2126 PART 6 Disorders of the Cardiovascular System

pulmonary vascular diseases based on molecular phenotyping that, in

the future, may offer a guide for improved management decisions as

precision medicine strategies continue to evolve.

The current classification system, last revised in 2018 during the

Sixth World Symposium on Pulmonary Hypertension, recognizes five

PH categories listed here sequentially as groups 1–5: PAH; PH due to

left heart disease; PH due to chronic lung disease or sleep-disordered

breathing; CTEPH; and a group of miscellaneous diseases that rarely

(or inconsistently) cause PH.

Pulmonary Arterial Hypertension WHO group 1 PH, or PAH,

involves marked pulmonary arterial precapillary remodeling, including intimal fibrosis, increased medial thickness, pulmonary arteriolar

occlusion, and classic plexiform lesions. The hemodynamic criteria for

PAH are sustained elevation in resting mPAP >20 mmHg, PVR ≥3.0

WU, and PAWP or LVEDP of ≤15 mmHg based on RHC. Idiopathic

PAH (IPAH) is a progressive disease that leads to right heart failure and

early mortality. From the original National Institutes of Health registry

on IPAH in 1987, the average age at diagnosis was 36 years, with only

9% of patients with IPAH over the age of 60. However, contemporary

data now inclusive of numerous international registries suggest a different clinical profile. The mean age of PAH patients is reported to be

54–68 years old across studies. This reflects, in part, rising awareness

of this disease in the elderly. The prevalence of IPAH favors women to

men by ~3.1-fold; however, the hemodynamics at diagnosis are more

severe, and the prognosis is less favorable in men compared to women.

Diseases Associated with PAH Other forms of PAH that deserve

specific consideration are those associated with congenital heart disease with intracardiac shunt, connective tissue disease, portal hypertension, and HIV.

CONGENITAL HEART DISEASE PAH in the setting of congenital heart

disease is important to recognize since surgical correction may be indicated and when successful is associated with favorable prognosis. This

is particular salient today, as more congenital heart disease patients live

to adulthood and populate general medical practices. Still, referral to

adult congenital heart disease centers should be considered for patients

with suspected PAH, which in this population is subclassified into

four groups: Eisenmenger’s syndrome, systemic-to-pulmonary shunts,

coincidental or small defects causing shunts, and postoperative/closed

defects causing shunts. Surgical repair of congenital anatomic lesions

may be indicated prior to elevation in PVR >3.0 WU to avoid the development of Eisenmenger’s syndrome, a pathophysiologic consequence

of progressive pulmonary vascular remodeling due to a large-volume

left-to-right shunt that is associated with cyanosis, hyperviscosity,

weakness, and shortened life span.

CONNECTIVE TISSUE DISEASE Patients with connective tissue

disease–associated PAH are encountered relatively commonly in

clinical practice. Although case series link rheumatoid arthritis and

systemic lupus erythematosus with pulmonary vascular disease, the

predominant clinical phenotype is systemic sclerosis-associated PAH.

It is important to distinguish patients with limited cutaneous scleroderma from those with diffuse scleroderma because PH in the

former is likely PAH and PH in the latter often occurs in the setting

of interstitial lung disease. Although the average age of scleroderma

onset is between 30 and 50 years old, patients who eventually develop

scleroderma-associated PAH tend to be older at the time of scleroderma diagnosis. The development of PAH in scleroderma is particularly worrisome prognostically, although implementation of modern

therapies improves outcome.

PORTOPULMONARY HYPERTENSION Among patients with established

portal hypertension, 2–10% develop portopulmonary hypertension

independent of the cause of liver disease. Furthermore, portopulmonary hypertension is observed in patients with nonhepatic etiologies

of portal hypertension. A hyperdynamic circulatory state is common,

as in most patients with advanced liver disease; however, the same

pulmonary vascular remodeling observed in other forms of PAH is

seen in the pulmonary vascular bed in portopulmonary hypertension.

It is important to distinguish this process from hepatopulmonary

syndrome, which can also manifest with dyspnea and hypoxemia but

is pathophysiologically distinct from portopulmonary hypertension

in that abnormal vasodilation of the pulmonary vasculature leads to

intrapulmonary shunting. Portopulmonary hypertension is an established marker of adverse outcome in the post–liver transplant period

with 100% mortality reported in one study among patients with mPAP

≥50 mmHg.

HIV-PAH The true prevalence of HIV-PAH is not known; however,

this PAH subtype is an important cause of mortality in the HIVinfected population, and prognosis in these patients is among the least

favorable for all PH subgroups. There is no correlation between the

stage of HIV infection and the development of PAH.

Pulmonary Hypertension Associated with Left Heart

Disease Patients with PH due to left ventricular systolic dysfunction, aortic and mitral valve disease, and heart failure with preserved

ejection fraction (HFpEF) are classified in WHO group 2. The hallmark of this PH phenotype is elevated left atrial pressure with resulting

pulmonary venous hypertension. In left-sided systolic heart failure or

HFpEF, even mildly elevated mPAP is associated with adverse clinical

outcome. It should be noted that PH in the setting of mitral stenosis

or regurgitation is an indication for surgical (or percutaneous) valve

intervention.

Regardless of the cause of elevated left atrial pressure, the increased

pulmonary venous pressure indirectly leads to a rise in pulmonary

arterial pressure. Chronic pulmonary venous hypertension leading

to a reactive pulmonary arterial vasculopathy is considered in these

patients when PVR is ≥3 WU. Pathologically, this process is marked

by pulmonary arteriolar remodeling with intimal fibrosis and medial

hyperplasia akin to that seen in PAH, as well as pulmonary venule

sclerosis and thickening.

Pulmonary Hypertension Associated with Lung Disease

Intrinsic lung disease is the second most common cause of PH and has

been observed in both chronic obstructive pulmonary disease (COPD)

and interstitial lung disease. Additionally, PH is also diagnosed in diseases of mixed obstructive/restrictive pathophysiology: bronchiectasis,

cystic fibrosis, mixed obstructive-restrictive disease marked by fibrosis

in the lower lung zones, and emphysema predominantly in the upper

lung zones. When associated with chronic lung disease, PH is usually

modest. For example, 90% of COPD patients have mPAP >20 mmHg,

but an mPAP >35 mmHg is observed in only 5% of patients. Nonetheless, the subgroup of patients with primary lung disease and severe PH

is challenging clinically, as extensive pulmonary arterial involvement,

very low DlCO on pulmonary function testing, and inhibition of normal vasoreactivity are observed and are associated with poor outcome.

Sleep-disordered syndromes generally result in mild PH.

Pulmonary Hypertension Associated with Chronic

Thromboembolic Disease The development of PH after chronic

thromboembolic obstruction of the pulmonary arteries, termed

CTEPH, is well described. The incidence of CTEPH following a single pulmonary embolic event is difficult to determine accurately, but

probably is between 3 and 7% of patients. Importantly, 25% of patients

with CTEPH have no history of clinical venous thromboembolism,

suggesting that CTEPH may develop following a subclinical pulmonary embolism or through a diverse range of mechanisms. Obstruction

of the proximal pulmonary vasculature due to webbing, stricture, or

focal fibrotic occlusion signifies proximal vessel involvement. Distal

pulmonary arterioles remodel by luminal narrowing or obliteration.

Approximately 10–15% of patients will develop a disease very similar

clinically and pathologically to PAH after resection of the proximal

thrombus (Fig. 283-7).

■ OTHER DISORDERS AFFECTING THE

PULMONARY VASCULATURE

Sarcoidosis Patients with sarcoidosis can develop PH as a result

of lung involvement, and those who present with progressive dyspnea

Pulmonary Hypertension

2127CHAPTER 283

and PH require a thorough evaluation. In sarcoidosis, PH develops

mainly due to granulomatous inflammation of the pulmonary vessels,

although mechanical compression of pulmonary arteries by enlarged

lymph nodes is also reported.

Sickle Cell Disease Cardiovascular system abnormalities are

prominent in the clinical spectrum of sickle cell disease (and other

hemoglobinopathies), including PH, which occurs in 6–10% of patients.

The etiology is multifactorial, including hemolysis, hypoxemia, thromboembolism, chronically high CO, and chronic liver disease.

Schistosomiasis Globally, schistosomiasis is among the most

common causes of PH. The development of PH occurs in the setting

of hepatosplenic disease and portal hypertension. Studies suggest that

inflammation from the infection triggers maladaptive pulmonary

vascular changes. The diagnosis is confirmed by finding the parasite

ova in the urine or stool of patients with symptoms, which can be

difficult. The efficacy of therapies directed toward PH in these patients

is unknown.

■ PHARMACOLOGIC TREATMENT OF PAH

Prior to the availability of disease-specific therapy, the 1- and 3-year

mortality rates for IPAH or hereditary PAH were 68 and 48%,

respectively. In the current era, there are 14 U.S. Food and Drug

Administration (FDA)–approved medical therapies for PAH, and

standardized treatment strategies have been developed that emphasize early, aggressive pharmacotherapy initiated at a PH specialty

clinical center. Among optimally treated patients, the 1- and 3-year

survival rates have improved to 91 and 69%, respectively. All medical

therapies target the prostacyclin, NO•

, or endothelin receptor signaling pathways. Drug delivery methods now include oral, inhaled,

subcutaneous (including via surgically implanted devices), and intravenous routes.

Prostanoids In PAH, endothelial dysfunction and platelet activation cause an imbalance of arachidonic acid metabolites with

reduced prostacyclin levels and increased thromboxane A2

 production. Prostacyclin (PGI2

) activates cyclic adenosine monophosphate

(cAMP)–dependent pathways that mediate vasodilation. PGI2

 also has

antiproliferative effects on vascular smooth muscle and inhibits platelet

aggregation. Protein levels of prostacyclin synthase are decreased in

pulmonary arteries of patients with PAH. This imbalance of mediators

is offset therapeutically by the administration of either exogenous

prostacyclin (and analogues, termed prostanoids) or a prostacyclin

receptor agonist.

Epoprostenol was the first prostanoid available for the management

of PAH. Epoprostenol delivered as a continuous intravenous infusion

improves functional capacity and survival in PAH. The efficacy of

epoprostenol in WHO Functional Class (FC) III and IV PAH patients

was demonstrated in a clinical trial that showed improved quality of

life, mPAP, PVR, 6-MWD, and mortality. Treprostinil has a longer

half-life than epoprostenol (~4 h vs ~6 min), which allows for subcutaneous administration. Treprostinil has been shown to improve

pulmonary hemodynamics, symptoms, exercise capacity, and survival

in PAH. Inhaled prostacyclin provides the beneficial effects of infused

prostacyclin therapy without the inconvenience and side effects of

infusion catheters (e.g., risk of infection and infusion site reactions).

Both inhaled iloprost and treprostinil have been approved for patients

with PAH and severe heart failure symptoms. Oral prostacyclin is also

efficacious in clinical trials, but the maximal dose is modest and, therefore, generally reserved as a second-line therapy.

