Basic Sciences-The Human Body - The Respiratory

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First Edition

Britannica Educational PublishingMichael I. Levy: Executive EditorJ.E. Luebering: Senior Manager Marilyn L. Barton: Senior Coordinator, Production ControlSteven Bosco: Director, Editorial TechnologiesLisa S. Braucher: Senior Producer and Data EditorYvette Charboneau: Senior Copy EditorKathy Nakamura: Manager, Media AcquisitionKara Rogers: Senior Editor, Biomedical Sciences

Rosen Educational ServicesHeather M. Moore Niver: EditorNelson Sá: Art DirectorCindy Reiman: Photography ManagerMatthew Cauli: Designer, Cover DesignIntroduction by Amy Miller

Library of Congress Cataloging-in-Publication Data

The respiratory system / edited by Kara Rogers. p. cm. -- (The human body)“In association with Britannica Educational Publishing, Rosen Educational Services.”Includes bibliographical references and index.ISBN 978-1-61530-147-8 (library binding)1. Respiratory organs—Popular works. I. Rogers, Kara.QP121.R467 2011612.2—dc22

2010014243

Manufactured in the United States of America

On the cover: The human lungs are extraordinary organs that constantly pump crucial oxygen through airways and into the bloodstream. © www.istockphoto.com / Sebastian Kaulitzki

On page 10: Singing is one of many common activities that requires dynamic breath control. Chip Somodevilla/Getty Images

On pages 19, 41, 60, 87, 122, 159, 196, 226, 228, 230: A healthy set of lungs is the powerhouse behind the respiratory system. © www.istockphoto.com / nicoolay

CONTENTS

32

43

Introduction 10

Chapter 1: Anatomy and Function of the Human Respiratory System 19

The Design of the Respiratory System 19

Morphology of the Upper Airways 21 The Nose 21 The Pharynx 24Morphology of the Lower Airways 25 The Larynx 26 The Trachea and the Stem

Bronchi 28Structural Design of the Airway Tree 29The Lungs 31 Gross Anatomy 31 Pulmonary Segments 33 The Bronchi and Bronchioles 33 The Gas-Exchange Region 34 Blood Vessels, Lymphatic Vessels,

and Nerves 36 Lung Development 38

Chapter 2: Control and Mechanics of Breathing 41

Control of Breathing 41Central Organization of Respiratory

Neurons 44Chemoreceptors 46 Peripheral Chemoreceptors 46 Central Chemoreceptors 48 Muscle and Lung Receptors 49Variations in Breathing 50 Exercise 51 Sleep 52

51

The Mechanics of Breathing 53 The Lung–Chest System 55 The Role of Muscles 56 The Respiratory Pump and Its

Performance 57

Chapter 3: Gas Exchange and Respiratory Adaptation 60

Gas Exchange 60Transport of Oxygen 63Transport of Carbon Dioxide 65Gas Exchange in the Lung 68Abnormal Gas Exchange 69Interplay of Respiration, Circulation,

and Metabolism 73Adaptations 78 High Altitudes 79 Swimming and Diving 81

Chapter 4: Infectious Diseases of the Respiratory System 87

Upper Respiratory System Infections 88

Common Cold 88 Sore Throat 91 Pharyngitis 91 Sinusitis 92 Tonsillitis 94Lower Respiratory System

Infections 95 Laryngitis 95 Tracheitis 96 Croup 98 Infectious Bronchitis 99 Bronchiolitis 100 Influenza 102 Whooping Cough 105

61

77

Psittacosis 107 Pneumonia 108 Legionnaire Disease 113 Tuberculosis 114

Chapter 5: Diseases and Disorders of the Respiratory System 122

Disorders of the Upper Airway 122 Snoring 123 Sleep Apnea 124 Pickwickian Syndrome 126Diseases of the Pleura 126 Pleurisy 127 Pleural Effusion and Thoracic

Empyema 127 Pneumothorax 129Diseases of the Bronchi and

Lungs 130 Bronchiectasis 130 Chronic Bronchitis 131 Pulmonary Emphysema 133 Chronic Obstructive Pulmonary

Disease 136 Lung Congestion 138 Atelectasis 141 Lung Infarction 144 Cystic Fibrosis 145 Idiopathic Pulmonary Fibrosis 149 Sarcoidosis and Eosinophilic

Granuloma 149 Pulmonary Alveolar Proteinosis 150 Immunologic Conditions of the

Lung 151 Lung Cancer 152Diseases of the Mediastinum and

Diaphragm 156

123

115

165

167

Chapter 6: Allergic and Occupational Lung Diseases and Acute Respiratory Conditions 159

Allergic Lung Diseases 159 Asthma 160 Hay Fever 164 Hypersensitivity Pneumonitis 166Occupational Lung Disease 167 Silicosis 169 Black Lung 170 Asbestosis and Mesothelioma 171 Respiratory Toxicity of Glass and

Metal Fibres 173 Byssinosis 174 Respiratory Toxicity of Industrial

Chemicals 175 Disability and Attribution of

Occupational Lung Diseases 176Other Respiratory Conditions 177 Circulatory Disorders 177 Respiratory Distress Syndrome 179 Air Pollution 180 Carbon Monoxide Poisoning 183 Acidosis 184 Alkalosis and Hyperventilation 184 Hypoxia 186 Altitude Sickness 188 Barotrauma and Decompression

Sickness 189 Thoracic Squeeze 192 Drowning 193

Chapter 7: Approaches to Respiratory Evaluation and Treatment 196

Recognizing the Signs and Symptoms of Disease 196

181

202

219

Methods of Investigation 199 Pulmonary Function Test 202 Chest X-ray 203 Lung Ventilation/Perfusion

Scan 204 Bronchoscopy 205 Mediastinoscopy 208Types of Respiratory Therapy 210 Drug Therapies 211 Oxygen Therapy 214 Artificial Respiration 218 Thoracentesis 220 Hyperbaric Chamber 221 Lung Transplantation 223Conclusion 223

Glossary 226Bibliography 228Index 230

INTRODUCTION

The human lungs are amazing feats of nature. They pump vital oxygen through airways and into the

bloodstream every second of every day. Without this abil-ity, humans could not survive on Earth.

This book explains the science behind the amazing human respiratory system. It also sheds light on how eas-ily a healthy respiratory system can be damaged, whether by a viral or bacterial infection or through detrimental habits such as smoking. But there are many treatments to keep the airways free and clear, and this book also describes the many different approaches doctors can take to save patients’ lives and lungs.

The anatomy of the human respiratory system starts at the place where air fi rst enters the body—the nose. This structure provides humans with the sense of smell while also fi ltering, warming, and moistening inhaled air.

Air that passes through the nose travels to the phar-ynx, or throat, the cone-shaped passageway leading from the mouth and nose to the larynx, or voice box. The larynx is a hollow tube connected to the top of the windpipe, and this air canal to the lungs not only enables humans to speak but also keeps food out of the lower respiratory tract.

After passing through the larynx, air travels through the trachea, also known as the windpipe. Here, the air is cleansed and moistened before entering the lungs. The clean air then travels into the deep tissues of the lungs, eventually reaching the region where gas is exchanged, the centre of the respiratory system.

The right lung is slightly larger than the left lung because of the asymmetrical position of the heart. The right lung has 10 airway segments, and the left lung has 8 to 10. A thin membranous sac known as the pleura covers the lungs. Inside the lungs, there are numerous nerves and blood vessels. However, the most prominent feature of the lung interior are the many small air passages called

11

7 Introduction 7

bronchioles, which range in diameter from 3 mm (0.12 inch) to less than 1 mm (less than 0.04 inch).

The gas-exchange area, the region where oxygen is transferred to the blood and carbon dioxide is removed, is made up of three separate compartments for blood, air, and tissue. The tissue compartment supports the air and blood compartments and lets them come into close con-tact, which makes exchanging gases easier, but still keeps them separate. The exchange of carbon dioxide and oxy-gen takes place in tiny air sacs called alveoli, which look like cells in a honeycomb. The average adult lung has approximately 300 million alveoli.

Lungs also have two distinct blood circulation sys-tems. The first of these, the pulmonary system, is characterized by the transport of carbon dioxide–laden blood from the right side of the heart, through the pulmo-nary arteries, and to the lungs and by the subsequent transport of oxygen-rich blood from the lungs, through the pulmonary veins, and to the left atrium of the heart. From the heart, the oxygenated blood is pumped to the rest of the body, thereby delivering oxygen and other nutrients to organs distant from the lungs. The second blood system in the lungs, the bronchial circulation, com-prises the network of blood vessels supporting the conducting airways themselves. The bronchial circulation is a vital source of nourishment for the lung tissues.

The act of breathing, or respiration, is an automatic process, controlled by the brain. Thus, humans and other animals do not need to actively think about breathing in order for it to happen. A significant feature of the human respiratory system is its capacity to instantly adjust to internal and external stimuli on its own. A series of neural networks in the brain control the rate of breathing by communicating with the muscles in the chest and the

7 The Respiratory System 7

12

abdomen. One of the major abdominal muscles involved in breathing is the diaphragm, which functions to move air in and out of the lungs as it contracts and relaxes, respectively.

The neural networks controlling breathing receive information from special chemical sensors known as che-moreceptors, which are located throughout the body. Whereas some chemoreceptors respond to changes in oxygen and carbon dioxide levels in the bloodstream, oth-ers respond to chemical changes in the immediate external environment. Some chemoreceptors send signals to the brain when they detect noxious or toxic materials in air as it passes to the lungs. When stimulated, these receptors constrict the airways and cause breathing to become fast and shallow. This response represents the body’s attempt to prevent toxins from entering the lungs. In addition to the types of sensors described above, there also exist sen-sors that monitor the muscles that control breathing.

One of the most notable features of respiratory con-trol is the way in which neural communication between the body and the brain fine-tunes the rate of breathing in order to keep carbon dioxide pressure in the blood con-stant. This fine level of regulation is fundamental in maintaining the acid–base balance in the body. The effects of this are illustrated by the differences in respiration rate observed during exercise and during sleep. During exer-cise, metabolic rate and acid levels in muscle tissue increase. These effects trigger an increase in respiration rate, thereby increasing oxygen delivery to tissues and maintaining the body’s acid–base balance. In contrast, during sleep, metabolic rate slows and therefore respira-tion rate decreases and oxygen demand is low.

In the basic mechanics of breathing, air moves in and out of the lungs in response to pressure changes. The

13

7 Introduction 7

diaphragm is the major muscle that facilitates breathing, but it is assisted by a complex assembly of other muscle groups. The amount of air that the lungs pump changes dramatically depending on external or internal conditions. In adults, during vigorous breathing, the volume of air expired by the lungs can increase by as much as 25 times the normal resting level.

The lungs serve a fundamental role in ensuring that excess carbon dioxide is removed from the body. The pul-monary alveoli, the small air spaces in the lungs, transfer carbon dioxide from and add oxygen to blood. This exchange of gases takes place over an immense surface area. The carbon dioxide that is absorbed by the alveoli is expelled from the body during exhalation. The oxygen that the alveoli transfer to the blood is then circulated to the heart and the body’s other tissues.

Respiration, circulation, and metabolism all work together. The main purpose of respiration is to provide oxygen for the body’s cells. Oxygen is used by cells for the breakdown of nutrients, an activity that is necessary to supply energy to the cells and the body. Without oxygen, cells are unable to function properly. Oxygen deprivation, even for only a few minutes, can cause the brain and the heart to stop functioning, which can lead to death.

The atmospheric pressure of oxygen differs with respect to high versus low altitudes on Earth. At high alti-tudes, oxygen is present at lower levels than it is at low altitudes. People who live at high altitudes adapt to this decrease in oxygen availability. However, acclimatization, in which the body works to more efficiently utilize oxygen in the air, is a gradual process. Mountain climbers ascend-ing to extreme heights must spend several days at camps established increasingly farther up the mountainside, hik-ing up during the day and descending down to camp to

14


sleep at night. This enables the body to adjust to the decreased availability of oxygen. If these precautions are not taken, as climbers make their way up the mountain, the body’s tissues become deprived of oxygen, which can lead to high-altitude pulmonary edema, in which the body circulates additional blood to the lungs, but the blood leaks into the air sacs. Essentially, death is caused by drowning.

Various infectious diseases caused by viruses and bac-teria can produce difficulties in breathing. The common cold is an acute infection of the upper respiratory tract that can sometimes spread to the lower respiratory tis-sues. Other common upper respiratory conditions include sore throat and pharyngitis, which can arise as a result of infection. Inflammation of respiratory tissues can some-times be severe and chronic. For example, many people have their tonsils removed after suffering from chronic tonsillitis.

In the lower respiratory system, bacteria can cause inflammation of the trachea, a condition known as trache-itis, as well as bacterial pneumonia, which can be particularly dangerous in infants and in the elderly. Before antibiotics were widely available, pneumonia was a wide-spread and notoriously deadly disease. Although bacteria sometimes cause pneumonia, certain viruses and fungi can also cause the disease. Pneumonia also often affects per-sons with impaired immune systems, because these individuals are unable to defend against infectious organisms.

Tuberculosis is another example of a respiratory dis-ease caused by bacteria. In the 18th and 19th centuries, it was a leading cause of death, and in the first decade of the 21st century, the emergence of drug-resistant tuberculosis bacteria has resulted in a resurgence of the disease. The

15

7 Introduction 7

1616

tuberculosis bacteria spread slowly in the lungs and cause hard nodules (tubercles), or large cheese-like masses, to form. This process leads to the eventual breakdown of respiratory tissues, resulting in the formation of cavities in the lungs. Eventually, blood vessels in the lungs burst, and the infected person coughs up bright red blood.

Influenza is a common, seasonal respiratory illness that is caused by viral infection. Infection is accompanied by fever, chills, muscle pains, headaches, and stomach pain. It is a highly contagious disease too. Every few decades, a strain of influenza virus gives rise to a pandemic, an outbreak of the illness that occurs on a global scale and is characterized by rapid spread. One of the deadliest influenza pandemics was that of 1918–19, which caused between 25 million and 50 million deaths worldwide.

Many respiratory conditions arise from noninfectious causes. For example, snoring is caused by blocked airways, which may be associated with obesity. A severe form of snoring is sleep apnea, in which the collapse of the airways leads to intermittent stoppages in breathing. Sleep apnea causes affected individuals to awaken periodically through the night.

Some respiratory diseases are inherited. One of the best-characterized inherited conditions is cystic fibro-sis, the primary symptom of which is the production of a thick, sticky mucus that blocks the airways and the digestive tract. For some diseases of the respiratory system, no cause has been identified, despite extensive research. One example is idiopathic pulmonary fibrosis, which results in progressive shortness of breath until a person can no longer breathe. The term idiopathic means “of unknown cause,” and thus is used to describe diseases of uncertain origin.

A respiratory disease of major concern in the world today is lung cancer. Lung cancer can arise as a result of a


17

7 Introduction 7

variety of factors, although tobacco smoking is the pri-mary cause. Doctors first described the symptoms of lung cancer in the mid-19th century. In the early 20th century, it was still considered rare. Now, however, lung cancer is the leading cause of cancer deaths worldwide, resulting in an estimated 1.3 million fatalities each year.

Breathing problems caused by allergies to environ-mental conditions are fairly common. Today, more than 7 percent of children and 9 percent of adults suffer from asthma, most likely resulting from exposure to air pollu-tion, tobacco smoke, and even cockroaches.

Some respiratory diseases arise as a result of occupa-tional, or work, factors. The best-known occupational lung disease is black lung, which affects coal miners who inhale coal dust for many years. Construction workers and insulators exposed to asbestos often suffer from asbesto-sis, or white lung disease. Breathing asbestos can also cause the cancerous condition known as mesothelioma.

There is hope for those who suffer from respiratory diseases and disorders. Scientists are constantly research-ing and developing new and different treatments for respiratory ailments. Many treatments, however, have been around for years and are readily available. Nasal decongestants and antihistamines are examples of com-monly used remedies.

Several vaccines have been developed to prevent ill-nesses such as influenza. Antiviral drugs capable of treating viral respiratory infections have emerged and become widely available. The antiviral agents Tamiflu (oseltamivir) and Relenza (zanamivir) played an important role in treat-ing persons affected by influenza during the H1N1 influenza pandemic of 2009. In addition to vaccines and antivirals, antibiotics are vitally important for the treat-ment of respiratory infections that are caused by bacteria, particularly pneumonia and tuberculosis.

Lung cancer treatments may consist of surgery, che-motherapy, and radiation. Treatment may also be based on the results of genetic screening, which can identify muta-tions that render some lung cancers susceptible to certain drugs. Sometimes a person’s lung becomes so diseased that the only hope for survival is a lung transplant.

The best thing a person can do for his or her lungs is to prevent them from becoming diseased in the fi rst place. As this book shows, the human respiratory system is a fi nely tuned feat of engineering, and the consequences of neglecting or damaging that fragile system can be drastic. A healthy set of lungs is nothing to take for granted.


19

CHAPTER CHAPTER CHAPTER CHAPTER CHAPTER CHAPTER 111

19

Our respiratory system provides us with the funda-mental ability to breathe: to inhale and exhale air

from our lungs. Breathing, or respiration, is fundamental to survival, and though we possess the ability to consciously control the rate of our breathing, it is otherwise an auto-matic process, occurring without our having to think about it. Yet, as simple as it is for us to inhale and exhale, support-ing this process are a number of complex actions that occur within our bodies. These actions encompass not only mus-cular movements but also cellular and chemical processes.

The respiratory system consists of two divisions: upper airways and lower airways. The transition between these two divisions is located where the pathways of the respira-tory and digestive systems cross, just at the top of the larynx (or voice box). The upper airway system comprises the nose and the paranasal cavities (or sinuses), the phar-ynx (or throat), and part of the oral cavity. The lower airway system consists of the larynx, the trachea, the stem bronchi, and all the airways that branch extensively within the lungs, such as the intrapulmonary bronchi, the bron-chioles, and the alveolar ducts.

the design of the respiratory systeM

The human gas–exchanging organ, the lung, is located in the thorax (or chest), where its delicate tissues are

ANATOMY AND FUNCTION OF THE HUMAN

RESPIRATORY SYSTEM

20


The lungs serve as the gas-exchanging organ for the process of respiration. Encyclopædia Britannica, Inc.

protected by the bony and muscular thoracic cage. The lung provides the body with a continuous fl ow of oxygen and clears the blood of the gaseous waste product, carbon dioxide. Atmospheric air is pumped in and out regularly through a system of pipes, called conducting airways,

21

7 Anatomy and Function of the Human Respiratory System 7

which connect the gas–exchange region inside the body with the environment outside the body.

For respiration, the collaboration of other organ sys-tems is essential. The diaphragm, as the main respiratory muscle, and the intercostal muscles of the chest wall play an essential role by generating, under the control of the central nervous system, the pumping action on the lung. The muscles expand and contract the internal space of the thorax, whose bony framework is formed by the ribs and the thoracic vertebrae. Other elements fundamental to the process of respiration include the blood, which acts as a carrier of gases, and the circulatory system (i.e., the heart and the blood vessels), which pumps blood from the heart to the lungs and the rest of the body.

Morphology of the upper airways

The nose, sinuses, and pharynx of the upper airways serve the vital role of filtering and warming air as it enters the respiratory tract. The filtering process is vital to clearing inhaled air of dust and other debris, and it protects against the passage into the lungs of potentially infectious foreign agents. The oral cavity, through which air may be inhaled or exhaled, is sometimes also considered a part of the upper airways. In addition to fulfilling a fundamental role in respiration, the structures of the upper respiratory tract also have other important functions, such as enabling the sensation of smell.

The Nose

The nose is the external protuberance of an internal space, the nasal cavity. It is subdivided into a left and right canal by a thin medial cartilaginous and bony wall, the nasal


22

septum. Each canal opens to the face by a nostril and into the pharynx by the choana. The floor of the nasal cavity is formed by the palate, which also forms the roof of the oral cavity. The complex shape of the nasal cavity results from projections of bony ridges, the superior, middle, and infe-rior turbinate bones (or conchae), from the lateral wall. The passageways thus formed below each ridge are called the superior, middle, and inferior nasal meatuses.

On each side, the intranasal space communicates with a series of neighbouring air-filled cavities within the skull (the paranasal sinuses) and also, via the nasolacrimal duct, with the lacrimal apparatus in the corner of the eye. The duct drains the lacrimal fluid into the nasal cavity. This fact explains why nasal respiration can be rapidly impaired or even impeded during weeping: the lacrimal fluid is not only overflowing into tears, it is also flooding the nasal cavity.

The paranasal sinuses are sets of paired single or mul-tiple cavities of variable size. Most of their development takes place after birth, and they reach their final size around age 20. The sinuses are located in four different skull bones: the maxilla, frontal, ethmoid, and sphenoid bones. Correspondingly, they are called the maxillary sinus, which is the largest cavity; the frontal sinus; the eth-moid sinuses; and the sphenoid sinus, which is located in the upper posterior wall of the nasal cavity. The sinuses have two principal functions: because they are filled with air, they help keep the weight of the skull within reason-able limits, and they serve as resonance chambers for the human voice.

The nasal cavity with its adjacent spaces is lined by a respiratory mucosa. Typically, the mucosa of the nose con-tains mucus-secreting glands and venous plexuses. Its top cell layer, the epithelium, consists principally of two cell types, ciliated and secreting cells. This structural design

23

Sagittal view of the human nasal cavity. Encyclopædia Britannica, Inc.

refl ects the particular ancillary functions of the nose and of the upper airways in general with respect to respira-tion. They clean, moisten, and warm the inspired air, preparing it for intimate contact with the delicate tissues of the gas-exchange area. During expiration through the nose, the air is dried and cooled, a process that saves water and energy.

Two regions of the nasal cavity have a different lining. The vestibule, at the entrance of the nose, is lined by skin that bears short thick hairs called vibrissae. In the roof of the nose, the olfactory organ with its sensory epithelium checks the quality of the inspired air. About two dozen olfactory nerves convey the sensation of smell from the


24


Sagittal section of the pharynx. Encyclopædia Britannica, Inc.

olfactory cells through the bony roof of the nasal cavity to the central nervous system.

The Pharynx

For the anatomical description, the pharynx can be divided into three fl oors. The upper fl oor, the nasopharynx, is primarily a passageway for air and secretions from the nose to the oral pharynx. It is also connected to the tym-panic cavity of the middle ear through the auditory tubes that open on both lateral walls. The act of swallowing briefl y opens the normally collapsed auditory tubes and allows the middle ears to be aerated and pressure differ-ences to be equalized. In the posterior wall of the

25

nasopharynx is located a lymphatic organ, the pharyngeal tonsil. When it is enlarged (as in tonsil hypertrophy), it may interfere with nasal respiration and alter the reso-nance pattern of the voice.

The middle floor of the pharynx connects anteriorly to the mouth and is therefore called the oral pharynx or oro-pharynx. It is delimited from the nasopharynx by the soft palate, which roofs the posterior part of the oral cavity.

The lower floor of the pharynx is called the hypophar-ynx. Its anterior wall is formed by the posterior part of the tongue. Lying directly above the larynx, it represents the site where the pathways of air and food cross each other: air from the nasal cavity flows into the larynx, and food from the oral cavity is routed to the esophagus directly behind the larynx. The epiglottis, a cartilaginous, leaf-shaped flap, functions as a lid to the larynx and, during the act of swallowing, controls the traffic of air and food.

Morphology of the lower airways

The major structures of the lower airways include the lar-ynx, trachea, and lungs. The first two of these provide a canal for the passage of air to the lungs, while the lungs themselves receive the air and facilitate the process of gas exchange. The lungs reside within the thoracic cavity (chest cavity), which is the second–largest hollow space of the body. The cavity is enclosed by the ribs, the vertebral column, and the sternum (or breastbone) and is separated from the abdominal cavity (the body’s largest hollow space) by a muscular and membranous partition, the dia-phragm. Also residing within the thoracic cavity is the tracheobronchial tree: the heart, the vessels transporting blood between the heart and the lungs, the great arteries bringing blood from the heart out into general circulation,



26

and the major veins into which the blood is collected for transport back to the heart.

The chest cavity is lined with a serous membrane, so called because it exudes a thin fluid, or serum. This portion of the chest membrane is called the parietal pleura. The membrane continues over the lung, where it is called the visceral pleura, and over part of the esophagus, the heart, and the great vessels, as the mediastinal pleura, the medi-astinum being the space and the tissues and structures between the two lungs. Because the atmospheric pressure between the parietal pleura and the visceral pleura is less than that of the outer atmosphere, the two surfaces tend to touch, friction between the two during the respiratory movements of the lung being eliminated by the lubricat-ing actions of the serous fluid. The pleural cavity is the space, when it occurs, between the parietal and the vis-ceral pleura.

The Larynx

The larynx is an organ of complex structure that serves a dual function: as an air canal to the lungs and a controller of its access, and as the organ of phonation. Sound is pro-duced by forcing air through a sagittal slit formed by the vocal cords, the glottis. This causes not only the vocal cords but also the column of air above them to vibrate. As evidenced by trained singers, this function can be closely controlled and finely tuned. Control is achieved by a num-ber of muscles innervated by the laryngeal nerves. For the precise function of the muscular apparatus, the muscles must be anchored to a stabilizing framework.

The laryngeal skeleton consists of almost a dozen pieces of cartilage, most of them minute, interconnected by ligaments and membranes. The largest cartilage of the larynx, the thyroid cartilage, is made of two plates fused

27

anteriorly in the midline. At the upper end of the fusion line is an incision, the thyroid notch; below it is a forward projection, the laryngeal prominence. Both of these struc-tures are easily felt through the skin. The angle between the two cartilage plates is sharper and the prominence more marked in men than in women, which has given this structure the common name of Adam’s apple.

Behind the shieldlike thyroid cartilage, the vocal cords span the laryngeal lumen. They correspond to elastic liga-ments attached anteriorly in the angle of the thyroid shield and posteriorly to a pair of small pyramidal pieces of cartilage, the arytenoid cartilages. The vocal ligaments are part of a tube, resembling an organ pipe, made of elas-tic tissue. Just above the vocal cords, the epiglottis is also attached to the back of the thyroid plate by its stalk. The cricoid, another large cartilaginous piece of the laryngeal skeleton, has a signet-ring shape. The broad plate of the ring lies in the posterior wall of the larynx and the narrow arch in the anterior wall. The cricoid is located below the thyroid cartilage, to which it is joined in an articulation reinforced by ligaments. The transverse axis of the joint allows a hingelike rotation between the two cartilages. This movement tilts the cricoid plate with respect to the shield of the thyroid cartilage and hence alters the dis-tance between them. Because the arytenoid cartilages rest upright on the cricoid plate, they follow its tilting move-ment. This mechanism plays an important role in altering length and tension of the vocal cords. The arytenoid carti-lages articulate with the cricoid plate and hence are able to rotate and slide to close and open the glottis.

Viewed frontally, the lumen of the laryngeal tube has an hourglass shape, with its narrowest width at the glottis. Just above the vocal cords there is an additional pair of mucosal folds called the false vocal cords or the vestibular folds. Like the true vocal cords, they are also formed by the free end



28

of a fibroelastic membrane. Between the vestibular folds and the vocal cords, the laryngeal space enlarges and forms lateral pockets extending upward. This space is called the ventricle of the larynx. Because the gap between the ves-tibular folds is always larger than the gap between the vocal cords, the latter can easily be seen from above with the laryngoscope, an instrument designed for visual inspection of the interior of the larynx.

The muscular apparatus of the larynx comprises two functionally distinct groups. The intrinsic muscles act directly or indirectly on the shape, length, and tension of the vocal cords. The extrinsic muscles act on the larynx as a whole, moving it upward (e.g., during high-pitched pho-nation or swallowing) or downward. The intrinsic muscles attach to the skeletal components of the larynx itself. The extrinsic muscles join the laryngeal skeleton cranially to the hyoid bone or to the pharynx and caudally to the sternum.

The Trachea and the Stem Bronchi

Below the larynx lies the trachea, a tube about 10 to 12 cm (4 to 5 inches) long and 2 cm (0.8 inch) wide. Its wall is stiffened by 16 to 20 characteristic horseshoe-shaped, incomplete cartilage rings that open toward the back and are embedded in a dense connective tissue. The dorsal wall contains a strong layer of transverse smooth muscle fibres that spans the gap of the cartilage. The interior of the trachea is lined by the typical respiratory epithelium. The mucosal layer contains mucous glands.

At its lower end, the trachea divides in an inverted Y into the two stem (or main) bronchi, one each for the left and right lung. The right main bronchus has a larger diameter, is oriented more vertically, and is shorter than the left main bronchus. The practical consequence of

29

this arrangement is that foreign bodies passing beyond the larynx will usually slip into the right lung. The struc-ture of the stem bronchi closely matches that of the trachea.

structural design of the airway tree

The hierarchy of the dividing airways, and partly also of the blood vessels penetrating the lung, largely deter-mines the internal lung structure. Functionally, the intrapulmonary airway system can be subdivided into three zones: a proximal, purely conducting zone; a periph-eral, purely gas-exchanging zone; and a transitional zone in between, where both functions grade into one another. From a morphological point of view, however, it makes sense to distinguish the relatively thick-walled, purely air-conducting tubes from those branches of the airway tree structurally designed to permit gas exchange.

The structural design of the airway tree is functionally important because the branching pattern plays a role in determining air flow and particle deposition. In modeling the human airway tree, it is generally agreed that the air-ways branch according to the rules of irregular dichotomy. Regular dichotomy means that each branch of a treelike structure gives rise to two daughter branches of identical dimensions. In irregular dichotomy, however, the daugh-ter branches may differ greatly in length and diameter. The models calculate the average path from the trachea to the lung periphery as consisting of about 24 to 25 genera-tions of branches. Individual paths, however, may range from 11 to 30 generations. The transition between the conductive and the respiratory portions of an airway lies on average at the end of the 16th generation, if the trachea is counted as generation zero.



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The conducting airways comprise the trachea, the two stem bronchi, the bronchi, and the bronchioles. Their function is to further warm, moisten, and clean the inspired air and distribute it to the gas-exchanging zone of the lung. They are lined by the typical respiratory epithe-lium with ciliated cells and numerous interspersed mucus-secreting goblet cells. Ciliated cells are present far down in the airway tree, their height decreasing with the narrowing of the tubes, as does the frequency of goblet cells. In bronchioles the goblet cells are completely replaced by another type of secretory cells named Clara cells. The epithelium is covered by a layer of low-viscosity fluid, within which the cilia exert a synchronized, rhyth-mic beat directed outward. In larger airways, this fluid layer is topped by a blanket of mucus of high viscosity. The mucus layer is dragged along by the ciliary action and car-ries the intercepted particles toward the pharynx, where they are swallowed. This design can be compared to a con-veyor belt for particles, and indeed the mechanism is referred to as the mucociliary escalator.

Whereas cartilage rings or plates provide support for the walls of the trachea and bronchi, the walls of the bron-chioles, devoid of cartilage, gain their stability from their structural integration into the gas-exchanging tissues. The last purely conductive airway generations in the lung are the terminal bronchioles. Distally, the airway struc-ture is greatly altered by the appearance of cuplike outpouchings from the walls. These form minute air chambers and represent the first gas-exchanging alveoli on the airway path. In the alveoli, the respiratory epithe-lium gives way to a particularly flat lining layer that permits the formation of a thin air–blood barrier. After several generations of such respiratory bronchioles, the alveoli are so densely packed along the airway that an airway wall

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proper is missing, and the airway consists of alveolar ducts. The final generations of the airway tree end blindly in the alveolar sacs.

the lungs

Humans have two lung organs, a right and a left, which are located in the chest cavity and are responsible for adding oxygen to and removing carbon dioxide from the blood. In humans each lung is encased in a thin membranous sac called the pleura, and each is connected with the trachea by its main bronchus (large air passageway) and with the heart by the pulmonary arteries.

Gross Anatomy

Together, the lungs occupy most of the intrathoracic space. The space between them is filled by the mediasti-num, which corresponds to a connective tissue space containing the heart, major blood vessels, the trachea with the stem bronchi, the esophagus, and the thymus gland. The right and left lungs are slightly unequal in size. The right lung represents 56 percent of the total lung volume and is composed of three lobes, a superior, middle, and inferior lobe, separated from each other by a deep hori-zontal and an oblique fissure. The left lung, smaller in volume because of the asymmetrical position of the heart, has only two lobes separated by an oblique fissure.

In the thorax, the two lungs rest with their bases on the diaphragm, while their apexes extend above the first rib. Medially, they are connected with the mediastinum at the hilum, a circumscribed area where airways, blood and lymphatic vessels, and nerves enter or leave the lungs. The parietal pleura and the visceral pleura that line the inside


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Anatomy of the human lungs. Encyclopædia Britannica, Inc.

of the thoracic cavities and the lung surface, respectively, are in direct continuity at the hilum. Depending on the subjacent structures, the parietal pleura can be subdivided into three portions: mediastinal, costal, and diaphrag-matic pleurae. The presence of pleural recesses form a kind of reserve space, so the pleural cavity is larger than the lung volume.

During inspiration, the recesses are partly opened by the expanding lung, thus allowing the lung to increase in volume. Although the hilum is the only place where the lungs are secured to surrounding structures, the lungs are maintained in close apposition to the thoracic wall by a negative pressure between visceral and parietal pleurae. A thin fi lm of extracellular fl uid between the pleurae enables

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the lungs to move smoothly along the walls of the cavity during breathing. If the serous membranes become inflamed (pleurisy), respiratory movements can be pain-ful. If air enters a pleural cavity (pneumothorax), the lung immediately collapses owing to its inherent elastic prop-erties, and breathing is abolished on this side.

Pulmonary Segments

The lung lobes are subdivided into smaller units, the pul-monary segments. There are 10 segments in the right lung and 8 to 10 segments in the left lung, depending on the classification. Unlike the lobes, the pulmonary segments are not delimited from each other by fissures but by thin membranes of connective tissue containing veins and lym-phatics; the arterial supply follows the segmental bronchi. These anatomical features are important because patho-logical processes may be limited to discrete units, and the surgeon can remove single diseased segments instead of whole lobes.

The Bronchi and Bronchioles

In the intrapulmonary bronchi, the cartilage rings of the stem bronchi are replaced by irregular cartilage plates. Furthermore, a layer of smooth muscle is added between the mucosa and the fibrocartilaginous tunic. The bronchi are ensheathed by a layer of loose connective tissue that is continuous with the other connective tissue elements of the lung and hence is part of the fibrous skeleton span-ning the lung from the hilum to the pleural sac. This outer fibrous layer contains, besides lymphatics and nerves, small bronchial vessels to supply the bronchial wall with blood from the systemic circulation. Bronchioles are



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small conducting airways ranging in diameter from three to less than one millimetre. The walls of the bronchioles lack cartilage and seromucous glands. Their lumen is lined by a simple cuboidal epithelium with ciliated cells and Clara cells, which produce secretions. The bronchiolar wall also contains a well-developed layer of smooth mus-cle cells, capable of narrowing the airway. Abnormal spasms of this musculature cause the clinical symptoms of bronchial asthma.

The Gas-Exchange Region

The gas-exchange region comprises three compartments: air, blood, and tissue. Whereas air and blood are continu-ously replenished, the function of the tissue compartment is twofold: it provides the stable supporting framework for the air and blood compartments, and it allows them to come into close contact with each other (thereby facilitat-ing gas exchange) while keeping them strictly confined. The respiratory gases diffuse from air to blood, and vice versa, through the 160 square metres (about 1,722 square feet) of internal surface area of the tissue compartment. The gas-exchange tissue proper is called the pulmonary parenchyma, while the supplying structures, conductive airways, lymphatics, and non-capillary blood vessels belong to the non-parenchyma.

The gas-exchange region begins with the alveoli of the first generation of respiratory bronchioles. Distally, the frequency of alveolar outpocketings increases rapidly, until after two to four generations of respiratory bron-chioles, the whole wall is formed by alveoli. The airways are then called alveolar ducts and, in the last generation, alveolar sacs. On average, an adult human lung has about 300 million alveoli. They are polyhedral structures, with a

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diameter of about 250 to 300 micrometres, and open on one side, where they connect to the airway. The alveolar wall, called the interalveolar septum, is common to two adjacent alveoli. It contains a dense network of capillaries, the smallest of the blood vessels, and a skeleton of con-nective tissue fibres. The fibre system is interwoven with the capillaries and particularly reinforced at the alveolar entrance rings. The capillaries are lined by flat endothelial cells with thin cytoplasmic extensions.

The interalveolar septum is covered on both sides by the alveolar epithelial cells. A thin, squamous cell type, the type I pneumocyte, covers between 92 and 95 percent of the gas-exchange surface; a second, more cuboidal cell type, the type II pneumocyte, covers the remaining sur-face. The type I cells form, together with the endothelial cells, the thin air–blood barrier for gas exchange, whereas type II cells are secretory. Type II pneumocytes produce a surface-tension-reducing material, the pulmonary surfac-tant, which spreads on the alveolar surface and prevents the tiny alveolar spaces from collapsing. Before it is released into the airspaces, pulmonary surfactant is stored in the type II cells in the form of lamellar bodies. These granules are the conspicuous ultrastructural features of this cell type. On top of the epithelium, alveolar macro-phages creep around within the surfactant fluid. They are large cells, and their cell bodies abound in granules of vari-ous content, partly foreign material that may have reached the alveoli, or cell debris originating from cell damage or normal cell death. Ultimately, the alveolar macrophages are derived from the bone marrow, and their task is to keep the air–blood barrier clean and unobstructed.

