

FIGURE 23-1 Airway inflammation. Inhaled antigen

activates mast cells and TH2 cells in the airway. They in

turn induce the production of mediators of inflammation

(such as histamine and leukotrienes) and cytokines

including interleukin 4 and interleukin 5. Interleukin 5

travels to the bone marrow and causes terminal

differentiation of eosinophils. Circulating eosinophils

enter the area of allergic inflammation and begin

migrating to the lung by rolling, through interactions

with selectins, and eventually adhering to endothelium

through the binding of integrins to members of the

immunoglobulin superfamily of adhesion proteins:

vascular-cell adhesion molecule 1 (VCAM-1) and

intercellular adhesion molecule 1 (ICAM-1). As the

eosinophils enter the matrix of the airway through the

influence of various chemokines and cytokines, their

survival is prolonged by interleukin 4 and

granulocyte-macrophage colony-stimulating factor

(GM-CSF). On activation, the eosinophil releases

inflammatory mediators, such as leukotrienes and

granule proteins, to injure airway tissues. In addition,

eosinophils can generate GM-CSF to prolong and

potentiate their survival and contribution to persistent

airway inflammation. MCP-1, monocyte chemotactic

protein; MIP-1α, macrophage inflammatory protein;

RANTES, chemokine ligand 5. Adapted with permission

from Busse WW, Lemanske RF Jr. Asthma. N Engl J Med.

2001;344:350.

hyperreactivity of asthmatic patients correlates with the clinical course of their disease, which is characterized by periods

of remissions and exacerbations. During times of remission, a

more intense stimulus is required to produce bronchospasm than

during times of increased symptoms. Numerous theories have

been proposed to explain the bronchial hyperreactivity found in

asthma, yet none fully explains the phenomenon. Inflammation

appears to be the primary process in the pathogenesis of bronchial

hyperreactivity; however, neurogenic imbalances in the airways

also may play a significant role.5 Inflamed airways are hyperreactive (i.e., irritable). Hyperreactivity can be measured in the

physician’s office by having the patient inhale small concentrations of nebulized methacholine or histamine or by exercise (e.g.,

treadmill). The concentration of aerosolized methacholine or

histamine that decreases the forced expiratory volume in 1 second (FEV1) by 20% is referred to as the PD20 or the PC20 (provocative dose or concentration that decreases the FEV1 by 20%).2 An

indicator of optimal anti-inflammatory therapy is an increase in

the PD20 with time as the airways become less inflamed and

therefore less hyperreactive.

Another concept related to inflammation is “late-phase” versus “early-phase” asthma (Fig. 23-2). The inhalation of specific

allergens in atopic asthmatic patients produces immediate bronchoconstriction (measured by a drop in peak expiratory flow

[PEF] or FEV1) that spontaneously improves in an hour or is

reversed easily by inhalation of a β2-agonist. Although this early

asthmatic response (EAR) is blocked by the preadministration of

β2-agonists, cromolyn, or theophylline, a second bronchoconstrictive response often occurs 4 to 12 hours later. This late asthmatic response (LAR) often is more severe, more prolonged, and

more difficult to reverse with bronchodilators than is the EAR.

The LAR is associated with the influx of inflammatory cells and

mediators as described previously. Bronchodilators do not block

the LAR to allergen challenge; corticosteroids block the LAR but

do not affect the EAR; and cromolyn blocks both.2

Pathologic changes found at autopsy performed on asthmatic patients include (a) marked hypertrophy and hyperplasia

of the bronchial smooth muscle, (b) mucous gland hypertrophy

and excessive mucus secretion, and (c) denuded epithelium and

mucosal edema owing to an exudative inflammatory reaction

and inflammatory cell infiltration.1 Hyperinflation of the lungs

from air trapping with extensive mucous plugging is found at

Time (hours)

IAR LAR

Allergen

exposure

0 1 345678

FEV1 (L)

FIGURE 23-2 Typical immediate and late asthmatic responses

seen after exposure to relevant allergen. Immediate asthmatic

response (IAR) occurs within minutes, whereas late asthmatic

response (LAR) occurs several hours after exposure. Patients may

demonstrate isolated IAR, isolated LAR, or dual responses. FEV1,

forced expiratory volume in 1 second. Adapted with permission from

Herfindal ET, Gourley DR, eds. Textbook of Therapeutics Drug and

Disease Management. 7th ed. Baltimore, MD: Lippincott Williams &

Wilkins; 2003.