Selexipag is an oral nonprostanoid diphenylpyrazine derivative that

binds the prostaglandin I2

 (IP) receptor with high affinity. The active

metabolite of selexipag has a prolonged half-life in comparison with

prostanoid analogues and permits twice-daily dosing. The efficacy

of selexipag was evaluated in patients with PAH in New York Heart

Association (NYHA) FC II to III on background therapy with either

an endothelin-1 (ET-1) receptor antagonist or sildenafil, or both. This

trial represents the largest randomized placebo-controlled trial among

patients with PAH ever completed, enrolling 1156 patients treated for

a median of 1.4 years. Selexipag reduced the risk of hospitalization and

the risk of disease progression by 43% (p < .0001) compared to those

who received placebo. There were no significant differences in mortality between the two study groups, and the side effect profile was similar

to that of prostacyclins.

Endothelin Receptor Antagonists Endothelin receptor antagonists (ERAs) inhibit the detrimental effects of ET-1, a potent endogenous vasoconstrictor and vascular smooth muscle mitogen. In PAH,

ET-1 associates positively with PVR and mPAP, and inversely with CO

and 6-MWD. The ET-1 signaling axis is complex and cell type–specific:

ET type A (ETA) and type B (ETB) receptors expressed in pulmonary

artery smooth muscle cells mediate vasoconstriction, whereas human

pulmonary artery endothelial cells express ETB receptors that promote

ET-1 clearance and vasodilation through endothelial nitric oxide synthase activation and prostacyclin release.

The three ERAs approved for use in the United States are the nonselective ETA/B receptor antagonists bosentan and macitentan and the

selective ETA antagonist ambrisentan. Studies have shown that bosentan improves hemodynamics and exercise capacity and delays clinical

worsening. The randomized, placebo-controlled, phase 3 Bosentan

Randomized Trial of Endothelin Antagonist Therapy (BREATHE)-1

trial comparing bosentan to placebo demonstrated improved symptoms, 6-MWD, and WHO FC in patients treated with bosentan.

The Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary

1cm

A B C

FIGURE 283-7 Chronic thromboembolic pulmonary hypertension (CTEPH) imaging findings and surgical endarterectomy specimen. A. Contrast-enhanced computed

tomography of the chest shows an obstructive vascular pattern involving segmental pulmonary arteries (yellow arrows) in a 63-year-old man with exertional dyspnea and

remote history of pulmonary embolism. B. Still image of a pulmonary angiography of the right lung (submaximal injection shown) shows pulmonary artery stricture, webbing,

and severe dearborization that is classic for CTEPH. C. Fibrotic, chronic clot specimens resected during surgical pulmonary endarterectomy, which is curative in most

CTEPH patients. (Panel C is reproduced with permission from IM Lang, M Madani: Update on chronic thromboembolic pulmonary hypertension. Circulation 130:508, 2014.)

2128 PART 6 Disorders of the Cardiovascular System

Arterial Hypertension Patients (EARLY) study comparing bosentan

to placebo demonstrated improved PVR and 6-MWD in patients with

WHO FC II.

Several studies, including the phase 3, placebo-controlled Ambrisentan in Pulmonary Arterial Hypertension, (ARIES)-1 trial, have demonstrated that ambrisentan improves exercise tolerance, WHO FC,

hemodynamics, and quality of life in patients with PAH. More recently,

the Study with an Endothelin Receptor Antagonist in Pulmonary

Arterial Hypertension to Improve Clinical Outcome (SERAPHIN)

trial randomized 742 PAH patients to receive placebo or macitentan,

which is an ETA/B antagonist with optimized receptor binding affinity.

The majority of patients were on some form of background PAH therapy. Over an average treatment duration of 85 weeks, the hazard ratio

for achieving the composite primary endpoint of PAH-related clinical

worsening, which included death or disease progression, was decreased

by 45% in the 10-mg dose arm.

Nitric Oxide Pathway Effectors The gaseous, lipophilic molecule

NO•

 is generated by endothelial nitric oxide synthase in endothelial

cells and activates soluble guanylyl cyclase (sGC) to generate cGMP in

vascular smooth muscle cells and platelets. The cyclic nucleotide cGMP

is a second messenger that induces vasodilation through relaxation of

arterial smooth muscle cells and inhibits platelet activation. Phosphodiesterase type 5 (PDE-5) enzymes are highly expressed in lung vascular

tissue (and the corpus carvernosum of the penis). The PDE-5 inhibitors

prevent hydrolysis (inactivation) of cGMP to maximize NO•

-dependent

vasodilation, serving as the basis for use of this drug class in the treatment of PH (and erectile dysfunction). The two PDE-5 inhibitors used

for the treatment of PAH are sildenafil and tadalafil. Both agents have

been shown to improve hemodynamics and 6-MWD.

Riociguat increases bioactive cGMP by (1) stabilizing the molecular

interaction between NO•

 and sGC, and (2) directly stimulating sGC

independent of NO•

 bioavailability. Riociguat significantly improved

exercise capacity, pulmonary hemodynamics, WHO FC, and time

to clinical worsening in patients with PAH and is the sole approved

pharmacotherapy for CTEPH patients for whom surgical pulmonary

endarterectomy is ineffective or contraindicated.

■ APPROACH TO PAH TREATMENT

The approach to PAH treatment has evolved substantially from the

prior era in which success was defined by delaying mortality in endstage disease. Now, treatment aims to achieve a low clinical risk profile,

defined as a 1-year mortality risk of <5%. Generally, this describes a

patient with minimal symptoms, WHO FC I or II, 6-WMD >440 m,

and cardiac index ≥2.5 L/min per m2

. To accomplish this goal, most

patients will ultimately require two or more PAH pharmacotherapies

in addition to risk factor modification (such as a low-sodium diet),

diuretic use, supplemental oxygen, and prescription (or supervised)

exercise. Combination pharmacotherapy has a number of hypothetical

advantages: as multiple pathogenic intermediaries are identified and

the neoplastic nature of PAH is recognized increasingly, it is clear

that targeting the diverse pathobiologic and pathophysiologic events

involved in vascular remodeling is needed to optimize treatment. The

concept of combination therapy in PAH is modeled after other complex diseases in which a similar approach has been effective, including

HIV, cancer, and heart failure.

The role of early, aggressive therapy with combination oral treatments was addressed in the landmark Initial Use of Ambrisentan plus

Tadalafil in Pulmonary Arterial Hypertension (AMBITION) trial.

Treatment-naïve, incident PAH patients (n = 500) were randomized

to a combination of ambrisentan and tadalafil, ambrisentan monotherapy, or tadalafil monotherapy. Up-front combination therapy with

ambrisentan and tadalafil was associated with a 50% lower risk of

clinical worsening (composite of death, lung transplantation, hospitalization for PAH worsening, and worsening PAH) when compared with

the monotherapy groups. This difference was driven primarily by the

delay in time to first hospitalization. Importantly, initial combination

therapy was not associated with an increase in adverse events. Registry

data suggest that patients on dual therapy with a PDE-5 inhibitor plus

ERA combinations alternative to the drugs studied in AMBITION also

have better outcomes compared to patients treated with monotherapy,

suggesting that the attendant benefit from combination therapy may

not be drug-specific (Fig. 283-8).

The paradigm shift toward early, aggressive pharmacotherapy in

PAH is expanding to up-front triple combination therapy. Although

limited currently to smaller prospective studies in highly selected

patients, initiation of intravenous epoprostenol, bosentan, and sildenafil in one report was associated with sustained clinical and hemodynamic improvement and 100% survival at 3 years.

■ UNMET AND FUTURE RESEARCH NEEDS IN

PULMONARY HYPERTENSION

Despite substantial gains in quality of life and survival in PAH, elevated patient mortality and limited quality of life remain at unacceptable levels. Improved awareness among clinicians and patients could

lead to more timely diagnosis that will affect the response to therapy

and survival. Patients should also have the option of referral to a

specialty center that focuses on treatment of patients with pulmonary

vascular disease, which will ensure their access to state-of-the-art

(multidisciplinary) care. Presently, only three classes of therapy exist

for patients with PAH, and these do not reverse vascular remodeling

sufficiently to provide a definitive long-term (>10 year) clinical benefit. In addition, the role of currently available drugs in early-stage disease is not known and requires further investigation (Table 283-2).

Treatments that address fibrosis and metabolic changes in pulmonary

vascular cells are needed. Finally, disease-specific treatments are

lacking for PH due to left heart disease or lung disease. Therefore,

developing therapeutics for these large and vulnerable populations is

of paramount importance.

Treatment-Naïve PAH

Vasoreactivity test

Risk

assessment

Calcium channel

blockers Rx

High

risk

Triple therapy

Low-int

risk

Combination

oral therapy

Procedural therapy

(lung transplant)

Combination therapy

(including IV)

FIGURE 283-8 Treatment strategy overview for patients with newly diagnosed

pulmonary arterial hypertension (PAH). Incident, treatment-naïve patients

diagnosed with PAH should be assessed with vasoreactivity testing at the time of

right heart catheterization. Patients with a positive vasoreactivity test indicating

an acute and robust vasodilatory response following administration of nitric oxide

(or other approved pulmonary vasodilator) are treated with high-dose oral calcium

channel blocker therapy (Rx) and have a favorable prognosis, but compose a

minority (<5%) of all PAH patients. Among patients with a negative vasoreactivity

study, treatment selection is determined by clinical risk: high-risk patients, such as

those with advanced heart failure or syncope, are treated with combination drug

therapy, including intravenous prostacyclin therapy. Low- or intermediate (Int)-risk

patients are initiated on combination oral therapy, which generally includes an

endothelin receptor antagonist and phosphodiesterase type 5 inhibitor. Subsequent

add-on therapy (i.e., triple therapy) is considered in patients who deteriorate

clinically or fail to improve. Lung transplantation or other surgical strategies are

considered in patients with severe PAH refractory to maximal medical treatment.

Pulmonary Hypertension

2129CHAPTER 283

Acknowledgement

Dr. Aaron Waxman contributed to this chapter in the 20th edition and

some material from that chapter has been retained here.

■ FURTHER READING

Banerjee D et al: Sexual health and health-related quality of life

among women with pulmonary arterial hypertension. Pulm Circ

8:2045894018788277, 2018.

Galiè N et al: Initial use of ambrisentan plus tadalafil in pulmonary

arterial hypertension. N Engl J Med 373:834, 2015.

Ghofrani HA et al: Riociguat for the treatment of pulmonary arterial

hypertension. N Engl J Med 369:330, 2013.

Humbert M et al: Pathology and pathobiology of pulmonary hypertension: State of the art and research perspectives. Eur Respir J

53:1801887, 2019.

Maron BA, Galie N: Diagnosis, treatment, and clinical management

of pulmonary arterial hypertension in the contemporary era: A

review. JAMA Cardiol 1:1056, 2016.

Maron BA et al: Association of borderline pulmonary hypertension

with mortality and hospitalization in a large patient cohort: Insights

from the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Circulation 133:1240, 2016.