The tissue space between the endothelium of the cap-illaries and the epithelial lining is occupied by the interstitium. It contains connective tissue and interstitial



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fluid. The connective tissue comprises a system of fibres, amorphous ground substance, and cells (mainly fibro-blasts), which seem to be endowed with contractile properties. The fibroblasts are thought to control capil-lary blood flow or, alternatively, to prevent the accumulation of extracellular fluid in the interalveolar septa. If for some reason the delicate fluid balance of the pulmonary tissues is impaired, an excess of fluid accumu-lates in the lung tissue and within the airspaces. This pathological condition is called pulmonary edema. As a consequence, the respiratory gases must diffuse across longer distances, and proper functioning of the lung is severely jeopardized.

Blood Vessels, Lymphatic Vessels, and Nerves

With respect to blood circulation, the lung is a complex organ. It has two distinct but not completely separate vas-cular systems: a low-pressure pulmonary system and a high-pressure bronchial system. The pulmonary (or lesser) circulation is responsible for the oxygen supply of the organism. Blood, low in oxygen content but laden with carbon dioxide, is carried from the right heart through the pulmonary arteries to the lungs. On each side, the pulmo-nary artery enters the lung in the company of the stem bronchus and then divides rapidly, following relatively closely the course of the dividing airway tree. After numer-ous divisions, small arteries accompany the alveolar ducts and split up into the alveolar capillary networks. Because intravascular pressure determines the arterial wall struc-ture, the pulmonary arteries, which have on average a pressure five times lower than systemic arteries, are much flimsier than systemic arteries of corresponding size. The oxygenated blood from the capillaries is collected by

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venules and drained into small veins. These do not accom-pany the airways and arteries but run separately in narrow strips of connective tissue delimiting small lobules. The interlobular veins then converge on the intersegmental septa. Finally, near the hilum the veins merge into large venous vessels that follow the course of the bronchi. Generally, four pulmonary veins drain blood from the lung and deliver it to the left atrium of the heart.

The bronchial circulation has a nutritional function for the walls of the larger airways and pulmonary vessels. The bronchial arteries originate from the aorta or from an intercostal artery. They are small vessels and generally do not reach as far into the periphery as the conducting airways. With a few exceptions, they end several genera-tions short of the terminal bronchioles. They split up into capillaries surrounding the walls of bronchi and vessels and also supply adjacent airspaces. Most of their blood is naturally collected by pulmonary veins. Small bronchial veins exist, however, originating from the peribronchial venous plexuses and draining the blood through the hilum into the azygos and hemiazygos veins of the poste-rior thoracic wall.

The lymph is drained from the lung through two distinct but interconnected sets of lymphatic vessels. The superfi-cial, subpleural lymphatic network collects the lymph from the peripheral mantle of lung tissue and drains it partly along the veins toward the hilum. The deep lymphatic sys-tem originates around the conductive airways and arteries and converges into vessels that mostly follow the bronchi and arterial vessels into the mediastinum.

Within the lung and the mediastinum, lymph nodes exert their filtering action on the lymph before it is returned into the blood through the major lymphatic ves-sels, called bronchomediastinal trunks. Lymph drainage



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paths from the lung are complex. The precise knowledge of their course is clinically relevant, because malignant tumours of the lung spread via the lymphatics.

The pleurae, the airways, and the vessels are inner-vated by afferent and efferent fibres of the autonomic nervous system. Parasympathetic nerve fibres from the vagus nerve (10th cranial nerve) and sympathetic branches of the sympathetic nerve trunk meet around the stem bronchi to form the pulmonary autonomic nerve plexus, which penetrates into the lung along the bronchial and vascular walls. The sympathetic fibres mediate a vasocon-strictive action in the pulmonary vascular bed and a secretomotor activity in the bronchial glands. The para-sympathetic fibres stimulate bronchial constriction. Afferent fibres to the vagus nerve transmit information from stretch receptors, and those to the sympathetic centres carry sensory information (e.g., pain) from the bronchial mucosa.

Lung Development

After early embryogenesis, during which the lung primor-dium is laid down, the developing human lung undergoes four consecutive stages of development, ending after birth. The names of the stages describe the actual mor-phology of the prospective airways. The pseudoglandular stage exists from 5 to 17 weeks; the canalicular stage, from 16 to 26 weeks; the saccular stage, from 24 to 38 weeks; and finally the alveolar stage, from 36 weeks of fetal age to about 1 ½ to 2 years after birth.

The lung appears around the 26th day of intrauterine life as a ventral bud of the prospective esophagus. The bud separates distally from the gut, divides, and starts to grow into the surrounding mesenchyme. The epithelial compo-nents of the lung are thus derived from the gut (i.e., they

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are of endodermal origin), and the surrounding tissues and the blood vessels are derivatives of the mesoderm.

Following rapid successive dichotomous divisions, the lung begins to look like a gland, giving the first stage of development (pseudoglandular) its name. At the same time the vascular connections also develop and form a capillary plexus around the lung tubules. Toward week 17, all the conducting airways of the lung are preformed, and it is assumed that, at the outermost periphery, the tips of the tubules represent the first structures of the prospec-tive gas-exchange region.

During the canalicular stage, the future lung periphery develops further. The prospective airspaces enlarge at the expense of the intervening mesenchyme, and their cuboi-dal epithelium differentiates into type I and type II epithelial cells or pneumocytes. Toward the end of this stage, areas with a thin prospective air–blood barrier have developed, and surfactant production has started. These structural and functional developments give a prema-turely born fetus a small chance to survive at this stage.

During the saccular stage, further generations of airways are formed. The tremendous expansion of the prospective respiratory airspaces causes the formation of saccules and a marked decrease in the interstitial tis-sue mass. The lung looks more and more “aerated,” but it is filled with fluid originating from the lungs and from the amniotic fluid surrounding the fetus. Some weeks before birth, alveolar formation begins by a septation process that subdivides the saccules into alveoli. At this stage of lung development, the infant is born. At birth the intrapulmonary fluid is rapidly evacuated and the lung fills with air with the first breaths. Simultaneously, the pulmonary circulation, which before was practically bypassed and very little perfused, opens up to accept the full cardiac output.



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The newborn lung is far from being a miniaturized version of the adult lung. It has only about 20 million to 50 million alveoli, or 6 to 15 percent of the full adult com-plement. Therefore, alveolar formation is completed in the early postnatal period. Although it was previously thought that alveolar formation could continue to age eight and beyond, it is now accepted that the bulk of alve-olar formation is concluded much earlier, probably before age two. Even with complete alveolar formation, the lung is not yet mature. The newly formed interalveolar septa still contain a double capillary network instead of the single one of the adult lungs. This means that the pulmo-nary capillary bed must be completely reorganized during and after alveolar formation to mature. Only after full microvascular maturation, which is terminated sometime between ages two and fi ve, is the lung development com-pleted, and the lung can enter a phase of normal growth.

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CHAPTER CHAPTER 2

The respiratory system is intimately associated with the brain and central nervous system. Indeed, the

diaphragm and the muscles of the chest are innervated by neurons that connect to regions of the brain known as the pons and medulla oblongata. These regions are involved in the control of autonomic nervous activity and therefore regulate internal organs without any conscious recognition or effort. Thus, breathing is an automated function in which nerve impulses sent from the brain stimulate the respiratory muscles to contract, thereby producing the mechanical forces associated with inhalation and exhalation. These impulses give rise to every breath, and in healthy individu-als they are sent faithfully for life.

control of breathing

Breathing is an automatic and rhythmic act produced by networks of neurons in the hindbrain (the pons and medulla). The neural networks direct muscles that form the walls of the thorax and abdomen and produce pressure gradients that move air into and out of the lungs. The respiratory rhythm and the length of each phase of respi-ration are set by reciprocal stimulatory and inhibitory interconnection of these brain-stem neurons.

An important characteristic of the human respiratory system is its ability to adjust breathing patterns to changes in both the internal milieu and the external environment. Ventilation increases and decreases in proportion to

CONTROL AND MECHANICS OF BREATHING


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swings in carbon dioxide production and oxygen con-sumption caused by changes in metabolic rate. The respiratory system is also able to compensate for distur-bances that affect the mechanics of breathing, such as the airway narrowing that occurs in an asthmatic attack. Breathing also undergoes appropriate adjustments when the mechanical advantage of the respiratory muscles is altered by postural changes or by movement.

This flexibility in breathing patterns in large part arises from sensors distributed throughout the body that send signals to the respiratory neuronal networks in the brain. Chemoreceptors detect changes in blood oxygen levels and change the acidity of the blood and brain. Mechanoreceptors monitor the expansion of the lung, the size of the airway, the force of respiratory muscle contrac-tion, and the extent of muscle shortening.

Although the diaphragm is the major muscle of breath-ing, its respiratory action is assisted and augmented by a complex assembly of other muscle groups. Intercostal muscles inserting on the ribs, abdominal muscles, and muscles such as the scalene and sternocleidomastoid that attach both to the ribs and to the cervical spine at the base of the skull also play an important role in the exchange of air between the atmosphere and the lungs. In addition, laryngeal muscles and muscles in the oral and nasal phar-ynx adjust the resistance of movement of gases through the upper airways during both inspiration and expiration. Although the use of these different muscle groups adds considerably to the flexibility of the breathing act, they also complicate the regulation of breathing. These same muscles are used to perform a number of other functions, such as speaking, chewing and swallowing, and maintain-ing posture.

Perhaps because the “respiratory” muscles are employed in performing nonrespiratory functions, breathing can be

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Singing demands a strong diaphragm to control breath. Shutterstock.com

7 Control and Mechanics of Breathing 7


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influenced by higher brain centres and even controlled vol-untarily to a substantial degree. An outstanding example of voluntary control is the ability to suspend breathing by holding one’s breath. Input into the respiratory con-trol system from higher brain centres may help optimize breathing so that not only are metabolic demands satis-fied by breathing but ventilation also is accomplished with minimal use of energy.

central organization of respiratory neurons

The respiratory rhythm is generated within the pons and medulla. Three main aggregations of neurons are involved: a group consisting mainly of inspiratory neurons in the dorsomedial medulla, a group made up of inspiratory and expiratory neurons in the ventrolateral medulla, and a group in the rostral pons consisting mostly of neurons that discharge in both inspiration and expiration. It is cur-rently thought that the respiratory cycle of inspiration and expiration is generated by synaptic interactions within these groups of neurons.

The inspiratory and expiratory medullary neurons are connected to projections from higher brain centres and from chemoreceptors and mechanoreceptors; in turn they drive cranial motor neurons, which govern the activity of muscles in the upper airways and the activity of spinal motor neurons, which supply the diaphragm and other thoracic and abdominal muscles. The inspiratory and expiratory medullary neurons also receive input from nerve cells responsible for cardiovascular and temperature regulation, allowing the activity of these physiological sys-tems to be coordinated with respiration.

Neurally, inspiration is characterized by an augment-ing discharge of medullary neurons that terminates

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abruptly. After a gap of a few milliseconds, inspiratory activity is restarted, but at a much lower level, and gradu-ally declines until the onset of expiratory neuron activity. Then the cycle begins again. The full development of this pattern depends on the interaction of several types of respiratory neurons: inspiratory, early inspiratory, off-switch, post-inspiratory, and expiratory.

Early inspiratory neurons trigger the augmenting dis-charge of inspiratory neurons. This increase in activity, which produces lung expansion, is caused by self-excitation of the inspiratory neurons and perhaps by the activity of an as yet undiscovered upstream pattern generator. Off-switch neurons in the medulla terminate inspiration, but pontine neurons and input from stretch receptors in the lung help control the length of inspiration. When the vagus nerves are sectioned or pontine centres are destroyed, breathing is characterized by prolonged inspiratory activ-ity that may last for several minutes. This type of breathing, which occasionally occurs in persons with diseases of the brain stem, is called apneustic breathing.

Post-inspiratory neurons are responsible for the declin-ing discharge of the inspiratory muscles that occurs at the beginning of expiration. Mechanically, this discharge aids in slowing expiratory flow rates and probably assists the efficiency of gas exchange. It is believed by some that these post-inspiratory neurons have inhibitory effects on both inspiratory and expiratory neurons and therefore play a significant role in determining the length of the respira-tory cycle and the different phases of respiration.

As the activity of the post-inspiratory neurons sub-sides, expiratory neurons discharge and inspiratory neurons are strongly inhibited. There may be no periph-eral manifestation of expiratory neuron discharge except for the absence of inspiratory muscle activity, although in upright humans the lower expiratory intercostal muscles



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and the abdominal muscles may be active even during quiet breathing. Moreover, as the demand to breathe increases (for example, with exercise), more expiratory intercostal and abdominal muscles contract. As expiration proceeds, the inhibition of the inspiratory muscles gradually dimin-ishes and inspiratory neurons resume their activity.

cheMoreceptors

One way in which breathing is controlled is through feed-back by chemoreceptors. There are two kinds of respiratory chemoreceptors: arterial chemoreceptors, which monitor and respond to changes in the partial pressure of oxygen and carbon dioxide in the arterial blood, and central chemore-ceptors in the brain, which respond to changes in the partial pressure of carbon dioxide in their immediate envi-ronment. Ventilation levels behave as if they were regulated to maintain a constant level of carbon dioxide partial pres-sure and to ensure adequate oxygen levels in the arterial blood. Increased activity of chemoreceptors caused by hypoxia or an increase in the partial pressure of carbon dioxide augments both the rate and depth of breathing, which restores partial pressures of oxygen and carbon dioxide to their usual levels. Conversely, too much ventila-tion depresses the partial pressure of carbon dioxide, which leads to a reduction in chemoreceptor activity and a diminution of ventilation. During sleep and anesthesia, lowering carbon dioxide levels three to four millimetres of mercury below values occurring during wakefulness can cause a total cessation of breathing (apnea).

Peripheral Chemoreceptors

Hypoxia, or the reduction of oxygen supply to tissues to less than physiological levels (produced, for example, by a

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trip to high altitudes), stimulates the carotid and aortic bodies, the principal arterial chemoreceptors. The two carotid bodies are small organs located in the neck at the bifurcation of each of the two common carotid arteries into the internal and external carotid arteries. This organ is extraordinarily well perfused and responds to changes in the partial pressure of oxygen in the arterial blood flow-ing through it rather than to the oxygen content of that blood (the amount of oxygen chemically combined with hemoglobin). The sensory nerve from the carotid body increases its firing rate hyperbolically as the partial pres-sure of oxygen falls.

In addition to responding to hypoxia, the carotid body increases its activity linearly as the partial pressure of car-bon dioxide in arterial blood is raised. This arterial blood parameter rises and falls as air enters and leaves the lungs, and the carotid body senses these fluctuations, responding more to rapid than to slow changes in the partial pressure of carbon dioxide. Larger oscillations in the partial pres-sure of carbon dioxide occur with breathing as metabolic rate is increased. The amplitude of these fluctuations, as reflected in the size of carotid body signals, may be used by the brain to detect changes in the metabolic rate and to produce appropriate adjustment in ventilation.

The carotid body communicates with medullary respi-ratory neurons through sensory fibres that travel with the carotid sinus nerve, a branch of the glossopharyngeal nerve. Microscopically, the carotid body consists of two different types of cells. The type I cells are arranged in groups and are surrounded by type II cells. The type II cells are generally not believed to have a direct role in che-moreception. Fine sensory nerve fibres are found in juxtaposition to type I cells, which, unlike type II cells, contain electron-dense vesicles. Acetylcholine, catechol-amines, and neuropeptides such as enkephalins, vasoactive



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intestinal peptide, and substance P, are located within the vesicles. It is believed that hypoxia and hypercapnia (excessive carbon dioxide in the blood) cause the release of one or more of these neuroactive substances from the type I cells, which then act on the sensory nerve.

It is possible to interfere independently with the responses of the carotid body to carbon dioxide and oxy-gen, which suggests that the same mechanisms are not used to sense or transmit changes in oxygen or carbon dioxide. The aortic bodies located near the arch of the aorta also respond to acute changes in the partial pressure of oxygen, but less well than the carotid body responds to changes in the partial pressure of carbon dioxide. The aor-tic bodies are responsible for many of the cardiovascular effects of hypoxia.

Central Chemoreceptors

Carbon dioxide is one of the most powerful stimulants of breathing. As the partial pressure of carbon dioxide in arterial blood rises, ventilation increases nearly linearly. Ventilation normally increases by two to four litres per minute with each one millimetre of mercury increase in the partial pressure of carbon dioxide. Carbon dioxide increases the acidity of the fluid surrounding the cells but also easily passes into cells and thus can make the interior of cells more acidic. It is not clear whether the receptors respond to the intracellular or extracellular effects of car-bon dioxide or acidity.

Even if both the carotid and aortic bodies are removed, inhaling gases that contain carbon dioxide stimulates breathing. This observation shows that there must be additional receptors that respond to changes in the partial pressure of carbon dioxide. Current thinking places these receptors near the undersurface (ventral part) of the

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medulla. The same areas of the ventral medulla also con-tain vasomotor neurons that are concerned with the regulation of blood pressure. Some investigators argue that respiratory responses produced at the ventral medul-lary surface are direct and are caused by interference with excitatory and inhibitory inputs to respiration from these vasomotor neurons. They believe that respiratory chemo-receptors that respond to carbon dioxide are more diffusely distributed in the brain.

Muscle and Lung Receptors

Receptors in the respiratory muscles and in the lung can also affect breathing patterns. These receptors are partic-ularly important when lung function is impaired, because they can help maintain tidal volume and ventilation at normal levels.

Changes in the length of a muscle affect the force it can produce when stimulated. Generally, there is a length at which the force generated is maximal. Receptors, called spindles, in the respiratory muscles measure muscle length and increase motor discharge to the diaphragm and intercostal muscles when increased stiffness of the lung or resistance to the movement of air caused by dis-ease impedes muscle shortening. Tendon organs, another receptor in muscles, monitor changes in the force pro-duced by muscle contraction. Too much force stimulates tendon organs and causes decreasing motor discharge to the respiratory muscles and may prevent the muscles from damaging themselves.

Inflation of the lungs in animals stops breathing by a reflex described by German physiologist Ewald Hering and Austrian physiologist Josef Breuer. The Hering-Breuer reflex is initiated by lung expansion, which excites stretch receptors in the airways. Stimulation of these receptors,



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which send signals to the medulla by the vagus nerve, shortens inspiratory times as tidal volume (the volume of air inspired) increases, accelerating the frequency of breathing. When lung inflation is prevented, the reflex allows inspiratory time to be lengthened, helping to pre-serve tidal volume.

There are also receptors in the airways and in the alve-oli that are excited by rapid lung inflations and by chemicals such as histamine, bradykinin, and prostaglan-dins. The most important function of these receptors, however, may be to defend the lung against noxious mate-rial in the atmosphere. When stimulated, these receptors constrict the airways and cause rapid shallow breathing, which inhibits the penetration of injurious agents into the bronchial tree. These receptors are supplied, like the stretch receptors, by the vagus nerve. Some of these receptors (called irritant receptors) are innervated by myelinated nerve fibres, others (the J receptors) by unmy-elinated fibres. Stimulation of irritant receptors also causes coughing.

Variations in breathing

Variations in breathing result from changes in metabolic demands in the tissues of the body. For example, during exercise, increased levels of oxygen are needed to fuel muscle function, and thus breathing generally becomes deeper and the number of breaths taken per minute increases. At the opposite end of the spectrum, during sleep, the body’s metabolic rate slows, and thus breathing typically becomes lighter. However, the association between sleep and breathing is more complicated than this because brain activity changes as a person progresses through the different stages of sleep. This in turn leads to fluctuations in breathing patterns.

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Mechanoreceptors, arterial chemoreceptors, and thermal receptors all work in concert during exercise to enhance ventilation. Shutterstock.com

Exercise

One of the remarkable features of the respiratory control system is that ventilation increases suffi ciently to keep the partial pressure of carbon dioxide in arterial blood nearly unchanged despite the large increases in metabolic rate that can occur with exercise, thus preserving acid–base homeostasis. A number of signals arise during exercise that can augment ventilation. Sources of these signals include mechanoreceptors in the exercising limbs; the arterial chemoreceptors, which can sense breath-by-breath oscillations in the partial pressure of carbon dioxide; and thermal receptors, because body tempera-ture rises as metabolism increases.



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The brain also seems to anticipate changes in the met-abolic rate caused by exercise, because parallel increases occur in the output from the motor cortex to the exercis-ing limbs and to respiratory neurons. Changes in the concentration of potassium and lactic acid in the exercis-ing muscles acting on unmyelinated nerve fibres may be another mechanism for stimulation of breathing during exercise. It remains unclear, however, how these various mechanisms are adjusted to maintain acid–base balance.

Sleep

During sleep, body metabolism is reduced, but there is an even greater decline in ventilation so that the partial pres-sure of carbon dioxide in arterial blood rises slightly and arterial partial pressure of oxygen falls. The effects on ven-tilatory pattern vary with sleep stage. In slow-wave sleep, breathing is diminished but remains regular, whereas in rapid eye movement sleep, breathing can become quite erratic. Ventilatory responses to inhaled carbon dioxide and to hypoxia are less in all sleep stages than during wake-fulness. Sufficiently large decreases in the partial pressure of oxygen or increases in the partial pressure of carbon dioxide will cause arousal and terminate sleep.

During sleep, ventilation may swing between periods when the amplitude and frequency of breathing are high and periods in which there is little attempt to breathe, or even apnea (cessation of breathing). This rhythmic waxing and waning of breathing, with intermittent periods of apnea, is called Cheyne-Stokes breathing, after the physi-cians who first described it. The mechanism that produces the Cheyne-Stokes ventilation pattern is still argued, but it may entail unstable feedback regulation of breathing. Similar swings in ventilation sometimes occur in persons with heart failure or with central nervous system disease.

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In addition, ventilation during sleep may intermit-tently fall to low levels or cease entirely because of partial or complete blockage of the upper airways. In some indi-viduals, this intermittent obstruction occurs repeatedly during the night, leading to severe drops in the levels of blood oxygenation. The condition, termed sleep apnea syndrome, occurs most commonly in the elderly, in the newborn, in males, and in the obese. Because arousal is often associated with the termination of episodes of obstruction, sleep is of poor quality, and complaints of excessive daytime drowsiness are common. Snoring and disturbed behaviour during sleep may also occur.

In some persons with sleep apnea syndrome, portions of the larynx and pharynx may be narrowed by fat deposits or by enlarged tonsils and adenoids, which increase the likelihood of obstruction. Others, however, have normal upper airway anatomy, and obstruction may occur because of discoordinated activity of upper airway and chest wall muscles. Many of the upper airway muscles, like the tongue and laryngeal adductors, undergo phasic changes in their electrical activity synchronous with respiration, and the reduced activity of these muscles during sleep may lead to upper airway closure.

the Mechanics of breathing

Air moves in and out of the lungs in response to differ-ences in pressure. When the air pressure within the alveolar spaces falls below atmospheric pressure, air enters the lungs (inspiration), provided the larynx is open. When the air pressure within the alveoli exceeds atmospheric pressure, air is blown from the lungs (expiration). The flow of air is rapid or slow in proportion to the magnitude of the pressure difference. Because atmospheric pressure remains relatively constant, flow is determined by how


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The diaphragm contracts and relaxes, forcing air in and out of the lungs. Encyclopædia Britannica, Inc.

much above or below atmospheric pressure the pressure within the lungs rises or falls.

Alveolar pressure fl uctuations are caused by expansion and contraction of the lungs resulting from tensing and relaxing of the muscles of the chest and abdomen. Each small increment of expansion transiently increases the space enclosing lung air. There is, therefore, less air per unit of volume in the lungs and pressure falls. A difference in air pressure between atmosphere and lungs is created, and air fl ows in until equilibrium with atmospheric pres-sure is restored at a higher lung volume. When the muscles of inspiration relax, the volume of chest and lungs

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decreases, lung air becomes transiently compressed, its pressure rises above atmospheric pressure, and flow into the atmosphere results until pressure equilibrium is reached at the original lung volume. This, then, is the sequence of events during each normal respiratory cycle: lung volume change leading to pressure difference, result-ing in flow of air into or out of the lung and establishment of a new lung volume.

The Lung–Chest System

The forces that normally cause changes in volume of the chest and lungs stem not only from muscle contraction but from the elastic properties of both the lung and the chest. A lung is similar to a balloon in that it resists stretch, tending to collapse almost totally unless held inflated by a pressure difference between its inside and outside. This tendency of the lung to collapse or pull away from the chest is measurable by carefully placing a blunt needle between the outside of the lung and the inside of the chest wall, thereby allowing the lung to sep-arate from the chest at this particular spot. The pressure measured in the small pleural space so created is substan-tially below atmospheric pressure at a time when the pressure within the lung itself equals atmospheric pres-sure. This negative (below-atmospheric) pressure is a measure, therefore, of the force required to keep the lung distended. The force increases (pleural pressure becomes more negative) as the lung is stretched and its volume increases during inspiration. The force also increases in proportion to the rapidity with which air is drawn into the lung and decreases in proportion to the force with which air is expelled from the lungs. In summary, the pleural pressure reflects primarily two forces:



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1. the force required to keep the lung inflated against its elastic recoil and

2. the force required to cause airflow in and out of the lung.

Because the pleural pressure is below atmospheric pressure, air is sucked into the chest and the lung collapses (pneumothorax) when the chest wall is perforated, as by a wound or by a surgical incision.

The force required to maintain inflation of the lung and to cause airflow is provided by the chest and dia-phragm, which are in turn stretched inward by the pull of the lungs. The lung– chest system thus acts as two opposed coiled springs, the length of each of which is affected by the other. Were it not for the outward traction of the chest on the lungs, these would collapse. And were it not for the inward traction of the lungs on the chest and diaphragm, the chest would expand to a larger size and the diaphragm would fall from its dome-shaped position within the chest.

The Role of Muscles

The respiratory muscles displace the equilibrium of elas-tic forces in the lung and chest in one direction or the other by adding muscular contraction. During inspiration, muscle contraction is added to the outward elastic force of the chest to increase the traction on the lung required for its additional stretch. When these muscles relax, the additional retraction of lung returns the system to its equilibrium position.

Contraction of the abdominal muscles displaces the equilibrium in the opposite direction by adding increased abdominal pressure to the retraction of lungs, thereby fur-ther raising the diaphragm and causing forceful expiration. This additional muscular force is removed on relaxation

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and the original lung volume is restored. During ordinary breathing, muscular contraction occurs only on inspira-tion, expiration being accomplished “passively” by elastic recoil of the lung.

At total relaxation of the muscles of inspiration and expiration, the lung is distended to a volume—called the functional residual capacity—of about 40 percent of its maximum volume at the end of full inspiration. Further reduction of the lung volume results from maximal con-traction of the expiratory muscles of chest and abdomen. The volume in these circumstances is known as the resid-ual volume; it is about 20 percent of the volume at the end of full inspiration (known as the total lung capacity). Additional collapse of the lung to its “minimal air” can be accomplished only by opening the chest wall and creating a pneumothorax.

The membranes of the surface of the lung (visceral pleura) and on the inside of the chest (parietal pleura) are normally kept in close proximity (despite the pull of lung and chest in opposite directions) by surface tension of the thin layer of fluid covering these surfaces. The strength of this bond can be appreciated by the attempt to pull apart two smooth surfaces, such as pieces of glass, separated by a film of water.

The Respiratory Pump and Its Performance

The energy expended on breathing is used primarily in stretching the lung– chest system and thus causing airflow. It normally amounts to 1 percent of the basal energy requirements of the body but rises substantially during exercise or illness. The respiratory pump is versatile, capa-ble of increasing its output 25 times, from a normal resting level of about six litres (366 cubic inches) per minute to 150 litres (9,154 cubic inches) per minute in adults. Pressures


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A cough clears the airways with an abrupt opening of the larynx. © www.istockphoto.com / Jason Lugo

within the lungs can be raised to 130 centimetres of water (about 1.8 pounds per square inch) by the so-called Valsalva maneuver—a forceful contraction of the chest and abdom-inal muscles against a closed glottis (i.e., with no space between the vocal cords). Airfl ow velocity, normally reach-ing 30 litres per minute in quiet breathing, can be raised voluntarily to 400 litres per minute.

Cough is accomplished by suddenly opening the larynx during a brief Valsalva maneuver. The resultant high-speed jet of air is an effective means of clearing the airways of excessive secretions or foreign particles. The beating of cilia (hairline projections) from cells lining the airways

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normally maintains a steady flow of secretions toward the nose, cough resulting only when this action cannot keep pace with the rate at which secretions are produced. An infant takes 33 breaths per minute with a tidal volume (the amount of air breathed in and out in one cycle) of 15 milli-litres, totaling about 0.5 litre (approximately one pint) per minute as compared to adult values of 14 breaths, 500 mil-lilitres, and seven litres, respectively.

If the force of surface tension is responsible for the adherence of parietal and visceral pleurae, it is reasonable to question what keeps the lungs’ alveolar walls (also fluid-covered) from sticking together and thus eliminating alveolar airspaces. In fact, such adherence occasionally does occur and is one of the dreaded complications of pre-mature births. Normal lungs, however, contain a substance (a phospholipid surfactant) that reduces surface tension and keeps alveolar walls separated.


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CHAPTER CHAPTER 3

Inhaled air is rich in oxygen, which is needed to support

the functions of the body’s various tissues. For inhaled oxygen to reach these tissues, however, it must fi rst undergo a process of gas exchange that occurs at the level of the alveoli in the lungs. Blood vessels that pass along-side the alveoli membranes absorb the oxygen and, in exchange, transfer carbon dioxide to the alveoli. The oxy-gen is then distributed by the blood to the tissues, whereas the carbon dioxide is expelled from the alveoli during exhalation. At high altitudes or during activities such as deep-sea diving, the respiratory system, as well as other organ systems, adapt to variations in atmospheric pres-sure. This process of adaptation is necessary to maintain normal physiological function.

gas exchange

Respiratory gases—oxygen and carbon dioxide—move between the air and the blood across the respiratory exchange surfaces in the lungs. The structure of the human lung provides an immense internal surface that facilitates gas exchange between the alveoli and the blood in the pul-monary capillaries. The area of the alveolar surface in the adult human is about 160 square metres (1,722 square feet). Gas exchange across the membranous barrier between the alveoli and capillaries is enhanced by the thin nature of the membrane, about 0.5 micrometre, or ¹/¹00 of the diameter of a human hair.

GAS EXCHANGE AND RESPIRATORY ADAPTATION

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Changes in the atmosphere’s pressure occur when deep-sea diving and require the respiratory system to adapt. Shutterstock.com

7 Gas Exchange and Respiratory Adaptation 7


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Respiratory gases move between the environment and the respiring tissues by two principal mechanisms, con-vection and diffusion. Convection, or mass flow, is responsible for movement of air from the environment into the lungs and for movement of blood between the lungs and the tissues. Respiratory gases also move by dif-fusion across tissue barriers such as membranes. Diffusion is the primary mode of transport of gases between air and blood in the lungs and between blood and respiring tissues in the body. The process of diffusion is driven by the dif-ference in partial pressures of a gas between two locales. In a mixture of gases, the partial pressure of each gas is directly proportional to its concentration. The partial pressure of a gas in fluid is a measure of its tendency to leave the fluid when exposed to a gas or fluid that does not contain that gas. A gas will diffuse from an area of greater partial pressure to an area of lower partial pressure regard-less of the distribution of the partial pressures of other gases. There are large changes in the partial pressures of oxygen and carbon dioxide as these gases move between air and the respiring tissues. The partial pressure of car-bon dioxide in this pathway is lower than the partial pressure of oxygen, caused by differing modes of transport in the blood, but almost equal quantities of the two gases are involved in metabolism and gas exchange.

Oxygen and carbon dioxide are transported between tissue cells and the lungs by the blood. The quantity trans-ported is determined both by the rapidity with which the blood circulates and the concentrations of gases in blood. The rapidity of circulation is determined by the output of the heart, which in turn is responsive to overall body requirements. Local flows can be increased selectively, as occurs, for example, in the flow through skeletal muscles during exercise. The performance of the heart and circula-

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tory regulation are, therefore, important determinants of gas transport.

Oxygen and carbon dioxide are too poorly soluble in blood to be adequately transported in solution. Specialized systems for each gas have evolved to increase the quanti-ties of those gases that can be transported in blood. These systems are present mainly in the red cells, which make up 40 to 50 percent of the blood volume in most mam-mals. Plasma, the cell-free, liquid portion of blood, plays little role in oxygen exchange but is essential to carbon dioxide exchange.

transport of oxygen

Oxygen is poorly soluble in plasma, so less than 2 percent of oxygen is transported dissolved in plasma. Most oxygen is bound to hemoglobin, a protein contained within red cells. Hemoglobin is composed of four iron-containing ring structures (hemes) chemically bonded to a large pro-tein (globin). Each iron atom can bind and then release an oxygen molecule. Enough hemoglobin is present in nor-mal human blood to permit transport of about 0.2 ml of oxygen per ml of blood. The quantity of oxygen bound to hemoglobin is dependent on the partial pressure of oxy-gen in the lung to which blood is exposed. The curve representing the content of oxygen in blood at various partial pressures of oxygen, called the oxygen-dissociation curve, is a characteristic S-shape because binding of oxy-gen to one iron atom influences the ability of oxygen to bind to other iron sites. In alveoli at sea level, the partial pressure of oxygen is sufficient to bind oxygen to essen-tially all available iron sites on the hemoglobin molecule.

Not all of the oxygen transported in the blood is transferred to the tissue cells. The amount of oxygen



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extracted by the cells depends on their rate of energy expenditure. At rest, venous blood returning to the lungs still contains 70 to 75 percent of the oxygen that was pres-ent in arterial blood. This reserve is available to meet increased oxygen demands. During extreme exercise the quantity of oxygen remaining in venous blood decreases to 10 to 25 percent. At the steepest part of the oxygen-dissociation curve (the portion between 10 and 40 mm of mercury partial pressure), a relatively small decline in the partial pressure of oxygen in the blood is associated with a relatively large release of bound oxygen.

Hemoglobin binds not only to oxygen but to other substances as well, including hydrogen ions (which deter-mine the acidity, or pH, of the blood), carbon dioxide, and 2,3-diphosphoglycerate (2,3-DPG; a salt in the red blood cells that plays a role in liberating oxygen from hemoglobin in the peripheral circulation). Although these substances do not bind to hemoglobin at the oxygen-binding sites, with the binding of oxygen, changes in the structure of the hemoglobin molecule occur that affect its ability to bind other gases or substances. Conversely, binding of these sub-stances to hemoglobin affects the affinity of hemoglobin for oxygen. (Affinity denotes the tendency of molecules of different species to bind to one another.) Increases in hydro-gen ions, carbon dioxide, or 2,3-DPG decrease the affinity of hemoglobin for oxygen, and the oxygen-dissociation curve shifts to the right. Because of this decreased affin-ity, an increased partial pressure of oxygen is required to bind a given amount of oxygen to hemoglobin. A rightward shift of the curve is thought to be of benefit in releasing oxygen to the tissues when needs are great in relation to oxygen delivery, as occurs with anemia or extreme exercise. Reductions in normal concentrations of hydrogen ions, carbon dioxide, and 2,3-DPG result in an increased affinity of hemoglobin for oxygen, and the curve is shifted

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to the left. This displacement increases oxygen binding to hemoglobin at any given partial pressure of oxygen and is thought to be beneficial if the availability of oxygen is reduced, as occurs at extreme altitude.

Temperature changes affect the oxygen-dissociation curve similarly. An increase in temperature shifts the curve to the right (decreased affinity; enhanced release of oxy-gen), whereas a decrease in temperature shifts the curve to the left (increased affinity). The range of body tempera-ture usually encountered in humans is relatively narrow, so that temperature-associated changes in oxygen affinity have little physiological importance.

transport of carbon dioxide

Transport of carbon dioxide in the blood is considerably more complex. A small portion of carbon dioxide, about 5 percent, remains unchanged and is transported dissolved in blood. The remainder is found in reversible chemical combinations in red blood cells or plasma. Some carbon dioxide binds to blood proteins, principally hemoglobin, to form a compound known as carbamate. About 88 per-cent of carbon dioxide in the blood is in the form of bicarbonate ion. The distribution of these chemical spe-cies between the interior of the red blood cell and the surrounding plasma varies greatly, with the red blood cells containing considerably less bicarbonate and more carba-mate than the plasma.

Less than 10 percent of the total quantity of carbon dioxide carried in the blood is eliminated during passage through the lungs. Complete elimination would lead to large changes in acidity between arterial and venous blood. Furthermore, blood normally remains in the pulmonary capillaries less than a second, an insufficient time to elimi-nate all carbon dioxide.