568Section 3 Pulmonary Disorders

TABLE 23-1

Classifying Asthma Severity in Children 0 to 4 Years of Age

Classifying Severity in Children who are not Currently Taking Long-term Control Medication

Classification of Asthma Severity (Children 0–4 Years of Age)

Persistent

Components of Severity Intermittent Mild Moderate Severe

Impairment Symptoms ≤2 days/wk >2 days/wk

but not daily

Daily Throughout the

day

Nighttime awakenings 0 1–2×/mo 3–4×/mo >l×/wk

SABA use for symptom control

(not prevention of EIB)

≤2 days/wk >2 days/wk

but not daily

Daily Several times per

day

Interference with normal activity None Minor limitation Some limitation Extremely limited

Risk Exacerbations requiring oral

systemic corticosteroids

0–1/y ≥2 exacerbation in 6 months requiring oral corticosteroids or ≥4

wheezing episodes in 1 year lasting >1 day AND risk factors for

persistent asthma

Consider severity and interval since last exacerbation.

←−−−−−−−−−−− Frequency and severity may fluctuate with time. −−−−−−−−−−−→

Exacerbations of any severity may occur in patients in any severity category.

Level of severity is determined by both impairment and risk. Assess impairment domain by caregiver’s recall of previous 2–4 weeks. Assign severity to

the most severe category in which any feature occurs.

At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity. For treatment purposes,

patients who had ≥2 exacerbations requiring oral corticosteroids in the past 6 months, or ≥4 wheezing episodes in the past year, and who have risk

factors for persistent asthma may be considered the same as patients who have persistent asthma, even in the absence of impairment levels consistent

with persistent asthma.

Classifying Severity in Patients After Asthma Becomes Well Controlled, by Lowest Level of Treatment Required to Maintain Control

Classification of Asthma Severity

Persistent

Intermittent Mild Moderate Severe

Lowest level of treatment required to maintain control Step 1 Step 2 Step 3 or 4 Step 5 or 6

(See Fig. 23-7 for treatment steps.)

EIB, exercise-induced bronchospasm; SABA, short-acting inhaled β2-agonist.

Reprinted from National Institutes of Health. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood

Institute; 2007. NIH publication 07-4051.

autopsy in patients who have died of acute asthma attacks, but

these changes also are seen at autopsy in asthmatic patients dying

of other causes. The bronchial smooth muscle hypertrophy and

mucus hypersecretion are secondary to the chronic inflammatory response.17

For an animation describing asthma, go to

http://thepoint.lww.com/AT10e.

Symptoms

The heterogeneity of asthma is reflected best in its clinical presentation. Classically, patients with asthma present with intermittent

episodes of expiratory wheezing, coughing, and dyspnea. Some

patients, however, experience chest tightness or a chronic cough

that is not associated with wheezing. There is a wide spectrum

of disease severity, ranging from patients with occasional, mild

bouts of breathlessness to patients who wheeze daily despite continuous high dosages of medication. In addition, the severity of

asthma may be influenced by environmental factors (e.g., specific

seasonal allergens). Symptoms often are associated with exercise

and sleep (refer to Case 23-11, Case 23-12, and Case 23-14).

Classification of asthma severity is of major importance in

defining initial long-term treatment. Within three age groups,

EPR-3 uses the classifications of intermittent, mild persistent,

moderate persistent, and severe persistent asthma (Tables 23-1–

23-3). The frequency of symptoms is a key component of asthma

classification.1 For example, mild persistent asthma is defined as

symptoms more than two times per week or nocturnal symptoms (including early morning chest tightness) more than two

times per month. Many clinicians are unaware that this level of

symptoms is defined as persistent asthma. This classification is

of major significance when selecting long-term drug therapy in

that daily use of anti-inflammatory agents is an essential part of

management for persistent asthma.1

Diagnosis and Monitoring

HISTORY

The diagnosis of asthma is based primarily on a detailed history of

intermittent symptoms of wheezing, chest tightness, shortness

of breath, and coughing. These episodes may be worse seasonally

(e.g., springtime or late summer and early fall) or in association

with exercise. History of nocturnal symptoms with awakening

in the early morning is a critical component to assess. In addition,

history of symptoms after exposure to other common triggers

(e.g., cats, perfume, secondhand tobacco smoke) is typical (Table

23-4). A positive family history and the presence of rhinitis or

atopic dermatitis also are significant. After a careful history is

obtained, skin testing may be useful in identifying triggering

569Asthma Chapter 23

TABLE 23-2

Classifying Asthma Severity in Children 5 to 11 Years of Age

Classifying Severity in Children who are not Currently Taking Long-term Control Medication