Opotowsky AR: Clinical evaluation and management of pulmonary

hypertension in the adult with congenital heart disease. Circulation

131:200, 2015.

Simonneau G et al: Haemodynamic definitions and updated clinical

classification of pulmonary hypertension. Eur Respir J 53:pii:1801913,

2019.

Sitbon O et al: Selexipag for the treatment of pulmonary arterial

hypertension. N Engl J Med 373:2522, 2015.

TABLE 283-2 FDA-Approved Therapies for the Treatment of Pulmonary Arterial Hypertension (PAH)

GENERIC NAME

ROUTE OF

ADMINISTRATION DRUG CLASS INDICATION

Epoprostenol IV Prostacyclin derivative Treatment of PAH to improve exercise capacity

Iloprost Inhaled Prostacyclin derivative Treatment of PAH to improve a composite endpoint consisting of exercise

tolerance, symptoms (NYHA class), and lack of deterioration

Treprostinil IV or SC Prostacyclin derivative Treatment of PAH to diminish symptoms associated with exercise

Treprostinil Inhaled Prostacyclin derivative Treatment of PAH to improve exercise ability

Treprostinil Oral Prostacyclin derivative Treatment of PAH to improve exercise ability

Selexipeg Oral Selective IP receptor agonist Treatment of PAH to improve a composite endpoint lack of clinical

deterioration

Bosentan Oral Endothelin receptor antagonist Treatment of PAH to improve exercise capacity and to decrease clinical

worsening

Ambrisentan Oral Endothelin receptor antagonist Treatment of PAH to improve exercise capacity and delay clinical

worsening

Macitentan Oral Endothelin receptor antagonist Treatment of PAH to improve a composite endpoint of delay of clinical

worsening

Sildenafil Oral or IV PDE5 inhibitor Treatment of PAH to improve exercise capacity and delay clinical

worsening

Tadalafil Oral PDE5 inhibitor Treatment of PAH to improve exercise ability

Riociguat Oral Soluble guanylyl cyclase stimulator Treatment of PAH to improve exercise ability

Abbreviations: FDA, U.S. Food and Drug Administration; IV, intravenous; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; PDE5,

phosphodiesterase-5; SC, subcutaneous.

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Section 1 Diagnosis of Respiratory

Disorders

Disorders of the Respiratory System PART 7

284 Approach to the Patient

with Disease of the

Respiratory System

Bruce D. Levy

The majority of diseases of the respiratory system present with cough

and/or dyspnea and fall into one of three major categories: (1) obstructive; (2) restrictive; and (3) vascular diseases. Obstructive pathophysiology is most common and primarily results from airway diseases,

such as asthma, chronic obstructive pulmonary disease (COPD),

bronchiectasis, and bronchiolitis. Diseases resulting in restrictive

pathophysiology include parenchymal lung diseases, abnormalities

of the chest wall and pleura, and neuromuscular disease. Pulmonary

embolism, pulmonary hypertension, and pulmonary venoocclusive

disease are examples of disorders of the pulmonary vasculature.

Although many specific diseases fall into these major categories, both

infective and neoplastic processes can affect the respiratory system and

result in myriad pathologic findings, including those listed in the three

categories above (Table 284-1).

Disorders can also be grouped according to gas exchange abnormalities, including hypoxemia, hypercarbia, or combined impairment;

however, many respiratory disorders do not manifest as gas exchange

abnormalities.

As with the evaluation of most patients, the approach to a patient

with a respiratory system disorder begins with a thorough history

and a focused physical examination. Many patients will subsequently

undergo pulmonary function testing, chest imaging, blood and sputum

analysis, a variety of serologic or microbiologic studies, and diagnostic

procedures, such as bronchoscopy. This stepwise approach is discussed

in detail below.

■ HISTORY

Dyspnea and Cough The cardinal symptoms of respiratory disease are dyspnea and cough (Chaps. 37 and 38). Dyspnea has many

causes, some of which are not predominantly due to lung pathology.

The words a patient uses to describe shortness of breath can suggest

certain etiologies for dyspnea. Patients with obstructive lung disease

often complain of “chest tightness” or “inability to get a deep breath,”

whereas patients with congestive heart failure more commonly report

“air hunger” or a sense of suffocation.

The tempo of onset and the duration of a patient’s dyspnea are

likewise helpful in determining the etiology. Acute shortness of breath

is usually associated with sudden physiologic changes, such as acute

airway narrowing (e.g., laryngeal edema, bronchospasm, or mucus

plugging), acute hypoxemia (e.g., pulmonary edema, pneumonia, or

pulmonary embolism), or sudden changes in the work of breathing

(e.g., pneumothorax). Patients with COPD and idiopathic pulmonary

fibrosis (IPF) experience a gradual progression of dyspnea on exertion,

punctuated by acute exacerbations of shortness of breath. In contrast,

most asthmatics do not have daily symptoms, but experience intermittent episodes of dyspnea, cough, and chest tightness that are usually

associated with specific triggers, such as an upper respiratory tract

infection or exposure to allergens.

Specific questioning should focus on factors that incite dyspnea as

well as on any intervention that helps resolve the patient’s shortness of

breath. Asthma is commonly exacerbated by specific triggers, although

this can also be true of COPD. Many patients with lung disease report

dyspnea on exertion. Determining the degree of activity that results in

shortness of breath gives the clinician a gauge of the patient’s degree of

disability. Many patients adapt their level of activity to accommodate

progressive limitation. For this reason, it is important, particularly in

older patients, to delineate the activities in which they engage and how

these activities have changed over time. Dyspnea on exertion is often

an early symptom of underlying lung or heart disease and warrants a

thorough evaluation.

For cough, the clinician should inquire about the duration of the

cough, whether or not it is associated with sputum production, and any

specific triggers that induce it. Acute cough productive of phlegm is

often a symptom of infection of the respiratory system, including processes affecting the upper airway (e.g., sinusitis, tracheitis), the lower

airways (e.g., bronchitis, bronchiectasis), and the lung parenchyma

(e.g., pneumonia). Both the quantity and quality of the sputum,

including whether it is blood-streaked or frankly bloody, should be

determined. Hemoptysis warrants urgent evaluation as delineated in

Chap. 39.

Chronic cough (defined as that persisting for >8 weeks) is commonly

associated with obstructive lung diseases, particularly asthma, COPD,

and chronic bronchiectasis, as well as “nonrespiratory” diseases, such

as gastroesophageal reflux and postnasal drip. Diffuse parenchymal

lung diseases, including IPF, frequently present as a persistent, nonproductive cough. All causes of cough are not respiratory in origin, and

assessment should encompass a broad differential, including cardiac

and gastrointestinal diseases as well as psychogenic causes.

Additional Symptoms Patients with respiratory disease may

report wheezing, which is suggestive of airways disease, particularly

asthma. Hemoptysis can be a symptom of a variety of lung diseases,

including infections of the respiratory tract, bronchogenic carcinoma,

and pulmonary embolism. In addition, chest pain or discomfort can be

respiratory in origin. As the lung parenchyma is not innervated with

TABLE 284-1 Categories of Respiratory Disease

CATEGORY EXAMPLES

Obstructive pathophysiology—

airway disease

Asthma

Chronic obstructive pulmonary disease

(COPD)

Bronchiectasis

Bronchiolitis

Restrictive pathophysiology—

parenchymal disease

Idiopathic pulmonary fibrosis (IPF)

Asbestosis

Desquamative interstitial pneumonitis (DIP)

Sarcoidosis

Restrictive pathophysiology—

neuromuscular weakness

Amyotrophic lateral sclerosis (ALS)

Guillain-Barré syndrome

Myasthenia gravis

Restrictive pathophysiology—

chest wall/pleural disease

Kyphoscoliosis

Ankylosing spondylitis

Chronic pleural effusions

Pulmonary vascular disease Pulmonary embolism

Pulmonary arterial hypertension (PAH)

Pulmonary venoocclusive disease

Vasculitis

Malignancy Bronchogenic carcinoma (non-small-cell and

small-cell lung cancer)

Metastatic disease

Infectious diseases Pneumonia

Bronchitis

Tracheitis

2132 PART 7 Disorders of the Respiratory System

pain fibers, pain in the chest from respiratory disorders usually results

from either diseases of the parietal pleura (e.g., pneumothorax) or

pulmonary vascular diseases (e.g., pulmonary hypertension). As many

diseases of the lung can result in strain on the right side of the heart,

patients may also present with symptoms of cor pulmonale, including

abdominal bloating or distention and pedal edema (Chap. 257).

Additional History A thorough social history is an essential

component of the evaluation of patients with respiratory disease. All

patients should be asked about current or previous cigarette smoking,

as this exposure is associated with many diseases of the respiratory

system, including COPD, bronchogenic lung cancer, and select parenchymal lung diseases (e.g., desquamative interstitial pneumonitis

and pulmonary Langerhans cell histiocytosis). For most of these disorders, increased cigarette smoke exposure (i.e., cigarette pack-years)

increases the risk of disease. E-cigarette or vaping use can lead to

acute or subacute lung injury (i.e., E-cigarette or vaping use-associated

lung injury [EVALI]). Secondhand smoke also increases risk for some

respiratory disorders, so patients should also be asked about parents,

spouses, or housemates who smoke. Possible inhalational exposures

at work (e.g., asbestos, silica) or home (e.g., wood smoke, excrement

from pet birds) should be explored (Chap. 289). Travel predisposes to

certain infections of the respiratory tract, most notably tuberculosis.

Potential exposure to fungi is increased in specific geographic regions

or climates (e.g., Histoplasma capsulatum), so exposures to these

regions should be determined.

Associated symptoms of fever and chills should raise the suspicion

of infective etiologies, both pulmonary and systemic. A comprehensive

review of systems may suggest rheumatologic or autoimmune disease

presenting with respiratory tract manifestations. Questions should

focus on joint pain or swelling, rashes, dry eyes, dry mouth, or constitutional symptoms. In addition, carcinomas from a variety of primary

sources commonly metastasize to the lung and cause respiratory symptoms. Finally, therapy for other conditions, including both irradiation

and medications, can result in diseases of the chest.

Physical Examination The clinician’s suspicion of respiratory

disease often begins with the patient’s vital signs. The respiratory rate

is informative, whether elevated (tachypnea) or depressed (hypopnea).

In addition, pulse oximetry should be measured, as many patients with

respiratory disease have hypoxemia, either at rest or with exertion.

The first step of the physical examination is inspection. Patients with

respiratory disease may be in distress and using accessory muscles of

respiration to breathe. Severe kyphoscoliosis can result in restrictive

pathophysiology. Inability to complete a sentence in conversation is

generally a sign of severe impairment and should result in an expedited

evaluation of the patient.

Percussion of the chest is used to establish diaphragm excursion

and lung size. In the setting of decreased breath sounds, percussion is

used to distinguish between pleural effusions (dull to percussion) and

pneumothorax (hyper-resonant note).

The role of palpation is limited in the respiratory examination. Palpation can demonstrate subcutaneous air in the setting of barotrauma.