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Hemoglobin acts as a natural buffering agent for the acidity that occurs when carbon dioxide reacts with water. Shutterstock.com

Carbon dioxide enters blood in the tissues because its local partial pressure is greater than its partial pressure in blood fl owing through the tissues. As carbon dioxide enters the blood, it combines with water to form carbonic acid (H 2 CO 3 ), a relatively weak acid, which dissociates into hydrogen ions (H + ) and bicarbonate ions (HCO 3

- ). Blood acidity is minimally affected by the released hydrogen ions because blood proteins, especially hemoglobin, are effec-tive buffering agents. (A buffer solution resists change in acidity by combining with added hydrogen ions and, essentially, inactivating them.) The natural conversion of carbon dioxide to carbonic acid is a relatively slow process. Carbonic anhydrase, a protein enzyme present inside the

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red blood cell, catalyzes this reaction with sufficient rapid-ity that it is accomplished in only a fraction of a second. Because the enzyme is present only inside the red blood cell, bicarbonate accumulates to a much greater extent within the red cell than in the plasma. The capacity of blood to carry carbon dioxide as bicarbonate is enhanced by an ion transport system inside the red blood cell mem-brane that simultaneously moves a bicarbonate ion out of the cell and into the plasma in exchange for a chloride ion. The simultaneous exchange of these two ions, known as the chloride shift, permits the plasma to be used as a storage site for bicarbonate without changing the electri-cal charge of either the plasma or the red blood cell. Only 26 percent of the total carbon dioxide content of blood exists as bicarbonate inside the red blood cell, while 62 percent exists as bicarbonate in plasma. The bulk of bicar-bonate ions is first produced inside the cell, however, then transported to the plasma. A reverse sequence of reactions occurs when blood reaches the lung, where the partial pressure of carbon dioxide is lower than in the blood.

Hemoglobin acts in another way to facilitate the trans-port of carbon dioxide. Amino groups of the hemoglobin molecule react reversibly with carbon dioxide in solution to yield carbamates. A few amino sites on hemoglobin are oxylabile, that is, their ability to bind carbon dioxide depends on the state of oxygenation of the hemoglobin molecule. The change in molecular configuration of hemo-globin that accompanies the release of oxygen leads to increased binding of carbon dioxide to oxylabile amino groups. Thus, release of oxygen in body tissues enhances binding of carbon dioxide as carbamate. Oxygenation of hemoglobin in the lungs has the reverse effect and leads to carbon dioxide elimination.

Only 5 percent of carbon dioxide in the blood is trans-ported free in physical solution without chemical change



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or binding, yet this pool is important, because only free carbon dioxide easily crosses biologic membranes. Virtually every molecule of carbon dioxide produced by metabolism must exist in the free form as it enters blood in the tissues and leaves capillaries in the lung. Between these two events, most carbon dioxide is transported as bicarbonate or carbamate.

gas exchange in the lung

The introduction of air into the alveoli allows the removal of carbon dioxide and the addition of oxygen to venous blood. Because ventilation is a cyclic phenomenon that occurs through a system of conducting airways, not all inspired air participates in gas exchange. A portion of the inspired breath remains in the conducting airways and does not reach the alveoli where gas exchange occurs. This portion is approximately one-third of each breath at rest but decreases to as little as 10 percent during exercise, because of the increased size of inspired breaths.

In contrast to the cyclic nature of ventilation, blood flow through the lung is continuous, and almost all blood entering the lungs participates in gas exchange. The efficiency of gas exchange is critically dependent on the uniform distribution of blood flow and inspired air throughout the lungs. In health, ventilation and blood flow are extremely well matched in each exchange unit throughout the lungs. The lower parts of the lung receive slightly more blood flow than ventilation because grav-ity has a greater effect on the distribution of blood than on the distribution of inspired air. Under ideal circum-stances, partial pressures of oxygen and carbon dioxide in alveolar gas and arterial blood are identical. Normally there is a small difference between oxygen tensions in alveolar gas and arterial blood because of the effect of

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gravity on matching and the addition of a small amount of venous drainage to the bloodstream after it has left the lungs. These events have no measurable effect on carbon dioxide partial pressures because the difference between arterial and venous blood is so small.

abnorMal gas exchange

Lung disease can lead to severe abnormalities in blood gas composition. Because of the differences in oxygen and carbon dioxide transport, impaired oxygen exchange is far more common than impaired carbon dioxide exchange. Mechanisms of abnormal gas exchange are grouped into four categories: hypoventilation, shunting, ventilation–blood flow imbalance, and limitations of diffusion.

If the quantity of inspired air entering the lungs is less than is needed to maintain normal exchange—a condition known as hypoventilation—the alveolar partial pressure of carbon dioxide rises and the partial pressure of oxygen falls almost reciprocally. Similar changes occur in arterial blood partial pressures because the composition of alveo-lar gas determines gas partial pressures in blood perfusing the lungs. This abnormality leads to parallel changes in both gas and blood and is the only abnormality in gas exchange that does not cause an increase in the normally small difference between arterial and alveolar partial pres-sures of oxygen.

In shunting, venous blood enters the bloodstream without passing through functioning lung tissue. Shunting of blood may result from abnormal vascular (blood ves-sel) communications or from blood flowing through unventilated portions of the lung (e.g., alveoli filled with fluid or inflammatory material). A reduction in arterial blood oxygenation is seen with shunting, but the level of carbon dioxide in arterial blood is not elevated even



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though the shunted blood contains more carbon dioxide than arterial blood.

The differing effects of shunting on oxygen and carbon dioxide partial pressures are the result of the different configurations of the blood-dissociation curves of the two gases. As noted earlier, the oxygen-dissociation curve is S-shaped and plateaus near the normal alveolar oxygen partial pressure, but the carbon dioxide–dissociation curve is steeper and does not plateau as the partial pressure of carbon dioxide increases. When blood perfusing the col-lapsed, unventilated area of the lung leaves the lung without exchanging oxygen or carbon dioxide, the content of carbon dioxide is greater than the normal carbon diox-ide content. The remaining healthy portion of the lung receives both its usual ventilation and the ventilation that normally would be directed to the abnormal lung. This lowers the partial pressure of carbon dioxide in the alveoli of the normal area of the lung. As a result, blood leaving the healthy portion of the lung has a lower carbon dioxide content than normal. The lower carbon dioxide content in this blood counteracts the addition of blood with a higher carbon dioxide content from the abnormal area, and the composite arterial blood carbon dioxide content remains normal. This compensatory mechanism is less efficient than normal carbon dioxide exchange and requires a mod-est increase in overall ventilation, which is usually achieved without difficulty. Because the carbon dioxide–dissocia-tion curve is steep and relatively linear, compensation for decreased carbon dioxide exchange in one portion of the lung can be counterbalanced by increased excretion of car-bon dioxide in another area of the lung.

In contrast, shunting of venous blood has a substantial effect on arterial blood oxygen content and partial pres-sure. Blood leaving an unventilated area of the lung has

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an oxygen content that is less than the normal content. In the healthy area of the lung, the increase in ventilation above normal raises the partial pressure of oxygen in the alveolar gas and, therefore, in the arterial blood. The oxy-gen-dissociation curve, however, reaches a plateau at the normal alveolar partial pressure, and an increase in blood partial pressure results in a negligible increase in oxygen content. Mixture of blood from this healthy portion of the lung (with normal oxygen content) and blood from the abnormal area of the lung (with decreased oxygen content) produces a composite arterial oxygen content that is less than the normal level. Thus, an area of healthy lung can-not counterbalance the effect of an abnormal portion of the lung on blood oxygenation because the oxygen-disso-ciation curve reaches a plateau at a normal alveolar partial pressure of oxygen. This effect on blood oxygenation is seen not only in shunting but in any abnormality that results in a localized reduction in blood oxygen content.

Mismatching of ventilation and blood flow is by far the most common cause of a decrease in partial pressure of oxygen in blood. There are minimal changes in blood carbon dioxide content unless the degree of mismatch is extremely severe. Inspired air and blood flow normally are distributed uniformly, and each alveolus receives approxi-mately equal quantities of both. As matching of inspired air and blood flow deviates from the normal ratio of 1 to 1, alveoli become either overventilated or underventilated in relation to their blood flow. In alveoli that are overven-tilated, the amount of carbon dioxide eliminated is increased, which counteracts the fact that there is less carbon dioxide eliminated in the alveoli that are relatively underventilated. Overventilated alveoli, however, cannot compensate in terms of greater oxygenation for under-ventilated alveoli because, a plateau is reached at the



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alveolar partial pressure of oxygen, and increased ventila-tion will not increase blood oxygen content. In healthy lungs there is a narrow distribution of the ratio of ventila-tion to blood flow throughout the lung that is centred around a ratio of 1 to 1. In disease, this distribution can broaden substantially so that individual alveoli can have ratios that markedly deviate from the ratio of 1 to 1. Any deviation from the usual clustering around the ratio of 1 to 1 leads to decreased blood oxygenation: the more dispa-rate the deviation, the greater the reduction in blood oxygenation. Carbon dioxide exchange, however, is not affected by an abnormal ratio of ventilation and blood flow as long as the increase in ventilation that is required to maintain carbon dioxide excretion in overventilated alveoli can be achieved.

A fourth category of abnormal gas exchange involves limitation of diffusion of gases across the thin membrane separating the alveoli from the pulmonary capillaries. A variety of processes can interfere with this orderly exchange. For oxygen, these include increased thickness of the alveolar–capillary membrane, loss of surface area available for diffusion of oxygen, a reduction in the alveo-lar partial pressure of oxygen required for diffusion, and decreased time available for exchange due to increased velocity of flow. These factors are usually grouped under the broad description of “diffusion limitation,” and any can cause incomplete transfer of oxygen with a resultant reduction in blood oxygen content. There is no diffusion limitation of the exchange of carbon dioxide because this gas is more soluble than oxygen in the alveolar–capillary membrane, which facilitates carbon dioxide exchange. The complex reactions involved in carbon dioxide trans-port proceed with sufficient rapidity to avoid being a significant limiting factor in exchange.

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interplay of respiration, circulation, and MetabolisM

The interplay of respiration, circulation, and metabolism is the key to the functioning of the respiratory system as a whole. For gas exchange that takes place in the lungs, cells set the demand for oxygen uptake and carbon diox-ide discharge. The circulation of the blood links the sites of oxygen use and uptake. The proper functioning of the respiratory system depends on both the ability of the system to make functional adjustments to varying needs and the design features of the sequence of struc-tures involved, which set the limit for respiration.

The main purpose of respiration is to provide oxygen to the cells at a rate adequate to satisfy their metabolic needs. This involves transport of oxygen from the lung to the tissues by means of the circulation of blood. In antiq-uity and the medieval period, the heart was regarded as a furnace where the “fire of life” kept the blood boiling. Modern cell biology has unveiled the truth behind the metaphor. Each cell maintains a set of furnaces, the mito-chondria, where, through the oxidation of foodstuffs such as glucose, the energetic needs of the cells are supplied. The precise object of respiration therefore is the supply of oxygen to the mitochondria.

Cell metabolism depends on energy derived from high-energy phosphates such as adenosine triphosphate (ATP), whose third phosphate bond can release a quan-tum of energy to fuel many cell processes, such as the contraction of muscle fibre proteins or the synthesis of protein molecules. In the process, ATP is degraded to adenosine diphosphate (ADP), a molecule with only two phosphate bonds. To recharge the molecule by adding the third phosphate group requires energy derived from



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the breakdown of foodstuffs, or substrates. Two pathways are available:

1. anaerobic glycolysis, or fermentation, which operates in the absence of oxygen; and

2. aerobic metabolism, which requires oxygen and involves the mitochondria.

The anaerobic pathway leads to acid waste products and is wasteful of resources: the breakdown of one mole-cule of glucose generates only two molecules of ATP. In contrast, aerobic metabolism has a higher yield (36 mol-ecules of ATP per molecule of glucose) and results in “clean wastes”—water and carbon dioxide, which are eas-ily eliminated from the body and are recycled by plants in the process of photosynthesis. For any sustained high-level cell activity, the aerobic metabolic pathway is therefore preferable. Because oxidative phosphorylation occurs only in mitochondria, and since each cell must produce its own ATP (it cannot be imported), the num-ber of mitochondria in a cell reflects its capacity for aerobic metabolism, or its need for oxygen.

The supply of oxygen to the mitochondria at an ade-quate rate is a critical function of the respiratory system, because the cells maintain only a limited store of high-energy phosphates and of oxygen, whereas they usually have a reasonable supply of substrates in stock. If oxygen supply is interrupted for a few minutes, many cells, or even the organism, will die.

Oxygen is collected from environmental air, trans-ferred to blood in the lungs, and transported by blood flow to the periphery of the cells where it is discharged to reach the mitochondria by diffusion. The transfer of oxygen to the mitochondria involves several structures and different modes of transports. It begins with

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ventilation of the lung, which is achieved by convection or mass flow of air through an ingeniously branched sys-tem of airways. In the most peripheral airways, ventilation of alveoli is completed by diffusion of oxygen through the air to the alveolar surface. The transfer of oxygen from alveolar air into the capillary blood occurs by diffu-sion across the tissue barrier. It is driven by the oxygen partial pressure difference between alveolar air and capillary blood and depends on the thickness (about 0.5 micrometre) and the surface area of the barrier. Convective transport by the blood depends on the blood flow rate (cardiac output) and on the oxygen capacity of the blood, which is determined by its content of hemo-globin in the red blood cells. The last step is the diffusive discharge of oxygen from the capillaries into the tissue and cells, which is driven by the oxygen partial pressure difference and depends on the quantity of capillary blood in the tissue. In this process the blood plays a central role and affects all transport steps: oxygen uptake in the lung, transport by blood flow, and discharge to the cells. Blood also serves as carrier for both respiratory gases: oxygen, which is bound to hemoglobin in the red blood cells, and carbon dioxide, which is carried by both plasma and red blood cells and which also serves as a buffer for acid–base balance in blood and tissues.

Metabolism, or, more accurately the metabolic rate of the cells, sets the demand for oxygen. At rest, a human consumes about 250 ml of oxygen each minute. With exercise this rate can be increased more than 10-fold in a normal healthy individual, but a highly trained athlete may achieve a more than 20-fold increase. As more and more muscle cells become engaged in doing work, the demand for ATP and oxygen increases linearly with work rate. This is accompanied by an increased cardiac output, essentially resulting from a higher heart rate, and by



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increased ventilation of the lungs. Consequently, the oxy-gen partial pressure difference across the air–blood barrier increases and oxygen transfer by diffusion is augmented. These dynamic adjustments to the muscles’ needs occur up to a limit that is twice as high in the athlete as in the untrained individual. This range of possible oxidative metabolism from rest to maximal exercise is called the aerobic scope. The upper limit to oxygen consumption is not conferred by the ability of muscles to do work, but rather by the limited ability of the respiratory system to provide or use oxygen at a higher rate. Muscle can do more work, but beyond the aerobic scope they must revert to anaerobic metabolism, with the result that waste products, mainly lactic acid, accumulate and limit the duration of work.

The limit to oxidative metabolism is therefore set by some features of the respiratory system, from the lung to the mitochondria. Knowing precisely what sets the limit is important for understanding respiration as a key vital process, but it is not straightforward, because of the complexity of the system. Much has been learned from comparative physiology and morphology, based on observations that oxygen consumption rates differ signif-icantly among species. For example, the athletic species in nature, such as dogs or horses, have an aerobic scope more than twofold greater than that of other animals of the same size; this is called adaptive variation. Then, oxy-gen consumption per unit body mass increases as animals become smaller, so that a mouse consumes six times as much oxygen per gram of body mass as a cow, a feature called allometric variation. Furthermore, the aerobic scope can be increased by training in an individual, but this induced variation achieves at best a 50 percent dif-ference between the untrained and the trained state, well below interspecies differences.

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Athletic animals such as dogs have an aerobic scope more than twice that of similarly sized animals. This difference arises from a phenomenon known as adaptive variation. Shutterstock.com

Within the aerobic scope the adjustments are caused by functional variation. For example, cardiac output is augmented by increasing heart rate. Mounting evidence indicates that the limit to oxidative metabolism is related to structural design features of the system. The total amount of mitochondria in skeletal muscle is strictly pro-portional to maximal oxygen consumption, in all types of variation. In training, the mitochondria increase in pro-portion to the augmented aerobic scope. Mitochondria set the demand for oxygen, and they seem able to con-sume up to fi ve millilitres of oxygen per minute and gram of mitochondria. If energy (ATP) needs to be produced at a higher rate, the muscle cells make more mitochondria.



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It is thus possible that oxygen consumption is limited at the periphery, at the last step of aerobic metabolism. But it is also possible that more central parts of the respira-tory system may set the limit to oxygen transport, mainly the heart, whose capacity to pump blood reaches a limit, both in terms of rate and of the size of the ventricles, which determines the volume of blood that can be pumped with each stroke. The issue of peripheral versus central limitation is still under debate. It appears, however, that the lung as a gas-exchanging organ has sufficient redun-dancy that it does not limit aerobic metabolism at the site of oxygen uptake. But, whereas the mitochondria, the blood, the blood vessels, and the heart can increase in number, rate, or volume to augment their capacity when energy needs increase, such as in training, the lung lacks this capacity to adapt. If this proves true, the lung may well constitute the ultimate limit for the respiratory sys-tem, beyond which oxidative metabolism cannot be increased by training.

adaptations

Adaptation of the respiratory system to different atmospheric pressures plays a fundamental role in main-taining the efficiency of gas exchange and gas transport in the blood. In the case of adaptation to high altitudes, the structure of the alveoli in the lungs, the levels of hemoglobin in the blood, and the structure and function of the energy-producing mitochondria in the cells of tis-sues may be affected. In the cases of swimming and diving, physiological changes are more acute in nature and are influenced by the immediate affects of decreased ventila-tion or by the affects of increased hydrostatic pressure on the body.

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At high altitudes, hikers and climbers acclimatize to low oxygen levels by using oxygen canisters, which heighten the partial pressure of oxygen at all stages. Barry C. Bishop/National Geographic/Getty Images

High Altitudes

Ascent from sea level to high altitude has well-known effects on respiration. The progressive fall in barometric pressure is accompanied by a fall in the partial pressure of oxygen, both in the ambient air and in the alveolar spaces of the lung. This very fall poses the major respiratory chal-lenge to humans at high altitude. Humans and some other mammalian species, such as cattle, adjust to the fall in oxy-gen pressure through the reversible and non-inheritable process of acclimatization, which, whether undertaken deliberately or not, commences from the time of exposure to high altitudes. Indigenous mountain species such as the



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llama, on the other hand, exhibit an adaptation that is her-itable and has a genetic basis.

Respiratory acclimatization in humans is achieved through mechanisms that heighten the partial pressure of oxygen at all stages, from the alveolar spaces in the lung to the mitochondria in the cells, where oxygen is needed for the ultimate biochemical expression of respiration. The decline in the ambient partial pressure of oxygen is offset to some extent by greater ventilation, which takes the form of deeper breathing rather than a faster rate at rest. Diffusion of oxygen across the alveolar walls into the blood is facilitated, and in some experimental animal studies the alveolar walls are thinner at altitude than at sea level. The scarcity of oxygen at high altitudes stimulates increased production of hemoglobin and red blood cells, which increases the amount of oxygen transported to the tissues. The extra oxygen is released by increased levels of inorganic phosphates in the red blood cells, such as 2,3-DPG. With a prolonged stay at altitude, the tissues develop more blood vessels, and, as capillary density is increased, the length of the diffusion path along which gases must pass is decreased—a factor augmenting gas exchange. In addition, the size of muscle fibres decreases, which also shortens the diffusion path of oxygen.

The initial response of respiration to the fall of oxy-gen partial pressure in the blood on ascent to high altitude occurs in two small nodules, the carotid bodies, attached to the division of the carotid arteries on either side of the neck. As the oxygen deprivation persists, the carotid bod-ies enlarge but become less sensitive to the lack of oxygen. The low oxygen partial pressure in the lung is associated with thickening of the small blood vessels in pulmonary alveolar walls and a slight increase in pulmonary blood pressure, thought to enhance oxygen perfusion of the lung apices.

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Indigenous mountain animals like the llama, alpaca, and vicuña in the Andes or the yak in the Himalayas are adapted rather than acclimatized to the low oxygen partial pressures of high altitude. Their hemoglobin has a high oxygen affinity, so full saturation of the blood with oxygen occurs at a lower partial pressure of oxygen. In contrast to acclimatized humans, these indigenous, adapted moun-tain species do not have increased levels of hemoglobin or of organic phosphates in the red cells. They do not develop small muscular blood vessels or an increased blood pres-sure in the lung, and their carotid bodies remain small.

Native human highlanders are acclimatized rather than genetically adapted to the reduced oxygen pressure. After living many years at high altitude, some highlanders lose this acclimatization and develop chronic mountain sickness, sometimes called Monge disease, after the Peruvian physician who first described it. This disease is characterized by greater levels of hemoglobin. In Tibet some infants of Han origin never achieve satisfactory acclimatization on ascent to high altitude. A chemodec-toma, or benign tumour, of the carotid bodies may develop in native highlanders in response to chronic exposure to low levels of oxygen.

Swimming and Diving

Fluid is not a natural medium for sustaining human life after the fetal stage. Human respiration requires ventila-tion with air. Nevertheless, all vertebrates, including humans, exhibit a set of responses that may be called a “diving reflex,” which involves cardiovascular and meta-bolic adaptations to conserve oxygen during diving into water. Other physiological changes are also observed, either artificially induced (as by hyperventilation) or resulting from pressure changes in the environment at the



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same time that a diver is breathing from an independent gas supply.

Hyperventilation, a form of overbreathing that increases the amount of air entering the pulmonary alve-oli, may be used intentionally by swimmers to prolong the time they are able to hold their breath underwater. Hyperventilation can be dangerous, and this danger is greatly increased if the swimmer descends to depth, as sometimes happens in snorkeling. The increased ven-tilation prolongs the duration of the breath-hold by reducing the carbon dioxide pressure in the blood, but it cannot provide an equivalent increase in oxygen. Thus the carbon dioxide that accumulates with exercise takes longer to reach the threshold at which the swimmer is forced to take another breath, but the oxygen content of the blood concurrently falls to unusually low levels. The increased environmental pressure of the water around the breath-holding diver increases the partial pressures of the pulmonary gases. This allows an adequate oxygen partial pressure to be maintained in the setting of reduced oxygen content, and consciousness remains unimpaired. When the accumulated carbon dioxide at last forces the swimmer to return to the surface, however, the progres-sively diminishing pressure of the water on his ascent reduces the partial pressure of the remaining oxygen. Unconsciousness may then occur in or under the water.

Divers who breathe from an apparatus that delivers gas at the same pressure as that of the surrounding water need not return to the surface to breathe and can remain at depth for prolonged periods. But this apparent advan-tage introduces additional hazards, many of them unique in human physiology. Most hazards result from the envi-ronmental pressure of water. Two factors are involved. At the depth of a diver, the absolute pressure, which is

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approximately one additional atmosphere for each 10-metre (33-foot) increment of depth, is one factor. The other factor, acting at any depth, is the vertical hydrostatic pressure gradient across the body. The effects of pressure are seen in many processes at the molecular and cellular level and include the physiological effects of the increased partial pressures of the respiratory gases, the increased density of the respiratory gases, the effect of changes of pressure upon the volumes of the gas-containing spaces in the body, and the consequences of the uptake of respira-tory gases into, and their subsequent elimination from, the blood and tissues of the diver, often with the forma-tion of bubbles. The multiple effects of submersion upon respiration are not easily separated from one another or clearly distinguishable from related effects of pressure upon other bodily systems.

The increased work of breathing, rather than cardiac or muscular performance, is the limiting factor for hard physical work underwater. Although the increased work of breathing may largely result from the effects of increased respiratory gas density upon pulmonary function, the use of underwater breathing apparatus adds significant exter-nal breathing resistance to the diver’s respiratory burden.

Arterial carbon dioxide pressure should remain unchanged during changes of ambient pressure, but the impaired alveolar ventilation at depth leads to some car-bon dioxide retention (hypercapnia). This may be compounded by an increased inspiratory content of car-bon dioxide, especially if the diver uses closed-circuit and semiclosed-circuit rebreathing equipment or wears an inadequately ventilated helmet. Alveolar oxygen levels can also be disturbed in diving. Hypoxia may result from fail-ure of the gas supply and may occur without warning. More commonly, the levels of inspired oxygen are



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increased. Oxygen in excess can be a poison. At a partial pressure greater than 1.5 bar (“surface equivalent value” = 150 percent), it may cause the rapid onset of convulsions, and after prolonged exposures at somewhat lower partial pres-sures it may cause pulmonary oxygen toxicity with reduced vital capacity and later pulmonary edema. In mixed-gas diving, inspired oxygen is therefore maintained at a partial pressure somewhere between 0.2 and 0.5 bar, but at great depths the inhomogeneity of alveolar ventilation and the limitations of gas diffusion appear to require oxygen pro-vision at greater than normal levels.

The maximum breathing capacity and the maximum voluntary ventilation of a diver breathing compressed air diminish rapidly with depth, approximately in proportion to the reciprocal of the square root of the increasing gas density. Thus the practice of using an inert gas such as helium as the oxygen diluent at depths where nitrogen becomes narcotic, like an anesthetic, has the additional advantage of providing a breathing gas of lesser density. The use of hydrogen, which in a mixture with less than 4 percent oxygen is noncombustible, provides a greater respiratory advantage for deep diving.

At the extreme depths now attainable by humans—some 500 metres (1,640 feet) in the sea and more than 680 metres (2,230 feet) in the laboratory—direct effects of pressure upon the respiratory centre may be part of the “high-pressure neurological syndrome” and may account for some of the anomalies of breathlessness (dyspnea) and respiratory control that occur with exercise at depth.

The term carbon dioxide retainer is commonly applied to a diver who fails to eliminate carbon dioxide in the nor-mal manner. An ability to tolerate carbon dioxide may increase the work capacity of a diver at depth but also may predispose him to other consequences that are less desirable. High values of end-tidal carbon dioxide with

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only moderate exertion may be associated with a dimin-ished tolerance to oxygen neurotoxicity, a condition that, if it occurs underwater, places the diver at great risk. Nitrogen narcosis is enhanced by the presence of excess carbon dioxide, and the physical properties of carbon dioxide facilitate the nucleation and growth of bubbles on decompression.

Independent of the depth of the dive are the effects of the local hydrostatic pressure gradient upon respiration. The supporting effect of the surrounding water pressure upon the soft tissues promotes venous return from ves-sels no longer solely influenced by gravity. And whatever the orientation of the diver in the water, this approxi-mates the effects of recumbency upon the cardiovascular and respiratory systems. Also, the uniform distribution of gas pressure within the thorax contrasts with the hydro-static pressure gradient that exists outside the chest. Intrathoracic pressure may be effectively lower than the pressure of the surrounding water, in which case more blood will be shifted into the thorax, or it may be effec-tively greater, resulting in less intrathoracic blood volume. The concept of a hydrostatic balance point within the chest, which represents the net effect of the external pressures and the effects of chest buoyancy, has proved useful in designing underwater breathing apparatuses.

Intrapulmonary gas expands exponentially during the steady return of a diver toward the surface. Unless vented, the expanding gas may rupture alveolar septa and escape into interstitial spaces. The extra-alveolar gas may cause a “burst lung” (pneumothorax) or the tracking of gas into the tissues of the chest (mediastinal emphysema), possibly extending into the pericardium or into the neck. More seriously, the escaped alveolar gas may be carried by the blood circulation to the brain (arterial gas embolism). This is a major cause of death among divers. Failure to exhale



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during ascent causes such accidents and is likely to occur if the diver makes a rapid emergency ascent, even from depths as shallow as 2 metres (6.6 feet). Other possible causes of pulmonary barotrauma include retention of gas by a diseased portion of lung and gas trapping due to dynamic airway collapse during forced expiration at low lung volumes.

Inadequacy of diver decompression, which may occur as a result of the diver’s failure to follow a correct decompression protocol or occasionally as a result of a diver’s idiosyncratic response to an apparently safe decompression procedure, can result in a sometimes life-threatening condition known as decompression sickness. Decompression sickness is caused by the for-mation of bubbles from gases that were dissolved in the tissues while the diver was at an increased environmen-tal pressure.

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Infectious diseases are among the most common condi-tions affecting the human respiratory system. These

diseases may be caused by a variety of agents, including viruses, bacteria, and molds. Infectious respiratory dis-eases can be divided into those that affect the upper respiratory tract and those that affect the lower respira-tory tract, with this division occurring at the anatomical level of the larynx. Thus, as considered here, upper respi-ratory infections include the common cold, pharyngitis, sinusitis, and tonsillitis, whereas lower respiratory infec-tions include laryngitis, tracheitis, and any condition of the bronchi and lungs. However, this distinction is com-plicated by the fact that diseases of the upper tissues can spread to the lower tissues.

Examples of severe lower respiratory infections include croup, various types of pneumonia, Legionnaire disease, and tuberculosis. Some conditions can cause extensive lung damage, requiring patient hospitaliza-tion, and may be highly contagious, resulting in patient isolation. In most cases, however, infectious diseases, whether of the upper or lower respiratory tract, can be effectively treated with prescription antimicrobial drugs. Other treatments may include the intravenous administration of fl uids and of medications that cannot be taken orally.

CHAPTER CHAPTER 4INFECTIOUS DISEASES OF THE RESPIRATORY

SYSTEM


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upper respiratory systeM infections

The nasal sinuses, pharynx, and tonsils are frequently the site of both acute and chronic infections. These condi-tions occur in both children and adults and are readily spread through exposure to infected individuals. Some of these infections may resolve on their own, with little or no medication. In other cases, however, an infection that spreads to the tissues of the lower respiratory tract may give rise to debilitating illness that requires extensive medical intervention.

Common Cold

The common cold is an acute viral infection that starts in the upper respiratory tract, sometimes spreads to the lower respiratory structures, and may cause secondary infections in the eyes or middle ears. More than 200 agents can cause symptoms of the common cold, includ-ing parainfluenza, influenza, respiratory syncytial viruses, and reoviruses. Rhinoviruses, however, are the most fre-quent cause, and some 100 different strains of rhinoviruses have been associated with coldlike illness in humans.

The popular term common cold reflects the feeling of chilliness on exposure to a cold environment that is part of the onset of symptoms. The feeling was originally believed to have a cause-and-effect relationship with the disease, but this is now known to be incorrect. The cold is caught from exposure to infected people, not from a cold environment, chilled wet feet, or drafts. People can carry the virus and communicate it without experiencing any of the symptoms themselves. Incubation is short, usually one to four days. The viruses start spreading from an infected person before the symptoms appear, and the

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7 Infectious Diseases of the Respiratory System 7

spread reaches its peak during the symptomatic phase. The incidence of colds peaks during the autumn, and minor epidemics commonly occur throughout the winter, but the reason for this incidence is unknown. It may result from the greater amount of time spent indoors, which increases the likelihood of close contact with those per-sons carrying cold viruses. Young children can contract between three and eight colds a year, usually coming into contact with the infectious agents in day care centres or preschools.

Cold symptoms vary from person to person, but in the individual the same symptoms tend to recur in succeed-ing bouts of infection. Symptoms may include sneezing, headaches, fatigue, chills, sore throat, inflammation of the nose (rhinitis), and nasal discharge. There is usually no fever. The nasal discharge is the first warning that one has caught a cold. Once a virus becomes established on the respiratory surface of the nose, its activities irritate the nose’s cells, which respond by pouring out streams of clear fluid. This fluid acts to dilute the virus and clear it from the nose. The sensory organs in the nose are stung by the inflammatory reaction, thereby setting up sneez-ing, a second method of expelling the virus. If the virus penetrates more deeply into the upper respiratory tract, coughing is added to the infected person’s symptoms in a further effort to get rid of the virus. Coughing can be dry or produce amounts of mucus. Symptoms abate as the host’s defenses increase, the clear fluid often changing to a thick, yellow-green fluid that is full of the debris of dead cells. The usual duration of the illness is about five to seven days, but lingering cough and postnasal discharge may persist for two weeks or more.

Diagnosis of a cold is usually made by medical history alone, but it is possible to take a culture for viruses. There is no effective antiviral agent available for the common

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Usually, the common cold does not involve a fever, but it can comprise sneez-ing, headaches, fatigue, chills, sore throat, rhinitis, and nasal discharge. Shutterstock.com

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cold. Therapy consists of treating the symptoms: relieving aches, fever, and nasal congestion. One of the greatest medical controversies in the past few decades has con-cerned the efficacy of vitamin C (ascorbic acid) in the prevention or treatment of the common cold. In many studies, administration of ascorbic acid has failed to pre-vent or decrease the symptoms of the common cold.

Sore Throat

Sore throat is a painful inflammation of the passage from the mouth to the pharynx or of the pharynx itself (pharyn-gitis). A sore throat may be a symptom of influenza or of other respiratory infections, a result of irritation by for-eign objects or fumes, or a reaction to certain drugs. Infections caused by a strain of streptococcal bacteria and viruses are often the primary cause of a sore throat. Generally, the throat reddens, and the tonsils may secrete pus and become swollen. Microbial agents producing soreness may remain localized or may spread (by way of lymph channels or the bloodstream) and produce such serious complications as rheumatic fever. In treating non-viral sore throat, antibiotics are often effective, as are antiseptic gargles. For a viral sore throat, treatment is aimed at relieving symptoms, which typically subside after one week.

Pharyngitis

Pharyngitis is an inflammatory illness of the mucous membranes and underlying structures of the pharynx. Inflammation usually involves the nasopharynx, uvula, soft palate, and tonsils. The illness can be caused by bacteria, viruses, mycoplasmas, fungi, and parasites and by recognized diseases of uncertain causes. Infection by



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Streptococcus bacteria may be a complication arising from a common cold. The symptoms of streptococcal phar-yngitis (commonly known as strep throat) are generally redness and swelling of the throat, a pustulant fluid on the tonsils or discharged from the mouth, extremely sore throat that is felt during swallowing, swelling of lymph nodes, and a slight fever; sometimes in children there are abdominal pain, nausea, headache, and irritability. Diagnosis is established by a detailed medical history and by physical examination, and the cause of pharyn-geal inflammation can be determined by throat culture. Usually only the symptoms can be treated: throat lozenges control sore throat and acetaminophen or aspirin control fever. If a diagnosis of streptococcal infection is estab-lished by culture, appropriate antibiotic therapy, usually with penicillin, is instituted. Within approximately three days the fever leaves, but the other symptoms may persist for another two to three days.

Viral pharyngitis infections also occur. They can pro-duce raised whitish to yellow lesions in the pharynx that are surrounded by reddened tissue. They cause fever, head-ache, and sore throat that last for 4 to 14 days. Lymphatic tissue in the pharynx may also become involved. A number of other infectious diseases may cause pharyngitis, includ-ing tuberculosis, syphilis, diphtheria, and meningitis.

Sinusitis

Sinusitis is acute or chronic inflammation of the mucosal lining of one or more paranasal sinuses (the cavities in the bones that adjoin the nose). Sinusitis commonly accompa-nies upper respiratory viral infections and in most cases requires no treatment. Purulent (pus-producing) sinusitis can occur, however, requiring treatment with antibiotics. Chronic cases caused by irritants in the environment or by

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impaired immune systems may require more extended treatment, including surgery.

The origin of acute sinus infection is much like that of ear infection. Normally the middle ear and the sinuses are sterile, but the adjacent mouth and nose have a var-ied bacterial flora. Under normal conditions, very small hairs called cilia move mucus along the lining of the nose and respiratory tract, keeping the sinuses clean. When ciliary function is damaged, infection can be established. Following a common cold, a decrease in ciliary function may permit bacteria to remain on the mucous membrane surfaces within the sinuses and to produce a purulent sinusitis. The organisms usually involved are Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, and many other penicillin-sensitive anaerobes. Common symptoms include facial pain, head-ache, and fever following previous upper respiratory viral illness. On physical examination, persons with sinusitis are usually found to have an elevation in body tempera-ture, nasal discharge, and sinus tenderness. Diagnosis can be confirmed by X-rays of the sinuses and cultures of material obtained from within the sinuses.

Treatment of acute sinusitis is directed primarily at overcoming the infecting organism by the use of systemic antibiotics such as penicillin and at encouraging drainage of the sinuses by the use of vasoconstricting nose drops and inhalations. If the infection persists, the pus localized in any individual sinus may have to be removed by means of a minor surgical procedure known as lavage, in which the maxillary or sphenoidal sinuses are irrigated with water or a saline solution.

Chronic sinusitis may follow repeated or neglected attacks of acute sinusitis, particularly if impaired breath-ing or drainage result from nasal polyps or obstructed sinus openings. It may also be caused by allergy to agents



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in the environment, such as fungi or pollen. The symp-toms of chronic sinusitis are a tendency to colds, purulent nasal discharge, obstructed breathing, loss of smell, and sometimes headache. Pain is not a feature of chronic sinusitis. If antibiotic therapy or repeated lavage do not alleviate the condition, steroidal medications may be given to relieve swelling and antihistamines to relieve allergic reactions. In severe cases endoscopic surgery may be necessary to remove obstructions.

Tonsillitis

Tonsillitis is an inflammatory infection of the tonsils caused by invasion of the mucous membrane by micro-organisms, usually hemolytic streptococci or viruses. The symptoms are sore throat, difficulty in swallowing, fever, malaise, and enlarged lymph nodes on both sides of the neck. The infection lasts about five days. The treatment includes bed rest until the fever has subsided, isolation to protect others from the infection, and warm throat irriga-tions or gargles with a mild antiseptic solution. Antibiotics or sulfonamides or both are prescribed in severe infec-tions to prevent complications.