Classification of Asthma Severity (Children 5–11 Years of Age)

Persistent

Components of Severity Intermittent Mild Moderate Severe

Impairment Symptoms ≤2 days/wk >2 days/wk but not

daily

Daily Throughout the day

Nighttime awakenings ≤2×/mo 3–4×/mo >1×/wk but not

nightly

Often 7×/wk

SABA use for symptom

control (not prevention

of EIB)

≤2 days/wk >2 days/wk but not

daily

Daily Several times per day

Interference with normal

activity

None Minor limitation Some limitation Extremely limited

Lung function  Normal FEV1

between

exacerbations

 FEV1 >80%

predicted

 FEV1>80%

predicted

 FEV1 = 60%–80%

predicted

 FEV1 <60%

predicted  FEV1/FVC >85%  FEV1/FVC >80%  FEV1/FVC

75%–80%

 FEV1/FVC <75%

Risk Exacerbations requiring

oral systemic

corticosteroids

0–1 in 1 year (see note) ≥2 in 1 year

(see note) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→

Consider severity and interval since last exacerbation. Frequency and ←−−−−−−−− −−−−−−−−→ severity may fluctuate with time for patients in any severity category.

Relative annual risk of exacerbations may be related to FEV1.

Level of severity is determined by both impairment and risk. Assess impairment domain by patient’s or caregiver’s recall of the previous 2–4 weeks and

spirometry. Assign severity to the most severe category in which any feature occurs.

At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity. In general, more frequent and

intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU admission indicate greater underlying disease severity. For

treatment purposes, patients who had ≥2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as

patients who have persistent asthma, even in the absence of impairment levels consistent with persistent asthma.

Classifying Severity in Patients After Asthma Becomes Well Controlled, by Lowest Level of Treatment Required to Maintain Control

Classification of Asthma Severity

Persistent

Intermittent Mild Moderate Severe

Lowest level of treatment required to Step 1 Step 2 Step 3 or 4 Step 5 or 6

maintain control

(See Fig. 23-8 for treatment steps.)

EIB, exercise-induced bronchospasm; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICU, intensive care unit; SABA, short-acting β2-agonist.

Reprinted from National Institutes of Health. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood

Institute; 2007. NIH publication 07-4051.

allergens, but it is only of supportive value in the diagnosis of

asthma.

PULMONARY FUNCTION TESTS

The diagnosis of asthma is based in part on demonstration of

reversible airway obstruction. A brief discussion of tests to detect

reversibility of airway obstruction is important. Furthermore, a

short summary of arterial blood gases (ABGs) is pertinent here

in assessing the severity of asthma exacerbations.

SPIROMETRY

Lung volumes often are measured to obtain information about

the size of the patient’s lungs because pulmonary diseases can

affect the volume of air that can be inhaled and exhaled. The tidal

volume is the volume of air inspired or expired during normal

breathing. The volume of air blown off after maximal inspiration

to full expiration is defined as the vital capacity (VC). The residual

volume (RV) is the volume of air left in the lung after maximal

expiration. The volume of air left after a normal expiration is the

functional residual capacity (FRC). Total lung capacity (TLC) is

the VC plus the RV. Patients with obstructive lung disease have

difficulty with expiration; therefore, they tend to have a decreased

VC, an increased RV, and a normal TLC. Classic restrictive lung

diseases (e.g., sarcoidosis, idiopathic pulmonary fibrosis) present

with decrements in all lung volumes.18 Patients also may have

mixed lesion diseases, in which case the classic findings are not

apparent until the disease has advanced considerably.