It can also be used as an adjunctive assessment to determine whether

an area of decreased breath sounds is due to consolidation (increased

tactile fremitus) or a pleural effusion (decreased tactile fremitus). To

detect unilateral disorders of ventilation, the symmetry and degree

of chest wall expansion can be assessed during a deep inspiration by

placing one’s thumbs together at the midline over the lower posterior

chest while grasping the lateral rib cage.

The majority of the manifestations of respiratory disease present as

abnormalities of auscultation. Wheezes are a manifestation of airway

obstruction. While most commonly a sign of asthma, peribronchial

edema in the setting of congestive heart failure can also result in diffuse wheezes, as can any other process that causes narrowing of small

airways. Wheezes can be polyphonic, involving multiple different size

airways (e.g., asthma), or monophonic, involving one size airway (e.g.,

bronchogenic carcinoma). For these reasons, clinicians must take care

not to attribute all wheezing to asthma.

Rhonchi are a manifestation of obstruction of medium-sized airways, most often with secretions. In the acute setting, this manifestation may be a sign of viral or bacterial bronchitis. Chronic rhonchi

suggest bronchiectasis or COPD. In contrast to expiratory wheezes and

rhonchi, stridor is a high-pitched, focal inspiratory wheeze, usually

heard over the neck as a manifestation of upper airway obstruction.

Crackles, or rales, are commonly a sign of alveolar disease. Processes that fill the alveoli with fluid may result in crackles, including

pulmonary edema and pneumonia. Crackles in pulmonary edema

are generally more prominent at the bases. Interestingly, diseases that

result in fibrosis of the interstitium (e.g., IPF) also result in crackles that

sound like Velcro being ripped apart. Although some clinicians make

a distinction between “wet” and “dry” crackles, this distinction has not

been shown to be a reliable way to differentiate among etiologies of

respiratory disease.

One way to help distinguish between crackles associated with alveolar fluid and those associated with interstitial fibrosis is to assess for

egophony. Egophony is the auscultation of the sound “AH” instead of

“EEE” when a patient phonates “EEE.” This change in note is due to

abnormal sound transmission through consolidated parenchyma and

is present in pneumonia but not in IPF. Similarly, areas of alveolar

filling have increased whispered pectoriloquy as well as transmission

of larger-airway sounds (i.e., bronchial breath sounds in a lung zone

where vesicular breath sounds are expected).

The lack or diminution of breath sounds can also help determine the

etiology of respiratory disease. Patients with emphysema often have a

quiet chest with diffusely decreased breath sounds. A pneumothorax

or pleural effusion may present with an area of absent breath sounds.

Other Systems Pedal edema, if symmetric, may suggest cor pulmonale; if asymmetric, it may be due to deep venous thrombosis and

associated pulmonary embolism. Jugular venous distention may also

be a sign of volume overload associated with right heart failure. Pulsus

paradoxus is an ominous sign in a patient with obstructive lung disease, as it is associated with significant negative intrathoracic (pleural)

pressures required for ventilation and impending respiratory failure.

As stated earlier, rheumatologic disease may manifest primarily as

lung disease. Owing to this association, particular attention should be

paid to joint and skin examination. Clubbing can be found in many

lung diseases, including cystic fibrosis, IPF, and lung cancer. Cyanosis

is seen in hypoxemic respiratory disorders that result in >5 g of deoxygenated hemoglobin/dL.

■ DIAGNOSTIC EVALUATION

The sequence of studies is dictated by the clinician’s differential

diagnosis, as determined by the history and physical examination.

Acute respiratory symptoms are often evaluated with multiple tests

performed at the same time in order to diagnose any life-threatening

diseases rapidly (e.g., pulmonary embolism or multilobar pneumonia).

In contrast, chronic dyspnea and cough can be evaluated in a more

protracted, stepwise fashion.

Pulmonary Function Testing (See also Chap. 286) The

initial pulmonary function test obtained is spirometry. This study is

an effort-dependent test used to assess for obstructive pathophysiology as seen in asthma, COPD, and bronchiectasis (Table 284-1). A

diminished-forced expiratory volume in 1 second (FEV1

)/forced

vital capacity (FVC) (often defined as <70%) is diagnostic of airflow

obstruction. In addition to measuring FEV1

 and FVC, the clinician

should examine the flow-volume loop (which is less effort-dependent).

A plateau of the inspiratory and expiratory curves suggests large-airway

obstruction in extrathoracic and intrathoracic locations, respectively.

Spirometry with symmetric decreases in FEV1

 and FVC warrants

further testing, including measurement of lung volumes and the diffusion capacity of the lung for carbon monoxide (DlCO). A total lung

capacity <80% of the patient’s predicted value defines restrictive pathophysiology. Restriction can result from parenchymal disease, neuromuscular weakness, or chest wall or pleural diseases (Table 284-1).

Restriction with impaired gas exchange, as indicated by a decreased

2133 Disturbances of Respiratory Function CHAPTER 285

The primary functions of the respiratory system—to oxygenate blood

and eliminate carbon dioxide—require virtual contact between blood

and fresh air, which facilitates diffusion of respiratory gases between

blood and gas. This process occurs in the lung alveoli, where blood

flowing through alveolar wall capillaries is separated from alveolar gas

by an extremely thin membrane of flattened endothelial and epithelial

cells, across which respiratory gases diffuse and equilibrate. Blood flow

through the lung is unidirectional via a continuous vascular path along

which venous blood absorbs oxygen from and loses CO2

 to inspired

gas. The path for airflow, in contrast, reaches a dead end at the alveolar

walls; thus, the alveolar space must be ventilated tidally, with inflow

of fresh gas and outflow of alveolar gas alternating periodically at the

respiratory rate (RR). To provide an enormous alveolar surface area

(typically 70 m2

) for blood-gas diffusion within the modest volume

of a thoracic cavity (typically 7 L), nature has distributed both blood

flow and ventilation among millions of tiny alveoli through multigenerational branching of both pulmonary arteries and bronchial airways.

Ideally, for the lung to be most efficient in exchanging gas, the fresh

gas ventilation of a given alveolus must be matched to its perfusion.

However, as a consequence of variations in tube lengths and calibers

along these pathways as well as the effects of gravity, tidal pressure

fluctuations, and anatomic constraints from the chest wall, the alveoli

vary in their relative ventilations and perfusions even in health.

For the respiratory system to succeed in oxygenating blood and

eliminating CO2

, it must be able to ventilate the lung tidally and

thus to freshen alveolar gas; it must provide for perfusion of the

individual alveolus in a manner proportional to its ventilation; and it

must allow adequate diffusion of respiratory gases between alveolar

gas and capillary blood. Furthermore, it must accommodate severalfold increases in the demand for oxygen uptake or CO2

 elimination

imposed by metabolic needs or acid-base derangement. Given these

multiple requirements for normal operation, it is not surprising that

many diseases disturb respiratory function. This chapter considers

in some detail the physiologic determinants of lung ventilation and

perfusion, elucidates how the matching distributions of these processes

and rapid gas diffusion allow normal gas exchange, and discusses how

common diseases derange these normal functions, thereby impairing

gas exchange—or at least increasing the work required by the respiratory muscles or heart to maintain adequate respiratory function.

■ VENTILATION

It is useful to conceptualize the respiratory system as three independently functioning components: the lung, including its airways; the

neuromuscular system; and the chest wall, which includes everything

that is not lung or active neuromuscular system. Accordingly, the

mass of the respiratory muscles is part of the chest wall, while the

force these muscles generate is part of the neuromuscular system;

the abdomen (especially an obese abdomen) and the heart (especially

an enlarged heart) are, for these purposes, part of the chest wall. Each

of these three components has mechanical properties that relate to its

enclosed volume (or—in the case of the neuromuscular system—the

respiratory system volume at which it is operating) and to the rate of

change of its volume (i.e., flow). The work of breathing required of the

neuromuscular system is the sum of the work due to volume-related

mechanical properties and the work from flow-related mechanical

properties required to move air throughout the airways to create this

volume change.

Volume-Related Mechanical Properties—Statics Figure 285-1

shows the volume-related properties of each component of the respiratory system. Because of both surface tension at the air-liquid interface

285 Disturbances of

Respiratory Function

Edward T. Naureckas, Julian Solway

DlCO, suggests parenchymal lung disease. Additional testing, such as

measurements of maximal inspiratory and expiratory pressures, can

help diagnose neuromuscular weakness. Normal spirometry, normal

lung volumes, and a low DlCO should prompt further evaluation for

pulmonary vascular disease.

Arterial blood gas testing is often helpful in assessing respiratory

disease. Hypoxemia, while usually apparent with pulse oximetry, can

be further evaluated with the measurement of arterial PO2

 and the calculation of an alveolar gas and arterial blood oxygen tension difference

([A–a]DO2

). Patients with diseases that cause ventilation-perfusion

mismatch or shunt physiology have an increased (A–a)DO2

 at rest.

Arterial blood gas testing also allows the measurement of arterial Pco2

.

Hypercarbia can accompany disorders of ventilation, as seen in severe

airway obstruction (e.g., COPD) or progressive restrictive physiology.

Chest Imaging (See Chap. A12) Most patients with disease of

the respiratory system undergo imaging of the chest as part of the

initial evaluation. Clinicians should generally begin with ultrasound

of the chest or a plain chest radiograph, preferably posterior-anterior

and lateral films. Ultrasound is often readily available and can help

rapidly diagnose pneumothorax, pleural effusion, and consolidation

of lung parenchyma. Chest radiographs give additional detail and can

reveal findings including opacities of the parenchyma, blunting of the

costophrenic angles, mass lesions, and volume loss. Of note, many

diseases of the respiratory system, particularly those of the airways and

pulmonary vasculature, are associated with a normal chest radiograph.

CT scan of the chest can also be useful to delineate parenchymal

processes, pleural disease, masses or nodules, and large airways. If the

test includes administration of intravenous contrast, the pulmonary

vasculature can be assessed with particular utility for determination of

pulmonary emboli. Intravenous contrast also allows lymph nodes to

be examined in greater detail. When coupled with positron emission

tomography (PET), lesions of the chest can be assessed for metabolic

activity, helping differentiate between malignancy and scar.

■ FURTHER STUDIES

Depending on the clinician’s suspicion, a variety of other studies may

be done. Concern about large-airway lesions may warrant bronchoscopy. This procedure may also be used to sample the alveolar space

with bronchoalveolar lavage or to obtain nonsurgical lung biopsies.

Blood testing may include assessment for hypercoagulable states in the

setting of pulmonary vascular disease, serologic testing for infectious

or rheumatologic disease, or assessment of inflammatory markers or

leukocyte counts (e.g., eosinophils). Genetic testing is increasingly

used for heritable lung diseases such as cystic fibrosis. Sputum evaluation for malignant cells or microorganisms may be appropriate. An

echocardiogram to assess right- and left-sided heart function is often

obtained. Finally, at times, a surgical lung biopsy is needed to diagnose

certain diseases of the respiratory system. All of these studies will be

guided by the preceding history, physical examination, pulmonary

function testing, and chest imaging.