The complications of acute streptococcal tonsillitis are proportional to the severity of the infection. The infection may extend upward into the nose, sinuses, and ears or downward into the larynx, trachea, and bronchi. Locally, virulent bacteria may spread from the infected tonsil to the adjoining tissues, resulting in a peritonsillar abscess. More serious are two distant complications—acute nephritis (kidney inflammation) and acute rheumatic fever, with or without heart involvement. Repeated acute infections may cause chronic inflammation of the tonsils, evidenced by tonsillar enlargement, repeated or persistent sore throat, and swollen lymph nodes in the neck. The

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treatment in this case is surgical removal (tonsillectomy). Scarlet fever, diphtheria, and trench mouth may also pro-duce acute tonsillitis. In diphtheria the tonsils are covered with a thick, whitish, adherent membrane; in trench mouth, with a grayish membrane that wipes off readily.

lower respiratory systeM infections

Infections of the lower respiratory system represent some of the most frequently occurring life-threatening condi-tions. For example, pneumonia, which can be caused by bacterial or viral infection or which may arise secondary to some other condition, is associated with a high rate of death in infants and the elderly. Likewise, the infectious disease tuberculosis, which is a major cause of lung disease globally, can be exceptionally difficult to treat and may cause progressive respiratory dysfunction. Thus, infec-tious diseases of the lower respiratory tissues sometimes require extensive medical attention, involving long-term antimicrobial therapy, in order to prevent potentially dis-abling damage to lung tissue.

Laryngitis

Laryngitis is an inflammation of the larynx that is caused by chemical or mechanical irritation or by bacterial infec-tion. Laryngitis is classified as simple, diphtheritic, tuberculous, or syphilitic. Simple laryngitis is usually asso-ciated with the common cold or similar infections. Nonbacterial agents such as chlorine gas, steam, or sulfur dioxide can also cause severe inflammation. Usually the mucous membrane lining the larynx is the site of prime infection. It becomes swollen and filled with blood, secretes a thick mucous substance, and contains many



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inflammatory cells. When the epiglottis, which closes the larynx during swallowing, becomes swollen and infected by influenza viruses, the larynx can become obstructed, and suffocation may result. Chronic laryngitis is produced by excessive smoking, alcoholism, or overuse of the vocal cords. The mucous membrane becomes dry and covered with polyps, small lumps of tissue that project from the surface. The wall of the larynx may thicken and become inflamed.

Diphtheritic laryngitis is caused by the spread of diph-theria from the region of the upper throat down to the larynx. It may cause a membrane of white blood cells, fibrin (blood clotting protein), and diseased skin cells to attach to and infiltrate the surface mucous membrane. When looser portions of this false membrane become dislodged from part of the larynx, they may consolidate at the vocal cords and cause an obstruction there. A similar type of membrane covering can occur in streptococcal infections.

Tuberculous laryngitis is a secondary infection spread from the initial site in the lungs. Tubercular nodule-like growths are formed in the larynx tissue. The bacteria die after infecting the tissue, leaving ulcers on the surface. There may be eventual destruction of the epiglottis and laryngeal cartilage.

Syphilitic laryngitis is one of the many complications of syphilis. In the second stage of syphilis, sores or mucous patches can form. As the disease advances to the third stage, tissue destruction is followed by healing and scar for-mation. The scars can distort the larynx, shorten the vocal cords, and produce a permanent hoarseness of the voice.

Tracheitis

Tracheitis is an inflammation and infection of the trachea. Most conditions that affect the trachea are bacterial or

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viral infections, although irritants like chlorine gas, sulfur dioxide, and dense smoke can injure the lining of the tra-chea and increase the likelihood of infections. Acute infections occur suddenly and usually subside quickly. Common bacterial causes of acute infections are pneumo-cocci, streptococci, Neisseria organisms, and staphylococci. The infections produce fever, fatigue, and swelling of the mucous membrane lining the trachea. Infections may last for a week or two and then pass. Generally, they do not cause significant damage to the tissue unless they become chronic. Chronic infections recur over a number of years and cause progressive degeneration of tissue. Irritants such as heavy smoking and alcoholism may invite infec-tions. The walls of the trachea during chronic infection contain an excess of white blood cells. Blood vessels increase in number, and the walls thicken because of an increase in elastic and muscle fibres. The mucous glands may become swollen, and small polyplike formations occasionally grow. Degenerated tissue is eventually replaced by a fibrous scar tissue.

Diphtheria, smallpox, tuberculosis, and syphilis all afflict the trachea. Diphtheria usually involves the upper mouth and throat, but the trachea may also be attacked. A false membrane composed of white blood cells and fibrin (clotting protein) coat the surface of the trachea. Typhoid causes swelling and ulceration in the lymph tissue. It can occasionally ulcerate the cartilage of the trachea and destroy tissue. In smallpox, pustules and ulcers, such as those that occur on the external skin, form in the mucous membrane. Intense blood congestion, hemorrhages, and degeneration of the tracheal tissue can occur. Tuberculosis causes nodules and ulcers that start on the membrane and progress through the tissue to the cartilage. The cartilage deteriorates and sometimes breaks apart causing severe pain and swelling. Syphilis forms lesions that erode the



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tissue, and can cause thickening and stiffening of the spaces between the cartilage.

Croup

Croup is an acute respiratory illness of young children that is characterized by a harsh cough, hoarseness, and difficult breathing. It is most often caused by an infection of the airway in the region of the larynx and trachea. Some cases result from allergy or physical irritation of these tissues. The symptoms are caused by inflammation of the laryn-geal membranes, spasms of the laryngeal muscles, or inflammation around the trachea. In some cases, inflam-mation occurs around the bronchial tree.

Viral infections are the most common cause of croup, the most frequent being those with the parainfluenza and influenza viruses. Such infections are most prevalent among children younger than age three, and they strike most frequently in late fall and winter. Generally, the onset of viral croup is preceded by the symptoms of the com-mon cold for several days. Most children with viral croup can be treated at home with the inhalation of mist from an appropriate vaporizer. Epinephrine and corticosteroids have also been used to reduce swelling of the airway. In cases of severe airway obstruction, hospitalization may be necessary.

Bacterial croup, also called epiglottitis, is a more seri-ous condition that is often caused by Haemophilus influenzae type B. It is characterized by marked swelling of the epiglottis, a flap of tissue that covers the air pas-sage to the lungs and that channels food to the esophagus. The onset is usually abrupt, with high fever and breathing difficulties. Because of the marked swelling of the epi-glottis, there is obstruction at the opening of the trachea, making it necessary for the patient to sit and lean

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forward to maximize the airflow. Epiglottitis generally strikes children between ages three and seven. Children with epiglottitis require prompt medical attention. An artificial airway must be opened, preferably by inserting a tube down the windpipe. Patients are given antibiotics, which generally relieve the inflammation within 24 to 72 hours. The occurrence of epiglottitis has decreased in the Western world owing to an effective vaccine against H. influenzae.

Infectious Bronchitis

Infectious bronchitis is an inflammation of all or part of the bronchial tree (the bronchi), through which air passes into the lungs. The most obvious symptoms are a sensa-tion of chest congestion and a mucus-producing cough.

Under ordinary circumstances, the sensitive mucous membranes lining the inner surfaces of the bronchi are well protected from inhaled infectious organisms by the filtering function of the nose and throat and by the cough reflex. Under certain circumstances, however, organisms do enter the airways and initiate a sudden and rapid attack, resulting usually in a relatively brief disease called acute infectious bronchitis. Acute infectious bronchitis is an episode of recurrent coughing and mucus produc-tion lasting several days to several weeks. It is most frequently caused by viruses responsible for upper respi-ratory infections. Therefore, it is often part of the common cold and is a common sequel to influenza, whooping cough, and measles. Acute bronchitis can also be caused by bacteria such as Streptococcus, particularly in people who have underlying chronic lung disease. In addi-tion, it is sometimes precipitated by chemical irritants such as toxic gases or the fumes of strong acids, ammonia, or organic solvents.



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Treatment of acute bronchitis is largely symptomatic and of limited benefit. Steam inhalation, bronchodila-tors, and expectorants will usually relieve the symptoms. Bacterial acute bronchitis responds to treatment with an appropriate antibiotic. Another form of bronchitis, discussed in a later chapter, is a long-standing, repetitive condition, called chronic bronchitis, which results in protracted and often permanent damage to the bron-chial mucosa.

Bronchiolitis

Bronchiolitis refers to inflammation of the small airways. Bronchiolitis probably occurs to some extent in acute viral disorders, particularly in children between ages one and two, and particularly in infections with respiratory syncytial virus. In some cases the inflammation may be severe enough to threaten life, but it normally clears spon-taneously, with complete healing in all but a very small percentage of cases. In adults, acute bronchiolitis of this kind is not a well-recognized clinical syndrome, though there is little doubt that in most patients with chronic bronchitis, acute exacerbations of infection are associated with further damage to small airways. In isolated cases, an acute bronchiolitis episode is followed by a chronic oblit-erative condition, or this may develop slowly over time. This pattern of occurrence has only recently been recog-nized. In addition to patients acutely exposed to gases, in whom such a syndrome may follow the acute exposure, patients with rheumatoid arthritis may develop a slowly progressive obliterative bronchiolitis that may prove fatal. An obliterative bronchiolitis may appear after bone mar-row replacement for leukemia and may cause shortness of breath and disability.

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Welding in enclosed spaces often results in exposure to oxides of nitrogen, but a short cough and progressive shortness of breath may not be evident for hours. Monty Rakusen/Cultura/Getty Images

Exposure to oxides of nitrogen, which may occur from inhaling gas in silos, when welding in enclosed spaces such as boilers, after blasting underground, or in fi res involv-ing plastic materials, is characteristically not followed by acute symptoms. These develop some hours later, when the victim develops a short cough and progressive shortness of breath. A chest radiograph shows patchy infl ammatory change, and the lesion is an acute bron-chiolitis. Symptomatic recovery may mask incomplete resolution of the infl ammation.

An infl ammation around the small airways, known as a respiratory bronchiolitis, is believed to be the earliest change that occurs in the lung in cigarette smokers,



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although it does not lead to symptoms of disease at that stage. The inflammation is probably reversible if smoking is discontinued. It is not known whether those who develop this change (after possibly only a few years of smoking) are or are not at special risk of developing the long-term changes of chronic bronchitis and emphysema.

Influenza

Influenza, also known simply as the flu (or grippe), is an acute viral infection of the upper or lower respiratory tract that is marked by fever, chills, and a generalized feel-ing of weakness and pain in the muscles, together with varying degrees of soreness in the head and abdomen. The flu may affect individuals of all ages, though the high-est incidence of the disease is among children and young adults, and it is generally more frequent during the colder months of the year.

Transmission and Symptoms

Influenza viruses are transmitted from person to person through the respiratory tract, by such means as inhalation of infected droplets resulting from coughing and sneez-ing. As the virus particles gain entrance to the body, they selectively attack and destroy the ciliated epithelial cells that line the upper respiratory tract, bronchial tubes, and trachea. The incubation period of the disease is one to two days, after which the onset of symptoms is abrupt, with sudden and distinct chills, fatigue, and muscle aches. The temperature rises rapidly to 38–40 °C (101–104 °F). A diffuse headache and severe muscular aches throughout the body are experienced, often accompanied by irritation or a sense of rawness in the throat. In three to four days the temperature begins to fall, and the person begins to recover. Symptoms associated with respiratory tract

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infection, such as coughing and nasal discharge, become more prominent and may be accompanied by lingering feelings of weakness. Death may occur, usually among older people already weakened by other debilitating disor-ders, and is caused in most of those cases by complications such as pneumonia or bronchitis.

Treatment and Prevention

The antiviral drugs amantadine and rimantadine have beneficial effects on cases of influenza involving a strain of virus known as influenza type A. However, viral resistance to these agents has been observed, thereby reducing their effectiveness. A newer category of drugs, the neuramini-dase inhibitors, which includes oseltamivir (Tamiflu) and zanamivir (Relenza), was introduced in the late 1990s; these drugs inhibit influenza A, as well as a strain of virus known as influenza type B. Other than this, the standard treatment remains bed rest, ingestion of fluids, and the use of analgesics to control fever. It is recommended that children and teenagers with the flu not be given aspirin, as treatment of viral infections with aspirin is associated with Reye syndrome, a very serious illness.

Individual protection against the flu may be bolstered by injection of a vaccine containing two or more circulat-ing influenza viruses. These viruses are produced in chick embryos and rendered noninfective; standard commercial preparations ordinarily include the type B influenza virus and several of the A subtypes. Protection from one vacci-nation seldom lasts more than a year, and yearly vaccination may be recommended, particularly for those individuals who are unusually susceptible to influenza or whose weak condition could lead to serious complications in case of infection. However, routine immunization in healthy people is also recommended. In order to prevent human-infecting bird flu viruses from mutating into more



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dangerous subtypes, public health authorities try to limit the viral “reservoir” where antigenic shift may take place by ordering the destruction of infected poultry flocks.

Oseltamivir (Tamiflu)

Oseltamivir is an antiviral drug that is active against both influenza type A and influenza type B viruses. Oseltamivir and a similar agent called zanamivir (marketed as Relenza) were approved in 1999 by the U.S. Food and Drug Administration and represented the first members in a new class of antiviral drugs known as neuraminidase inhibitors. Oseltamivir is marketed as Tamiflu by the U.S.-based pharmaceutical company Hoffman–La Roche, Inc.

Oseltamivir can be given orally. Through the inhibi-tion of neuraminidase, a glycoprotein on the surface of influenza viruses, the drug decreases the release of virus from infected cells, increases the formation of viral aggre-gates, and decreases the spread of the virus through the body. Oseltamivir is effective when administered within two days of symptom onset. The drug can also be used to prevent flu in adults and children who take the medication once daily for a period of at least 10 days. There is evidence that the most common subtype of influenza type A virus, known as H1N1, has developed resistance to oseltamivir.

Zanamivir (Relenza)

Zanamivir is an antiviral drug that is active against both influenza type A and influenza type B viruses. It is sold under the trade name Relenza by the pharmaceutical company GlaxoSmithKline. Zanamivir is given by inhala-tion only. By inhibiting the neuraminidase glycoprotein on the surface of the influenza virus, zanamivir decreases the release of virus from infected cells, increases the for-mation of viral aggregates, and decreases the spread of the virus through the body. If taken within 30 hours of

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Bordetella pertussis , the causative agent of whooping cough, isolated and coloured with Gram stain. Centers for Disease Control and Prevention (CDC) (Image Number: 2121)

the onset of infl uenza, zanamivir can shorten the dura-tion of the illness. Zanamivir, when taken once daily for 10 to 28 days, can prevent infl uenza infection in some adults and children.

Whooping Cough

Whooping cough, or pertussis, is an acute, highly com-municable respiratory disease. It is characterized in its typical form by paroxysms of coughing followed by a long-drawn inspiration, or “whoop.” The coughing ends with the expulsion of clear, sticky mucus and often with vomiting. Whooping cough is caused by the bacterium Bordatella pertussis .



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Whooping cough is passed from one person directly to another by inhalation of droplets expelled by cough-ing or sneezing. Beginning its onset after an incubation period of approximately one week, the illness progresses through three stages—catarrhal, paroxysmal, and conva-lescent—which together last six to eight weeks. Catarrhal symptoms are those of a cold, with a short dry cough that is worse at night, red eyes, and a low-grade fever. After one to two weeks the catarrhal stage passes into the distinctive paroxysmal period, variable in duration but commonly lasting four to six weeks. In the paroxysmal state, there is a repetitive series of coughs that are exhausting and often result in vomiting. The infected person may appear blue, with bulging eyes, and be dazed and apathetic, but the periods between coughing paroxysms are comfortable. During the convalescent stage there is gradual recovery. Complications of whooping cough include pneumonia, ear infections, slowed or stopped breathing, and occasion-ally convulsions and indications of brain damage.

Whooping cough is worldwide in distribution and among the most acute infections of children. The disease was first adequately described in 1578; undoubtedly it had existed for a long time before that. About 100 years later, the name pertussis (Latin: “intensive cough”) was intro-duced in England. In 1906 at the Pasteur Institute, the French bacteriologists Jules Bordet and Octave Gengou isolated the bacterium that causes the disease. It was first called the Bordet-Gengou bacillus, later Haemophilus per-tussis, and still later Bordetella pertussis. The first pertussis immunizing agent was introduced in the 1940s and soon led to a drastic decline in the number of cases. Now included in the DPT (diphtheria, tetanus, and pertussis) vaccine, it confers active immunity against whooping cough to children. Immunization is routinely begun at two months of age and requires five shots for maximum

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protection. A booster dose of pertussis vaccine should be given between 15 and 18 months of age, and another booster is given when the child is between four and six years old. Later vaccinations are in any case thought to be unnecessary, because the disease is much less severe when it occurs in older children, especially if they have been vaccinated in infancy.

The diagnosis of the disease is usually made on the basis of its symptoms and is confirmed by specific cul-tures. Treatment includes erythromycin, an antibiotic that may help to shorten the duration of illness and the period of communicability. Infants with the disease require careful monitoring because breathing may tempo-rarily stop during coughing spells. Sedatives may be administered to induce rest and sleep, and sometimes the use of an oxygen tent is required to ease breathing.

Psittacosis

Psittacosis, also known as ornithosis (or parrot fever), is an infectious disease of worldwide distribution caused by a bacterial parasite (Chlamydia psittaci) and transmitted to humans from various birds. The infection has been found in about 70 different species of birds; parrots and para-keets (family Psittacidae, from which the disease is named), pigeons, turkeys, ducks, and geese are the princi-pal sources of human infection.

The association between the human disease and sick parrots was first recognized in Europe in 1879, although a thorough study of the disease was not made until 1929–30, when severe outbreaks, attributed to contact with imported parrots, occurred in 12 countries of Europe and America. During the investigations conducted in Germany, England, and the United States, the causative agent was revealed. Strict regulations followed concerning



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importation of psittacine birds, which undoubtedly reduced the incidence of the disease but did not prevent the intermittent appearance of cases. The infection was later found in domestic stocks of parakeets and pigeons and subsequently in other species. Infected turkeys, ducks, or geese have caused many cases among poultry handlers or workers in processing plants.

Psittacosis usually causes only mild symptoms of ill-ness in birds, but in humans it can be fatal if untreated. Humans usually contract the disease by inhaling dust par-ticles contaminated with the excrement of infected birds. The bacterial parasite thus gains access to the body and multiplies in the blood and tissues. In humans psittacosis may cause high fever and pneumonia. Other symptoms include chills, weakness, head and body aches, and an ele-vated respiratory rate. The typical duration of the disease is two to three weeks, and convalescence often is pro-tracted. Before modern antibiotic drugs were available, the case fatality rate was approximately 20 percent, but penicillin and the tetracycline drugs reduced this figure almost to zero.

Pneumonia

Pneumonia is an inflammation and solidification of the lung tissue as a result of infection, inhalation of foreign particles, or irradiation. Many organisms, including viruses and fungi, can cause pneumonia, but the most common causes are bacteria, in particular species of Streptococcus and Mycoplasma. Although viral pneumonia does occur, viruses more commonly play a part in weakening the lung, thus inviting secondary pneumonia caused by bacteria. Fungal pneumonia can develop very rapidly and may be fatal, but it usually occurs in hospitalized persons who, because of impaired immunity, have reduced resistance to

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infection. Contaminated dusts, when inhaled by previ-ously healthy individuals, can sometimes cause fungal lung diseases. Pneumonia can also occur as a hypersensitivity, or allergic response, to agents such as mold, humidifiers, and animal excreta or to chemical or physical injury (e.g., smoke inhalation).

Bacterial Pneumonia

Streptococcal pneumonia, caused by Streptococcus pneu-moniae, is the single most common form of pneumonia, especially in hospitalized patients. The bacteria may live in the bodies of healthy persons and cause disease only after resistance has been lowered by other illness or infec-tion. Viral infections such as the common cold promote streptococcal pneumonia by causing excessive secretion of fluids in the respiratory tract. These fluids provide an environment in which the bacteria flourish.

Patients with bacterial pneumonia typically expe-rience a sudden onset of high fever with chills, cough, chest pain, and difficulty in breathing. As the disease pro-gresses, coughing becomes the major symptom. Sputum discharge may contain flecks of blood. Any chest pains result from the tenderness of the trachea (windpipe) and muscles from severe coughing. Diagnosis usually can be established by taking a culture of the organism from the patient’s sputum and by chest X-ray examination. Treatment is with specific antibiotics and supportive care, and recovery generally occurs in a few weeks. In some cases, however, the illness may become very severe, and it is sometimes fatal, particularly in elderly people and young children. Death from streptococcal pneumonia is caused by inflammation and significant and extensive bleeding in the lungs that results in the eventual cessa-tion of breathing. Streptococcal bacteria release a toxin called pneumolysin that damages the blood vessels in the



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lungs, causing bleeding into the air spaces. Antibiotics may exacerbate lung damage because they are designed to kill the bacteria by breaking them open, which leads to the further release of pneumolysin. Research into the development of aerosol agents that stimulate blood clotting and that can be inhaled into the lungs and possibly be used in conjunction with traditional therapies for streptococcal pneumonia is ongoing.

Mycoplasmal pneumonia, caused by Mycoplasma pneu-moniae, an extremely small organism, usually affects children and young adults; few cases beyond age 50 are seen. Most outbreaks of this disease are confined to fami-lies, small neighbourhoods, or institutions, although epidemics can occur. M. pneumoniae grows on the mucous membrane that lines the surfaces of internal lung struc-tures; it does not invade the deeper tissues—muscle fibres, elastic fibres, or nerves. The bacteria can produce an oxi-dizing agent that might be responsible for some cell damage. Usually the organism does not invade the mem-brane that surrounds the lungs, but it does sometimes inflame the bronchi and alveoli.

Another bacterium, Klebsiella pneumoniae, although it has little ability to infect the lungs of healthy persons, pro-duces a highly lethal pneumonia that occurs almost exclusively in hospitalized patients with impaired immu-nity. Other bacterial pneumonias include Legionnaire disease, caused by Legionella pneumophilia; pneumonia sec-ondary to other illnesses caused by Staphylococcus aureus and Hemophilus influenzae; and psittacosis, an atypical infectious form.

Viral and Fungal Pneumonia

Viral pneumonias are primarily caused by respiratory syn-cytial, parainfluenza, and influenza viruses. Symptoms of

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these pneumonias include runny nose, decreased appe-tite, and low-grade fever, usually followed by respiratory congestion and cough. Diagnosis is established by physi-cal examination and chest X-rays. Nonbacterial pneumonia is treated primarily with supportive care. In general, the prognosis is excellent.

Tuberculosis should always be considered a possibil-ity in any patient with pneumonia, and skin testing is included in the initial examination of patients with lung problems. Fungal infections such as coccidioidomycosis and histoplasmosis should also be considered, particularly if the patient was recently exposed to excavations, back-yard swimming pools, old sheds or barns, or dust storms. Other fungal and protozoan parasites (such as Pneumocystis carinii ) are common in patients receiving immunosup-pressive drugs or in patients with cancer, AIDS, or other chronic diseases. Pneumocystis carinii pneumonia has been one of the major causes of death among AIDS patients.

Hypersensitivity Pneumonia

Hypersensitivity pneumonias are a spectrum of disorders that arise from an allergic response to the inhalation of a variety of organic dusts. These pneumonias may occur following exposure to moldy hay or sugarcane, room humidifiers, and air-conditioning ducts, all of which con-tain the fungus Actinomyces. Other fungi found in barley, maple logs, and wood pulp may cause similar illnesses. In addition, people exposed to rats, gerbils, pigeons, parakeets, and doves may develop manifestations of hypersensitivity pneumonia. Initially, these patients experience fever with chills, cough, shortness of breath, headache, muscle pain, and malaise, all of which may subside in a day if there is no further exposure. A more insidious form of hypersensitivity pneumonia is



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associated with persistent malaise, fever, weight loss, and cough. Diagnosis is established by medical history, physi-cal examination, and specific laboratory tests. Treatment consists of removing the patient from the offending envi-ronment, bed rest, and supportive care.

Other Causes of Pneumonia

Pneumonia can also result from inhalation of oil droplets. This type of disease, known as lipoid pneumonia, occurs most frequently in workers exposed to large quantities of oily mist and in the elderly. Oil that is being swallowed may be breathed into the respiratory tract, or, less often, it may come from the body itself when the lung is physically injured. Scar tissue forms as a result of the presence of the oil. Ordinarily no treatment is necessary.

Inflammation of lung tissues may result from X-ray treatment of tumours within the chest. The disease makes its appearance from 1 to 16 weeks after exposure to high-dose X-rays has ceased. (The level of radiation in a routine chest X-ray is too low to cause significant damage to liv-ing tissue.) Recovery is usual unless too great an area of lung tissue is involved.

Pneumonia in Immunocompromised Persons

For some years prior to 1980, it had been known that if the immune system was compromised by immunosuppressive drugs (given, for example, before organ transplantation to reduce the rate of rejection), the patient was at risk for developing pneumonia from organisms or viruses not nor-mally pathogenic. Patients with AIDS may develop pneumonia from cytomegalovirus or Pneumocystis infec-tions, capable of causing invasive pneumonic lesions in the setting of reduced immunity. Such infections are a major cause of illness in these patients, are difficult to treat, and may prove fatal. Infections with fungi such as

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Candida also occur. The diagnosis and management of these cases has become a challenging and time-consuming responsibility for respiratory specialists in locations with large numbers of AIDS cases.

Legionnaire Disease

Legionnaire disease is a form of pneumonia caused by the bacillus Legionella pneumophila. The name of the dis-ease (and of the bacterium) is derived from a 1976 state convention of the American Legion, a U.S. military vet-erans’ organization, at a Philadelphia hotel where 182 Legionnaires contracted the disease, 29 of them fatally. The largest known outbreak of Legionnaire disease, con-firmed in more than 300 people, occurred in Murcia, Spain, in 2001.

Typically, but not uniformly, the first symptoms of Legionnaire disease are general malaise and headache, fol-lowed by high fever, often accompanied by chills. Coughing, shortness of breath, pleurisy-like pain, and abdominal distress are common, and occasionally some mental confusion is present. Although healthy individuals can contract Legionnaire disease, the most common patients are elderly or debilitated individuals or persons whose immunity is suppressed by drugs or disease. People who have cirrhosis of the liver caused by excessive inges-tion of alcohol also are at higher risk of contracting the disease.

Although it is fairly well documented that the disease is rarely spread through person-to-person contact, the exact source of outbreaks is often difficult to determine. It is sus-pected that contaminated water in central air-conditioning units can serve to disseminate L. pneumophila in droplets into the surrounding atmosphere. Potable water and drain-age systems are suspect, as is water at construction sites.



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Once in the body, L. pneumophila enters the lungs, where cells of the immune system called macrophages immediately attempt to kill the bacteria by a process called phagocyto-sis. However, L. pneumophila is able to evade phagocytosis and take control of the macrophage to facilitate bacterial replication. Eventually, the macrophage dies and bursts open, releasing large numbers of bacteria into the lungs and thus repeating the cycle of macrophage ingestion and bacterial replication. In some cases, this cycle of infection can lead to severe pneumonia, coma, and death.

Measurement of Legionella protein in the urine is a rapid and specific test for detecting the presence of L. pneumophila. Treatment for Legionnaire disease is with antibiotics. Pontiac fever, an influenza-like illness charac-terized by fever, headache, and muscle pain, represents a milder form of Legionella infection.

Tuberculosis

Tuberculosis is an infectious disease that is caused by the tubercle bacillus, Mycobacterium tuberculosis. In most forms of the disease, the bacillus spreads slowly and widely in the lungs, causing the formation of hard nodules (tubercles) or large cheeselike masses that break down the respiratory tissues and form cavities in the lungs. Blood vessels also can be eroded by the advancing disease, causing the infected person to cough up bright red blood.

During the 18th and 19th centuries, tuberculosis reached near-epidemic proportions in the rapidly urban-izing and industrializing societies of Europe and North America. Indeed, “consumption,” as it was then known, was the leading cause of death for all age groups in the Western world from that period until the early 20th cen-tury, at which time improved health and hygiene brought about a steady decline in its mortality rates. Since the

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Tuberculosis reached near-epidemic proportions in the 18th and 19th centu-ries, but in areas with poor hygiene standards, it continues to be a fatal disease continually complicated by drug-resistant strains. Fox Photos/Hulton Archive/Getty Images

1940s, antibiotic drugs have reduced the span of treat-ment to months instead of years, and drug therapy has done away with the old TB sanatoriums where patients at one time were nursed for years while the defensive prop-erties of their bodies dealt with the disease.

Today, in less-developed countries where population is dense and hygienic standards poor, tuberculosis remains a major fatal disease. The prevalence of the disease has increased in association with the HIV/AIDS epidemic; an estimated one out of every four deaths from tuberculosis involves an individual coinfected with HIV. In addition, the successful elimination of tuberculosis as a major threat to public health in the world has been complicated by the



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rise of new strains of the tubercle bacillus that are resis-tant to conventional antibiotics. Infections with these strains are often difficult to treat and require the use of combination drug therapies, sometimes involving the use of five different agents.

The Course of Tuberculosis

The tubercle bacillus is a small, rod-shaped bacterium that is extremely hardy; it can survive for months in a state of dryness and can also resist the action of mild dis-infectants. Infection spreads primarily by the respiratory route directly from an infected person who discharges live bacilli into the air. Minute droplets ejected by sneez-ing, coughing, and even talking can contain hundreds of tubercle bacilli that may be inhaled by a healthy person. There the bacilli become trapped in the tissues of the body, are surrounded by immune cells, and finally are sealed up in hard, nodular tubercles. A tubercle usually consists of a centre of dead cells and tissues, cheeselike (caseous) in appearance, in which can be found many bacilli. This centre is surrounded by radially arranged phagocytic (scav-enger) cells and a periphery containing connective tissue cells. The tubercle thus forms as a result of the body’s defensive reaction to the bacilli. Individual tubercles are microscopic in size, but most of the visible manifestations of tuberculosis, from barely visible nodules to large tuber-culous masses, are conglomerations of tubercles.

In otherwise healthy children and adults, the primary infection often heals without causing symptoms. The bacilli are quickly sequestered in the tissues, and the infected per-son acquires a lifelong immunity to the disease. A skin test taken at any later time may reveal the earlier infection and the immunity, and a small scar in the lung may be visible by X-ray. In this condition, sometimes called latent

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tuberculosis, the affected person is not contagious. In some cases, however, sometimes after periods of time that can reach 40 years or more, the original tubercles break down, releasing viable bacilli into the bloodstream. From the blood the bacilli create new tissue infections else-where in the body, most commonly in the upper portion of one or both lungs. This causes a condition known as pulmonary tuberculosis, a highly infectious stage of the disease. In some cases the infection may break into the pleural space between the lung and the chest wall, causing a pleural effusion, or collection of fluid outside the lung. Particularly among infants, the elderly, and immunocom-promised adults (organ transplant recipients or AIDS patients, for example), the primary infection may spread through the body, causing miliary tuberculosis, a highly fatal form if not adequately treated. In fact, once the bacilli enter the bloodstream, they can travel to almost any organ of the body, including the lymph nodes, bones and joints, skin, intestines, genital organs, kidneys, and bladder. An infection of the meninges that cover the brain causes tuberculous meningitis; before the advent of spe-cific drugs, this disease was always fatal, though most affected people now recover.

The onset of pulmonary tuberculosis is usually insidi-ous, with lack of energy, weight loss, and persistent cough. These symptoms do not subside, and the general health of the patient deteriorates. Eventually, the cough increases, the patient may have chest pain from pleurisy, and there may be blood in the sputum, an alarming symptom. Fever develops, usually with drenching night sweats. In the lung, the lesion consists of a collection of dead cells in which tubercle bacilli may be seen. This lesion may erode a neighbouring bronchus or blood vessel, causing the patient to cough up blood (hemoptysis). Tubercular lesions



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may spread extensively in the lung, causing large areas of destruction, cavities, and scarring. The amount of lung tis-sue available for the exchange of gases in respiration decreases, and if untreated the patient will die from fail-ure of ventilation and general toxemia and exhaustion.

Other Mycobacterial Infections

Another species of bacteria, M. bovis, is the cause of bovine tuberculosis. M. bovis is transmitted among cattle and some wild animals through the respiratory route, and it is also excreted in milk. If the milk is ingested raw, M. bovis readily infects humans. The bovine bacillus may be caught in the tonsils and may spread from there to the lymph nodes of the neck, where it causes caseation of the node tissue (a condition formerly known as scrofula). The node swells under the skin of the neck, finally eroding through the skin as a chronic discharging ulcer. From the gastrointestinal tract, M. bovis may spread into the blood-stream and reach any part of the body. It shows, however, a great preference for bones and joints, where it causes destruction of tissue and eventually gross deformity. Tuberculosis of the spine, or Pott disease, is characterized by softening and collapse of the vertebrae, often resulting in a hunchback deformity. Pasteurization of milk kills tubercle bacilli, and this, along with the systematic identi-fication and destruction of infected cattle, has led to the disappearance of bovine tuberculosis in humans in many countries.

The AIDS epidemic has given prominence to a group of infectious agents known variously as nontuberculosis mycobacteria, atypical mycobacteria, and mycobacteria other than tuberculosis (MOTT). This group includes such Mycobacterium species as M. avium (or M. avium-intracellulare), M. kansasii, M. marinum, and M. ulcerans.

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These bacilli have long been known to infect animals and humans, but they cause dangerous illnesses of the lungs, lymph nodes, and other organs only in people whose immune systems have been weakened. Among AIDS patients, atypical mycobacterial illnesses are common complications of HIV infection. Treatment is attempted with various drugs, but the prognosis is usually poor owing to the AIDS patient’s overall condition.

Diagnosis and Treatment of Tuberculosis

The diagnosis of pulmonary tuberculosis depends on finding tubercle bacilli in the sputum, in the urine, in gas-tric washings, or in the cerebrospinal fluid. The primary method used to confirm the presence of bacilli is a spu-tum smear, in which a sputum specimen is smeared onto a slide, stained with a compound that penetrates the organ-ism’s cell wall, and examined under a microscope. If bacilli are present, the sputum specimen is cultured on a special medium to determine whether the bacilli are M. tuber-culosis. An X-ray of the lungs may show typical shadows caused by tubercular nodules or lesions. The prevention of tuberculosis depends on good hygienic and nutritional conditions and on the identification of infected patients and their early treatment. A vaccine, known as BCG vac-cine, is composed of specially weakened tubercle bacilli. Injected into the skin, it causes a local reaction, which confers some immunity to infection by M. tuberculosis for several years. It has been widely used in some countries with success; its use in young children in particular has helped to control infection in the developing world. The main hope of ultimate control, however, lies in preventing exposure to infection, and this means treating infectious patients quickly, possibly in isolation until they are nonin-fectious. In many developed countries, individuals at risk



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for tuberculosis, such as health care workers, are regularly given a skin test (tuberculin test) to show whether they have had a primary infection with the bacillus.

Today, the treatment of tuberculosis consists of drug therapy and methods to prevent the spread of infectious bacilli. Historically, treatment of tuberculosis consisted of long periods, often years, of bed rest and surgical removal of useless lung tissue. In the 1940s and ’50s several anti-microbial drugs were discovered that revolutionized the treatment of patients with tuberculosis. As a result, with early drug treatment, surgery is rarely needed. The most commonly used antituberculosis drugs are isonia-zid and rifampicin (rifampin). These drugs are often used in various combinations with other agents, such as eth-ambutol, pyrazinamide, or rifapentine, in order to avoid the development of drug-resistant bacilli. Patients with strongly suspected or confirmed tuberculosis undergo an initial treatment period that lasts two months and con-sists of combination therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide. These drugs may be given daily or two times per week. The patient is usually made noninfectious quite quickly, but complete cure requires continuous treatment for another four to nine months. The length of the continuous treatment period depends on the results of chest X-rays and sputum smears taken at the end of the two-month period of initial therapy. Continuous treatment may consist of once daily or twice weekly doses of isoniazid and rifampicin or isoniazid and rifapentine.

If a patient does not continue treatment for the required time or is treated with only one drug, bacilli will become resistant and multiply, making the patient sick again. If subsequent treatment is also incomplete, the sur-viving bacilli will become resistant to several drugs.

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Multidrug-resistant tuberculosis (MDR TB) is a form of the disease in which bacilli have become resistant to iso-niazid and rifampicin. MDR TB is treatable but is extremely difficult to cure, typically requiring two years of treatment with agents known to have more severe side effects than isoniazid or rifampicin. Extensively drug-resistant tuberculosis (XDR TB) is a rare form of MDR TB. XDR TB is characterized by resistance to not only isoniazid and rifampin but also a group of bactericidal drugs known as fluoroquinolones and at least one amino-glycoside antibiotic, such as kanamycin, amikacin, or capreomycin. Aggressive treatment using five different drugs, which are selected based on the drug sensitivity of the specific strain of bacilli in a patient, has been shown to be effective in reducing mortality in roughly 50 percent of XDR TB patients. In addition, aggressive treatment can help prevent the spread of strains of XDR TB bacilli.

In 1995, in part to prevent the development and spread of MDR TB, the World Health Organization began encouraging countries to implement a compliance pro-gram called directly observed therapy (DOT). Instead of taking daily medication on their own, patients are directly observed by a clinician or responsible family member while taking larger doses twice a week. Although some patients consider DOT invasive, it has proved successful in controlling tuberculosis.