The spirometer also can be used to evaluate the performance

of the patient’s lungs, thorax, and respiratory muscles in moving air into and out of the lungs. Forced expiratory maneuvers

amplify the ventilation abnormalities produced. The single most

useful test for ventilatory dysfunction is the forced expiratory volume (FEV). The FEV is measured by having the patient exhale

into the spirometer as forcefully and completely as possible

after maximal inspiration. The resulting volume curve is plotted against time (Fig. 23-3) so that expiratory flow can be

ncrease caloric intake, unless weight loss is desired. A plan that

includes gradual weight loss is appropriate for J.K. based on his

obesity.

Respiratory status should be evaluated every 8 hours in hospitalized patients, to help recognize pulmonary edema and pulmonary aspiration. Auscultation with a stethoscope should be

conducted at least two times per week, but simple observation of

the patient’s breathing pattern is adequate at other times unless

altered respirations are noted. Coughing or respiratory distress

may be indications of aspiration or other developing respiratory

problems. Vital signs also may provide clues to aspiration or other

problems, such as dehydration, fluid overload, or infection.

In addition to monitoring for complications, monitoring

for response to EN and changes in nutritional status is recommended. This should occur routinely in patients receiving

either short-term or long-term EN. Chapter 35, Basic Nutrition

and Patient Assessment, discusses parameters used for nutrition

assessment and on-going monitoring of nutritional status.

Gastrointestinal Complications

Assessment of GI symptoms is important for determining EN tolerance because GI complications are frequently associated with

tube feeding. Abdominal distension and bloating should be evaluated at least every 8 hours while J.K. is hospitalized. Abdominal

distension may be an indication of accumulating formula. The

possibility of falsely low GRV due to malposition or collapse of

the tube during withdrawal of gastric fluid should be considered

if abdominal distension occurs when GRV is low. Gas formation

secondary to lactose intolerance or rapid increases in fiber intake,

and poor gastric emptying secondary to a high-fat formula, medications, recent surgery, critical illness, or an underlying disease

such as diabetes are among the conditions associated with distension. When considerable distension is present, the formula

should be held temporarily, and the patient evaluated further to

rule out a contraindication to EN.

Nausea, vomiting, abdominal cramping, diarrhea, and constipation are other GI symptoms monitored as indicators of EN

tolerance. J.K. has some of these symptoms associated with his

gastroparesis, and disease associated symptoms should not be

confused with feeding intolerance. Vomiting creates the most

immediate concern because tube displacement and pulmonary

aspiration can occur. Nausea and vomiting commonly occur with

a high GRV, severe gastric distension, poor gastric emptying during gastric feeding, GI tract obstruction, or poor GI motility.

Diarrhea occurs in 2% to 70% of patients, depending on the definition used, and is one of the most difficult problems for patients

and caregivers to address.35–40,74 Predisposing illnesses, including diabetes mellitus, GI infections, pancreatic insufficiency, and

malabsorption syndromes, are more likely to cause diarrhea in

patients receiving EN than the formula itself.34,38,75 J.K. has type

2 diabetes; however, at this time, diarrhea has not been reported

as a problem.

Formula-related GI infections could occur from contamination of an opened can or package. Sources of contamination

include the water used for reconstitution or dilution, transfer

to the delivery bag, formula kept in the delivery bag for a prolonged period, and poorly cleaned feeding bags or administration

sets. Water used to flush the tube can also be a source of contamination; therefore, current practice recommendations are to

use sterile water as the flush solution for immunocompromised

patients.37 Closed enteral feeding systems using ready-to-hang

bags of formula decrease contamination by reducing manipulation of the bag and formula, and are commonly used in the hospital setting. Concurrent drug therapy (e.g., antibiotics) is another

major contributor to diarrhea in tube-fed patients, potentially

accounting for 61% of diarrhea cases.38

Bolus feeding into the jejunum can lead to diarrhea and

abdominal cramping, as well as nausea and vomiting. Because J.K.

is being fed into the jejunum, he should remain on a continuous

infusion protocol. Initiation of EN with a hypertonic formula, a

rapid rate of infusion or a large volume, and use of formula at

refrigerator temperature are other factors often cited as causing

GI symptoms. Although controlled studies have not supported

these factors as significant contributors to GI intolerance, subjective evidence suggests they are important. Constipation is most

likely to occur with long-term tube feeding in nonambulatory