Acknowledgement

Patricia Kritek contributed to this chapter in the 20th edition, and some

material from that chapter has been retained here.

■ FURTHER READING

Achilleos A: Evidence-based evaluation and management of chronic

cough. Med Clin North Am 100:1033, 2016.

Bohadana A et al: Fundamentals of lung auscultation. N Engl J Med

370:744, 2014.

Koenig SJ et al: Thoracic ultrasonography for the pulmonary specialist. Chest 140:1332, 2011.

Parshall MB et al: An official American Thoracic Society statement:

Update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 185:435, 2012.

Pellegrino R et al: Interpretive strategies for lung function tests. Eur

Respir J 26:948, 2005.

2134 PART 7 Disorders of the Respiratory System

between alveolar wall lining fluid and alveolar gas and elastic recoil of

the lung tissue itself, the lung requires a positive transmural pressure

difference between alveolar gas and its pleural surface to stay inflated;

this difference is called the elastic recoil pressure of the lung, and it

increases with lung volume. The lung becomes rather stiff at high volumes, so that relatively small volume changes are accompanied by large

changes in transpulmonary pressure; in contrast, the lung is compliant

at lower volumes, including those at which tidal breathing normally

occurs. At zero inflation pressure, even normal lungs retain some air

in the alveoli. Because the small peripheral airways are tethered open

by outward radial pull from inflated lung parenchyma attached to

adventitia, as the lung deflates during exhalation, those small airways

are pulled open progressively less, and eventually close, trapping some

gas in the alveoli. This effect can be exaggerated with age and especially

with obstructive airway diseases, resulting in gas trapping at quite large

lung volumes.

The elastic behavior of the passive chest wall (i.e., in the absence

of neuromuscular activation) differs markedly from that of the lung.

Whereas the lung tends toward full deflation with no distending (transmural) pressure, the chest wall encloses a large volume when pleural

pressure equals body surface (atmospheric) pressure. Furthermore, the

chest wall is compliant at high enclosed volumes, readily expanding

even further in response to increases in transmural pressure. The chest

wall also remains compliant at small negative transmural pressures

(i.e., when pleural pressure falls slightly below atmospheric pressure),

but as the volume enclosed by the chest wall becomes quite small in

response to large negative transmural pressures, the passive chest wall

becomes stiff due to squeezing together of ribs and intercostal muscles,

diaphragm stretch, displacement of abdominal contents, and straining

of ligaments and bony articulations. Under normal circumstances, the

lung and the passive chest wall enclose essentially the same volume,

the only difference being the volumes of the pleural fluid and of the

lung parenchyma (normally both quite small in the absence of disease). For this reason and because the lung and chest wall function in

mechanical series, the pressure required to displace the passive respiratory system (lungs plus chest wall) at any volume is simply the sum

of the elastic recoil pressure of the lungs and the transmural pressure

across the chest wall. When plotted against respiratory system volume,

this relationship assumes a sigmoid shape, exhibiting stiffness at high

lung volumes (imparted by the lung), stiffness at low lung volumes

(imparted by the chest wall or sometimes by airway closure), and compliance in the middle range of lung volumes where normal tidal breathing occurs. In addition, a passive resting point of the respiratory system

is attained when alveolar gas pressure equals body surface pressure

(i.e., when the transrespiratory system pressure is zero). At this volume

(called the functional residual capacity [FRC]), the outward recoil of

the chest wall is balanced exactly by the inward recoil of the lung.

As these recoils are transmitted through the pleural fluid, the lung is

pulled both outward and inward simultaneously at FRC, and thus, its

pressure falls below atmospheric pressure (typically, −5 cmH2

O).

–60 –40 –20 0

Passive

respiratory system

Chest wall

–80 20 40 60 80

TLC

FRC

Lungs

RV

Pressure (cmH2O)

Volume

Expiratory muscles

Inspiratory muscles

FIGURE 285-1 Pressure-volume curves of the isolated lung, isolated chest wall, combined respiratory system, inspiratory muscles, and expiratory muscles. FRC, functional

residual capacity; RV, residual volume; TLC, total lung capacity.

Tidal

volume

Total

lung

capacity

Functional

residual

capacity Residual

volume

Vital

capacity

Expiratory

reserve

volume

FIGURE 285-2 Spirogram demonstrating a slow vital capacity maneuver and various

lung volumes.

The normal passive respiratory system would equilibrate at the FRC

and remain there were it not for the actions of the respiratory muscles.

The inspiratory muscles act on the chest wall to generate the equivalent

of positive pressure across the lungs and passive chest wall, while the

expiratory muscles generate the equivalent of negative transrespiratory

pressure. The maximal pressures these sets of muscles can generate

vary with the lung volume at which they operate. This variation is

due to length-tension relationships in striated muscle sarcomeres and

to changes in mechanical advantage as the angles of insertion change

with lung volume (Fig. 285-1). Nonetheless, under normal conditions,

the respiratory muscles are substantially “overpowered” for their roles

and generate more than adequate force to drive the respiratory system

to its stiffness extremes, as determined by the lung (total lung capacity

[TLC]) or by chest wall or airway closure (residual volume [RV]); the

airway closure always prevents the adult lung from emptying completely under normal circumstances. The excursion between full and

minimal lung inflation is called vital capacity (VC; Fig. 285-2) and

is readily seen to be the difference between volumes at two unrelated

stiffness extremes—one determined by the lung (TLC) and the other by

the chest wall or airways (RV). Thus, although VC is easy to measure

(see below), it provides little information about the intrinsic properties

of the respiratory system. As will become clear, it is much more useful

for the clinician to consider TLC and RV individually.

Flow-Related Mechanical Properties—Dynamics The

passive chest wall and active neuromuscular system both exhibit

mechanical behaviors related to the rate of change of volume, but

these behaviors become quantitatively important only at markedly

supraphysiologic breathing frequencies (e.g., during high-frequency

mechanical ventilation), and thus will not be addressed here. In contrast, the dynamic airflow properties of the lung substantially affect its

ability to ventilate and contribute importantly to the work of breathing,

and these properties are often deranged by disease. Understanding

dynamic airflow properties is, therefore, worthwhile.

2135 Disturbances of Respiratory Function CHAPTER 285

As with the flow of any fluid (gas or liquid) in any tube, maintenance

of airflow within the pulmonary airways requires a pressure gradient that

falls along the direction of flow, the magnitude of which is determined

by the flow rate and the frictional resistance to flow. During quiet tidal

breathing, the pressure gradients driving inspiratory or expiratory flow

are small owing to the very low frictional resistance of normal pulmonary

airways (Raw, normally <2 cmH2

O/L/s). However, during rapid exhalation,

another phenomenon reduces flow below that which would have been

expected if frictional resistance were the only impediment to flow. This

phenomenon is called dynamic airflow limitation, and it occurs because

the bronchial airways through which air is exhaled are collapsible rather

than rigid (Fig. 285-3). An important anatomic feature of the structure of

the pulmonary airways is their tree like branching. While the individual

airways in each successive generation, from most proximal (trachea) to

most distal (respiratory bronchioles), are smaller than those of the parent

generation, their number increases exponentially such that the summed

cross-sectional area of the airways becomes very large toward the lung

periphery. Because flow (volume/time) is constant along the airway

tree, the velocity of airflow (flow/summed cross-sectional area) is much

greater in the central airways than in the peripheral airways. During

exhalation, gas leaving the alveoli must, therefore, gain velocity as it proceeds toward the mouth. The energy required for this “convective” acceleration is drawn from the component of gas energy manifested as its local

pressure, which reduces intraluminal gas pressure, airway transmural

pressure, airway size (Fig. 285-3), and flow. This phenomenon is the

Bernoulli effect, the same effect that keeps an airplane airborne, generating a lifting force by decreasing pressure above the curved upper

surface of the wing due to acceleration of air flowing over the wing. If an

individual attempts to exhale more forcefully, the local velocity increases

further and reduces airway size further, resulting in no net increase in

flow. Under these circumstances, flow has reached its maximum possible

value, or its flow limit. Lungs normally exhibit such dynamic airflow

limitation. This limitation can be assessed by spirometry, in which an

individual inhales fully to TLC and then forcibly exhales to RV. One

useful spirometric measure is the volume of air exhaled during the forced

expiratory volume in 1 s (FEV1

), as discussed later. Maximal expiratory

flow at any lung volume is determined by gas density, airway crosssection and distensibility, elastic recoil pressure of the lung, and frictional

pressure loss to the flow-limiting airway site. Under normal conditions,

maximal expiratory flow falls with lung volume (Fig. 285-4), primarily because of the dependence of lung recoil pressure on lung volume

(Fig. 285-1). In pulmonary fibrosis, lung recoil pressure is increased at

any lung volume, and thus the maximal expiratory flow is elevated when

considered in relation to lung volume. Conversely, in emphysema, lung

recoil pressure is reduced; this reduction is a principal mechanism by

which maximal expiratory flows fall. Diseases that narrow the airway

lumen at any transmural pressure (e.g., asthma or chronic bronchitis)

or that cause excessive airway collapsibility (e.g., tracheomalacia) also

reduce maximal expiratory flow.

The Bernoulli effect also applies during inspiration, but the more

negative pleural pressures during inspiration lower the pressure outside

of the airways, thereby increasing transmural pressure and promoting

airway expansion. Thus, inspiratory airflow limitation seldom occurs

due to diffuse pulmonary airway disease. Conversely, extrathoracic

airway narrowing (e.g., due to a tracheal adenoma or post-tracheostomy

stricture) can lead to inspiratory airflow limitation (Fig. 285-4).

The Work of Breathing In health, the elastic (volume changerelated) and dynamic (flow-related) loads that must be overcome to ventilate the lungs at rest are small, and the work required of the respiratory

muscles is minimal. However, the work of breathing can increase considerably due to a metabolic requirement for substantially increased ventilation, an abnormally increased mechanical load, or both. As discussed

below, the rate of ventilation is primarily set by the need to eliminate

 _ Transmural pressure +

Luminal area

FIGURE 285-3 Luminal area versus transmural pressure relationship. Transmural

pressure represents the pressure difference across the airway wall from inside to

outside.

Flow

TLC

RV

Expiratory Inspiratory

Expiratory Inspiratory

Expiratory Inspiratory

A B C

Volume

Flow

TLC

RV Volume

Flow

TLC

RV Volume

Flow

TLC

RV

Expiratory Inspiratory

D

Flow

TLC

RV

Expiratory Inspiratory

E

FIGURE 285-4 Flow-volume loops. A. Normal. B. Airflow obstruction. C. Fixed central airway obstruction (either above or below the thoracic inlet). D. Variable upper airway

obstruction (above the thoracic inlet) E. Variable lower airway obstruction (below the thoracic inlet). RV, residual volume; TLC, total lung capacity.