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CHAPTER CHAPTER 5

There exists a wide variety of noninfectious diseases and disorders of the human respiratory system.

These conditions can be classifi ed according to the spe-cifi c anatomical regions of the respiratory tract that they affect. Thus, there are diseases of the upper airways; dis-eases of the pleura; diseases of the larynx, trachea, bronchial tree, and lungs; and diseases of the mediastinum and diaphragm. Although these divisions provide a gen-eral outline of the ways in which diseases may affect the lung, they are by no means rigid. It is common for more than one part of the system to be involved in any particu-lar disease process, and disease in one region frequently leads to involvement of other parts.

Important examples of diseases and disorders of the respiratory system include sleep apnea, emphysema, and cystic fi brosis. Many noninfectious respiratory conditions are chronic and thus may ultimately result in progressive defi ciency in respiratory function. The causes of the vari-ous diseases and disorders are diverse, ranging from inherited genetic mutations to smoking to trauma. Treatment for this group of conditions is similarly varied, and in many cases therapy may include not only the admin-istration of medications but invasive surgery as well.

diseases of the upper airway

The nose, sinuses, palate, and nasopharynx are all suscep-tible to disease. Conditions affecting these tissues may

DISEASES AND DISORDERS OF THE RESPIRATORY SYSTEM

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Although snoring bears the brunt of many jokes, loud interrupted snoring can indicate sleep apnea, a potentially life-threatening condition. © www.istockphoto.com / Stephanie Horrocks

7 Diseases and Disorders of the Respiratory System 7

result from a number of different causes, such as congeni-tal structural abnormalities or malignant neoplastic changes (i.e., cancer). Such cancers are typically more common in smokers than in nonsmokers.

Snoring

Snoring is a rough, hoarse noise produced upon the intake of breath during sleep and caused by the vibration of the soft palate and vocal cords. It is often associated with obstruction of the nasal passages, which necessitates breathing through the mouth. Snoring is more common in the elderly because the loss of tone in the oropharyngeal


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musculature promotes vibration of the soft palate and pharynx. It is also more common in men than in women, and it occurs most often in obese persons. Children’s snor-ing usually results from enlarged tonsils or adenoids. Whatever the cause, snoring is always associated with mouth breathing and can be corrected by removing obstructions to normal nasal breathing or by altering sleeping position so that the affected individual does not lie on his back. Loud interrupted snoring is a regular feature of sleep apnea, a common and potentially life-threatening condition that generally requires treatment.

Sleep Apnea

Sleep apnea is a respiratory condition characterized by pauses in breathing during sleep. The word apnea is derived from the Greek apnoia, meaning “without breath.” There are three types of sleep apnea: obstructive, which is the most common form and involves the collapse of tissues of the upper airway; central, which is very rare and results from failure of the central nervous system to activate breathing mechanisms; and mixed, which involves charac-teristics of both obstructive and central apneas. In obstructive sleep apnea (OSA), airway collapse is eventu-ally terminated by a brief awakening, at which point the airway reopens and the person resumes breathing. In severe cases this may occur once every minute during sleep and in turn may lead to profound sleep disruption. In addition, repetitive interruption of normal breathing can lead to a reduction in oxygen levels in the blood.

Obstructive sleep apnea is most often caused by exces-sive fat in the neck area. Thus, the condition has a strong association with certain measures of obesity, such as neck size, body weight, or body-mass index. In men shirt size is a useful predictor, with the likelihood of OSA increasing

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with a collar greater than about 42 cm (16.5 inches). Other causes of the condition include medical disorders, such as hypothyroidism or tonsillar enlargement. The condition is also more common in patients with a set-back chin (ret-rognathia), and it may be for this reason that patients of East Asian heritage are more likely to have sleep apnea without being overweight.

The most common symptom of OSA is sleepiness, with many patients describing sleep as unrefreshing. Sleep disturbance may cause difficulty concentrating, worsen short-term memory, and increase irritability. The bed partner is likely to describe heavy snoring (OSA is exceptionally unusual without snoring) and may have observed the apneic pauses, with the resumption of breathing usually described as a gasp or a snort. Patients with OSA and sleepiness are at increased risk of motor vehicle accidents; the magnitude of the increased risk is the subject of some debate but is thought to be between three- and sevenfold. The risk returns to normal after treatment. Patients with severe OSA—those who stop breathing more often than once every two minutes—are at risk of other diseases, including ischemic heart disease, hypertension, and insulin resistance. However, it is less certain that these diseases are caused by OSA; it is more likely that they are secondary consequences of obesity and a sedentary lifestyle.

Treatment typically involves continuous positive air-way pressure (CPAP), which uses a mask (facial or nasal) during sleep to blow air into the upper airway. Although CPAP does not treat the condition itself, which can be resolved only by weight loss or treatment of underlying conditions, it does prevent airway collapse and thus relieves daytime sleepiness. Some patients with sleep apnea may be treated with a dental device to advance the lower jaw, though surgery is seldom recommended.



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Pickwickian Syndrome

Pickwickian syndrome, also known as obesity hypoventi-lation syndrome, is a complex of respiratory and circulatory symptoms associated with extreme obesity. The name originates from the fat boy depicted in Charles Dickens’s The Pickwick Papers, who showed some of the same traits. (By some definitions, to be obese is to exceed one’s ideal weight by 20 percent or more; an extremely obese person would exceed the optimum weight by a much larger per-centage.) This condition often occurs in association with sleep apnea.

In pickwickian syndrome the rate of breathing is chronically decreased below the normal level. Because of inadequate removal of carbon dioxide by the lungs, levels of carbon dioxide in the blood increase, leading to respira-tory acidosis. In more severe instances, oxygen in the blood is also significantly reduced.

Individuals who have pickwickian syndrome often com-plain of slow thinking, drowsiness, and fatigue. Low blood oxygen causes the small blood vessels entering the lungs to constrict, thus increasing pressure in the vessels that supply the lungs. The elevated pressure stresses the right ventricle of the heart, ultimately causing right heart failure. Finally, excessive fluid accumulates throughout the body (periph-eral edema), especially beneath the skin of the lower legs.

diseases of the pleura

The most common disease of the pleura is caused by inflammation and is referred to as pleurisy. Other condi-tions of the pleura may arise from inflammatory or neoplastic processes that lead to fluid accumulation (pleu-ral effusion) between the two pleural layers, in the space known as the pleural cavity. The pleural membranes of the

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lungs are also vulnerable to perforation and spontaneous rupture, enabling air to enter the pleural cavity. This causes spontaneous pneumothorax, a partial or occasionally complete collapse of the lung. Mesothelioma, a cancer of the pleura, may occur many years after inhalation of asbes-tos fibres. The cancerous cells of the pleura can eventually metastasize and invade nearby and distant tissues, includ-ing tissues of the neck and head.

Pleurisy

Pleurisy, also called pleuritis, is an inflammation of the pleura, the membranes that line the thoracic cavity and fold in to cover the lungs. Pleurisy may be characterized as dry or wet. In dry pleurisy, little or no abnormal fluid accu-mulates in the pleural cavity, and the inflamed surfaces of the pleura produce an abnormal sound called a pleural friction rub when they rub against one another during res-piration. This rubbing may be felt by the affected person or heard through a stethoscope applied to the surface of the chest. In wet pleurisy, fluids produced by the inflamed tissues accumulate within the pleural cavity, sometimes in quantities sufficient to compress the underlying lung and cause shortness of breath.

Because the pleura is well supplied with nerves, pleu-risy can be very painful. Pleurisy is commonly caused by infection in the underlying lung and, rarely, by diffuse inflammatory conditions such as lupus erythematosus. Treatment of pleurisy includes pain relief, fluid evacua-tion, and treatment of the underlying disease.

Pleural Effusion and Thoracic Empyema

Pleural effusion, or hydrothorax, is an accumulation of watery fluid in the pleural cavity. There are many causes of



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pleural effusion, including pneumonia, tuberculosis, and the spread of a malignant tumour from a distant site to the pleural surface. Pleural effusion often develops as a result of chronic heart failure because the heart cannot pump fluid away from the lungs, and fluid that seeps from the lungs places additional stress on the dysfunctioning heart. Large pleural effusions can cause disabling short-ness of breath.

If symptoms of pleural effusion develop, a tube is inserted through the chest wall into the pleural space to drain the fluid. Under certain conditions, such as malig-nant disease of the pleura (i.e., mesothelioma), pleural effusion can be treated by introducing an irritating sub-stance called a sclerosing agent into the pleural space in order to stimulate an inflammatory reaction of the pleural surfaces. As the inflammation heals, tissue adhesions obliterate the pleural space, thereby preventing the accu-mulation of more fluid. Examples of sclerosing agents that cause an inflammatory reaction of the pleural surfaces include talc, doxycycline, and bleomycin.

The accumulation of pus in the pleural cavity is known as thoracic empyema, or pyothorax. This condition is often the result of a microbial, usually bacterial, infection within the pleural cavity. The most common cause is lung inflammation (pneumonia) resulting in the spread of infection from the lung to the bordering pleural mem-brane. It may also be caused by a lung abscess or some forms of tuberculosis. When the bronchial tree is involved in the infection, air may get into the pleural cavity. The presence of both air and pus inside the pleural cavity is known as pneumothorax.

Thoracic empyema may be characterized by fever, coughing, shortness of breath, and weight loss, and the presence of fluid as ascertained by a chest X-ray. Treatment is directed at drainage of small amounts of pus through

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a needle or larger amounts through a drainage tube. Video-assisted thoracic surgery or open-chest surgery is sometimes needed to eviscerate thick or compartmental-ized pus from the pleural space. Antibiotics are used to treat the underlying infection.

Pneumothorax

Pneumothorax is a condition in which air accumulates in the pleural space, causing it to expand and thus com-press the underlying lung, which may then collapse. There are three major types of pneumothorax: trau-matic pneumothorax, spontaneous pneumothorax, and tension pneumothorax.

Traumatic pneumothorax is the accumulation of air caused by penetrating chest wounds (knife stabbing, gun-shot) or other injuries to the chest wall, after which air is sucked through the opening and into the pleural sac. Spontaneous pneumothorax is the passage of air into the pleural sac from an abnormal connection created between the pleura and the bronchial system as a result of bullous emphysema or some other lung disease. The symptoms of spontaneous pneumothorax are a sharp pain in one side of the chest and shortness of breath.

Tension pneumothorax is a life-threatening condition that can occur as a result of trauma, lung infection, or medical procedures, such as high-pressure mechanical ventilation, chest compression during cardiopulmonary resuscitation (CPR), or thoracoscopy (closed-lung biopsy). In contrast to traumatic pneumothorax and spontaneous pneumothorax, in tension pneumothorax air that becomes trapped in the pleural space cannot escape. As a result, with each breath the patient inhales, air and pressure accumulate within the chest. When the lung on the affected side of the chest collapses, the heart, blood



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vessels, and airways are pushed to the centre of the chest, thereby compressing the other lung. This leads to decreases in blood pressure, consciousness, and breathing that in turn may lead to shock and death.

Most pneumothoraxes can be treated by inserting a tube through the chest wall. This procedure allows air to escape from the chest cavity, which enables the lung to re-expand. In some cases, a catheter connected to a vacuum system is required to re-expand the lung. While small pneumothoraxes may resolve spontaneously, others may require surgery to prevent recurrences.

diseases of the bronchi and lungs

Diseases of the bronchi and lungs are often associated with significant impairments in respiration. In fact, many of these conditions are associated with irreversible lung damage. Whereas several diseases of the bronchi and lungs, including bronchiectasis and cystic fibrosis, may be present in childhood, others (such as pulmonary emphy-sema and chronic obstructive pulmonary disease) occur in adulthood and are frequently associated with excessive exposure to tobacco smoke.

Bronchiectasis

Bronchiectasis is believed to usually begin in childhood, possibly after a severe attack of pneumonia. It consists of a dilatation of major bronchi. The bronchi become chron-ically infected, and excess sputum production and episodes of chest infection are common. In some cases, clubbing (swelling of the fingertips and, occasionally, of the toes) may occur. The disease may also develop as a consequence of airway obstruction or of undetected (and

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therefore untreated) aspiration into the airway of small foreign bodies, such as parts of plastic toys. Bronchiectasis may also develop as a consequence of inherited condi-tions, of which the most important is the familial disease cystic fibrosis.

Management of the condition includes antibiotics to fight lung infections, medications to dilate the airways and to relieve pain, enzyme therapy to thin the mucus, and postural drainage and percussion to loosen mucus in the lungs so it can be expelled through coughing. These thera-pies, in addition to others, have helped control pulmonary infections and have markedly improved survival in affected persons, many of whom, who would formerly have died in childhood, now reach adult life.

Chronic Bronchitis

The chronic cough and sputum production of chronic bronchitis were once dismissed as nothing more than “smoker’s cough,” without serious implications. But the striking increase in mortality from chronic bronchitis and emphysema that occurred after World War II in all Western countries indicated that the long-term conse-quences of chronic bronchitis could be serious. This common condition is characteristically produced by ciga-rette smoking. After about 15 years of smoking, significant quantities of mucus are coughed up in the morning, due to an increase in size and number of mucous glands lining the large airways. The increase in mucous cells and the development of chronic bronchitis may be enhanced by breathing polluted air. For example, chronic bronchitis is sometimes caused by prolonged inhalation of environ-mental irritants, particularly in areas of uncontrolled coal burning, or of organic substances such as hay dust. In some countries chronic bronchitis is caused by daily



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inhalation of wood smoke from improperly ventilated cooking stoves.

The changes are not confined to large airways, though these produce the dominant symptom of chronic sputum production. Changes in smaller bronchioles lead to oblit-eration and inflammation around their walls. All these changes together, if severe enough, can lead to distur-bances in the distribution of ventilation and perfusion in the lung, causing a fall in arterial oxygen tension and a rise in carbon dioxide tension. By the time this occurs, the ventilatory ability of the patient, as measured by the velocity of a single forced expiration, is severely compro-mised; in a cigarette smoker, ventilatory ability has usually been declining rapidly for some years. It is not clear what determines the severity of these changes. Some people can smoke for decades without evidence of significant airway changes, whereas others may experi-ence severe respiratory compromise after 15 years or less of exposure. Smoking-related chronic bronchitis often occurs in association with emphysema; the coexistence of these two conditions is known as chronic obstructive pulmonary disease.

For current smokers the most important treatment of chronic bronchitis is the cessation of smoking. The mucus-producing cough will subside within weeks or months and may resolve altogether. Unfortunately, nar-rowing of the bronchi and obstruction of airflow may continue to progress even after smoking ceases, though the rate of progression generally slows. Because the dam-age to the bronchial tree is largely irreversible, treatment is mainly symptomatic, consisting of expectorants and bronchodilators. Occasionally, drugs to suppress parox-ysmal coughing may be necessary, but they must be used sparingly because they can be addictive and because expectoration is necessary. Of primary importance is

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the prevention of superimposed infections, either by careful watching for early signs or by using prophylactic antibiotics. Adjusting the patient’s living and working environments to the largely irreversible condition is an essential factor in treatment.

Pulmonary Emphysema

This irreversible disease consists of destruction of alveo-lar walls. It occurs in two forms, centrilobular emphysema, in which the destruction begins at the centre of the lob-ule, and panlobular (or panacinar) emphysema, in which alveolar destruction occurs in all alveoli within the lobule simultaneously. In advanced cases of either type, this dis-tinction can be difficult to make. Centrilobular emphysema is the form most commonly seen in cigarette smokers, and some observers believe it is confined to smokers. It is more common in the upper lobes of the lung (for unknown reasons). By the time the disease has developed, some impairment of ventilatory ability has probably occurred. Panacinar emphysema may also occur in smokers, but it is the type of emphysema characteristically found in the lower lobes of patients with a deficiency in the antiproteo-lytic enzyme known as alpha-1 antitrypsin. Similar to centrilobular emphysema, panacinar emphysema causes ventilatory limitation and eventually blood gas changes. Other types of emphysema, of less importance than the two major varieties, may develop along the dividing walls of the lung (septal emphysema) or in association with scars from other lesions.

A major step forward in understanding the develop-ment of emphysema followed the identification, in Sweden, of families with an inherited deficiency of alpha-1 antitrypsin, an enzyme essential for lung integrity. Members of affected families who smoked cigarettes


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Emphysema destroys the walls of the alveoli of the lungs, resulting in a loss of surface area available for the exchange of oxygen and carbon dioxide dur-ing breathing. This produces symptoms of shortness of breath, coughing, and wheezing. In severe emphysema, diffi culty in breathing leads to decreased oxy-gen intake, which causes headaches and symptoms of impaired mental ability. Encyclopædia Britannica, Inc.

commonly developed panacinar emphysema in the lower lobes, unassociated with chronic bronchitis but leading to ventilatory impairment and disability. Intense investiga-tion of this major clue led to the “protease-antiprotease” theory of emphysema. It is postulated that cigarette smok-ing either increases the concentration of protease enzymes released in the lung (probably from white blood cells) or impairs the lung’s defenses against these enzymes or both. Although many details of the essential biochemical steps at the cellular level remain to be clarifi ed, this represents a major step forward in understanding a disease whose

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genesis was once ascribed to overinflation of the lung (like overdistending a bicycle tire).

Chronic bronchitis and emphysema are distinct pro-cesses. Both may follow cigarette smoking, however, and they commonly occur together, so determination of the extent of each during life is not easy. In general, significant emphysema is more likely if ventilatory impairment is constant, gas transfer in the lung (usually measured with carbon monoxide) is reduced, and the lung volumes are abnormal. Development of high-resolution computerized tomography has greatly improved the accuracy of detec-tion of emphysema. Some people with emphysema suffer severe incapacity before age 60. Thus, emphysema is not a disease of the elderly only. An accurate diagnosis can be made from pulmonary function tests, careful radiological examination, and a detailed history. The physical exami-nation of the chest reveals evidence of airflow obstruction and overinflation of the lung, but the extent of lung destruction cannot be reliably gauged from these signs, and therefore laboratory tests are required.

The prime symptom of emphysema, which is always accompanied by a loss of elasticity of the lung, is shortness of breath, initially on exercise only, and associated with loss of normal ventilatory ability and increased obstruc-tion to expiratory airflow. The expiratory airflow from a maximum inspiration is measured by the “forced expira-tory volume in one second,” or FEV1, and is a predictor of survival of emphysema. Chronic hypoxemia (lowered oxy-gen tension) often occurs in severe emphysema and leads to the development of increased blood pressure in the pulmonary circulation, which in turn leads to failure of the right ventricle of the heart. The symptoms and signs of right ventricular failure include swelling of the ankles (edema) and engorgement of the neck veins. These are portents of advanced lung disease in this condition. The



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hypoxemia may also lead to an increase in total hemoglo-bin content and in the number of circulating red blood cells, as well as to psychological depression, irritability, loss of appetite, and loss of weight. Thus, the advanced syndrome of chronic obstructive lung disease may cause such shortness of breath that the afflicted person has dif-ficulty walking, talking, and dressing, as well as numerous other symptoms.

The slight fall in ventilation that normally accompa-nies sleep may exacerbate the failure of lung function in chronic obstructive lung disease, leading to a further fall in arterial oxygen tension and an increase in pulmonary arterial pressure. Unusual forms of emphysema also occur. In one form the disease appears to be unilateral, involving one lung only and causing few symptoms. Unilateral emphysema is believed to result from a severe bronchiolitis in childhood that prevented normal matu-ration of the lung on that side. “Congenital lobar emphysema” of infants is usually a misnomer, since there is no alveolar destruction. It is most commonly caused by overinflation of a lung lobe due to developmental malfor-mation of cartilage in the wall of the major bronchus. Such lobes may have to be surgically removed to relieve the condition. Bullous emphysema can occur in one or both lungs and is characterized by the presence of one or several abnormally large air spaces surrounded by rela-tively normal lung tissue. This disease most commonly occurs between ages 15 and 30 and usually is not recog-nized until a bullous air space leaks into the pleural space, causing a pneumothorax.

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease characterized by the

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combination of signs and symptoms of emphysema and bronchitis. It is a common disease, and each year about 30,000 people in the United Kingdom and roughly 119,000 people in the United States die from COPD. Sources of noxious particles that can cause COPD include tobacco smoke, air pollution, and the burning of certain fuels in poorly ventilated areas. In rare cases COPD has been associated with a genetic defect that results in defi-ciency of alpha-1 antitrypsin. Although primarily a lung disease, it is increasingly recognized that COPD has sec-ondary associations, including muscle weakness and osteoporosis. Identifying and treating these secondary problems via pulmonary rehabilitation (supervised exer-cise) and other methods may improve the functional status of the lungs.

COPD is distinguished pathologically by the destruc-tion of lung tissue, which is replaced by holes characteristic of emphysema, and by a tendency for excessive mucus production in the airway, which gives rise to symptoms of bronchitis. These pathological characteristics are realized physiologically as difficulty in exhaling (called flow limita-tion), which causes increased lung volume and manifests as breathlessness. Other early symptoms of the condition include a “smoker’s cough” and daily sputum production. Coughing up blood is not a feature of COPD and when present raises concern about a second, tobacco-related condition, particularly lung cancer. Patients with COPD are vulnerable to episodic worsening of their condition (called exacerbation). Exacerbations are triggered by infection, either bacterial or viral. Therefore, antibiotics, which work against bacteria, are not always required. Frequent exacerbations, particularly if severe enough to warrant hospital admission, indicate a poor prognosis.

The only therapeutic intervention shown to alter the course of COPD is removal of the noxious trigger, which



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can be accomplished in most cases by cessation of smok-ing. Treatments used in the early stages of disease include vaccination against influenza and pneumococcal pneu-monia and administration of drugs that widen the airways (i.e., bronchodilators). Inhaled corticosteroids are commonly prescribed, especially for patients with frequent exacerbations. Short courses (typically five days) of oral corticosteroids are given for exacerbations but generally are not used in the routine management of COPD. A six- to eight-week course of pulmonary reha-bilitation often benefits patients who have symptoms despite inhaler therapy. This should be followed by a community/home maintenance program or by repeat courses every two years.

In COPD patients with low blood–oxygen levels, the prescription of home oxygen can reduce hospital admis-sion and extend survival but does not alter the progression of lung disease. Some COPD patients do not find oxygen attractive, since they need to use it for 16 hours each day to derive benefit, which leads to further difficulties in mobility. In addition, oxygen is extremely flammable, and the prescription of oxygen for patients who smoke remains controversial because of the risk for explosion. Specialized centres can offer treatments for patients with advanced disease, including noninvasive ventilation and surgical options (i.e., lung transplantation and lung-volume reduction).

Lung Congestion

Lung congestion is characterized by distention of blood vessels in the lungs and filling of the alveoli with blood as a result of an infection, high blood pressure, or cardiac insufficiencies (i.e., inability of the heart to function ade-quately). Active congestion of the lungs is caused by

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infective agents or irritating gases, liquids, and particles. The alveolar walls and the capillaries in them become dis-tended with blood. Passive congestion is due either to high blood pressure in the capillaries, caused by a cardiac disorder, or to relaxation of the blood capillaries followed by blood seepage.

Left-sided heart failure—inability of the left side of the heart to pump sufficient blood into the general circu-lation—causes back pressure on the pulmonary vessels delivering oxygenated blood to the heart. The blood pres-sure becomes high in the alveolar capillaries, and they begin to distend. Eventually the pressure becomes too great, and blood escapes through the capillary wall into the alveoli, flooding them. Mitral stenosis, narrowing of the valve between the upper and lower chambers in the left side of the heart, causes chronic passive congestion. Iron pigment from the blood that congests the alveoli spreads throughout the lung tissue and causes deteriora-tion of tissue and formation of scar tissue. The walls of the alveoli also thicken and gas exchange is greatly impaired. The affected person shows difficulty in breathing, there is a bloody discharge, and the skin takes on a bluish tint as the disease progresses.

Passive congestion caused by relaxation of the blood vessels occurs in bedridden patients with weak heart action. Blood accumulates in the lower part of the lungs, although there is usually enough unaffected lung tissue for respiration. The major complication arises in mild cases of pneumonia, when the remaining functioning tissue becomes infected.

Pulmonary edema is much the same as congestion except that the substance in the alveoli is the watery plasma of blood, rather than whole blood, and the precipitating causes may somewhat differ. Inflammatory edema results from influenza or bacterial pneumonia. In


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X-ray showing lung congestion caused by congestive heart failure. Dr. Thomas Hooten/Centers for Disease Control and Prevention (CDC) (Image Number: 6241)

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mechanical edema the capillary permeability is broken down by the same type of heart disorders and irritants as in congestion. It can occur, for unknown reasons, after reinflation of a collapsed lung. After an operation, if too great a volume of intravenous fluids is given, the blood pressure rises and edema ensues. Excessive irradiation and severe allergic reactions may also produce this disorder.

The lungs become pale, wet, enlarged, and heavy. It may take only one or two hours for two to three quarts of liquid to accumulate. Acute cases can be fatal in 10 to 20 minutes. A person with pulmonary edema experiences dif-ficulty in breathing, with deep gurgling rattles in the throat. The person’s skin turns blue, and, because he or she is too weak to clear the fluids, the person may actually drown in the lung secretions.

Atelectasis

Atelectasis is characterized primarily by the absence of air in the lungs. The term is derived from the Greek words ateles and ektasis, literally meaning “incomplete expansion” in reference to the lungs. The term atelectasis can also be used to describe the collapse of a previously inflated lung, either partially or fully, because of specific respiratory dis-orders. There are three major types of atelectasis: adhesive, compressive, and obstructive.

Adhesive atelectasis is seen in premature infants who are unable to spontaneously breathe and in some infants after only a few days of developing breathing difficulties; their lungs show areas in which the alveoli, or air sacs, are not expanded with air. These infants usually suffer from a disorder called respiratory distress syndrome, in which the surface tension inside the alveolus is altered so that the alveoli are perpetually collapsed. This is typically caused by a failure to develop surface-active material


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X-ray showing changes in the right upper pulmonary lung fi eld that are characteristic of atelectasis. Dr. Thomas Hooten/Centers for Disease Control and Prevention (CDC) (Image Number: 6242)

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(surfactant) in the lungs. Treatment for infants with this syndrome includes replacement therapy with surfactant.

Compressive atelectasis is caused by an external pres-sure on the lungs that drives the air out. Collapse is complete if the force is uniform or is partial when the force is localized. Local pressure can result from tumour growths, an enlarged heart, or elevation of the diaphragm. The ducts and bronchi leading to the alveoli are squeezed together by the pressure upon them.

Obstructive atelectasis may be caused by foreign objects lodged in one of the major bronchial passage-ways, causing air trapped in the alveoli to be slowly absorbed by the blood. It may also occur as a complica-tion of abdominal surgery. The air passageways in the lungs normally secrete a mucous substance to trap dust, soot, and bacterial cells, which frequently enter with inhaled air. When a person undergoes surgery, the anes-thetic stimulates an increase in bronchial secretions. Generally, if these secretions become too abundant, they can be pushed out of the bronchi by coughing or strong exhalation of air. After abdominal surgery, the breathing generally becomes more shallow because of the sharp pain induced by the breathing movements, and the mus-cles beneath the lungs may be weakened. Mucous plugs can result that cause atelectasis. Other causes of obstruc-tion include tumours or infection.

The symptoms in extreme atelectasis include low blood oxygen content, which manifests as a bluish tint to the skin, absence of respiratory movement on the side involved, displacement of the heart toward the affected side, and consolidation of the lungs into a smaller mass. If a lung remains collapsed for a long period, the respiratory tissue is replaced by fibrous scar tissue, and respiratory function can-not be restored. Treatment for obstructive and compressive



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atelectasis is directed toward removal of any obstruction or compressive forces.

Lung Infarction

Lung infarction is the death of one or more sections of lung tissue due to deprivation of an adequate blood supply. The section of dead tissue is called an infarct. The cessation or lessening of blood flow results ordinarily from an obstruction in a blood vessel that serves the lung. The obstruction may be a blood clot that has formed in a dis-eased heart and has traveled in the bloodstream to the lungs, or air bubbles in the bloodstream (both of these are instances of embolism), or the blockage may be by a clot that has formed in the blood vessel itself and has remained at the point where it was formed (such a clot is called a thrombus). Ordinarily, when the lungs are healthy, such blockages fail to cause death of tissue because the blood finds its way by alternative routes. If the lung is congested, infected, or inadequately supplied with air, however, lung infarctions can follow blockage of a blood vessel.

Because neither the lung tissue nor the pleural sac sur-rounding the lungs has sensory endings, infarcts that occur deep inside the lungs produce no pain; those extending to the outer surface cause fluids and blood to seep into the space between the lungs and the pleural sac. The sac dis-tends with the excess fluid and there may be difficulty in inflating the lungs. When pain is present it indicates pleu-ral involvement. The pain may be localized around the rib cage, shoulders, and neck, or it may be lower, near the muscular diaphragm that separates the chest cavity from the abdomen. One explanation for the pain is that it is from tension on the sensitive nerve endings in the mem-brane lining the chest. Pain is most severe on inhalation.

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The symptoms of infarcts are generally spitting up of blood, coughing, fever, moderate difficulty in breathing, increased heartbeat, pleural rubbing, diminished breath sounds, and a dull sound heard when the chest is tapped. The blood shows an increase in number of white blood cells and sedimentation rate (clumping of red blood cells). Infarcts that do not heal within two or three days gener-ally take two to three weeks to heal. The dead tissue is replaced by scar tissue.

Cystic Fibrosis

Cystic fibrosis, also known as mucoviscidosis, is an inher-ited metabolic disorder, the chief symptom of which is the production of a thick, sticky mucus that clogs the respira-tory tract and the gastrointestinal tract. Cystic fibrosis was not recognized as a separate disease until 1938 and was then classified as a childhood disease because mortality among afflicted infants and children was high. However, by the mid-1980s, more than half of all victims of cystic fibrosis survived into adulthood owing to aggressive ther-apeutic measures.

Cystic fibrosis is an inherited disorder mainly affect-ing people of European ancestry. It is estimated to occur in 1 per 2,000 live births in these populations and is par-ticularly concentrated in people of northwestern European descent. It is much less common among people of African ancestry (about 1 per 17,000 live births) and is very rare in people of Asian ancestry. The disorder was long known to be recessive (i.e., only persons inheriting a defective gene from both parents will manifest the disease). The disease has no manifestations in heterozygotes (i.e., those indi-viduals who have one normal copy and one defective copy of the particular gene involved). However, when both



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parents are heterozygous, they may expect that, on the basis of chance, one out of four of their offspring will have the disease. In 1989 the defective gene responsible for cys-tic fibrosis was isolated. The gene, called cystic fibrosis transmembrane conductance regulator, or CFTR, lies in the middle of chromosome 7 and encodes a protein of the same name, designated CFTR.

Cystic fibrosis affects the functioning of the body’s exocrine glands (e.g., the mucus-secreting and sweat glands) in the respiratory and digestive systems. Within the cells of the lungs and gut, the CFTR protein trans-ports chloride across cell membranes and regulates other channels. These functions are critical for maintaining and adjusting the fluidity of mucous secretions. Most cases of cystic fibrosis are caused by a mutation that corresponds to the production of a CFTR protein that lacks the amino acid phenylalanine. As a result, chloride and sodium ions accumulate within cells, thereby drawing fluid into the cells and causing dehydration of the mucus that normally coats these surfaces. The thick, sticky mucus accumulates in the lungs, plugging the bronchi and making breathing difficult. This results in chronic respiratory infections, often with Staphylococcus aureus or Pseudomonas aeruginosa. Chronic cough, recurrent pneumonia, and the progressive loss of lung function are the major manifestations of lung disease, which is the most common cause of death of per-sons with cystic fibrosis.

In the digestive system, the abnormally thick mucous secretions interfere with the passage of digestive enzymes and thus block the body’s absorption of essential nutri-ents. The resulting maldigestion and malabsorption of food can cause affected individuals to become malnour-ished despite an adequate diet. Bulky, greasy, foul-smelling stools are often the first signs of cystic fibrosis. About 10

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percent of infants with cystic fibrosis have intestinal obstruction at birth due to very thick secretions. In addi-tion, mutations in the CFTR gene are associated with degeneration of the ductus deferens and sterility in adult males who have cystic fibrosis.

Cystic fibrosis causes the sweat glands to produce sweat that has an abnormally high salt content. The high salt content in perspiration is the basis for the “sweat test,” which is the definitive diagnostic test for the pres-ence of cystic fibrosis. Mutations associated with cystic fibrosis can be detected in screening tests. These tests are effective in the identification of adult carriers (heterozy-gotes), who may pass a mutation on to their offspring, as well as in the identification of newborns who may be at risk for the disorder.

The treatment of cystic fibrosis includes the intake of pancreatic enzyme supplements and a diet high in calo-ries, protein, and fat. Vigorous physical therapy on a daily basis is used to loosen and drain the mucous secretions that accumulate in the lungs. Medications such as dornase alfa, a recombinant form of the enzyme deoxyribonucle-ase, are given to thin mucus, facilitating its clearance from the lungs through coughing. In addition, bronchodilators can be used to relax the smooth muscles that line the air-ways and cause airway constriction, making it easier for patients to breathe. These agents may be administered by means of an inhaler or a nebulizer, which is powered by a compressor that sprays aerosolized drug into the airways. The anti-inflammatory agent ibuprofen has been shown to slow the deterioration of lung tissue in some cystic fibrosis patients. In severe cases, lung transplantation may be considered. Many patients with cystic fibrosis regularly take antibiotics, sometimes in aerosolized form, in order to fight lung infections.



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Among the most promising treatments under inves-tigation for cystic fibrosis is gene therapy. Gene therapy first emerged as a potential form of treatment in 1990, when researchers successfully restored CFTR chloride channel function in cultured lung and airway epithelial cells that carried CFTR mutations. The researchers used recombinant DNA technology to generate viral vectors containing normal copies of the CFTR gene. These vectors were then transfected into the cultured cells, which subsequently incorporated the normal genes into their DNA. This success led to the first clini-cal trial of gene therapy for cystic fibrosis in 1993. The same technology was used to insert the CFTR gene into a replication-deficient adenovirus that was then admin-istered into the noses and lungs of patients. This first trial initially appeared to be successful, since increased expression of the CFTR protein was observed shortly after treatment. However, the patients experienced severe side effects, including lung inflammation and signs of viral infection. Since the 1990s, gene therapy for cystic fibrosis has undergone significant refine-ment, and the outcomes of clinical trials are marked by steady improvement. However, the natural defense sys-tems of the lungs and airways have proved significant obstacles to cellular uptake of the viral vector carrying the normal CFTR gene. As a result, the development of an effective gene delivery system has become a major focus of cystic fibrosis gene therapy. Delivery systems under investigation include cationic polymer vectors, cationic liposomes, and adenovirus associated virus. The latter, which can bind to a type of receptor expressed in high numbers on the surfaces of lung cells, has proved particularly effective in laboratory studies using human lung tissue.

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Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is also known as crypto-genic fibrosing alveolitis. This is a generally fatal lung disease of unknown cause that is characterized by pro-gressive fibrosis of the alveolar walls. The disease most commonly manifests between ages 50 and 70, with insidi-ous onset of shortness of breath on exertion. A dry cough is common as well. Sharp crackling sounds, called rales or “Velcro crackles,” are heard through a stethoscope applied to the back in the area of the lungs. Computerized tomog-raphy (CT) imaging shows fibrosis and cysts that characteristically form in a rim around the lower outer portions of both lungs. In addition, pulmonary function testing shows a reduction in lung volume. Lung biopsies confirm the diagnosis by showing fibrosis with a lack of inflammation.

The disease causes progressive shortness of breath with exercise and ultimately produces breathlessness at rest. Hypoxemia (decreased levels of oxygen in the blood) initially occurs with exercise and later at rest and can be severe. Some individuals have clubbed fingertips and toes. The average duration of survival from diagnosis is four to six years; however, some people live 10 years or longer. Aside from administration of supplemental oxygen, there is no effective treatment. Some individuals may benefit from single or double lung transplantation.

Sarcoidosis and Eosinophilic Granuloma

Sarcoidosis is a disease of unknown cause characterized by the development of small aggregations of cells, or granulo-mas, in different organs; the lung is commonly involved. Other common changes are enlargement of the lymph



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glands at the root of the lung, skin changes, inflammation in the eye, and liver dysfunction. Occasionally, nerve sheaths are inflamed, leading to signs of involvement in the affected area. The kidney is not commonly involved, but some changes in blood calcium levels occur in a small percentage of cases. In most cases the disease is first detected on chest radiographs. Evidence of granulomas in the lung may be visible, but often there is little interfer-ence with lung function. The disease usually remits without treatment within a year or so, but in a small pro-portion of cases it progresses, leading finally to lung fibrosis and respiratory failure. The granulomatous inflam-mation in sarcoidosis can be controlled by long-term administration of a corticosteroid such as prednisone.

Eosinophilic granuloma, also known as histiocytosis X, is a disease associated with the excess production of histiocytes, a subgroup of immune cells. It causes lesions in lung tissue and sometimes also in bone tissue. Eosinophilic granuloma is a lung condition that may spon-taneously “burn out,” leaving the lung with some permanent cystic changes. Although its cause is unknown, the incidence is greatly increased in cigarette smokers.

Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis is a respiratory disorder caused by the filling of large groups of alveoli with exces-sive amounts of surfactant, a complex mixture of protein and lipid (fat) molecules. The alveoli are air sacs, minute structures in the lungs in which the exchange of respira-tory gases occurs. The gas molecules must pass through a cellular wall, the surface of which is generally covered by a thin film of surfactant material secreted from the alveo-lar cells. When too much surfactant is released from the alveolar cells, or when the lung fails to remove the

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surfactant, gas exchange is greatly hindered and the symp-toms of alveolar proteinosis occur.

The disease manifests itself in laboured breathing at rest or shortness of breath with exertion, and it is often accompanied by chest pain and a dry cough. There may also be general fatigue and weight loss. The skin becomes tinged with blue in the most serious cases, an indication that blood is not being adequately oxygenated or rid of carbon dioxide. X-rays most frequently show evidence of excess fluids in the lungs.

The precipitating cause of the disease is unknown. Persons affected are usually between ages 20 and 50. The disease can exist without causing symptoms for consider-able periods, and spontaneous improvement has been known to occur; it is sometimes fatal, but rarely so, if treated. Treatment involves removal of the material by a rinsing out of the lungs (lavage). One lung at a time is rinsed with a saltwater solution introduced through the windpipe. The fluids drawn back out of the lungs have been found to have a high content of fat. Sometimes the lesions totally clear up after one procedure, but subse-quent treatments are often necessary.

Immunologic Conditions of the Lung

The lung is often affected by generalized diseases of the blood vessels. Wegener granulomatosis, an acute inflam-matory disease of the blood vessels believed to be of immunologic origin, is an important cause of pulmonary blood vessel inflammation. Acute hemorrhagic pneumo-nitis occurring in the lung in association with changes in the kidney is known as Goodpasture syndrome. The con-dition has been successfully treated by exchange blood transfusion, but its cause is not fully understood. Pulmonary hemorrhage also occurs as part of a condition



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known as pulmonary hemosiderosis, which results in the accumulation of the iron-containing substance hemosid-erin in the lung tissues.

The lung may also be involved in a variety of ways in the disease known as systemic lupus erythematosus, which is also believed to have an immunologic basis. Pleural effu-sions may occur, and the lung parenchyma may be involved. These conditions have only recently been recognized and differentiated; accurate diagnosis has been much improved by refinements in radiological methods, by the use of pul-monary function tests, and especially by improvement in thoracic surgical techniques and anesthesia that have made lung biopsy much less dangerous than it formerly was.

The common condition of rheumatoid arthritis may be associated with scattered zones of interstitial fibrosis in the lung or with solitary isolated fibrotic lesions. More rarely, a slowly obliterative disease of small airways (bron-chiolitis) occurs, leading finally to respiratory failure.

Lung Cancer

Lung cancer is a disease characterized by uncontrolled growth of cells in the lungs. Lung cancer was first described by doctors in the mid-19th century. In the early 20th cen-tury it was considered relatively rare, but by the end of the century it was the leading cause of cancer-related death among men in more than 25 developed countries. In the 21st century, lung cancer emerged as the leading cause of cancer deaths worldwide, resulting in an estimated 1.3 mil-lion deaths each year. In women, lung cancer is the second leading cause of death from cancer globally, following breast cancer. In the United States, however, it has sur-passed breast cancer. The rapid increase in the worldwide prevalence of lung cancer was attributed mostly to the increased use of cigarettes following World War I.

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Causes and Symptoms

Lung cancer occurs primarily in persons between ages 45 and 75. In countries with a prolonged history of cigarette smoking, between 80 and 90 percent of all cases are caused by smoking. Heavy smokers have a greater likelihood of developing the disease than do light smokers. The risk is also greater for those who started smoking at a young age.

Passive inhalation of cigarette smoke (sometimes called secondhand smoke) is linked to lung cancer in nonsmokers. According to the American Cancer Society, secondhand smoke accounts for an estimated 3,400 deaths from lung cancer in nonsmoking adults in the United States each year. Other risk factors include exposure to radon gas and asbestos; smokers exposed to these sub-stances run a greater risk of developing lung cancer than do nonsmokers. Uranium and pitchblende miners, chro-mium and nickel refiners, welders, and workers exposed to halogenated ethers also have an increased incidence, as do some workers in hydrocarbon-related processing, such as coal processors, tar refiners, and roofers. Lung cancer is rarely caused directly by inherited mutations.

Tumours can begin anywhere in the lung, but symp-toms do not usually appear until the disease has reached an advanced stage or spread to another part of the body. The most common symptoms include shortness of breath, a persistent cough or wheeze, chest pain, bloody sputum, unexplained weight loss, and susceptibility to lower respi-ratory infections. In cases where the cancer has spread beyond the lungs, visible lumps, jaundice, or bone pain may occur.

Types of Lung Cancer

Once diagnosed, the tumour’s type and degree of invasive-ness are determined. Of the two basic forms, small-cell



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carcinoma accounts for 20 to 25 percent of all cases and non-small-cell carcinoma is responsible for the remainder.

Small-cell carcinoma (SCLC), also called oat-cell carci-noma, is rarely found in people who have never smoked. It is characterized by cells that are small and round, oval, or shaped like oat grains. SCLC is the most aggressive type of lung cancer. Because it tends to spread quickly before symptoms become apparent, the survival rate is very low.

Non-SCLCs consist primarily of three types of tumour: squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma. Adenocarcinoma accounts for some 25 to 30 percent of cases worldwide, but it is the most common type of lung cancer in the United States. Cells of adenocarci-noma are cube- or column-shaped, and they form structures that resemble glands and are sometimes hollow. Tumours often originate in the smaller, peripheral bronchi. Symptoms at the time of diagnosis often reflect invasion of the lymph nodes, pleura, and both lungs or metastasis to other organs.

Some 25 to 30 percent of primary lung cancers are squa-mous cell carcinomas, also called epidermoid carcinomas. This tumour is characterized by flat, scalelike cells, and it often develops in the larger bronchi of the central portion of the lungs. Squamous cell carcinoma tends to remain localized longer than other types and thus is generally more responsive to treatment.

About 10 percent of all lung cancers are large-cell car-cinomas. There is some dispute as to whether these constitute a distinct type of cancer or are merely a group of unusual squamous cell carcinomas and adenocarcino-mas. Large-cell carcinomas can begin in any part of the lung and tend to grow very quickly.

Diagnosis, Treatment, and Prevention

Lung cancers are often discovered during examinations for other conditions. Cancer cells may be detected in sputum;

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a needle biopsy may be used to remove a sample of lung tissue for analysis; or the large airways of the lungs (bron-chi) can be viewed directly with a bronchoscope for signs of cancer. Noninvasive methods include X-rays, computed tomography (CT) scans, positron emission tomography (PET) scans, and magnetic resonance imaging (MRI). There are also several blood tests that may be used to detect proteins and other substances known to be associ-ated with lung cancer. For example, abnormal fluctuations in the serum levels of parathormone or the presence in the blood of a protein called cytokeratin 19 fragment or of sub-stances known as carcinogenic antigens may be indicative of malignant lung disease. Most cases are usually diagnosed well after the disease has spread (metastasized) from its original site. For this reason, lung cancer has a poorer prog-nosis than many other cancers. Even when it is detected early, the five-year survival rate is about 50 percent.

As with most cancers, treatments for lung cancer include surgery, chemotherapy, and radiation. The choice of treatment depends on the patient’s general health, the stage or extent of the disease, and the type of cancer. The type of treatment an individual patient receives may also be based on the results of genetic screening, which can identify mutations that render some lung cancers suscep-tible to specific drugs.

Surgery involves the removal of a cancerous segment (segmentectomy), a lobe of the lung (lobectomy), or the entire lung (pneumonectomy). Lung surgery is serious and can lead to complications such as pneumonia or bleeding. Although removal of an entire lung does not prohibit oth-erwise healthy people from ultimately resuming normal activity, the already poor condition of many patients’ lungs results in long-term difficulty in breathing after surgery.

Radiation may be used alone or in conjunction with surgery—either before surgery to shrink tumours or



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following surgery to destroy small amounts of cancerous tissue. Radiation treatment may be administered as exter-nal beams or surgically implanted radioactive pellets (brachytherapy). Side effects include vomiting, diarrhea, fatigue, or additional damage to the lungs. Chemotherapy uses chemicals to destroy cancerous cells, but these chem-icals also attack normal cells to varying degrees, causing side effects that are similar to radiation therapy. An exper-imental technology that has shown promise in the treatment of lung cancer is microwave ablation, which relies on heat derived from microwave energy to kill can-cer cells. Early studies in small subsets of patients have demonstrated that microwave ablation can shrink and possibly even eliminate some lung tumours.

The probability of developing lung cancer can be greatly reduced by avoiding smoking. Smokers who quit also reduce their risk significantly. Testing for radon gas and avoiding exposure to coal products, asbestos, and other airborne carcinogens also lowers risk.

diseases of the MediastinuM and diaphragM

The mediastinum comprises the fibrous membrane in the centre of the thoracic cavity, together with the many important structures situated within it. Enlargement of lymph glands in this region is common, particularly in the presence of lung tumours or as part of a generalized enlargement of lymphatic tissue in disease. Primary tumours of mediastinal structures may arise from the thy-mus gland or the lower part of the thyroid gland; noninvasive cysts of different kinds are also found in the mediastinum.

Mediastinal emphysema occurs when a pocket of air forms within the mediastinum and thus surrounds the

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heart and central blood vessels. This usually occurs as a result of lung rupture. When the alveoli of the lungs rupture because of traumatic injury or lung disease, the released air seeks an area of escape. One pathway that the air can fol-low is through the lung tissue into the mediastinum, where accumulating air can cause sufficient pressure to impair normal heart expansion and blood circulation.

Mediastinal emphysema is one of the maladies that can afflict underwater divers who breathe compressed air. As a diver descends, the external pressure upon his or her body increases. The air the diver breathes is more dense and concentrated than the air breathed on the surface. While the diver remains deeply submerged, there is no difficulty; when he or she begins to ascend again, however, the external pressure decreases, and the lungs begin to expand because the air inside has less pressure to contain it. If the diver breathes normally or exhales as he or she ascends at a moderate rate, the extra gas pressure is relieved by exhaling. If the diver holds his or her breath, rises too rapidly, or has respiratory obstructions such as cysts, mucus plugs, or scar tissue, which do not permit suf-ficient release of air, the lungs become overinflated and rupture. Air bubbles can then enter the veins and capillar-ies of the circulatory system directly, causing an air embolism, or they can travel through the lung tissue to other areas of the body.

In mediastinal emphysema the air bubbles usually pass along the outside of blood vessels and the bronchi until they reach the mediastinal cavity. This area contains the heart, major blood vessels, main bronchi, and the trachea. Air trapped in the mediastinum expands as the diver con-tinues to rise. The pressure may cause intense pain beneath the rib cage and in the shoulders; the expanding air may compress the respiratory passageways, making breathing difficult, and collapse blood vessels vital to circulation.



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The symptoms of mediastinal emphysema may range from pain under the breastbone, shock, and shallow breathing to unconsciousness, respiratory failure, and cyanosis (blue colouring of the skin). In cases in which the symptoms are not severe, the air will be absorbed by the body, or it may be removed by inserting a long hypodermic needle into the mediastinum to draw off the air. If there is respiratory or circulatory distress, the victim must be recompressed in a hyperbaric chamber so that the body can resume its essential functions before the air is removed.

Diseases and disorders that affect the diaphragm can cause fundamental changes in respiratory function. For example, bilateral diaphragmatic paralysis can lead to a severe reduction in vital capacity, especially when the sub-ject is recumbent (lying down). In many cases the cause of the paralysis cannot be determined. Paralysis of the dia-phragm on one side is more common and better tolerated than bilateral paralysis, although some shortness of breath on exertion is often present. The function of the dia-phragm may be compromised when the lung is highly overinfl ated, as occurs in emphysema; diaphragmatic fatigue may limit the exercise capability of affected per-sons. In some persons the diaphragm may be incompletely formed at birth; this can lead to herniation of the abdomi-nal viscera through the diaphragm.

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CHAPTER CHAPTER 6

Allergic and occupational lung diseases comprise

two groups of conditions that are associated with the exposure to and inhalation of particulate matter. In the case of allergies, affected persons are highly sensitive to substances such as dust or pollen. In occupational disease, however, exposure to harmful irritants, such as asbestos and coal dust, causes respiratory disease in otherwise healthy workers. For most affected persons, reducing exposure to the irritant relieves the symptoms of their condition. In some cases of occupational exposure, severe respiratory disease may ensue, leading to cancer and sub-stantial loss of lung function.

Respiratory function can be severely compromised by a variety of other conditions, many of which are acute in nature. For example, traumatic conditions, such as respi-ratory distress syndrome, require immediate medical administration of oxygen and ultimately mechanical ven-tilation in order to prevent lung collapse and death. Carbon monoxide poisoning, altitude sickness, decom-pression sickness, and drowning are other examples of acute conditions that can result in respiratory failure.

allergic lung diseases

There are at least three reasons why the lungs are particu-larly liable to be involved in allergic responses. First, the lungs are exposed to the outside environment, and, hence,

ALLERGIC AND OCCUPATIONAL LUNG DISEASES AND ACUTE RESPIRATORY CONDITIONS


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particles of foreign substances such as pollen may be deposited directly in the lungs; second, the walls of the bronchial tree contain smooth muscle that is very likely to be stimulated to contract if histamine is released by cells affected by the allergic reaction; and, third, the lung con-tains a very large vascular bed, which may be involved in any general inflammatory response. It is therefore not sur-prising to find that sensitivity phenomena are common and represent an important aspect of pulmonary disease as a whole. The most common and most important of these is asthma.

Asthma

Asthma is a chronic disorder of the lungs in which inflamed airways are prone to constrict, causing episodes of wheez-ing, chest tightness, coughing, and breathlessness that range in severity from mild to life-threatening. Asthmatic episodes may begin suddenly or may take days to develop. Although an initial episode can occur at any age, approxi-mately half of all cases occur in persons younger than age 10, boys being affected more often than girls. Among adults, however, women are affected more often than men.

When asthma develops in childhood, it is often associated with an inherited susceptibility to allergens— substances, such as pollen, dust mites, or animal dander, that may induce an allergic reaction. In adults, asthma may develop in response to allergens, but viral infections, aspi-rin, weather conditions, and exercise may cause it as well. In addition, stress may exacerbate symptoms. Adults who develop asthma may also have chronic rhinitis, nasal pol-yps, or sinusitis. Adult asthma is sometimes linked to exposure to certain materials in the workplace, such as chemicals, wood dusts, and grains. These substances pro-voke both allergic and nonallergic forms of the disease. In

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7 Allergic and Occupational Lung Diseases and Acute Respiratory Conditions 7

During normal breathing, inhaled air travels through two main channels (primary bronchi) that branch within each lung into smaller, narrower pas-sages (bronchioles) and fi nally into the tiny, terminal bronchial tubes. During an asthma attack, smooth muscles that surround the airways spasm, which results in tightening of the airways; swelling and infl ammation of the inner airway space (lumen) cause fl uid buildup and infi ltration by immune cells and excessive secretion of mucus into the airways. Consequently, air is obstructed from circulating freely in the lungs and cannot be expired. Encyclopædia Britannica, Inc.

most of these cases, symptoms will subside if the causative agent is removed from the workplace.

Asthma is classifi ed based on the degree of symptom severity, which can be divided into four categories: mild intermittent, mild persistent, moderate persistent, and severe persistent. Although the mechanisms underlying an asthmatic episode are not fully understood, in general


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it is known that exposure to an inciting factor stimulates the release of chemicals from the immune system. These chemicals can cause spasmodic contraction of the smooth muscle surrounding the bronchi, swelling and inflamma-tion of the bronchial tubes, and excessive secretion of mucus into the airways. The inflamed, mucus-clogged air-ways act as a one-way valve (i.e., air is inspired but cannot be expired). The obstruction of airflow may resolve spon-taneously or with treatment.

A number of medications are used to prevent and con-trol the symptoms of asthma and to reduce the frequency and severity of episodes. Asthma medications are catego-rized into three main types: anti-inflammatory agents, which suppress inflammation; bronchodilators, which relax smooth muscle constriction and open the airways; and leukotriene modifiers, which interrupt the chemi-cal signaling within the body that leads to constriction and inflammation. These medications may be taken on a long-term daily basis to maintain and control persistent asthma (long-term control medications), or they may be used to provide rapid relief from constriction of airways (quick-relief medications). Long-term control medica-tions include corticosteroids, which are the most potent and effective anti-inflammatory medications available; cromolyn sodium and nedocromil, which are anti-inflam-matory medications often prescribed for children; long-acting beta2-agonists and methylxanthines (e.g., the-ophylline), which are bronchodilators; and zileuton and zafirlukast, which are leukotriene modifiers. Quick-relief medications may include bronchodilators, such as short-acting beta2-agonists and ipratropium bromide, or systemic corticosteroids. Agents that block enzymes called phos-phodiesterases, which are involved in mediating airway constriction and inflammation, are in clinical trials. These

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drugs are designed to be long-lasting—administered once per day via inhalation—and are expected to be safer than traditional medications, which may cause cardiovascular damage. A prolonged asthma attack that does not respond to medication is called status asthmaticus. A person with this condition must be hospitalized to receive oxygen and other treatment.

In addition to managing asthma with medications, persons who suffer from the disease are advised to mini-mize their exposure to the substances that trigger asthma. The ability to recognize the early warning signs of an impending episode is important, and individuals can mon-itor the level of airflow obstruction in their lungs by using a pocket-size device called a peak flow meter.

In developed countries and especially in urban areas, the number of asthma cases has increased steadily. Today asthma affects more than 7 percent of children and about 9 percent of adults. Reasons for this dramatic surge in asthma cases, particularly among children, are not entirely clear. Air pollution, crowded living conditions, smoking, exposure to secondhand smoke, and even cock-roaches have been blamed for the increase. However, in many underdeveloped tropical regions of the world, very few people are affected by allergies or asthma. In those areas, millions of people are infected with Necator ameri-canus, a species of hookworm. Studies have shown that hookworms reduce the risk of asthma by decreasing the activity of the human host’s immune system. In 2006 a clinical trial conducted in a small number of patients demonstrated that deliberate infection with 10 hook-worm larvae, too few to cause hookworm disease, can relieve symptoms of allergy and asthma. Further investi-gation of this “helminthic therapy” in larger sample populations is under way.



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There has been some controversy concerning increased rates of asthma in countries where childhood vaccination is widespread. Although not yet successfully confirmed, studies have indicated that only one vaccine, pertussis vaccine, may give rise to asthma. In a reverse scenario, protection against asthma conferred by BCG vaccination (for defense against tuberculosis) has been proved only in children with a history of allergic rhinitis (hay fever). Antibiotics may also interfere with immune development. Children who are given broad-spectrum antibiotics (effec-tive against multiple microorganisms) before two years of age are three times more likely to develop asthma than are children who are not given such antibiotics.

Hay Fever

Hay fever, also known as allergic rhinitis, is a common sea-sonal condition caused by allergy to grasses and pollens. Seasonally recurrent bouts of sneezing, nasal congestion, and tearing and itching of the eyes caused by allergy to the pollen of certain plants, chiefly those depending upon the wind for cross-fertilization, such as ragweed in North America and timothy grass in Great Britain.

In allergic persons contact with pollen releases hista-mine from the tissues, which irritates the small blood vessels and mucus-secreting glands. Symptoms may be aggravated by emotional factors. Antihistamine drugs and inhaled corticosteroids provide symptomatic relief. The most effective long-term treatment is immunotherapy, desensitization by injections of an extract of the causative pollen administered once or twice a week for one or more years. Hay fever, like other allergic diseases, shows a famil-ial tendency and may be associated with other allergic disorders, such as dermatitis or asthma.

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Giant ragweed ( Ambrosia trifi da ) is a common cause of hay fever. Ragweed pollen is typically dispersed in the air from late summer to mid-fall in many areas of central and eastern North America. Louise K. Broman—Root Resources



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Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis is an important group of conditions in which the lung is sensitized by contact with a variety of agents and in which the response to reexpo-sure consists of an acute pneumonitis, with inflammation of the smaller bronchioles, alveolar wall edema, and a greater or lesser degree of airflow obstruction due to smooth muscle contraction. In more chronic forms of the condition, granulomas, or aggregations of giant cells, may be found in the lung. Inflammation can lead to widespread lung fibrosis and chronic respiratory impairment.

One of these illnesses is the so-called farmer’s lung, caused by the inhalation of spores from moldy hay (ther-mophilic Actinomyces). This causes an acute febrile illness with a characteristically fine opacification (clouding, or becoming opaque) in the basal regions of the lung on the chest radiograph. Airflow obstruction in small airways is present, and there may be measurable interference with diffusion of gases across the alveolar wall. If untreated, the condition may become chronic, with shortness of breath persisting after the radiographic changes have disap-peared. Farmer’s lung is common in Wisconsin, on the eastern seaboard of Canada, in the west of England, and in France. Education of farmers and their families and the wearing of a simple mask can completely prevent the condition.

A similar group of diseases occurs in those with close contact with birds. Variously known as pigeon breeder’s lung or bird fancier’s lung, these represent different kinds of allergic responses to proteins from birds, particularly proteins contained in the excreta of pigeons, budgerigars (parakeets), and canaries. An acute hypersensitivity pneu-monitis may also occur in those cultivating mushrooms (particularly where this is done below ground), after

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exposure to redwood sawdust, or in response to a variety of other agents. An infl uenza-like illness resulting from exposure to molds growing in humidifi er systems in offi ce buildings (“humidifi er fever”) has been well documented. It is occasionally attributable to Aspergillus , but sometimes the precise agent cannot be identifi ed. The disease may present as an atypical nonbacterial pneumonia and may be labeled a viral pneumonia if careful inquiry about possible contacts with known agents is not made.

occupational lung disease

Occupational lung diseases are caused by the inhalation of a variety of organic or inorganic dusts or chemical

Some species of the fungi genus Aspergillus can cause allergic reactions and mild pneumonia in susceptible individuals. Runk/Schoenberger from Grant Heilman



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irritants, usually over a prolonged period of time. The lung diseases that result from the inhalation of such irritants are known medically as pneumoconioses. The type and severity of disease depends on the composition of the dust; small quantities of some substances, notably silica and asbestos, produce grave reactions, while milder irri-tants produce symptoms of lung disease only with massive exposure. Much evidence indicates that the smoking of cigarettes in particular aggravates the symptoms of many of the pneumoconiosis diseases.

Typically, the early symptoms of mild pneumoconioses include chest tightness, shortness of breath, and cough, progressing to more serious breathing impairment, chronic bronchitis, and emphysema in the most severe cases. Inhaled dust collects in the alveoli, or air sacs, of the lung, causing an inflammatory reaction that converts nor-mal lung tissue to fibrous scar tissue and thus reduces the elasticity of the lung. If enough scar tissue forms, lung function is seriously impaired, and the clinical symptoms of pneumoconiosis are manifested. The total dust load in the lung, the toxic effects of certain types of dust, and infections of the already damaged lung can accelerate the disease process.

Among inorganic dusts, silica, encountered in numer-ous occupations, is the most common cause of severe pneumoconiosis. As little as 5 or 6 grams (about 0.2 ounce) in the lung can produce disease. Graphite, tin, barium, chromate, clay, iron, and coal dusts are other inorganic substances known to produce pneumoconiosis, although silica exposure is also involved in many cases. Pneumoconioses associated with these substances usually result only from continued exposure over long periods. Asbestos, beryllium, and aluminum dusts can cause a more severe pneumoconiosis, often after relatively brief

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exposure to massive amounts of dust. Asbestosis has also been associated with cancers of the lung and other organs.

Prolonged exposure to organic dusts such as spores of molds from hay, malt, sugarcane, mushrooms, and barley can produce lung disease through a severe allergic response within a few hours of exposure, even in previ-ously nonallergic persons. Brown lung disease in textile workers is also a form of pneumoconiosis, caused by fibres of cotton, flax, or hemp that, when inhaled, stimulate histamine release. Histamines cause the air passages to constrict, impeding exhalation.

Chemical irritants that have been implicated in lung disease include sulfur dioxide, nitrogen dioxide, ammonia, acid, and chloride, which are quickly absorbed by the lining of the lungs. The chemicals themselves may scar the deli-cate lung tissues, and their irritant effect may cause large amounts of fluid to accumulate in the lungs. Once exposure to the chemical ceases, the patient may recover completely or may suffer from chronic bronchitis or asthma.

Silicosis

Silicosis is a chronic disease of the lungs that is caused by the inhalation of silica dust over long periods of time. (Silica is the chief mineral constituent of sand and of many kinds of rock.) The disease occurs most commonly in min-ers, quarry workers, stonecutters, tunnelers, and workers whose jobs involve grinding, sandblasting, polishing, and buffing. Silicosis is one of the oldest industrial diseases, having been recognized in knife grinders and potters in the 18th century, and it remains one of the most common dust-induced respiratory diseases in the developed world.

In most instances, 10 to 20 years of occupational expo-sure to silica dust are needed for silicosis to develop. The



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disease rarely occurs with exposures to concentrations of less than 6,000,000 particles of silica per cubic foot (about 210,000 per litre) of air. Only very small silica par-ticles less than 10 microns (0.0004 inch) in diameter penetrate to the finer air passages of the lungs, and parti-cles of one to three microns do the most damage.

The symptoms of silicosis are shortness of breath that is followed by coughing, difficulty in breathing, and weak-ness. These symptoms are all related to a fibrosis that reduces the elasticity of the lung. In the actual disease process, the tiny particles of inhaled silica are taken up in the lungs by scavenger cells, called macrophages, that serve to protect the body from bacterial invasion. Silica particles, however, cannot be digested by the macrophages and instead kill them. The killed cells accumulate and form nodules of fibrous tissue that gradually enlarge to form fibrotic masses. These whorls of fibrous tissue may spread to involve the area around the heart, the open-ings to the lungs, and the abdominal lymph nodes. Lung volume is reduced, and gas exchange is poor. Silicosis pre-disposes a person to tuberculosis, emphysema, and pneumonia. In the past a large proportion of sufferers of silicosis died of tuberculosis, though this has changed with the availability of drug therapies for that disease.

There is no cure for silicosis, and, since there is no effective treatment, control of the disease lies mainly in prevention. The use of protective face masks and proper ventilation in the workplace and periodic X-ray monitor-ing of workers’ lungs has helped lessen the incidence of the disease.

Black Lung

Black lung, also known as coal-worker’s pneumoconiosis, is a respiratory disorder caused by repeated inhalation of

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coal dust over a period of years. The disease gets its name from a distinctive blue-black marbling of the lung caused by accumulation of the dust. Georgius Agricola, a German mineralogist, first described lung disease in coal miners in the 16th century, and it is now widely recog-nized. It may be the best known occupational illness in the United States.

The disease is most commonly found among miners of hard coal, but it also occurs in soft-coal miners and graph-ite workers. Onset of the disease is gradual. Symptoms usually appear only after 10 to 20 years of exposure to coal dust, and the extent of disease is clearly related to the total dust exposure. It is not clear, however, whether coal itself is solely responsible for the disease, as coal dust often is contaminated with silica, which causes similar symptoms. There is strong evidence that tobacco smoking aggravates the condition. The early stages of the disease (when it is called anthracosis) usually have no symptoms, but in its more advanced form it frequently is associated with pul-monary emphysema or chronic bronchitis and can be disabling; tuberculosis is also more common in victims of black lung.

Asbestosis and Mesothelioma

The widespread use of asbestos as an insulating material during World War II, and later in flooring, ceiling tiles, brake linings, and as a fire protectant sprayed inside buildings, led to a virtual epidemic of asbestos-related disease 20 years later. The first disease recognized to be caused by asbestos was asbestosis, which produces char-acteristic changes in the lungs that can be identified in chest X-rays and that can impair lung function at an early stage. Later it was discovered that exposure to much less asbestos than was needed to cause asbestosis led to



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thickening of the pleura, and, when both cigarette smok-ing and asbestos exposure occurred, there was a major increase in the risk for lung cancer. The risks from smoking and from significant asbestos exposure are mul-tiplicative in the case of lung cancer. A malignant tumour of the pleura known as mesothelioma is caused almost exclusively by inhaled asbestos. Often a period of 20 years or more elapses between exposure to asbestos and the development of a tumour.

As far as is known, all the respiratory changes associ-ated with asbestos exposure are irreversible. Malignant mesothelioma is rare and unrelated to cigarette smoking, but survival after diagnosis is less than two years. In most cases, thickening of the pleura is not associated with dis-turbance of lung function or with symptoms of exposure to asbestos, although in occasional cases pleuritis is very aggressive and thus may produce symptoms. It is not yet understood exactly why asbestos devastates the tissues of the lungs. Asbestos has been suspected to play a role in stimulating certain cellular events, such as the genera-tion of harmful reactive molecules and the activation of damaging inflammatory processes. These events could contribute to the scarring and fibrosis that are character-istic of inhalation of asbestos fibres.

Not all types of asbestos are equally dangerous. The risk of mesothelioma in particular appears to be much higher if crocidolite, a blue asbestos that comes from South Africa, is inhaled than if chrysotile is inhaled. But exposure to any type of asbestos is believed to increase the risk of lung cancer, especially when associated with ciga-rette smoking. While the removal of asbestos from buildings has greatly alleviated the risk of exposure to asbestos for many people, inhalation of asbestos remains a significant risk for the workers removing the material. All

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industrialized countries have imposed strict regulations for handling asbestos, and the workforce is generally aware of the material’s dangers.

There is no curative therapy for asbestosis or meso-thelioma. Treatment is aimed at managing symptoms, preventing infections, and delaying disease progression. Individuals with asbestosis often receive annual vaccina-tions against influenza and pneumococcal pneumonia. In some cases, aerosol medications that thin mucous secretions and oxygen that is supplied by a portable tank are necessary to maintain adequate oxygen intake. In other cases, lung transplantation is required. Individuals with mesothelioma often undergo chemotherapy and radiation therapy, which may prolong survival for a short period of time.

Respiratory Toxicity of Glass and Metal Fibres

The increasing use of human-made mineral fibres (as in fibreglass and rock wool) has led to concern that these may also be dangerous when inhaled. Present evidence suggests that they do increase the risk of lung cancer in persons occupationally exposed to them. Standards for maximal exposure have been proposed.

The toxicity of beryllium, known as berylliosis, was first discovered when it was widely used in the manufac-ture of fluorescent light tubes shortly after World War II. Although beryllium is no longer used in the fluorescent light industry, it is still important in the manufacture of metal alloys and ceramics. Berylliosis involves the lungs but occasionally affects only the skin. There are two forms: an acute illness occurring most frequently in workers extracting beryllium metal from ore or manufacturing



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beryllium alloys, and a slow-developing chronic disease occurring in scientific and industrial workers who are exposed to beryllium-containing fumes and dust.

The acute disease involves both skin and lungs, caus-ing a burning rash, eye irritation, nasal discharge, a cough, and chest tightness. The skin disease is caused by direct contact with beryllium salts and the lung disease by inha-lation of metal dust or beryllium compounds. Most of those affected by acute berylliosis recover within a few months, but a small number of patients develop a highly fatal inflammation of the lung within 72 hours after a brief, massive exposure to beryllium. The chronic disease may occur more than 15 years after exposure, although the later it develops, the milder it is likely to be. It generally causes shortness of breath, especially after exercise, exhaustion, and a dry cough and can produce a permanent, though moderate, disability.

Byssinosis

Byssinosis, or brown lung, is a respiratory disorder caused by inhalation of an endotoxin produced by bacte-ria in the fibres of cotton, flax, hemp, and other textiles. Byssinosis is common among textile workers, who often inhale significant amounts of cotton dust. Cotton dust may stimulate inflammation that damages the normal structure of the lung and causes the release of histamine, which constricts the air passages. As a result, breathing becomes difficult. Over time the dust accumulates in the lung, producing a typical discoloration that gives the dis-ease its common name.

Byssinosis was first recognized in the 17th century and was widely known in Europe and England by the early 19th century. Today it is seen in most cotton-producing

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regions of the world. Several years of exposure to cotton dust are needed before byssinosis develops, and workers with lower grade disease usually recover completely upon leaving the industry or moving into an area with less dust. Persons with mild byssinosis have a “Monday feeling” of chest tightness and shortness of breath on the first day of work after a weekend or holiday. As exposure continues, this feeling persists throughout the week, and in advanced stages, byssinosis causes chronic, irrevers-ible obstructive lung disease. Because cotton is by far the most common cause of byssinosis, this form of the con-dition has been variably known as cotton-dust asthma and cotton-mill fever.

Respiratory Toxicity of Industrial Chemicals

Toluene diisocyanate, used in the manufacture of polyure-thane foam, may cause occupational asthma in susceptible individuals at very low concentrations. In higher concen-trations, such as may occur with accidental spillage, it causes a transient flulike illness associated with airflow obstruction. Prompt recognition of this syndrome has led to modifications in the industrial process involved.

Although the acute effects of exposure to many of these gases and vapours are well documented, there is less certainty about the long-term effects of repeated low-level exposures over a long period of time. This is particularly the case when the question of whether work in a generally dusty environment has contributed to the development of chronic bronchitis or later emphysema. In other words, whether such nonspecific exposures increase the risk of these diseases in cigarette smokers.

Many chemicals can damage the lung in high concen-tration: these include oxides of nitrogen, ammonia,



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chlorine, oxides of sulfur, ozone, gasoline vapour, and ben-zene. In industrial accidents, such as occurred in 1985 in Bhopal, India, and in 1976 in Seveso, near Milan, people in the neighbourhood of chemical plants were acutely exposed to lethal concentrations of these or other chemi-cals. The custom of transporting dangerous chemicals by rail or road has led to the occasional exposure of bystand-ers to toxic concentrations of gases and fumes. Although in many cases recovery may be complete, it seems clear that long-term damage may occur.

Disability and Attribution of Occupational Lung Diseases

Occupational lung diseases are of social and legal impor-tance. In such cases, respiratory specialists must assess the extent of an individual’s disability and then form an opinion on whether an individual’s disability can be attributed to an occupational hazard. Pulmonary func-tion testing and tests of exercise capability provide a good indication of the impact of a disease on the physical ability of a patient. However, it is much more difficult to decide how much of a patient’s disability is attributable to occupational exposure. If the exposure is historically known to cause a specific lesion in a significant percent-age of exposed persons, such as mesothelioma in workers exposed to asbestos, attribution may be fairly straight-forward. In many cases, however, the exposure may cause only generalized pulmonary changes or lung lesions for which the precise cause cannot be determined. These instances may be complicated by a history of cigarette smoking. Physicians asked to present opinions on attrib-utability before a legal body frequently must rely on the application of probability statistics to the individual case, a not wholly satisfactory procedure.

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other respiratory conditions

Other respiratory conditions, ranging from poor pulmo-nary circulation to carbon monoxide poisoning, comprise a diverse group of diseases and disorders. The causative factors of these conditions may include accidents, toxic gases, environmental pollutants, and metabolic disorders. In addition, conditions arising from exposure to extremes in atmospheric pressure, which occurs during mountain climbing and diving, account for an important set of illnesses that can contribute to severe respiratory dysfunc-tion in persons of otherwise exceptional health.

Circulatory Disorders

The lung is commonly involved in disorders of the circula-tion. The most important and common of these is blockage of a branch of the pulmonary artery by blood clot, which has usually formed in the veins of the legs or of the pelvis. The resulting pulmonary embolism leads to changes in the lung supplied by the affected artery. When severe, these changes are known as a pulmonary infarc-tion. The consequences of embolism range from sudden death, when the infarction is massive, to an increased respiratory rate, slight fever, and occasionally some pleu-ritic pain over the site of the infarction.

An individual is at an increased risk for pulmonary embolism whenever his or her circulation is sluggish. This occurs most often during a postoperative period when the affected individual is immobilized in bed. Early mobilization after surgery or childbirth is considered an important preventive measure. Repetitive pulmonary emboli may lead to chronic pulmonary thromboembo-lism, in which the pressure in the main pulmonary artery is persistently increased. Over time, a clot is replaced with



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an adherent fibrous material in the pulmonary arteries, causing shortness of breath on exertion and, ultimately, right ventricular heart failure. The obstructing lesions can be surgically removed in some instances, thereby relieving symptoms of breathlessness.

In primary pulmonary hypertension, a condition of unknown origin, a marked increase in pulmonary arterial pressure occurs as a result of progressive narrowing and obliteration of small pulmonary arteries. Primary pulmo-nary hypertension leads to enlargement of the heart and eventual failure of the right ventricle of the heart, usually after increasing disability with severe shortness of breath. In addition to chest X-rays and basic pulmonary function tests, a diagnosis of pulmonary hypertension is often con-firmed following an electrocardiogram (EKG) to assess electrical function of the heart, an echocardiogram to determine whether the heart is enlarged and to evaluate the flow of blood through the heart, and cardiac catheter-ization to measure pressure in the pulmonary artery and right ventricle of the heart.

Treatment of primary pulmonary hypertension is aimed at alleviating symptoms. Because of the variability in physiological response to certain drugs and because of the progressive nature of the disease, affected individuals require careful, long-term evaluation and treatment. While some medications such as calcium channel block-ers may be taken orally, others such as prostacyclin are given by continuous intravenous infusion supplied through a portable battery-powered pump. Prostacyclin can some-times be given in oral or inhaled forms. In some cases, lung transplantation is necessary.