2136 PART 7 Disorders of the Respiratory System

carbon dioxide, and thus, ventilation increases during exercise (sometimes by >20-fold) and during metabolic acidosis as a compensatory

response. Naturally, the work rate required to overcome the elasticity of

the respiratory system increases with both the depth and the frequency

of tidal breaths, while the work required to overcome the dynamic load

increases with total ventilation. A modest increase of ventilation is most

efficiently achieved by increasing tidal volume but not RR, which is the

normal ventilatory response to lower-level exercise. At higher levels of

exercise, deep breathing persists, but RR also increases.

The work of breathing also increases when disease reduces the compliance of the respiratory system or increases the resistance to airflow.

The former occurs commonly in diseases of the lung parenchyma

(interstitial processes or fibrosis, alveolar filling diseases such as pulmonary edema or pneumonia, or substantial lung resection), and the

latter occurs in obstructive airway diseases such as asthma, chronic

bronchitis, emphysema, and cystic fibrosis. Furthermore, severe airflow obstruction can functionally reduce the compliance of the respiratory system by leading to dynamic hyperinflation. In this scenario,

expiratory flows slowed by the obstructive airways disease may be

insufficient to allow complete exhalation during the expiratory phase

of tidal breathing; as a result, the “functional residual capacity (FRC)”

from which the next breath is inhaled is greater than the static FRC.

With repetition of incomplete exhalations of each tidal breath, the

operating FRC becomes dynamically elevated, sometimes to a level that

approaches TLC. At these high lung volumes, the respiratory system is

much less compliant than at normal breathing volumes, and thus, the

elastic work of each tidal breath is also increased. The dynamic pulmonary hyperinflation that accompanies severe airflow obstruction causes

patients to sense difficulty in inhaling—even though the root cause of

this pathophysiologic abnormality is expiratory airflow obstruction.

Adequacy of Ventilation As noted above, the respiratory control

system that sets the rate of ventilation responds to chemical signals,

including arterial CO2

 and oxygen tensions and blood pH, and to

volitional needs, such as the need to inhale deeply before playing a

long phrase on the trumpet. Disturbances in ventilation are discussed

in Chap. 296. The focus of this chapter is on the relationship between

ventilation of the lung and CO2

 elimination.

At the end of each tidal exhalation, the conducting airways are filled

with alveolar gas that did not reach the mouth when expiratory flow

stopped. During the ensuing inhalation, fresh gas immediately enters the

airway tree at the mouth, but the gas first entering the alveoli at the start

of inhalation is that same alveolar gas in the conducting airways that had

just left the alveoli. Accordingly, fresh gas does not enter the alveoli until

the volume of the conducting airways has been inspired. This volume is

called the anatomic dead space (VD). Quiet breathing with tidal volumes

smaller than the anatomic dead space introduces no fresh gas into the

alveoli at all; only that part of the inspired tidal volume (VT) that is

greater than the VD introduces fresh gas into the alveoli. The dead space

can be further increased functionally if some of the inspired tidal volume

is delivered to a part of the lung that receives no pulmonary blood flow

and thus cannot contribute to gas exchange (e.g., the portion of the lung

distal to a large pulmonary embolus). In this situation, exhaled minute

ventilation (V⋅

E

= VT × RR) includes a component of dead space ventilation (V⋅

D= VD × RR) and a component of fresh gas alveolar ventilation

(V⋅

A= [VT − VD] × RR). CO2

 elimination from the alveoli is equal to V⋅

A

times the difference in CO2

 fraction between inspired air (essentially

zero) and alveolar gas (typically ~5.6% after correction for humidification of inspired air, corresponding to 40 mmHg). In the steady state, the

alveolar fraction of CO2

 is equal to metabolic CO2

 production divided

by alveolar ventilation. Because, as discussed below, alveolar and arterial

CO2

 tensions are equal, and because the respiratory controller normally

strives to maintain arterial Pco2

 (Paco2

) at ~40 mmHg, the adequacy of

alveolar ventilation is reflected in Paco2

 If the Paco2

 falls much below

40 mmHg, alveolar hyperventilation is present; if the Paco2

 exceeds

40 mmHg, alveolar hypoventilation is present. Ventilatory failure is characterized by extreme alveolar hypoventilation.

As a consequence of oxygen uptake of alveolar gas into capillary

blood, alveolar oxygen tension falls below that of inspired gas. The rate

of oxygen uptake (determined by the body’s metabolic oxygen consumption) is related to the average rate of metabolic CO2

 production,

and their ratio—the “respiratory quotient” (R = V⋅

co2

/V⋅

o2

)—depends

largely on the fuel being metabolized. For a typical American diet, R is

usually around 0.85. Together, these phenomena allow the estimation

of alveolar oxygen tension, according to the following relationship,

known as the alveolar gas equation:

Pao2

 = Fio2 × (Pbar - Ph2

o) - Paco2

/R

The alveolar gas equation also highlights the influences of inspired

oxygen fraction Fio2

 barometric pressure (Pbar), and vapor pressure of

water (Ph2

o = 47 mmHg at 37°C) in addition to alveolar ventilation

(which sets Paco2

) in determining Pao2

. An implication of the alveolar

gas equation is that severe arterial hypoxemia rarely occurs as a pure

consequence of alveolar hypoventilation at sea level while an individual

is breathing air. The potential for alveolar hypoventilation to induce

severe hypoxemia with otherwise normal lungs increases as Pbar falls

with increasing altitude.

■ GAS EXCHANGE

Diffusion For oxygen to be delivered to the peripheral tissues, it

must pass from alveolar gas into alveolar capillary blood by diffusing

through alveolar membrane. The aggregate alveolar membrane is

highly optimized for this process, with a very large surface area and

minimal thickness. Diffusion through the alveolar membrane is so

efficient in the human lung that in most circumstances hemoglobin of

a red blood cell becomes fully oxygen saturated by the time the cell has

traveled just one-third the length of the alveolar capillary. Thus, the

uptake of alveolar oxygen is ordinarily limited by the amount of blood

transiting the alveolar capillaries rather than by the rapidity with which

oxygen can diffuse across the membrane; consequently, oxygen uptake

from the lung is said to be “perfusion limited” rather than diffusion

limited. CO2

 also equilibrates rapidly across the alveolar membrane.

Therefore, the oxygen and CO2

 tensions in capillary blood leaving a

normal alveolus are essentially equal to those in alveolar gas. Only

in rare circumstances (e.g., at high altitude or in high-performance

athletes exerting maximal effort) is oxygen uptake from normal lungs

diffusion limited. Diffusion limitation can also occur in interstitial lung

disease if substantially thickened alveolar walls remain perfused.

Ventilation/Perfusion Heterogeneity As noted above, for gas

exchange to be most efficient, ventilation to each individual alveolus

(among the millions of alveoli) should match perfusion to its accompanying capillaries. Because of the differential effects of gravity on lung

mechanics and blood flow throughout the lung and because of differences in airway and vascular architecture among various respiratory

paths, there is minor ventilation/perfusion heterogeneity even in the

normal lung; however, V⋅

/Q⋅

 heterogeneity can be particularly marked

in disease. Two extreme examples are (1) ventilation of unperfused

lung distal to a pulmonary embolus, in which ventilation of the physiologic dead space is “wasted” in the sense that it does not contribute

to gas exchange; and (2) perfusion of nonventilated lung (a “shunt”),

which allows venous blood to pass through the lung unaltered. When

mixed with fully oxygenated blood leaving other well-ventilated lung

units, shunted venous blood disproportionately lowers the mixed

arterial Pao2

 as a result of the nonlinear oxygen content versus PO2

relationship of hemoglobin (Fig. 285-5). Furthermore, the resulting

arterial hypoxemia is refractory to supplemental inspired oxygen. The

reason is that (1) raising the inspired Fio2

 has no effect on alveolar gas

tensions in nonventilated alveoli and (2) while raising inspired Fio2

increases Paco2

 in ventilated alveoli, the oxygen content of blood exiting ventilated units increases only slightly, as hemoglobin will already

have been nearly fully saturated and the solubility of oxygen in plasma

is quite small.

A more common occurrence than the two extreme examples given

above is a widening of the distribution of ventilation/perfusion ratios;

such V⋅

/Q⋅

 heterogeneity is a common consequence of lung disease.

In this circumstance, perfusion of relatively underventilated alveoli

2137 Disturbances of Respiratory Function CHAPTER 285

99

mmHg

40

mmHg 40 mmHg

(75%)

40 mmHg

(75%)

55 mmHg

(87.5%)

40 mmHg

(75%)

99 mmHg

(100%)

FIO2 = 0.21

650

mmHg

40

mmHg

40 mmHg

(75%)

40 mmHg

(75%)

56 mmHg

(88%)

40 mmHg

(75%)

650 mmHg

(100%)

FIO2 = 1 Shunt

99

mmHg

40

mmHg 40 mmHg

(75%)

45 mmHg

(79%)

58 mmHg

(89.5%)

40 mmHg

(75%)

99 mmHg

(100%)

FIO2 = 0.21

650

mmHg

200

mmHg 40 mmHg

(75%)

200 mmHg

(100%)

350 mmHg

(100%)

40 mmHg

(75%)

650 mmHg

(100%)

FIO2 = 1 V/Q

Heterogeneity

. .

FIGURE 285-5 Influence of air versus oxygen breathing on mixed arterial oxygenation in shunt and ventilation/perfusion heterogeneity. Partial pressure of oxygen (mmHg)

and oxygen saturations are shown for mixed venous blood, for end capillary blood (normal vs affected alveoli), and for mixed arterial blood. Fio2

 fraction of inspired oxygen;

V

⋅

/Q⋅

, ventilation/perfusion.

results in the incomplete oxygenation of exiting blood. When mixed

with well-oxygenated blood leaving higher V⋅

/Q⋅

 regions, this partially

reoxygenated blood disproportionately lowers arterial Pao2

, although

to a lesser extent than does a similar perfusion fraction of blood leaving

regions of pure shunt. In addition, in contrast to shunt regions, inhalation of supplemental oxygen raises the Pao2

 even in relatively underventilated low V⋅

/Q⋅

 regions, and so the arterial hypoxemia induced by

V

⋅

/Q⋅

 heterogeneity is typically responsive to oxygen therapy (Fig. 285-5).

In sum, arterial hypoxemia can be caused by substantial reduction of

inspired oxygen tension, severe alveolar hypoventilation, perfusion of relatively underventilated (low V⋅

/Q⋅

) or completely unventilated (shunt) lung

regions, and, in very unusual circumstances, limitation of gas diffusion.

■ PATHOPHYSIOLOGY

Although many diseases injure the respiratory system, this system

responds to injury in relatively few ways. For this reason, the pattern of

physiologic abnormalities may or may not provide sufficient information by which to discriminate among conditions.

Figure 285-6 lists abnormalities in pulmonary function testing that

are typically found in a number of common respiratory disorders and

highlights the simultaneous occurrence of multiple physiologic abnormalities. The coexistence of some of these respiratory disorders results in

more complex superposition of these abnormalities. Methods to measure

respiratory system function clinically are described later in this chapter.