Congestion of the lungs (pulmonary edema) and the development of fluid in the pleural cavity, with consequent shortness of breath, follows left ventricular failure, usually as a consequence of coronary arterial disease. When the

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valve between the left atrium of the heart and the left ven-tricle is thickened and deformed by rheumatic fever (mitral stenosis), chronic changes develop in the lung as a result of the increased pressure in the pulmonary circula-tion. These changes contribute to the shortness of breath and account for the blood staining of the sputum.

Respiratory Distress Syndrome

Respiratory distress syndrome is a condition that can affect infants or adults. In infants it is also called hya-line membrane disease. This complication is especially common in premature newborns. It is characterized by extremely laboured breathing, cyanosis (a bluish tinge to the skin or mucous membranes), and abnormally low levels of oxygen in the arterial blood. Before the advent of effective treatment, respiratory distress syndrome of infants was frequently fatal. Autopsies of children who had succumbed to the disorder revealed that the air sacs (alveoli) in their lungs had collapsed and a “glassy” (hya-line) membrane had developed in the alveolar ducts.

Although respiratory distress syndrome occurs mostly in premature, low-birth-weight infants (those weighing less than 2.5 kg, or approximately 5.5 pounds), it also some-times develops in full-term infants, particularly those born to diabetic mothers. The disorder arises because of a lack of surfactant, a pulmonary substance that prevents the alveoli from collapsing after the infant’s first breaths have been taken. The syndrome was formerly the leading cause of death in premature infants, but considerable success in saving affected infants has been achieved by using mechan-ical ventilators that deliver air under pressure into the alveoli. The most seriously affected newborns are treated for several days with an extracorporeal membrane oxygen-ator, which does the work of the lungs by oxygenating the



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blood and removing carbon dioxide. The continual air pressure provided by the ventilator prevents the collapse of the air sacs. As the infant’s lungs mature and begin to produce surfactant—usually within three to five days after birth—the child is weaned from the ventilator. Most chil-dren who survive have no aftereffects.

In adults, bacterial or viral pneumonia, exposure of the lung to gases, aspiration of material into the lung (includ-ing water in near-drowning episodes), or any generalized septicemia (blood poisoning) or severe lung injury may lead to sudden, widespread bilateral lung injury. This syn-drome is known as acute respiratory distress syndrome of adults. It was recognized as “shock lung” in injured sol-diers evacuated by helicopter to regional military hospitals during the Vietnam War. Many causes of respiratory dis-tress syndrome of adults have been identified. Acute respiratory distress syndrome carries about a 50 percent mortality rate. Life-support treatment with assisted ven-tilation rescues many patients, although superimposed infection or multiple organ failure can result in death. Recovery and repair of the lung may take months after clinical recovery from the acute event.

Air Pollution

The disastrous fog and attendant high levels of sulfur dioxide and particulate pollution (and probably also sulfu-ric acid) that occurred in London in the second week of December 1952 led to the deaths of more than 4,000 peo-ple during that week and the subsequent three weeks. Many, but not all, of the victims already had chronic heart or lung disease. Prize cattle at an agricultural show also died in the same period as a result of the air pollution. This episode spurred renewed attention to this problem, which had been intermittently considered since the 14th century

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Air pollution begins as emissions from sources such as industrial smokestacks. The pollutants released into the air may impact the respiratory health of people working in and living near such facilities. Photos.com/Jupiterimages

in England, and fi nally the passage of legislation banning open coal burning, the factor most responsible for the pollution. This form of pollution, common in many cities using coal as heating fuel, is associated with excess mortal-ity and increased prevalences of chronic bronchitis, respiratory tract infections in the young and old, and pos-sibly lung cancer. Today many industrial cities have legislation restricting the use of specifi c fuels and mandat-ing emission-control systems in factories.

In 1952 a different kind of air pollution was character-ized for the fi rst time in Los Angeles. The large number of automobiles in that city, together with the bright sun-light and frequently stagnant air, leads to the formation of photochemical smog. This begins with the emission



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of nitrogen oxide during the morning commuting hour, followed by the formation of nitrogen dioxide by oxygen-ation, and finally, through a complex series of reactions in the presence of hydrocarbons and sunlight, leads to the for-mation of ozone and peroxyacetyl nitrite and other irritant compounds. Eye irritation, chest irritation with cough, and possibly the exacerbation of asthma occur as a result.

Modern air pollution consists of some combination of the reducing form consequent upon sulfur dioxide emis-sions and the oxidant form, which begins as emissions of nitrogen oxides. Ozone is the most irritant gas known. In controlled exposure studies it reduces the ventilatory capability of healthy people in concentrations as low as 0.12 part per million. These levels are commonly exceeded in many places, including Mexico City, Bangkok, and São Paulo, where there is a high automobile density and the meteorologic conditions favour the formation of photo-chemical oxidants. Although acute episodes of communal air exposure leading to demonstrable mortality are unlikely, there is much concern over the possible long-term consequences of brief but repetitive exposures to oxidants and acidic aerosols. Such exposures are common in the lives of millions of people, and the impact of these exposures is an area of intense scientific investigation.

The indoor environment can be important in the genesis of respiratory disease. In developing countries, disease may be caused by inhalation of fungi from roof thatch materials or by the inhalation of smoke when the home contains no chimney. In developed countries, expo-sure to oxides of nitrogen from space heaters or gas ovens may promote respiratory tract infections in children. Inhalation of tobacco smoke in the indoor environment by nonsmokers impairs respiration, and repeated expo-sures may lead to lung cancer. A tightly sealed house may act as a reservoir for radon seeping in from natural sources.

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Carbon Monoxide Poisoning

Carbon monoxide poisoning is a common and dangerous hazard. British physiologist John Scott Haldane pioneered the study of the effects of carbon monoxide at the end of the 19th century, as part of his detailed analysis of atmo-spheres in underground mines. Carbon monoxide is produced by incomplete combustion, including combus-tion of gas in automobile engines, and for a long period it was a major constituent of domestic gas made from coal (its concentration in natural gas is much lower).

When the carbon monoxide concentration in the blood reaches 40 percent (when the hemoglobin is 40 per-cent saturated with carbon monoxide, leaving only 60 percent available to bind to oxygen), the subject feels dizzy and is unable to perform simple tasks. Judgment is also impaired. Hemoglobin’s affinity for carbon monoxide is 200 times greater than for oxygen, and in a mixture of these gases hemoglobin will preferentially bind to carbon monoxide. For this reason, carbon monoxide concentra-tions of less than 1 percent in inspired air seriously impair oxygen-hemoglobin binding capacity. The partial pressure of oxygen in the tissues in carbon monoxide poisoning is much lower than when the oxygen-carrying capacity of the blood has been reduced an equivalent amount by ane-mia, a condition in which hemoglobin is deficient. The immediate treatment for acute carbon monoxide poison-ing is assisted ventilation with 100 percent oxygen.

The carbon monoxide inhaled by smokers who smoke more than two packs of cigarettes a day may cause up to 10 percent hemoglobin saturation with carbon monoxide. A 4 percent increase in the blood carbon monoxide level in patients with coronary artery disease is believed to shorten the duration of exercise that may be taken before chest pain is felt.



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Acidosis

Acidosis is an abnormally high level of acidity, or low level of alkalinity, in the body fluids, including the blood. There are two primary types of acidosis: respiratory and meta-bolic. Respiratory acidosis results from inadequate excretion of carbon dioxide from the lungs. This may be caused by severe acute or chronic lung disease, such as pneumonia or emphysema, or by certain medications that suppress respiration in excessive doses, such as general anesthetic agents.

Metabolic acidosis occurs when acids are produced in the body faster than they are excreted by the kidneys or when the kidneys or intestines excrete excessive amounts of alkali from the body. Causes of metabolic acidosis include uncontrolled diabetes mellitus, shock, certain drugs or poisons, and renal failure, among others. Both respiratory and metabolic acidosis can be life-threatening and often require immediate medical attention.

Alkalosis and Hyperventilation

Alkalosis is an abnormally low level of acidity, or high level of alkalinity, in the body fluids, including the blood. Alkalosis may be either metabolic or respiratory in origin. Metabolic alkalosis results from either acid loss, which may be caused by severe vomiting or by the use of potent diuretics (substances that promote production of urine), or bicarbonate gain, which may be caused by excessive intake of bicarbonate or by the depletion of body fluid volume. Respiratory alkalosis results from hyperventila-tion, which may be caused by anxiety, asthma, congestive heart failure, pulmonary embolism, or pneumonia.

Hyperventilation is defined as a sustained abnormal increase in breathing. During hyperventilation the rate of

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The alveoli and capillaries in the lungs exchange oxygen for carbon dioxide. Imbalances in the exchange of these gases can lead to dangerous respiratory disorders, such as respiratory acidosis or hyperventilation. In addition, accu-mulation of fl uid in the alveolar spaces can interfere with gas exchange, causing symptoms such as shortness of breath. Encyclopædia Britannica, Inc.



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removal of carbon dioxide from the blood is increased. As the partial pressure of carbon dioxide in the blood decreases, respiratory alkalosis ensues. In turn, alkalosis causes constriction of the small blood vessels that supply the brain. Reduced blood supply to the brain can cause a variety of symptoms, including light-headedness and tin-gling of the fingertips. Severe hyperventilation can cause transient loss of consciousness.

Anxiety is the most common cause of hyperventila-tion. Panic disorder, a severe episodic form of anxiety, usually causes hyperventilation with resultant symptoms. Treatment of recurrent hyperventilation begins with a complete explanation by the patient of the condition and the symptoms it causes. Some people benefit from psy-chotherapy and medications to deal with the underlying anxiety.

Hypoxia

Hypoxia is a condition of the body in which the tissues are starved of oxygen. In its extreme form, where oxygen is entirely absent, the condition is called anoxia. There are four types of hypoxia: (1) the hypoxemic type, in which the oxygen pressure in the blood going to the tissues is too low to saturate the hemoglobin; (2) the anemic type, in which the amount of functional hemoglobin is too small, and hence the capacity of the blood to carry oxygen is too low; (3) the stagnant type, in which the blood is or may be normal but the flow of blood to the tissues is reduced or unevenly distributed; and (4) the histotoxic type, in which the tissue cells are poisoned and are therefore unable to make proper use of oxygen. Diseases of the blood, the heart and circulation, and the lungs may all produce some form of hypoxia.

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The hypoxemic type of hypoxia is due to one of two mechanisms:

1. a decrease in the amount of breathable oxy-gen—often encountered in pilots, mountain climbers, and people living at high altitudes—due to the reduced barometric pressure, or

2. cardiopulmonary failure in which the lungs are unable to efficiently transfer oxygen from the alveoli to the blood.

In the case of anemic hypoxia, either the total amount of hemoglobin is too small to supply the body’s oxygen needs, as in anemia or after severe bleeding, or hemoglo-bin that is present is rendered nonfunctional. Examples of the latter case are carbon monoxide poisoning and metho-globinuria, in both of which the hemoglobin is so altered by toxic agents that it becomes unavailable for oxygen transport, and thus of no respiratory value.

Stagnant hypoxia, in which blood flow through the capillaries is insufficient to supply the tissues, may be gen-eral or local. If general, it may result from heart disease that impairs the circulation, impairment of veinous return of blood, or trauma that induces shock. Local stagnant hypoxia may be due to any condition that reduces or pre-vents the circulation of the blood in any area of the body. Examples include Raynaud disease and Buerger disease, which restrict circulation in the extremities; the applica-tion of a tourniquet to control bleeding; ergot poisoning; exposure to cold; and overwhelming systemic infection with shock.

In histotoxic hypoxia the cells of the body are unable to use the oxygen, although the amount in the blood may be normal and under normal tension. Although



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characteristically produced by cyanide, any agent that decreases cellular respiration may cause it. Some of these agents are narcotics, alcohol, formaldehyde, acetone, and certain anesthetic agents.

Altitude Sickness

Altitude sickness, sometimes called mountain sickness, is an acute reaction to a change from sea level or other low-altitude environments to altitudes above 2,400 metres (8,000 feet). Altitude sickness was recognized as early as the 16th century. In 1878 French physiologist Paul Bert demonstrated that the symptoms of altitude sickness are the result of a deficiency of oxygen in the tissues of the body. Mountain climbers, pilots, and persons living at high altitudes are the most likely to be affected.

The symptoms of acute altitude sickness fall into four main categories:

1. respiratory symptoms such as shortness of breath upon exertion, and deeper and more rapid breathing;

2. mental or muscular symptoms such as weakness, fatigue, dizziness, lassitude, headache, sleep-lessness, decreased mental acuity, decreased muscular coordination, and impaired sight and hearing;

3. cardiac symptoms such as pain in the chest, palpitations, and irregular heartbeat; and

4. gastrointestinal symptoms such as nausea and vomiting.

The symptoms usually occur within six hours to four days after arrival at high altitude and disappear within two to five days as acclimatization occurs. Although most

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people gradually recover as they adapt to the low atmo-spheric pressure of high altitude, some persons experience a reaction that can be severe and, unless they return to low altitude, possibly fatal.

At higher altitudes, the air becomes thinner and the amount of breathable oxygen decreases. The lower baro-metric pressures of high altitudes lead to a lower partial pressure of oxygen in the alveoli, or air sacs in the lungs, which in turn decreases the amount of oxygen absorbed from the alveoli by red blood cells for transport to the body’s tissues. The resulting insufficiency of oxygen in the arterial blood supply causes the characteristic symp-toms of altitude sickness. The main protection against altitude sickness in aircraft is the use of pressurized air in cabins. Mountain climbers often use a mixture of pure oxygen and air to relieve altitude sickness while climbing high mountains. In addition, the prophylactic use of the diuretic acetazolamide initiated two to three days before ascent may prevent or mitigate acute altitude sickness.

A more serious type of altitude sickness, high altitude pulmonary edema (HAPE), occurs rarely among newcom-ers to altitude but more often affects those who have already become acclimated to high elevations and are returning after several days at sea level. In pulmonary edema, fluid accumulates in the lungs and prevents the victim from obtaining sufficient oxygen. The symptoms are quickly reversed when oxygen is given and the indi-vidual is evacuated to a lower area.

Barotrauma and Decompression Sickness

Barotrauma is any of several injuries arising from changes in pressure upon the body. Humans are adapted to live at an atmospheric pressure of 760 mm of mercury (the pres-sure at sea level), which differs from pressures experienced



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in underwater environments and in the upper atmo-spheres of space. Most body tissue is either solid or liquid and remains virtually unaffected by pressure changes. In certain cavities of the body, however, such as the ears, sinuses, lungs, and intestines, there are air pockets that either expand or contract in response to changes in pres-sure. Abrupt expansion or contraction of closed internal air spaces can injure or rupture surrounding tissues, such as the eardrum.

A fatal form of barotrauma can occur in submariners and divers. For example, if a person in a deeply submerged submarine rapidly surfaces without exhaling during the ascent, sudden expansion of air trapped within the thorax can burst one or both lungs. Another form of barotrauma may occur during mechanical ventilation for respiratory failure. Air pumped into the chest by the machine can overdistend and rupture a diseased portion of the lung. Subsequent breaths delivered by the ventilator are then driven into the mediastinum (the space between the lungs), the pleural spaces, or under the skin of the neck, face, and torso, causing subcutaneous emphysema (the trapping of air under the skin or in tissues).

In decompression sickness (also called “the bends” or caisson disease) the formation of gas bubbles in the body because of rapid transition from a high-pressure environment to one of lower pressure causes a variety of physiological effects. Pilots of unpressurized aircraft, underwater divers, and caisson workers are highly sus-ceptible to the sickness because their activities subject them to pressures different from the normal atmospheric pressure experienced on land. At atmospheric pressure the body tissues contain, in solution, small amounts of the gases that are present in the air. When a pilot ascends to a higher altitude, the external pressures upon his or her body decrease, and these dissolved gases come

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out of solution. If the ascent is slow enough, the gases have time to diffuse from the tissues into the bloodstream. The gases then pass to the respiratory tract and are exhaled from the body.

The pathogenesis of decompression sickness begins both with the mechanical effects of bubbles and their expansion in the tissues and blood vessels and with the surface effects of the bubbles upon the various compo-nents of the blood at the blood–gas interface. The lung plays a significant role in the pathogenesis and natural his-tory of this illness and may contribute to the clinical picture. Shallow, rapid respiration, often associated with a sharp retrosternal pain on deep inspiration, signals the onset of pulmonary decompression sickness, the “chokes.”

The major component of air that causes decompres-sion maladies is nitrogen. The oxygen breathed is used up by the cells of the body and the waste product carbon diox-ide is continuously exhaled. Conversely, nitrogen merely accumulates in the body until the tissue becomes saturated at the ambient pressure. When the pressure decreases, the excess nitrogen is released. Nitrogen is much more soluble in fatty tissue than in other types. Therefore, tissues with a high fat content (lipids) tend to absorb more nitrogen than do other tissues. The nervous system is composed of about 60 percent lipids. Bubbles forming in the brain, spinal cord, or peripheral nerves can cause paralysis and convul-sions (diver’s palsy), difficulties with muscle coordination and sensory abnormalities (diver’s staggers), numbness, nausea, speech defects, and personality changes. When bubbles accumulate in the joints, pain is usually severe and mobility is restricted. The term bends is derived from this affliction, as the affected person commonly is unable to straighten joints.

Small nitrogen bubbles trapped under the skin may cause a red rash and an itching sensation known as diver’s



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itches. Usually these symptoms pass in 10 to 20 minutes. Excessive coughing and difficulty in breathing, known as the chokes, indicate nitrogen bubbles in the respiratory system. Other symptoms include chest pain, a burning sensation while breathing, and severe shock. Relief from decompression sickness usually can be achieved only by recompression in a hyperbaric chamber followed by grad-ual decompression, but this process is not always able to reverse damage to tissues.

Thoracic Squeeze

Thoracic squeeze, or lung squeeze, is a type of baro-trauma involving compression of the lungs and thoracic cavity. It most commonly occurs during a breath-holding dive underwater. During the descent, an increase in pres-sure causes air spaces and gas pockets within the body to compress. Because the lung tissue is elastic and inter-spersed with tubules and sacs of air, it is capable of some enlargement when air is inhaled and some shrinkage when it is exhaled. Too much air causes rupture of lung tissue, while too little air causes compression and col-lapse of the lung walls.

As external pressure on the lungs is increased in a breath-holding dive (in which the diver’s only source of air is that held in his lungs), the air inside the lungs is compressed, and the size of the lungs decreases. If one descends to a depth of about 30 metres (100 feet), the lung shrinks to about one-fourth its size at the surface. Excessive compression of the lungs in this manner causes tightness and pain in the thoracic cavity. If compression continues, the delicate lung tissue may rupture and allow tissue fluids to enter the lung spaces and tubules. The outer linings of the lungs (pleural sacs) may separate from the chest wall, and the lung may collapse.

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The predominant symptom felt by the diver is pain when the pressure becomes too great, which can be relieved by ascending. If the thoracic squeeze has been sufficient to cause lung damage, the diver may have diffi-culty in breathing, may exhale frothy blood, and may even become unconscious. Artificial respiration may be neces-sary if the breathing has stopped. Any symptoms of thoracic squeeze call for prompt medical attention.

Animals such as seals and whales that descend to much greater depths than humans on a single breath of air have special adaptations to help them. The sperm whale is reported to dive to about 1,000 metres (3,300 feet), more than 10 times the depth that humans can tolerate. These aquatic mammals have been found to have more elastic chest cavities than humans; their lungs, even when reduced, do not separate from the chest wall; and their bodies are adapted to use the gases in the bloodstream more conservatively.

Drowning

Drowning is suffocation by immersion in a liquid, usually water. Water closing over the victim’s mouth and nose cuts off the body ’s supply of oxygen. Deprived of oxygen the victim stops struggling, loses consciousness, and gives up the remaining tidal air in his or her lungs. There the heart may continue to beat feebly for a brief interval, but even-tually it ceases. Until recently, the oxygen deprivation that occurs with immersion in water was believed to lead to irreversible brain damage if it lasted beyond three to seven minutes. It is now known that victims immersed for an hour or longer may be totally salvageable, physically and intellectually, although they lack evidence of life, having no measurable vital signs—heartbeat, pulse, or breath-ing—at the time of rescue. A fuller appreciation of the



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body’s physiological defenses against drowning has prompted modification of traditional therapies and inten-sification of resuscitative efforts, so that many people who once would have been given up for dead are being saved.

Although asphyxiation (lack of oxygen that causes unconsciousness) is common to all immersion incidents, actual aspiration of water into the lungs may or may not occur. Up to 15 percent of drownings are “dry,” presumably because the breath is held or because a reflex spasm of the larynx seals off the airway inlet at the throat. When aspi-ration does occur, the volume of fluid entering the lungs rarely exceeds a glassful. The lungs “fill with water” chiefly because of an abnormal accumulation of body fluids (pul-monary edema) that is a secondary complication of oxygen deprivation. Often, quantities of water are swallowed and later vomited spontaneously or during resuscitative pro-cedures. Vomiting after the protective laryngeal spasm has subsided can lead to aspiration of stomach contents.

A natural biological mechanism that is triggered by contact with extremely cold water, known as the mamma-lian diving reflex, enhances survival during submersion, thus permitting seagoing mammals to hunt for long peri-ods underwater. Scientists have determined that vestiges of the reflex persist in humans. The mechanism is power-ful in children. It diverts blood from the limbs, abdomen, and surface areas of the body to the heart and the brain. It also causes an interruption of respiratory efforts and reduces the rate of the heartbeat. Even though the heart functions at a slower rate, in other respects it performs normally. Actual arrest of circulatory processes is a rela-tively late development in the drowning sequence. In this suspended state, intracranial blood retains sufficient oxy-gen to meet the brain’s reduced metabolic needs, despite a total absence of respiratory gas exchange.

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In warm water the body’s need for oxygen is increased, so the oxygen deprivation caused by immersion is rapidly lethal or permanently damaging to the brain. Such warm-water drownings occur commonly in domestic bathtubs. Immersion in icy water causes body temperature and metabolism to fall rapidly (the thermal conductivity of water is 32 times greater than that of air). Immersion hypothermia—below normal body temperature—reduces cellular activity of tissues, slows the heart rate, and promotes unconsciousness. None of these effects is immi-nently life-threatening; survival following hypothermic coma is almost 75 percent. Rescue teams now continue the benefits of cold-water protection with “therapeutic hypothermia.” “Lifeless” immersion victims with core temperatures as low as 62.6 °F (17 °C) have survived.


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CHAPTER CHAPTER 7

The study of the anatomy, physiology, and pathology of the human respiratory system is known as pulmonol-

ogy, or respiratory medicine. One of the most important advances in the history of respiratory medicine was the development of the stethoscope in 1816 by French physi-cian René-Théophile-Hyacinthe Laënnec. This instrument enabled physicians to more precisely diagnose diseases of the chest and heart.

Today, many technological advances, particularly con-cerning techniques employing X-ray imaging or endoscopy, have contributed to improvements in the diagnosis and evaluation of respiratory disease. Likewise, drugs such as decongestants and antibiotics have substantially improved the treatment of allergic and infectious respiratory dis-eases. In addition, modern respiratory medicine is intimately associated with ongoing scientifi c research into the cellular and molecular processes that underlie respira-tory function. This expansion of scientifi c understanding has enabled important progress in respiratory medicine, especially in the area of disease prevention.

recognizing the signs and syMptoMs of disease

The symptoms of lung disease are relatively few. Cough is a particularly important sign of all diseases that affect any part of the bronchial tree. A cough productive of sputum is the most important manifestation of infl ammatory or

APPROACHES TO RESPIRATORY EVALUATION AND TREATMENT

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7 Approaches to Respiratory Evaluation and Treatment 7

malignant diseases of the major airways, of which bron-chitis is a common example. In severe bronchitis the mucous glands lining the bronchi enlarge greatly, and, commonly, 30 to 60 ml of sputum are produced in a 24-hour period, particularly in the fi rst two hours after awakening in the morning. An irritative cough without sputum may be caused by extension of malignant disease to the bronchial tree from nearby organs. The presence of blood in the sputum (hemoptysis) is an important sign that should never be disregarded. Although it may result simply from an exacerbation of an existing infection, it may also indicate the presence of infl ammation, capillary damage, or a tumour. Hemoptysis is also a classic sign of tuberculosis of the lungs.

The second most important symptom of lung disease is dyspnea, or shortness of breath. This sensation, of complex origin, may arise acutely, as when a foreign body is inhaled into the trachea, or with the onset of a severe attack of asthma. More often, it is insidious in onset and slowly progressive. What is noted is a slowly progressive diffi culty in completing some task, such as walking up a fl ight of stairs, playing golf, or walking uphill. The short-ness of breath may vary in severity, but in diseases such as emphysema, in which there is irreversible lung damage, it is constantly present. It may become so severe as to immobilize the victim, and tasks such as dressing cannot be performed without diffi culty. Severe fi brosis of the lung, resulting from occupational lung disease or arising from no identifi able antecedent condition, may also cause severe and unremitting dyspnea. Dyspnea is also an early symptom of congestion of the lung as a result of impaired function of the left ventricle of the heart. When this occurs, if the right ventricle that pumps blood through the lungs is functioning normally, the lung capil-laries become engorged, and fl uid may accumulate in


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small alveoli and airways. It is commonly dyspnea that first causes a patient to seek medical advice, but absence of the symptom does not mean that serious lung disease is not present, since, for example, a small lung cancer that is not obstructing an airway does not produce shortness of breath.

Chest pain may be an early symptom of lung disease, but it is most often associated with an attack of pneumo-nia, in which case it is due to an inflammation of the pleura that follows the onset of the pneumonic process. Pain associated with inflammation of the pleura is characteris-tically felt when a deep breath is taken. The pain disappears when fluid accumulates in the pleural space, a condition known as a pleural effusion. Acute pleurisy with pain may signal a blockage in a pulmonary vessel, which leads to acute congestion of the affected part. For example, pul-monary embolism, the occlusion of a pulmonary artery by a fat deposit or by a blood clot that has dislodged from a site elsewhere in the body, can cause pleurisy. Sudden blockage of a blood vessel injures the lung tissue to which the vessel normally delivers blood. In addition, severe chest pain may be caused by the spread of malignant dis-ease to involve the pleura, or by a tumour that arises from the pleura itself, such as a mesothelioma. Severe, intrac-table pain caused by such conditions may require surgery to cut the nerves that supply the affected segment. Fortunately, pain of this severity is rare.

To these major symptoms of lung disease—coughing, dyspnea, and chest pain—may be added several others. A wheeziness in the chest may be heard. This is caused by narrowing of the airways, such as occurs in asthma. Some diseases of the lung are associated with the swelling of the fingertips (and, rarely, of the toes) called “clubbing.” Clubbing may be a feature of bronchiectasis (chronic inflammation and dilation of the major airways), diffuse

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fibrosis of the lung from any cause, and lung cancer. In the case of lung cancer, this unusual sign may disappear after surgical removal of the tumour. In some lung diseases, the first symptom may be a swelling of the lymph nodes that drain the affected area, particularly the small nodes above the collarbone in the neck; enlargement of the lymph nodes in these regions should always lead to a suspicion of intrathoracic disease. Not infrequently, the presenting symptom of a lung cancer is caused by spread of the tumour to other organs. Thus, a hip fracture from bone metastases, cerebral signs from intracranial metastases, or jaundice from liver involvement may all be the first evi-dence of a primary lung cancer, as may sensory changes in the legs, since a peripheral neuropathy may also be the presenting evidence of these tumours.

The generally debilitating effect of many lung diseases is well recognized. A person with active lung tuberculosis or with lung cancer, for example, may be conscious of only a general feeling of malaise, unusual fatigue, or seemingly minor symptoms as the first indication of disease. Loss of appetite and loss of weight, a disinclination for physi-cal activity, general psychological depression, and some symptoms apparently unrelated to the lung, such as mild indigestion or headaches, may be diverse indicators of lung disease. Not infrequently, the patient may feel as one does when convalescent after an attack of influenza. Because the symptoms of lung disease, especially in the early stage, are variable and nonspecific, physical and radiographic examination of the chest are an essential part of the evalu-ation of persons with these complaints.

Methods of inVestigation

Physical examination of the chest remains important, as it may reveal the presence of an area of inflammation, a



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pleural effusion, or an airway obstruction. Methods of examination include physical inspection and palpation for masses, tender areas, and abnormal breathing pat-terns; percussion to gauge the resonance of the underlying lung; and auscultation (listening) with a stethoscope to determine pitch and loudness of breath sounds. The sounds detected with a stethoscope may reveal abnormali-ties of the airways, the lung tissue, or the pleural space. Examination of the sputum for bacteria allows the identi-fication of many infectious organisms and the institution of specific treatment; sputum examination for malignant cells is occasionally helpful.

The conventional radiological examination of the chest has been greatly enhanced by the technique of com-puterized tomography (CT). This technique produces a complete picture of the lungs by using X-rays to create two-dimensional images that are integrated into one image by a computer. While the resolution of computer-ized tomography is much better than most other visualization techniques, lung ventilation and perfusion scanning can also be helpful in detecting abnormalities of the lungs. In these techniques, a radioactive tracer mole-cule is either inhaled, in the case of ventilation scanning, or injected, in the case of perfusion scanning. The ventila-tion scan allows visualization of gas exchange in the bronchi and trachea, and the perfusion scan allows visual-ization of the blood vessels in the lungs. The combined results from ventilation and perfusion scanning are impor-tant for the detection of focal occlusion of pulmonary blood vessels by pulmonary emboli.

Although magnetic resonance imaging (MRI) plays a limited role in examination of the lung, because the tech-nique is not well suited to imaging air-filled spaces, MRI is useful for imaging the heart and blood vessels within the

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thorax. Positron emission tomography (PET) is used to distinguish malignant lung tissue from scar tissue on tis-sues such as the lymph nodes. Flexible fibre-optic bronchoscopes that can be inserted into the upper airway through the mouth are used to examine the larynx, tra-chea, and major bronchi. By feeding a surgical instrument through a special channel of the bronchoscope, physicians can collect fluid and small tissue samples from the airways. Tissue samples are examined for histological changes that indicate certain diseases and are cultured to determine whether harmful bacteria are present.

A number of tests are available to determine the functional status of the lung and the effects of disease on pulmonary function. Spirometry, the measurement of the rate and quantity of air exhaled forcibly from a full respiration, allows measurement of the ventilation capacity of the lungs and quantification of the degree of airflow obstruction. Ventilatory capability can be mea-sured with a peak flow meter, which is often used in field studies. More complex laboratory equipment is neces-sary to measure the volumes of gas in the lung; the distribution of ventilation within the lung; airflow resis-tance; the stiffness of the lung, or the pressure required to inflate it; and the rate of gas transfer across the lung, which is commonly measured by recording the rate of absorption of carbon monoxide into the blood (hemo-globin has a high affinity for carbon monoxide). Arterial blood gases and pH values indicate the adequacy of oxy-genation and ventilation and are routinely measured in patients in intensive care units. Tests of exercise capa-bility, in which workload, total ventilation, and gas exchange are compared before, during, and after exer-cise, are useful in assessing functional impairment and disability.


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A spirometry test measures lung capacity and degree of airfl ow obstruction. David McNew/Getty Images

Pulmonary Function Test

A pulmonary function test is a procedure used to measure various aspects of the working capacity and effi ciency of the lungs and to aid in the diagnosis of pulmonary disease. There are two general categories of pulmonary function tests: (1) those that measure ventilatory function, or lung volumes and the process of moving gas in and out of the lungs from ambient air to the alveoli (air sacs), and (2) those measuring respiratory function, or the transfer of gas between the alveoli and the blood. Tests of ventilatory function include the following measurements: residual

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volume (RV), air remaining within the chest after a maxi-mal expiration; functional residual capacity (FRC), the resting lung volume, or air within the chest at the end of a quiet expiration; tidal volume, volume of a breath; vital capacity, maximum air volume that can be expelled after a maximum inspiration; and total lung capacity (TLC), air volume within the chest in full inspiration. Except for the residual volume, which is measured by a dilution method, all the other volumes may be recorded with a spirometer; breathing movements may also be registered graphically on a spirogram.

Ventilation tests, which measure the capacity of the lungs to move air in and out, include maximal voluntary ventilation (MVV), maximal air volume expelled in 12 to 15 seconds of forced breathing; forced expiratory volume (FEV), maximum air volume expelled in a time interval; and maximal expiratory flow rate (MEFR), maximal flow rate of a single expelled breath, expressed in litres of air per minute. Tests of respiratory function include the mea-surement of blood oxygen and carbon dioxide and the rate at which oxygen passes from the alveoli into the small blood vessels, or capillaries, of the lungs.

Chest X-ray

X-ray imaging is a valuable diagnostic technique used in medicine. This approach produces an image known as a roentgenogram (or X-ray image) of internal structures. The image is made by passing X-rays through the body to produce a shadow image on specially sensitized film. The roentgenogram is named after German physicist Wilhelm Conrad Röntgen, who discovered X-rays in 1895.

One of the most common screening roentgenograms is the chest film, taken to look for infections such as



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tuberculosis and conditions such as heart disease and lung cancer. Treatment of tuberculosis detected by a roentgenogram can prevent more extensive infection, but, unfortunately, this technique is of little value in screening for lung cancer because the stage at which the disease is detectable by this method is too far advanced for treatment to be of value.

Lung Ventilation/Perfusion Scan

A lung ventilation/perfusion scan, or VQ (ventilation quo-tient) scan, is a test that measures both air flow (ventilation) and blood flow (perfusion) in the lungs. Lung ventilation/perfusion scanning is used most often in the diagnosis of pulmonary embolism, the blockage of one of the pul-monary arteries or of a connecting vessel. Pulmonary embolism is caused by a clot or an air bubble that has become lodged within a vessel or by the accumulation of fat along the inner walls of the vessel, thereby narrowing the passageway and hindering the flow of blood. The pro-cedure is also used to accurately identify damaged regions of lung tissue prior to surgery to remove the tissue. This approach may be taken for patients with advanced or rap-idly spreading lung cancer.

Lung ventilation/perfusion scanning uses radioiso-topes to trace the movement of air and blood through the lungs. To track the movement of air, the patient inhales a mixture of oxygen and nitrogen containing small amounts of radioactive xenon or technetium. A scanner that con-tains a radiation-sensitive camera is then used to collect images of the gamma rays emitted from the tracer as it circulates through the lungs. For the perfusion part of the scan, the patient receives an injection into the blood-stream of a radioactive albumin tracer (usually labeled

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with technetium), and another set of images is taken with the scanner.

In both ventilation and perfusion scans, normal air and blood flow are reflected in the even distribution of tracers within the lungs. Thus, the ventilation and perfu-sion scans match for a person with healthy lungs. In contrast, a mismatch between the two scans is indicative of disease. The appearance of hot spots, or areas where the tracers become highly concentrated and therefore produce bright areas in the images, highlight places within the lungs where air or blood have accumulated abnor-mally. Areas in the images known as cold spots appear very dark and point to regions within the lungs where tracers are relatively scarce. Depending on whether a dark area appears in a ventilation scan or in a perfusion scan, the tissues affected will be either oxygen- or blood-deprived. Nutrient deprivation renders the tissue highly susceptible to death.

Although the tracers used in lung ventilation/perfu-sion scanning are radioactive, the levels of radioactivity are exceptionally low and pose a very small risk to patients. In general, persons for whom the scanning procedure is not recommended include women who are pregnant or who are breast-feeding. If the results of lung ventilation/perfusion scanning reveal that a patient is at high risk for pulmonary embolism, he or she may subsequently undergo more invasive procedures, including angiography.

Bronchoscopy

Bronchoscopy is a medical examination of the bronchial tissues using a lighted instrument known as a bron-choscope. The procedure is commonly used to aid the diagnosis of respiratory disease in persons with persistent


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The trachea and major bronchi of the human lungs. Encyclopædia Britannica, Inc.

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cough or who are coughing up blood, as well as in persons who have abnormal chest findings following computer-ized axial tomography scanning or X-ray examination. Bronchoscopy is also employed to remove foreign objects from the airways, to deliver certain therapeutic agents directly into the lungs, and to assist in the placement of stents (tubes, typically made of expandable wire mesh) or in the resection (removal) of tissue in cases in which can-cerous growths block the airways.

There are two types of bronchoscopes. The most fre-quently used scope consists of a flexible tube containing a bundle of thin fibre-optic rods that project light onto the tissues being examined. A flexible bronchoscope may be passed through the nose to examine the upper airways or through the mouth to examine the trachea and lungs. Flexible scopes, because of their ability to bend and twist, can be used to examine bronchial passageways down to the level of the tertiary bronchi—the smallest passages preceding the bronchioles. The second type of scope, known as a rigid bronchoscope, consists of a metal tube that has a wide suction channel, which enables large vol-umes of fluid (e.g., blood) to be removed during an examination. Although rigid bronchoscopes have been replaced by flexible scopes for the majority of procedures, they remain superior for specific applications. They are used most often to examine the central airways when blockage by a foreign body is suspected and to resect dis-eased tissue in a procedure known as laser bronchoscopy. All bronchoscopes can be fitted with a small video camera that enables real-time visualization of the procedure. In addition, both flexible and rigid scopes have a channel through which instruments can be passed. The latter fea-ture is commonly employed for biopsy—the collection of tissues for histological study.



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Flexible bronchoscopy of the upper airways generally requires the use of a local anesthetic to numb the tissues. In contrast, rigid bronchoscopy, because of the discom-fort caused by the device, necessitates the use of general anesthesia, which can cause side effects in some people, including nausea and vomiting, upon waking. In addition, there are several important risks associated with the bron-choscopy procedure itself. For example, the movement of a bronchoscope through the airways often scratches super-ficial tissues, causing them to bleed. Bleeding is especially common following biopsy. In most cases, however, bleed-ing subsides without the need for medical intervention. The bronchoscope or the removal of tissue for biopsy may lead to the perforation of lung tissue, causing a con-dition known as pneumothorax, in which air enters the space between the pleural membranes lining the lungs and thoracic cavity. Another risk factor associated with bron-choscopy is the introduction of infectious agents into the lungs, which occurs when the instrument is not sanitized properly.

Mediastinoscopy

Mediastinoscopy is a medical examination of the medi-astinum using a lighted instrument known as a mediastinoscope. Because the region of the mediasti-num contains the heart, trachea, esophagus, and thymus gland, as well as a set of lymph nodes, mediastinoscopy can be used to evaluate and diagnose a variety of thoracic diseases, including tuberculosis and sarcoidosis (a dis-ease characterized by the formation of small grainy lumps within tissues). It fulfills an especially important role in the detection and diagnosis of cancers affecting the thoracic cavity, serving as one of the primary

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methods by which tissue samples are collected from the mediastinal lymph nodes for the staging of lung cancer. Staging involves the investigation of cells to assess the degree to which cancer has spread. Mediastinoscopy is also frequently used in conjunction with noninvasive cancer-detection techniques, including computerized axial tomography and positron emission tomography.

During mediastinoscopy, which is performed under general anesthesia, a surgeon first makes a small inci-sion in the patient’s neck, immediately above the sternum. This step of the procedure is known as medi-astinotomy. A mediastinoscope—a thin, light-emitting, flexible instrument—is then passed through the inci-sion and into the space between the lungs. By carefully maneuvering the scope in the space, the doctor is able to investigate the surfaces of the various structures. A video camera attached to the scope aids in the position-ing of the instrument and in the visual examination of the tissues. In cancer staging, tissue samples from the lymph nodes are collected by passing a biopsy instru-ment through a channel in the scope. This may also be performed for other tissues in the region that display signs of disease, such as abnormal growths or inflam-mation. The biopsy samples are then investigated for evidence of abnormalities, particularly for cellular defects associated with cancer and for the presence of infectious organisms.

Most patients recover within several days following mediastinoscopy, and the procedure is associated with a very low risk of complications. Severe complications—such as bleeding, pneumothorax (damage to the lungs that causes the leakage of air into the space between the lungs and thoracic cavity), infection, or paralysis of the vocal cords—occur in approximately 1 to 3 percent of patients.



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types of respiratory therapy

Respiratory therapy is primarily concerned with assisting or improving the respiratory function of individuals with acute or chronic lung disease. There are different methods of treatment employed in respiratory therapy, each of which may be tailored to a specific disease. One of the conditions frequently dealt with is obstruction of breath-ing passages, in which chest physiotherapy is used to facilitate clearing the airway of mucus or liquid secretion by suction. Chest percussion, performed manually or by means of a handheld percussor or vest, produces vibra-tions that help to loosen and mobilize secretions. Postural drainage is a technique in which the forces of gravity are used to promote the drainage of obstructing secretions.

Other forms of respiratory therapy include the use of aerosol treatments to relieve bronchospasm. Water is a major therapeutic agent in bronchopulmonary disease and may be used in the form of cold steam, hot steam, or a fog (as in an oxygen tent or a croup tent). Aerosol humidi-fiers called nebulizers may be powered by compressor machinery or by a hand-squeezed bulb to project medica-tion or water spray into the airway. Ultrasonic equipment may be used to propel very fine particles directly into the lungs, as in treatment of cystic fibrosis. Medications, such as bronchodilators, mucolytics, and antibiotics, can also be administered in an inhaled mist by means of an ultra-sonic nebulizer.

Therapy may involve the administration of gases for inhalation. Oxygen may be administered in controlled amounts to assist laboured breathing. A mixture of helium and oxygen is used to treat some diseases of airway obstruction. In addition, respiratory therapists are experts in the setup, adjustment, and maintenance of mechanical ventilators.

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Drug Therapies

There are many different types of drugs that may be used in the treatment of respiratory diseases. However, there are three groups, decongestants, antihistamines, and anti-biotics, that are of particular importance in the routine treatment of respiratory illness. In countries such as the United States, decongestants and antihistamines are avail-able over the counter, and thus they are used by many people. The relative safety and efficacy of these drugs has made them generally reliable medications. Antibiotics represent a group of drugs that revolutionized respiratory medicine following the introduction of penicillin in the 1940s. Of special importance in the treatment of respira-tory infections such as bacterial pneumonia is a class of antibiotics known as macrolides. Though the use of anti-biotics in the treatment of minor respiratory infections is today a controversial issue, due to the emergence of resis-tant organisms, these agents remain valuable in reducing mortality rates from respiratory diseases that at one time caused certain death in humans.

Decongestants

Decongestants are drugs used to relieve swelling of the nasal mucosa accompanying such conditions as the com-mon cold and hay fever. When administered in nasal sprays or drops or in devices for inhalation, decongestants shrink the mucous membranes lining the nasal cavity by contracting the muscles of blood vessel walls, thus reduc-ing blood flow to the inflamed areas. The constricting action chiefly affects the smallest arteries, the arterioles, although capillaries, veins, and larger arteries respond to some degree.

Decongestants are sympathomimetic agents. That is, they mimic the effects of stimulation of the sympathetic



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division of the autonomic nervous system. One of the chief drugs of the group is epinephrine, a neurotransmit-ter produced by the adrenal gland that is released at sympathetic nerve endings when the nerves are stimu-lated. The effect of its decongestant action resembles the blanching of the skin that occurs with anger or fright, in which epinephrine constricts the blood vessels of the skin.

The effectiveness of the other decongestants results from their chemical similarity to epinephrine. The oldest and most important decongestant is ephedrine, an alka-loid originally obtained from the leaves of ma huang, any of several species of shrubs of the genus Ephedra, which has been used in Chinese medicine for more than 5,000 years. Ephedrine and other decongestants are made by chemical synthesis. They include phenylephrine hydrochloride, amphetamine and several derivatives, and naphazoline hydrochloride. Because none of them has a sustained effect, they must be used repeatedly; too frequent use, however, results in absorption into the bloodstream, caus-ing anxiety, insomnia, dizziness, headache, or heart palpitations.

Antihistamines

Antihistamines are drugs that selectively counteract the pharmacological effects of histamine, following its release from certain large cells (mast cells) within the body. Antihistamines replace histamine at one or the other of the two receptor sites at which it becomes bound to various susceptible tissues, thereby preventing histamine-triggered reactions under such conditions as stress, inflammation, and allergy.

The antihistamines that were the first to be intro-duced are ones that bind at the so-called H1 receptor sites. They are therefore designated H1-blocking agents and oppose selectively all the pharmacological effects of

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histamine except those on gastric secretion. The devel-opment of these antihistamines dates from about 1937, when French researchers discovered compounds that protected animals against both the lethal effects of hista-mine and those of anaphylactic shock. The first antihistamines were derivatives of ethylamine. Aniline-type compounds, tested later and found to be more potent, were too toxic for clinical use. In 1942, the fore-runner of most modern antihistamines (an aniline derivative called Antergan) was discovered; subsequently, compounds that were more potent, more specific, and less toxic were prepared. More than 100 antihistaminic compounds soon became available for treating patients.

Because histamine is involved in the production of some symptoms of allergy and anaphylaxis, antihista-mines can control certain allergic conditions, among them hay fever and seasonal rhinitis. Nasal irritation and watery discharge are most readily relieved. Persons with urticaria, edema, itching, and certain sensitivity reac-tions respond well. Antihistamines are not usually beneficial in treating the common cold and asthma. Antihistamines with powerful antiemetic properties are used in the treatment of motion sickness and vomiting. Used in sufficiently large doses, nearly all antihistamines produce undesirable side effects. The incidence and severity of the side effects depend both on the patient and on the properties of the specific drug. The most common side effect in adults is drowsiness. Other side effects include gastrointestinal irritation, headache, blurred vision, and dryness of the mouth. If a patient’s condition does not improve after three days of treatment with antihistamines, it is unlikely that he or she will ben-efit from them. Antihistamines are readily absorbed from the alimentary tract, and most are rendered inactive by monoamine oxidase enzymes in the liver.



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During the 1970s an H2-blocking agent, cimetidine (Tagamet) was introduced. Compounds of this class sup-press histamine-induced gastric secretion and have proved extremely useful in treating gastric and duodenal ulcers.

Antibiotics

Antibiotics are among the most medically valuable drugs available in the modern era, and they are especially impor-tant in the treatment of bacterial respiratory infections. The principle governing the use of antibiotics is to ensure that the patient receives one to which the target bacte-rium is sensitive, at a high enough concentration to be effective (but not cause side effects), and for a sufficient length of time to ensure that the infection is totally eradi-cated. Antibiotics vary in their range of action. Some are highly specific, whereas others, such as the tetracyclines, act against a broad spectrum of different bacteria.

Antibiotics known as macrolides (e.g., erythromycin, clarithromycin, azithromycin) are particularly effective in the treatment of bacterial respiratory infections. These drugs are usually administered orally, but they can be given parenterally. Macrolides, which inhibit bacterial protein synthesis, are valuable in treating pharyngitis and pneumo-nia caused by Streptococcus in persons sensitive to penicillin. They are also used in treating pneumonias caused either by Mycoplasma species or by Legionella pneumophila (the organism that causes Legionnaire disease). Macrolides are also used to treat pharyngeal carriers of Corynebacterium diphtheriae, the bacillus responsible for diphtheria.

Oxygen Therapy

The medical administration of oxygen is an important means of treating respiratory disease. Oxygen therapy is used for acute conditions, in which tissues such as the

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brain and heart are at risk of oxygen deprivation, as well as for chronic diseases that are characterized by sustained low blood oxygen levels (hypoxemia).

In emergency situations, oxygen may be adminis-tered by citizen responders via mouth-to-mouth breaths in cardiopulmonary resuscitation (CPR) or by emer-gency medical personnel via a face mask placed over the victim’s mouth and nose that is attached to a small, por-table compressed-gas oxygen cylinder. For patients affected by chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), home oxygen therapy may be prescribed by a physician. In both the hospital and the home settings, oxygen may be delivered through a face mask or through a nasal cannula, a device inserted into the nostrils that is connected by tubing to an oxygen system. Some patients may require oxygen administration via a transtracheal catheter, which is inserted directly into the trachea by way of a hole made surgically in the neck.

Another form of therapy, known as hyperbaric oxygen therapy (HBOT), employs a pressurized oxygen chamber (hyperbaric chamber) into which pure oxygen is delivered via an air compressor. The high-pressure atmosphere has been shown to reduce air bubbles in the blood of persons affected by conditions such as air embolism (artery or vein blockage by a gas bubble) and decompression sickness. In addition, the high concentrations of oxygen made available to tissues have been shown to help stimulate the growth of new blood vessels (angiogenesis) in healing wounds and to slow the progression of infections caused by certain anaerobic bacteria. HBOT has been promoted as an alter-native therapy for certain conditions. These applications are controversial, however, because the procedure can potentially stimulate the generation of DNA-damaging free radicals.



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There are various stationary and portable oxygen- storage systems that can be used in the hospital or the home. Oxygen concentrators, which draw in surround-ing air and filter out nitrogen, provide a method of storing oxygen at concentrations greater than that occurring in ambient air. The stored oxygen can then be used by the patient when needed and is readily replenished. Stationary and portable oxygen concentrators have been developed for use in the home. Another form of oxygen storage is in compressed-gas cylinders, which maintain oxygen under high pressure and require the use of a regulator to modulate the flow of gas from the cylinder to the patient. Gas cylinders are often used in conjunction with oxygen-conserving devices that prevent oxygen leakage from the cylinder by releasing gas only when the patient inhales, as opposed to releasing gas constantly, which necessitates more-frequent cylinder replacement. Large stationary and small portable gas cylinders can be used in the hos-pital or the home. Oxygen also can be stored as a highly concentrated liquid. Oxygen turns to liquid only when it is kept at very cold temperatures. When it is released under pressure from cold storage, it is converted to a gas. Liquid oxygen can be stored in small or large insulated containers, which can be refilled at pharmacies or by delivery services.

Oxygen is usually administered in controlled amounts per minute, a measure known as the flow rate. Flow rate is determined based on measurements of a patient’s blood oxygen levels. Two tests that are commonly used to assess the concentration of oxygen in the blood include the arte-rial blood gas (ABG) test and the pulse oximetry test. In the ABG test, blood is drawn from an artery, and blood acidity, oxygen, and carbon dioxide levels are measured. In pulse oximetry, a probe, generally placed over the end of a finger, is used to indirectly determine hemoglobin satura-tion—the percent of hemoglobin molecules in the blood

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that are carrying oxygen. The device uses light-emitting diodes and a photodetector to measure light absorption in the capillaries. The difference between absorption read-ings during systole (when the heart contracts) and during diastole (when the heart relaxes) are used to calculate hemoglobin saturation.

If oxygen flow rate is too low, the patient will not receive enough oxygen and could be at risk of injury from severe hypoxemia, which can lead to tissue dysfunction and cell death. Likewise, adverse physiological effects may ensue if the flow rate is too high. For example, premature infants who receive excessive amounts of oxygen in their first days of life may develop a blinding disorder known as retinopathy of prematurity. Excess oxygen flow also can result in conditions such as barotrauma. For example, HBOT is associated with an increased risk of barotrauma of the ear. Bronchopulmonary dysplasia, a chronic disor-der affecting infants, is characterized by absent or abnormal repair of lung tissue following high-pressure or excessive oxygen administration. Oxygen therapy is con-traindicated in patients undergoing treatment with certain forms of chemotherapy, such as with the drug bleomycin. Bleomycin damages cancer cells by stimulat-ing the production of reactive oxygen species, a response that is amplified in the presence of excess oxygen, leading to the damage of healthy tissues.

In general, the use of home oxygen therapy can reduce hospital admission and extend survival in patients with diseases such as COPD. However, oxygen therapy does not alter the progression of lung disease. Also, because patients need to use oxygen for a significant portion of each day and because it can lead to additional difficulties in mobility, it does not appeal to some patients. Compressed-gas cylinders present a significant safety haz-ard in the home as well; if they are not secured and stored



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properly, they may cause explosions. Likewise, oxygen can readily spread fire, and thus there is a significant safety hazard associated with the use of oxygen in the presence of pilot lights, candles, or other sources of ignition. Furthermore, the prescription of oxygen for patients who smoke or who share a household with smokers is consid-ered controversial.

Artificial Respiration

Artificial respiration is breathing induced by some manip-ulative technique when natural respiration has ceased or is faltering. Such techniques, if applied quickly and properly, can prevent some deaths from drowning, choking, stran-gulation, suffocation, carbon monoxide poisoning, and electric shock. Resuscitation by inducing artificial respira-tion consists chiefly of two actions:

1. establishing and maintaining an open air pas-sage from the upper respiratory tract (mouth, throat, and pharynx) to the lungs and

2. exchanging air and carbon dioxide in the termi-nal air sacs of the lungs while the heart is still functioning. To be successful such efforts must be started as soon as possible and continued until the victim is again breathing.

The most widely used method of inducing artificial respiration is mouth-to-mouth breathing, which has been found to be more effective than the manual methods used in the past. The person using mouth-to-mouth breathing places the victim on his back, clears his mouth of foreign material and mucus, lifts the lower jaw forward and upward to open the air passage, places his own mouth over the vic-tim’s mouth in such a way as to establish a leak-proof seal,

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Mouth-to-mouth breathing is the most effective means of manual artifi cial respiration. Stockbyte/Getty Images



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and clamps the nostrils. He then alternately breathes into the victim’s mouth and lifts his own mouth away, permit-ting the victim to exhale. If the victim is a child, the rescuer may cover both the victim’s mouth and nose. The rescuer breathes 12 times each minute (15 times for a child and 20 for an infant) into the victim’s mouth.

Thoracentesis

Thoracentesis is a medical procedure used in the diagnosis and treatment of conditions affecting the pleural space. It is most often used to diagnose the cause of pleural effusion, the abnormal accumulation of fluid in the pleural space. Pleural effusion can result in difficulty in breathing and often occurs secondary to conditions that affect the heart or lungs, including heart failure, tumours, and lung infec-tions, such as tuberculosis and pneumonia. Thoracentesis is used therapeutically to relieve the symptoms associated with pleural effusion, as well as to prevent further com-plications associated with the condition, including pleural empyema.

Prior to thoracentesis, the results of chest percussion and imaging tests, such as chest X-rays or computerized axial tomography chest scans, are assessed to precisely locate the site of fluid accumulation and to evaluate the volume of fluid present. In the subsequent thoracentesis procedure, a needle is inserted through the chest wall and into the effusion site in the pleural space. Needle place-ment is sometimes guided by ultrasound to avoid puncturing nearby tissues, including the lungs, liver, and spleen. Once the needle is inserted, fluid is drawn out of the pleural cavity using a syringe or other aspiration tech-nique. For diagnostic applications, a small amount of fluid is drawn and then analyzed for the presence of a variety of substances, including infectious organisms, particles such

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as asbestos, and tumour cells. The results of these analyses frequently warrant further diagnostic testing, particularly upon detection of cancerous cells, which are suggestive of mesothelioma or lung cancer.

Thoracentesis is a relatively quick procedure, generally lasting about 10 to 15 minutes. However, for several hours afterward patients are often observed for the manifesta-tion of adverse effects. Minor complications associated with thoracentesis include pain and cough. More serious complications include pneumothorax, the accumulation of air in the pleural space, which occurs when a needle punctures the lungs; and aberrant stimulation of the vasovagal reaction, a reflex of the nervous system that causes heart rate to slow (bradycardia) and blood ves-sels in the lower extremities to dilate, leading to a drop in blood pressure and fainting (syncope). Thoracentesis is contraindicated in persons with bleeding disorders (i.e., coagulopathy).

Hyperbaric Chamber

A hyperbaric chamber, also known as a decompression chamber (or recompression chamber), is a sealed chamber in which a high-pressure environment is used primarily to treat decompression sickness, gas embolism, carbon mon-oxide poisoning, gas gangrene resulting from infection by anaerobic bacteria, tissue injury arising from radiation therapy for cancer, and wounds that are difficult to heal.

Experimental compression chambers first came into use around 1860. In its simplest form, the hyperbaric chamber is a cylindrical metal or acrylic tube large enough to hold one or more persons and equipped with an access hatch that retains its seal under high pressure. Air, another breathing mixture, or oxygen is pumped in by a compres-sor or allowed to enter from pressurized tanks. Pressures


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A hyperbaric chamber creates a high-pressure environment, which increases oxygen availability to the body in therapeutic treatment. Chris McGrath/Getty Images

used for medical treatment are usually 1.5 to 3 times higher than ordinary atmospheric pressure.

The therapeutic benefi ts of a high-pressure environ-ment derive from its direct compressive effects, from the increased availability of oxygen to the body (because of an increase in the partial pressure of oxygen), or from a combination of the two. In the treatment of decompres-sion sickness, for example, a major effect of the elevated pressure is shrinkage in the size of the gas bubbles that have formed in the tissues. In the treatment of carbon monoxide poisoning, the increased oxygen speeds clear-ance of carbon monoxide from the blood and reduces damage done to cells and tissues.

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Lung Transplantation

Early attempts at transplanting a single lung in patients with severe bilateral lung disease were not successful, but from the late 1970s bilateral lung transplantation had some striking results. Persons severely disabled by cystic fibrosis, emphysema, sarcoidosis, pulmonary fibrosis, or severe primary pulmonary hypertension can achieve nearly normal lung function several months after the pro-cedure. Because transplantation offers the only hope for persons with severe lung disease, who may be relatively young, the techniques are being pursued aggressively in specialized centres. Availability of donor lungs is sharply limited by the number of suitable donors; for example, many people who die of severe head injuries, which pre-sumably would leave the lungs intact, often have also suffered lung injury or lung infection. With proper selec-tion of donor organs and proper transplantation technique, survival at one year has been reported at 90 percent.

Many recipients of single or double lung trans-plantation develop bronchiolitis obliterans beginning several months or years after surgery. This complication is thought to represent gradual immunologic rejection of the transplanted tissue despite the use of immunosuppres-sant drugs. Brochiolitis obliterans and the constant risk of serious infection brought about by the use of immunosup-pressant drugs limit survival to approximately 40 to 60 percent five years after surgery.

conclusion

In the 21st century, respiratory medicine has continued to fulfill a vital role in advancing scientists’ understanding of respiratory disease and of the basic cellular and molecular processes that contribute to the normal function of the



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respiratory system. The negative influence of behaviours such as tobacco smoking on lung function is now well doc-umented, and this understanding has contributed to a more complete realization of the importance of preven-tion and early detection of diseases such as lung cancer. In fact, with health and environmental concerns at the fore-front, countries worldwide have initiated national and international programs aimed at reducing human expo-sure to pollutants. In many countries, these efforts have led to smoking bans in public areas and to governmental regulations limiting occupational exposure to irritants. Such progress promises to reduce the global mortality of lung cancer, mesothelioma, and similar preventable respi-ratory afflictions.

Significant advances also have occurred concerning scientists’ understanding of the genetic causes of respira-tory disorders and of the agents responsible for infectious respiratory diseases. For decades, basic knowledge of the viruses that cause the common cold eluded scientists. However, in 2009 researchers reported having mapped the genetic codes of rhinoviruses, which are the most fre-quent cause of the common cold. The genetic information was being used to establish an understanding of the relationships between the dozens of common-cold rhino-viruses and was expected to provide new insights that could potentially lead to the development of diagnostic tests and possibly even new drugs or vaccines. The impor-tance of understanding the evolutionary patterns of respiratory viruses is perhaps best illustrated by the vari-ous types of influenza virus. Influenza viruses circulate globally, acquiring genetic mutations that alter their infec-tious characteristics, sometimes drastically increasing their ability to infect and cause disease in humans. The influenza virus that produced the H1N1 pandemic of 2009 is at the centre of these ongoing investigations.

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Another important factor behind the advance of respi-ratory medicine has been the elucidation of cellular processes that underlie respiratory disease. For example, discoveries of cellular proteins that are involved in cancer and that facilitate the transport of infectious agents into cells have spurred the development of drugs designed to inhibit these pathological activities. In addition, the iden-tification of disease-associated metabolic changes within cells and tissues has played an important role in the devel-opment of various functional and diagnostic tests, such as the arterial blood gas test to determine blood oxygen lev-els in persons suffering from chronic respiratory disease. As researchers and physicians continue to uncover new information about the human respiratory system, these tests are likely to undergo a series of refinements and to be augmented by the development of new tests, as well as new treatments.


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GLOSSARY

apnea Cessation of breathing.convection The transfer of heat by movement of a

heated fl uid such as air or water. cricoid A large cartilaginous piece of the laryngeal skel-

eton with a signet-ring shape.diffusion Primary mode of transport of gases between

air and blood in the lungs and between blood and respiring tissues in the body.

epiglottis Cartilaginous, leaf-shaped fl ap; functions as a lid to the larynx and, during the act of swallowing, controls the traffi c of air and food.

extrinsic muscles Join the laryngeal skeleton cranially to the hyoid bone or to the pharynx and caudally to the sternum. Act on the larynx as a whole, moving it upward or downward.

glottis A sagittal slit formed by the vocal cords.glycolysis Fermentation, or transformation of glucose

into energy.hyperbaric chamber A sealed chamber in which a high-

pressure environment is used for medical treatment. Also known as a decompression chamber or recom-pression chamber.

hypercapnia Excess carbon dioxide retention.hyperventilation Form of overbreathing that

increases the amount of air entering the pulmonary alveoli.

hypoventilation When the quantity of inspired air entering the lungs is less than is needed to maintain normal exchange.

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7 Glossary 7

hypoxia Reduction of oxygen supply to tissues to less than physiological levels.

intrinsic muscles Attach to the skeletal components of the larynx and act directly or indirectly on the shape, length, and tension of the vocal cords.

larynx A complex organ that serves as an air canal to the lungs and a controller of its access, and as the organ of phonation.

metastasis Migration and spread of cancerous cells from a tumour to distant sites in the body, resulting in the development of secondary tumours.

nasopharynx Primarily a passageway for air and secre-tions from the nose to the oral pharynx.

neuraminidase A glycoprotein on the surface of influ-enza viruses.

paranasal sinuses Cavities in the bones that adjoin the nose.pharyngitis Painful inflammatory illness of the passage

from the mouth to the pharynx or of the pharynx itself. pleura In humans, a thin membranous sac encasing

each lung.pleural effusion Accumulation of watery fluid between

the membrane lining the thoracic cage and the mem-brane covering the lung.

purulent Pus-producing.rhinitis Inflammation of the mucous tissue of the nose.sinusitis Acute or chronic inflammation of the mucosal

lining of one or more paranasal sinuses.surfactant Substance that, when added to a liquid,

reduces its surface tension, thereby increasing its spreading and wetting properties.

thrombus Clot that forms in the blood vessel and remains at the point where it was formed.

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BIBLIOGRAPHY

Basic information about the respiratory system and the process of respiration is included in Andrew Davies and Carl Moores , The Respiratory System (2003); and Michael P. Hlastala and Albert J. Berger , Physiology of Respiration , 2nd. ed. (2001). Comprehensive coverage of the diseases of the human respiratory system is provided by Alfred P. Fishman and Jack A. Elias , Fishman’s Pulmonary Diseases and Disorders , 4th ed. (2008).

Control of breathing is described in Murray D. Altose and Yoshikazu Kawakami (eds.), Control of Breathing in Health and Disease (1999); and Jerome A. Dempsey and Allan I. Pack (eds.), Regulation of Breathing , 2nd ed. (1995). Abnormal breathing during sleep is covered by Nicholas A. Saunders and Colin E. Sullivan (eds.), Sleep and Breathing, 2nd ed. (1994).

Adaptations of the human respiratory system to high altitude are described in a comprehensive but readable manner in Donald Heath and David Reid Williams , High-Altitude Medicine and Pathology , 4th ed. (1995).

The effects of swimming and diving on respiration are detailed in Peter B. Bennett and David H. Elliott (eds.), The Physiology and Medicine of Diving , 4th ed. (1993).

The human respiratory system is described in David V. Bates , Peter T. Macklem , and Ronald V. Christie , Respiratory Function in Disease: An Introduction to the Integrated Study of the Lung , 2nd ed. (1971), a detailed text on impairment of lung function caused by disease; and Robert G. Fraser et al., Diagnosis of Diseases of the Chest , 2nd ed., 4 vol. (1977–79), with vol. 1 also available in a 3rd ed. (1988). H. Corwin Hinshaw and John F. Murray ,

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7 Bibliography 7

Diseases of the Chest, 4th ed. (1980), is a general textbook covering diagnosis and treatment of chest diseases; see also J. G. Scadding and Gordon Cumming (eds.), Scientific Foundations of Respiratory Medicine (1981). Steven E. Weinberger, Principles of Pulmonary Medicine, 3rd ed. (1998), is an introductory text in which respiratory pathophysiology is considered from the clinical vantage. Comprehensive texts include Gordon Cumming and Stephen J. Semple, Disorders of the Respiratory System, 2nd ed. (1980); John Crofton and Andrew Douglas, Respiratory Diseases, 3rd ed. (1981); and Ian R. Cameron and Nigel T. Bateman, Respiratory Disorders (1983). Alfred P. Fishman (ed.), Pulmonary Diseases and Disorders, 2nd ed., 3 vol. (1988), provides a comprehensive overview of patho-physiology as related to clinical syndromes. See also John F. Murray and Jay A. Nadel (eds.), Textbook of Respiratory Medicine, 2nd ed. (1994); and Andrew M. Churg et al. (eds.), Thurlbeck’s Pathology of the Lung, 3rd ed. (2005).

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INDEX

Aacid–base balance, 51, 52, 75acidosis, 184Actinomyces, 111Adam’s apple, 27adenosine triphosphate (ATP),

73, 74, 75, 77Agricola, Georgius, 171AIDS, 111, 112–113, 115, 117,

118–119air–blood barrier, 30, 35, 39alcoholism, 96, 97, 113alkalosis, 184–186altitude sickness, 159, 188–189alveoli, structure of, 34–35amantadine, 103anemia, 64, 186, 187anesthesia, 46, 152, 208, 209animals, 76, 79–80, 81, 193anthracosis, 171antibiotics, 91, 92, 93, 94, 107,

108, 109, 110, 114, 116, 129, 131, 137, 147, 164, 196, 210, 211, 214

antihistamines, 211, 212–214aortic body, 48apnea, 46, 52, 122, 124–125, 126arterial gas embolism, 85artifi cial respiration, 218–220asbestos, 127, 153, 159, 168–169,

171–173, 176, 221asbestosis, 171–173asphyxiation, 194

asthma, 42, 160–164, 169, 175, 182, 184, 197, 198, 213

atelectasis, 141–144

Bbarotrauma, 86, 189–192, 217Bert, Paul, 188bird fancier’s lung, 166black lung, 170–171Bordet, Jules, 106bradykinin, 50Breuer, Josef, 49bronchi, structure and function

of, 30, 33–34stem, structure of, 28–29

bronchiectasis,130–131, 198bronchioles, structure and

function of, 30, 33–34bronchiolitis, 100–102, 136,

152, 223bronchitis, 99–100, 102, 103,

131–133, 134, 135, 137, 168, 169, 171, 175, 181, 197

bronchopulmonary dysplasia, 217bronchoscopy, 205–208brown lung, 174Buerger disease, 187byssinosis, 174–175

Ccancer, 81, 111, 123, 127, 169

lung, 38, 152–156, 169, 172, 173,

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7 Index 7

181, 182, 198, 199, 204, 209, 221

cardiopulmonary resuscitation (CPR), 129, 215

carotid body, 47, 48, 80, 81central nervous system disease, 52Cheyne-Stokes breathing, 52chloride shift, 67chronic obstructive pulmonary

disease (COPD), 130, 136–138, 215, 217

Clara cells, 30, 34cold, common, 87, 88–91, 93, 94,

95, 98, 106, 213cause of, 88

corticosteroids, 98, 138, 161, 164

coughingblood, 117, 137, 145, 197, 207physiology of, 50, 58–59, 132types of, 105–106, 192,

196–197, 198croup, 87, 98–99cystic fibrosis, 122, 130, 131,

145–148, 210, 223

Ddecompression sickness, 86, 159,

189–192, 215, 221, 222decongestants, 196, 211–212diaphragm, 21, 25, 44, 56, 122, 143,

144, 156, 158diffusion limitation, 69, 72diphtheria, 92, 95, 97, 106, 214diving, 60, 78, 81–86, 157–158, 177,

190, 191–193drowning, 159, 180, 193–195, 218dyspnea, 84, 197–198

Eemphysema, 85, 102, 122, 127–129,

130, 132, 133–136, 137, 156–158, 168, 170, 171, 175, 184, 190, 197, 220, 223

eosinophilic granuloma, 149, 150epiglottis, 25, 27, 96, 98–99epiglottitis, 98–99epinephrine, 98, 212exercise (training), 46, 50, 51–52,

62, 64, 75–78, 84, 135, 137, 147, 158, 174, 183, 201

Ffarmer’s lung, 166fungi, 91, 94, 108, 111, 112, 182

Ggas exchange, abnormal, 69–72Gengou, Octave, 106glycolysis, 74goblet cells, 30Goodpasture syndrome, 151

HHaldane, John Scott, 183hay fever, 164, 211, 213hemoglobin, 47, 63, 64, 65, 66, 67,

75, 78, 80, 81, 136, 183, 186, 187, 201, 216–217

Hering, Ewald, 49Hering-Breuer reflex, 49high altitudes, 47, 65, 79–81, 187,

188–189, 190histamine, 50, 160HIV, 115, 119


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hookworm, 163hydrothorax, 127hygiene, 114–115, 119hyperbaric chamber, 215, 221–222hypercapnia, 83hypersensitivity pneumonitis,

166–167hyperventilation, 81–82, 184–186hypothyroidism, 125hypoventilation, 69, 126hypoxemia, 135–136, 149, 215, 217hypoxia, 46–48, 52, 83, 186–188

Iidiopathic pulmonary fibrosis, 149influenza, 88, 91, 93, 96, 98, 99,

102–105, 110, 114, 138, 139, 167, 199

bird flu, 103H1N1, 104vaccine, 103, 173

Kkidney, 94, 117, 150, 151, 184

LLaënnec, René-Théophile-

Hyacinthe, 196laryngitis, 87, 95–96larynx, structure and function of,

26–28Legionnaire disease, 87, 110,

113–114, 214leukemia, 100lungs

cancer of, 38, 152–156, 169, 172, 173, 181, 182, 198, 199, 204, 209, 221

collapse of, 55–56, 70, 127, 129, 141, 143, 159

congestion of, 138–141, 178, 197

development of, 38–40infarction, 144–145, 177size of, 31transplantation of, 138, 147,

149, 173, 178, 223lung ventilation/perfusion scan,

204–205

Mmeasles, 99mediastinoscopy, 208–209mediastinum, 26, 31, 37, 122,

156–158, 190, 208medulla, 41, 44, 45, 49, 50meningitis, 92, 117mesothelioma, 127, 128, 171–173,

176, 198, 221metabolism, 47, 50, 51–52, 68,

73–78, 81aerobic, 74, 76–77, 78anaerobic, 74, 76

Monge disease, 81mountain sickness, 81mucoviscidosis, 145

Nnephritis, 94nerves

laryngeal, 26

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7 Index 7

olfactory, 23–24sinus, 47vagus, 38, 45, 50

nitrogen narcosis, 85nose

cilia, 93congestion of, 91, 164inflammation of, 89structure and function of,

21–24, 99

Oobesity, 53, 124, 125, 126oseltamivir, 103, 104osteoporosis, 137oxygen therapy, 214–218

Pparasites, 91, 107, 108, 111parrot fever, 107penicillin, 92, 93, 108, 211, 214pertussis, 105–106, 107, 164pharyngitis, 87, 91–92, 214pharynx, structure and function

of, 24–25pickwickian syndrome, 126pleura, 26, 31–32, 57, 122, 126–130,

154, 172, 198pleural effusion, 126, 127–129,

152, 198, 200, 220pleurisy, 33, 113, 117, 126, 127, 198pneumoconiosis, 168–169, 170pneumonia, 87, 95, 103, 106,

108–113, 114, 128, 130, 138, 139, 146, 155, 167, 170, 173, 180, 184, 198, 211, 214, 220

pneumothorax, 33, 56, 85, 127,

128, 129–130, 136, 208, 209, 221

pollution, 131, 137, 180–182pons, 41, 44Pontiac fever, 114Pott disease, 118prostaglandins, 50psittacosis, 107–108, 110pulmonary alveolar proteinosis,

150–151pulmonary edema, 36, 84, 139,

141, 178, 189, 194pulmonary parenchyma, 34pyothorax, 128

RRelenza, 103, 104–105respiratory distress syndrome,

159, 179–180Reynaud disease, 187rheumatic fever, 91, 94, 179rheumatoid arthritis, 100rhinoviruses, 88rimantadine, 103Röntgen,Wilhelm Conrad, 203

Ssarcoidosis, 149–150, 208, 223scarlet fever, 95shunting, 69–71silicosis, 169–170sinuses, 19, 22, 88, 92, 122

function of, 22irrigation of, 93

sinusitis, 87, 92–94, 160sleep, 50, 52–53, 136


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smallpox, 97smell, 21, 23–24, 94smoking, 95, 97, 102, 122, 123, 130,

131–132, 133–135, 137, 138, 150, 153, 163, 171, 172, 175, 176, 182, 183, 218

sneezing,102, 106, 116, 164snoring, 53, 123–124sore throat, 91, 92, 94staphylococci, 97, 110, 146strep throat, 92streptococcal bacteria, 91, 92, 93,

96, 97, 99, 108, 109, 214surgery, 33, 56, 93, 94, 95, 122, 125,

129, 130, 136, 138, 143, 152, 155–156, 178, 198, 199, 209

swimming, 78, 81–86syphilis, 92, 96, 97

TTamiflu, 103, 104tetanus, 106thoracentesis, 220–221thoracic emphyema, 127–129thoracic squeeze, 192–193tonsillitis, 87, 94–95tonsils, 25, 53, 88, 91, 92, 94–95,

118, 124

trachea, structure and function of, 28–30

tracheitis, 87, 96–98trench mouth, 95tuberculosis, 87, 92, 95, 97, 111,

114–121, 128, 164, 170, 171, 197, 199, 204, 208, 220

typhoid, 97

Vvaccination, 103, 107, 119, 138,

164, 173Valsalva maneuver, 58ventilation–blood flow

imbalance, 69vestibular folds, 27–28vitamin C, 91vocal chords, false, 27–28

Wwhooping cough, 99, 105–107

Zzanamivir, 103, 104–105

Basic Sciences-The Human Body - The Respiratory

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