Ventilatory Restriction due to Increased Elastic Recoil—

Example: Idiopathic Pulmonary Fibrosis Idiopathic pulmonary

fibrosis raises lung recoil at all lung volumes, thereby lowering TLC,

FRC, and RV as well as forced vital capacity (FVC). Maximal expiratory

flows are also reduced from normal values but are elevated when

considered in relation to lung volumes. Increased flow occurs both

because the increased lung recoil drives greater maximal flow at any

lung volume and because airway diameters are relatively increased due

to greater radially outward traction exerted on bronchi by the stiff lung

parenchyma. For the same reason, airway resistance is also normal.

Destruction of the pulmonary capillaries by the fibrotic process results

in a marked reduction in diffusing capacity (see below). Oxygenation is

often severely reduced by persistent perfusion of alveolar units that are

relatively underventilated due to fibrosis of nearby (and mechanically

linked) lung due to those alveolar units already being stretched to their

maximum volume with little further increase in volume with inspiration. The flow-volume loop (see below) looks like a miniature version

of a normal loop but is shifted toward lower absolute lung volumes

and displays maximal expiratory flows that are increased for any given

volume over the normal tracing.

Ventilatory Restriction due to Chest Wall Abnormality—

Example: Moderate Obesity As the size of the average American

continues to increase, this pattern may become the most common of

pulmonary function abnormalities. In moderate obesity, the outward

recoil of the chest wall is blunted by the weight of chest wall fat and the

space occupied by intraabdominal fat. In this situation, preserved inward

recoil of the lung overbalances the reduced outward recoil of the chest

wall, and FRC falls. Because respiratory muscle strength and lung recoil

remain normal, TLC is typically unchanged (although it may fall in massive obesity) and RV is normal (but may be reduced in massive obesity).

Mild hypoxemia may be present due to perfusion of alveolar units that

are poorly ventilated because of airway closure in dependent portions of

2138 PART 7 Disorders of the Respiratory System

the lung during breathing near the reduced FRC. Flows remain normal,

as does the diffusion capacity of the lung for carbon monoxide Dlco

unless obstructive sleep apnea (which often accompanies obesity) and

associated chronic intermittent hypoxemia have induced pulmonary

arterial hypertension, in which case Dlco may be low.

Ventilatory Restriction due to Reduced Muscle Strength—

Example: Myasthenia Gravis In this circumstance, FRC remains

normal, as both lung recoil and passive chest wall recoil are normal.

However, TLC is low and RV is elevated because respiratory muscle

strength is insufficient to push the passive respiratory system fully

toward either volume extreme. Caught between the low TLC and the

elevated RV, FVC and FEV1

 are reduced as “innocent bystanders.” As

airway size and lung vasculature are unaffected, both Raw and Dlco

are normal. Oxygenation is normal unless weakness becomes so severe

that the patient has insufficient strength to reopen collapsed alveoli

during sighs, with resulting atelectasis.

Airflow Obstruction due to Decreased Airway Diameter—

Example: Acute Asthma During an episode of acute asthma,

luminal narrowing due to smooth muscle constriction as well as

inflammation and thickening within the small- and medium-sized

bronchi raise frictional resistance and reduce airflow. “Scooping” of the

flow-volume loop is caused by reduction of airflow, especially at lower

lung volumes. Often, airflow obstruction can be reversed by inhalation

of β2

-adrenergic agonists acutely or by treatment with inhaled steroids

chronically. TLC usually remains normal (although elevated TLC is

sometimes seen in long-standing asthma), but FRC may be dynamically elevated. RV is often increased due to exaggerated airway closure

at low lung volumes, and this elevation of RV reduces FVC. Because

central airways are narrowed, Raw is usually elevated. Mild arterial

hypoxemia is often present due to perfusion of relatively underventilated alveoli distal to obstructed airways (and is responsive to oxygen

supplementation), but Dlco is normal or mildly elevated.

Airflow Obstruction due to Decreased Elastic Recoil—

Example: Severe Emphysema Loss of lung elastic recoil in

severe emphysema results in pulmonary hyperinflation, of which

elevated TLC is the hallmark. FRC is more severely elevated due to

both loss of lung elastic recoil and dynamic hyperinflation—the same

phenomenon as auto-PEEP (auto–positive end-expiratory pressure),

which is the positive end-expiratory alveolar pressure that occurs

when a new breath is initiated before the lung volume is allowed to

return to FRC. RV is very severely elevated because of airway closure

and because exhalation toward RV may take so long that RV cannot be

reached before the patient must inhale again. Both FVC and FEV1

 are

markedly decreased, the former because of the severe elevation of RV

and the latter because loss of lung elastic recoil reduces the pressure

driving maximal expiratory flow and also reduces tethering open of

small intrapulmonary airways. The flow-volume loop demonstrates

marked scooping, with an initial transient spike of flow attributable

largely to expulsion of air from collapsing central airways at the onset

of forced exhalation. Otherwise, the central airways remain relatively

unaffected, so Raw is normal in “pure” emphysema. Loss of alveolar

surface and capillaries in the alveolar walls reduces DLco; however,

because poorly ventilated emphysematous acini are also poorly perfused (due to loss of their capillaries), arterial hypoxemia usually is not

seen at rest until emphysema becomes very severe. However, during

exercise, Pao2

 may fall precipitously if extensive destruction of the

pulmonary vasculature prevents a sufficient increase in cardiac output and mixed venous oxygen content falls substantially. Under these

circumstances, any venous admixture through low V⋅

/Q⋅

 units has a

particularly marked effect in lowering mixed arterial oxygen tension.

■ FUNCTIONAL MEASUREMENTS

Measurement of Ventilatory Function • LUNG VOLUMES

Figure 285-2 demonstrates a spirometry tracing in which the volume

of air entering or exiting the lung is plotted over time. In a slow vital

capacity maneuver, the patient inhales from FRC, fully inflating the

lungs to TLC, and then exhales slowly to RV; VC, the difference

between TLC and RV, represents the maximal excursion of the respiratory system. Spirometry discloses relative volume changes during

these maneuvers but cannot reveal the absolute volumes at which

they occur. To determine absolute lung volumes, two approaches are

commonly used: inert gas dilution and body plethysmography. In the

former, a known amount of a nonabsorbable inert gas (usually helium

or neon) is inhaled in a single large breath or is rebreathed from a

closed circuit; the inert gas is diluted by the gas resident in the lung at

the time of inhalation, and its final concentration reveals the volume

TLC

FRC

RV

FVC

FEV1

Raw

DLCO

Restriction due to

increased lung

elastic recoil

(pulmonary

fibrosis)

60%

60%

60%

60%

75%

1.0

60%

Restriction due to

chest wall

abnormality

(moderate

obesity)

95%

65%

100%

92%

92%

1.0

95%

Restriction due to

respiratory muscle

weakness

(myasthenia

gravis)

75%

100%

120%

60%

60%

1.0

80%

Obstruction

due to airway

narrowing

(acute

asthma)

100%

104%

120%

90%

35% pre-b.d.

75% post-b.d.

2.5

120%

Obstruction due to

decreased

elastic recoil

(severe

emphysema)

130%

220%

310%

60%

35% pre-b.d.

38% post-b.d.

1.5

40%

Flow

Volume

Flow

Volume

Flow

Volume Flow

Volume

Flow

Volume

FIGURE 285-6 Common abnormalities of pulmonary function (see text). Pulmonary function values are expressed as a percentage of normal predicted values, except

for Raw, which is expressed as cmH2

O/L/s (normal, <2 cmH2

O/L/s). The figures at the bottom of each column show the typical configuration of flow-volume loops in each

condition, including the flow-volume relationship during tidal breathing. b.d., bronchodilator; Dlco diffusion capacity of lung for carbon monoxide; FEV1

, forced expiratory

volume in 1 s; FRC, functional residual capacity; FVC, forced vital capacity; Raw, airways resistance; RV, residual volume; TLC, total lung capacity.

2139 Disturbances of Respiratory Function CHAPTER 285

of resident gas contributing to the dilution. A drawback of this method

is that regions of the lung that ventilate poorly (e.g., due to airflow

obstruction) may not receive much inspired inert gas and so do not

contribute to its dilution. Therefore, inert gas dilution (especially in the

single-breath method) often underestimates true lung volumes.

In the second approach, FRC is determined by measuring the compressibility of gas within the chest, which is proportional to the volume

of gas being compressed. The patient sits in a body plethysmograph

(a chamber usually made of transparent plastic to minimize claustrophobia) and, at the end of a normal tidal breath (i.e., when lung volume

is at FRC), is instructed to pant against a closed shutter, thus periodically compressing air within the lung slightly. Pressure fluctuations at

the mouth and volume fluctuations within the body box (equal but

opposite to those in the chest) are determined, and from these measurements, the thoracic gas volume is calculated by means of Boyle’s

law. Once FRC is obtained, TLC and RV are calculated by adding the

value for inspiratory capacity and subtracting the value for expiratory

reserve volume, respectively (both values having been obtained during

spirometry) (Fig. 285-2). The most important determinants of healthy

individuals’ lung volumes are height, age, and sex, but there is considerable additional normal variation beyond that accounted for by these

parameters. In addition, race influences lung volumes; on average, TLC

values are ~12% lower in African Americans and 6% lower in Asian

Americans than in Caucasian Americans. In practice, a mean “normal”

value is predicted by multivariate regression equations using height,

age, and sex, and the patient’s value is divided by the predicted value

(often with “race correction” applied) to determine “percent predicted.”

For most measures of lung function, 85–115% of the predicted value

can be normal; however, in health, the various lung volumes tend to

scale together. For example, if one is “normal big” with a TLC 110%

of the predicted value, all other lung volumes and spirometry values

will also approximate 110% of their respective predicted values. This

pattern is particularly helpful in evaluating airflow, as discussed below.

AIR FLOW As noted above, spirometry plays a key role in lung volume determination. Even more often, spirometry is used to measure

airflow, which reflects the dynamic properties of the lung. During an

FVC maneuver, the patient inhales to TLC and then exhales rapidly

and forcefully to RV; this method ensures that flow limitation has been

achieved, so that the precise effort made has little influence on actual

flow. The total amount of air exhaled is the FVC, and the amount of air

exhaled in the first second is the FEV1

; the FEV1

 is a flow rate, revealing

volume change per time. Like lung volumes, an individual’s maximal

expiratory flows should be compared with predicted values based on

height, age, and sex. While the FEV1

/FVC ratio is typically reduced in

airflow obstruction, this condition can also reduce FVC by raising RV,

sometimes rendering the FEV1

/FVC ratio “artifactually normal” with

the erroneous implication that airflow obstruction is absent. To circumvent this problem, it is useful to compare FEV1

 as a fraction of its

predicted value with TLC as a fraction of its predicted value. In health,

the results are usually similar. In contrast, even an FEV1

 value that is

95% of its predicted value may actually be relatively low if TLC is 110%

of its respective predicted value. In this case, airflow obstruction may

be present, despite the “normal” value for FEV1

.

The relationships among volume, flow, and time during spirometry

are best displayed in two plots—the spirogram (volume vs time) and

the flow-volume loop (flow vs volume) (Fig. 285-4). In conditions

that cause airflow obstruction, the site of obstruction is sometimes

correlated with the shape of the flow-volume loop. In diseases that

cause lower airway obstruction, such as asthma and emphysema,

flows decrease more rapidly with declining lung volumes, leading to

a characteristic scooping of the flow-volume loop. In contrast, fixed

upper-airway obstruction typically leads to inspiratory and/or expiratory flow plateaus (Fig. 285-4).

AIRWAYS RESISTANCE The total resistance of the pulmonary and

upper airways is measured in the same body plethysmograph used to

measure FRC. The patient is asked once again to pant, but this time

against a closed and then opened shutter. Panting against the closed

shutter reveals the thoracic gas volume as described above. When

the shutter is opened, flow is directed to and from the body box, so

that volume fluctuations in the box reveal the extent of thoracic gas

compression, which in turn reveals the pressure fluctuations driving

flow. Simultaneous measurement of flow allows the calculation of

lung resistance (as flow divided by pressure). In health, Raw is very low

(<2 cmH2

O/L/s), and half of the detected resistance resides within

the upper airway. In the lung, most resistance originates in the central

airways. For this reason, airways resistance measurement tends to be

insensitive to peripheral airflow obstruction.

RESPIRATORY MUSCLE STRENGTH To measure respiratory muscle

strength, the patient is instructed to exhale or inhale with maximal

effort against a closed shutter while pressure is monitored at the mouth.

Pressures >±60 cmH2

O at FRC are considered adequate and make it

unlikely that respiratory muscle weakness accounts for any other resting ventilatory dysfunction that is identified.

Measurement of Gas Exchange • DIFFUSING CAPACITY

(Dlco) This test uses a small (and safe) amount of carbon monoxide

(CO) to measure gas exchange across the alveolar membrane during

a 10-s breath hold. CO in exhaled breath is analyzed to determine the

quantity of CO crossing the alveolar membrane and combining with

hemoglobin in red blood cells. This “single-breath diffusing capacity”

(Dlco) value increases with the surface area available for diffusion and

the amount of hemoglobin within the capillaries, and it varies inversely

with alveolar membrane thickness. Thus, Dlco decreases in diseases

that thicken or destroy alveolar membranes (e.g., pulmonary fibrosis,

emphysema), curtail the pulmonary vasculature (e.g., pulmonary

hypertension), or reduce alveolar capillary hemoglobin (e.g., anemia).

Single-breath diffusing capacity may be elevated in acute congestive

heart failure, asthma, polycythemia, and pulmonary hemorrhage.

Arterial Blood Gases The effectiveness of gas exchange can be

assessed by measuring the partial pressures of oxygen and CO2

 in a

sample of blood obtained by arterial puncture. The oxygen content

of blood (CaO2

) depends on arterial saturation (%O2

Sat), which is set

by Pao2

 pH, and Paco2

 according to the oxyhemoglobin dissociation

curve. CaO2

 can also be measured by oximetry (see below):

CaO2

 (mL/dL) = 1.39 (mL/dL) × [hemoglobin] (g) × % O2

 Sat

+ 0.003 (mL/dL/mmHg) × Pao2

 (mmHg)

If hemoglobin saturation alone needs to be determined, this task can

be accomplished noninvasively with pulse oximetry.

Acknowledgment

The authors wish to acknowledge the contributions of Drs. Steven E.

Weinberger and Irene M. Rosen to this chapter in previous editions.

■ FURTHER READING

Bates JH: Systems physiology of the airways in health and obstructive

pulmonary disease. Wiley Interdiscip Rev Sys Biol Med 8:423, 2016.

Hughes JM et al: Effect of lung volume on the distribution of pulmonary blood flow in man. Respir Physiol 4:58, 1968.

Levitsky MG et al: Pulmonary Physiology, 8th ed. New York, McGraw Hill,

2013; http://accessmedicine.mhmedical.com/book.aspx?bookid=575.

Accessed June 6, 2017.

Macklem PT, Murphy BR: The forces applied to the lung in health

and disease. Am J Med 57:371, 1974.

Pederson OF, Ingram RH: Configuration of maximal expiratory

flow-volume curve: Model experiments with physiologic implications. J Appl Physiol 58:1305, 1985.

Prange HD: Respiratory Physiology: Understanding Gas Exchange.

New York, Chapman and Hill, 1996.

Weibel ER: Morphometric estimation of pulmonary diffusion capacity, I. Model and method. Respir Physiol 11:54, 1970.

West JB: Respiratory Physiology, The Essentials, 9th ed. Philadelphia,

Lippincott Williams & Wilkins, 2012.

Wiley Online Library: Comprehensive physiology: The respiratory

system. Available from http://www.comprehensivephysiology.com/

WileyCDA/Section/id-420557.html. Accessed August 12, 2016.

2140 PART 7 Disorders of the Respiratory System

Diagnostic procedures in respiratory disease encompass a wide array of

invasive and noninvasive modalities. Methods for acquiring diagnostic

specimens are described in this chapter, as are the various imaging

modalities at hand. Pulmonary function tests and measurements of

gas exchange are described in Chap. 284.

BEDSIDE PLEURAL PROCEDURES

■ THORACENTESIS

Thoracentesis, also known as pleurocentesis, refers to percutaneous

aspiration of fluid from the pleural space. The right and left pleural

spaces do not normally communicate with each other, and either can

be directly accessed between the thoracic ribs. The current standard

of care entails using point-of-care ultrasonography to mark the site of

needle puncture; this reduces the risks of “dry tap” as well as complications such as pneumothorax. Beside palliation of symptoms associated

with pleural effusion (most commonly dyspnea), thoracentesis may

be performed for diagnostic purposes. The range of hematologic, biochemical, microbiologic, and cytologic pleural fluid studies has largely

remained unchanged over the past few decades, as has the widespread

adoption of Light’s criteria for distinguishing exudates from transudates that were described in 1972. However, newer assays such as

mesothelin-1 testing for neoplastic diseases (chiefly mesothelioma)

have also become available more recently. More details on pleural

fluid testing are described in Chap. 294.

■ CLOSED PLEURAL BIOPSY

Closed pleural biopsy involves percutaneous sampling of the parietal

pleural lining. This procedure can be performed either “blindly” (typically with an Abrams needle) or by using imaging guidance such as

CT or ultrasound. Closed pleural biopsy without ultrasound guidance

is highly sensitive for pleural tuberculosis, owing to the diffuse pleural

involvement that is typically seen in those cases.

Image-guided closed pleural biopsy is most helpful in case of focal

pleural abnormalities such as pleural nodules, which are virtually

pathognomonic of malignant involvement. Limited studies have shown

high diagnostic yields of around 80–90% with this modality, but patient

selection is key as the diagnostic performance may be considerably

lower in the absence of a specific pleural abnormality that could be

visualized. Between CT and ultrasound imaging, only ultrasound is

typically performed in real-time during the act of obtaining the biopsy.

THORACIC SURGICAL PROCEDURES

■ THORACOSCOPY AND THORACOTOMY

Thoracoscopy and thoracotomy encompass a spectrum of surgical

procedures that involve accessing and operating within the pleural

space, either via one or more small entry ports using thoracoscopic

tools or via larger incisions as in thoracotomy (Fig. 286-1). Thoracoscopy varies in its scope considerably. An interventional pulmonologist

typically performs a pleuroscopy (also known as medical thoracoscopy)

and accesses the pleural space through a single port for parietal pleural

biopsy or for limited therapeutic purposes such as minor lysis of adhesions, thoracoscopic pleurodesis, or indwelling pleural catheter placement. This procedure can usually be performed safely under conscious

sedation. On the other hand, video-assisted thoracoscopic surgery

(VATS) and robotic-assisted thoracoscopic surgery (RATS) represent

more invasive procedures but with more controlled environments

entailing general anesthesia with single-lung ventilation, creation of

multiple entry ports, and several additional diagnostic and therapeutic

286 Diagnostic Procedures

in Respiratory Disease

George R. Washko, Hilary J. Goldberg,

Majid Shafiq

possibilities including, but not limited to, lung biopsy, lymph node

sampling, lobectomy, decortication, and creation of a pericardial window. Open thoracotomy uses wider incisions and more conventional

surgical techniques for performing all of the above as well as additional

tasks such as creation of a Clagett window for chronic bronchopleural

fistula with empyema.

■ MEDIASTINOSCOPY AND MEDIASTINOTOMY

Surgical access to the mediastinum, either through a small port (mediastinoscopy) or a wider incision (mediastinotomy), enables diagnostic

sampling of mediastinal structures such as mediastinal lymph nodes

as part of lung cancer staging. With the advent of endoscopic needlebased techniques (see below), surgery is no longer considered the firstline option for diagnostic lymph node sampling but is recommended in

cases of negative needle-based sampling where suspicion for malignant

nodal involvement remains sufficiently high.

BRONCHOSCOPY

Bronchoscopy, which entails passing a tube with a lighted camera

inside the lower respiratory tract, includes flexible and rigid bronchoscopy (termed after the physical properties of each bronchoscope).

Flexible bronchoscopy is by far the more commonly used form and

enables access to more distal parts of the respiratory tract. The rigid

bronchoscope, although limited to the central airways, has the added

advantage of providing a secure airway for ventilation; artificial breaths

can then be administered through the scope itself as part of a closed

circuit or through open jet ventilation. The rigid bronchoscope also

provides a conduit for diagnostic or therapeutic instruments to be

passed freely, rather than through the relatively constrained working

channel of a flexible bronchoscope. When bronchoscopy is limited to

diagnostic indications, the rigid bronchoscope is seldom used except

on occasion as a precautionary measure for anticipated severe bleeding

where having a more secure airway might be particularly advantageous

(e.g., in transbronchial cryobiopsy). Different types of diagnostic bronchoscopic procedures are described below.

Bronchoalveolar Lavage Bronchoalveolar lavage (BAL) is the

gold standard method for obtaining respiratory secretions for hematologic, biochemical, microbiological, and/or cytologic analyses. It

avoids the risk of salivary contamination, which may be seen in a

sputum specimen, and is particularly useful when sputum cannot be

obtained or when sampling of a specific pulmonary lobe or segment is

desired. After wedging the bronchoscope in a distal airway in order to

prevent fluid escape around the scope, sterile saline or distilled water is

instilled through the scope’s working channel (typically in one to three

aliquots of approximately 50 mL each). Immediately thereafter, suction is applied to aspirate as much of the fluid as possible. This allows

sampling of distal airways and lung parenchyma—areas not directly

viewable or accessible. If there is concern for alveolar hemorrhage,

serial BALs from the same site may show rising red blood cell counts

and even visibly bloodier returns with subsequent lavages.

FIGURE 286-1 Thoracoscopy demonstrating numerous parietal pleural nodules

in a patient with sarcoidosis-related pleural disease. Pleural biopsy revealed

nonnecrotizing granulomas. (Source: Majid Shafiq, MD, MPH)