COPD

Overview

To understand COPD, it helps to understand how the lungs work. The air that you breathe goes down your windpipe into tubes in your lungs called bronchial tubes or airways.

Within the lungs, your bronchial tubes branch many times into thousands of smaller, thinner tubes called bronchioles. These tubes end in bunches of tiny round air sacs called alveoli.

Small blood vessels called capillaries run along the walls of the air sacs. When air reaches the air sacs, oxygen passes through the air sac walls into the blood in the capillaries. At the same time, a waste product, called carbon dioxide (CO2) gas, moves from the capillaries into the air sacs. This process, called gas exchange, brings in oxygen for the body to use for vital functions and removes the CO2.

The airways and air sacs are elastic or stretchy. When you breathe in, each air sac fills up with air, like a small balloon. When you breathe out, the air sacs deflate and the air goes out.

In COPD, less air flows in and out of the airways because of one or more of the following:
• The airways and air sacs lose their elastic quality.
• The walls between many of the air sacs are destroyed.
• The walls of the airways become thick and inflamed.
• The airways make more mucus than usual and can become clogged.

In the United States, the term COPD includes two main conditions—emphysema and chronic bronchitis. In emphysema, the walls between many of the air sacs are damaged. As a result, the air sacs lose their shape and become floppy. This damage also can destroy the walls of the air sacs, leading to fewer and larger air sacs instead of many tiny ones. If this happens, the amount of gas exchange in the lungs is reduced.

In chronic bronchitis, the lining of the airways stays constantly irritated and inflamed, and this causes the lining to swell. Lots of thick mucus forms in the airways, making it hard to breathe.

Most people who have COPD have both emphysema and chronic bronchitis, but the severity of each condition varies from person to person. Thus, the general term COPD is more accurate.

Outlook

COPD is a major cause of disability, and it is the fourth leading cause of death in the United States. Currently, 16 million people are diagnosed with COPD. Many more people may have the disease and not even know it.

COPD develops slowly. Symptoms often worsen over time and can limit your ability to do routine activities. Severe COPD may prevent you from doing even basic activities like walking, cooking, or taking care of yourself.

Most of the time, COPD is diagnosed in middle-aged or older adults. The disease is not contagious, meaning it cannot be passed from person to person.

COPD has no cure yet, and doctors do not know how to reverse the damage to the lungs. However, treatments and lifestyle changes can help you feel better, stay more active, and slow the progress of the disease.

Causes

Long-term exposure to lung irritants that damage the lungs and the airways usually is the cause of COPD.

In the United States, the most common irritant that causes COPD is cigarette smoke. Pipe, cigar, and other types of tobacco smoke also can cause COPD, especially if the smoke is inhaled.

Breathing in secondhand smoke, which is in the air from other people smoking; air pollution; or chemical fumes or dusts from the environment or workplace also can contribute to COPD.

Rarely, a genetic condition called alpha-1 antitrypsin deficiency may play a role in causing COPD. People who have this condition have low blood levels of alpha-1 antitrypsin (AAT)—a protein made in the liver. Having a low level of the AAT protein can lead to lung damage and COPD if you are exposed to smoke or other lung irritants. If you have alpha-1 antitrypsin deficiency and also smoke, COPD can worsen very quickly.

Some people who have asthma can develop COPD. Asthma is a chronic lung disease that inflames and narrows the airways. Treatment usually can reverse the inflammation and narrowing that occurs in asthma.

Risk Factors

The main risk factor for COPD is smoking. Up to 75 percent of people who have COPD smoke or used to smoke. People who have a family history of COPD are more likely to develop the disease if they smoke.

Long-term exposure to other lung irritants also is a risk factor for COPD. Examples of other lung irritants include air pollution, chemical fumes and dusts from the environment or workplace, and secondhand smoke, which is smoke in the air from other people smoking.

Most people who have COPD are at least 40 years old when symptoms begin. Although uncommon, people younger than 40 can have COPD. This may occur, for example, if a person has a predisposing health issue, such as the genetic condition known as alpha-1 antitrypsin deficiency.

Screening and Prevention

You can take steps to prevent COPD before it starts. If you already have COPD, you can take steps to prevent complications and slow the progression of the disease.

Prevent COPD Before It Starts
The best way to prevent COPD is to not start smoking or to quit smoking. Smoking is the leading cause of COPD. If you smoke, talk with your doctor about programs and products that can help you quit.

If you have trouble quitting smoking on your own, consider joining a support group. Many hospitals, workplaces, and community groups offer classes to help people quit smoking. Ask your family members and friends to support you in your efforts to quit.

Also, try to avoid lung irritants that can contribute to COPD, such as air pollution, chemical fumes, dusts, and secondhand smoke, which is smoke in the air from other people smoking.

For more information about how to quit smoking, go to the Health Topics Smoking and Your Heart article and the National Heart, Lung, and Blood Institute's Your Guide to a Healthy Heart. Although these resources focus on heart health, they include basic information about how to quit smoking. For free help and support to quit smoking, you may call the National Cancer Institute’s Smoking Quitline at 1-877-44U-QUIT (1-877-448-7848).

Prevent Complications and Slow the Progression of COPD
If you have COPD, the most important step you can take is to quit smoking. Quitting can help prevent complications and slow the progression of the disease. You also should avoid exposure to the lung irritants mentioned above.

Follow your treatments for COPD exactly as your doctor prescribes. They can help you breathe easier, stay more active, and avoid or manage severe symptoms.

Talk with your doctor about whether and when you should get flu, or influenza, and pneumonia vaccines. These vaccines can lower your chances of getting these illnesses, which are major health risks for people who have COPD.

Signs, Symptoms, and Complications

Signs, Symptoms, and Complications At first, COPD may cause no symptoms or only mild symptoms. As the disease gets worse, symptoms usually become more severe. Common signs and symptoms of COPD include: • An ongoing cough or a cough that produces a lot of mucus; this is often called smoker's cough.
• Shortness of breath, especially with physical activity
• Wheezing or a whistling or squeaky sound when you breathe
• Chest tightness

If you have COPD, you also may often have colds or other respiratory infections such as the flu, or influenza.

Not everyone who has the symptoms described above has COPD. Likewise, not everyone who has COPD has these symptoms. Some of the symptoms of COPD are similar to the symptoms of other diseases and conditions. Your doctor can determine if you have COPD.

If your symptoms are mild, you may not notice them, or you may adjust your lifestyle to make breathing easier. For example, you may take the elevator instead of the stairs.

Over time, symptoms may become severe enough to cause you to see a doctor. For example, you may become short of breath during physical exertion.

The severity of your symptoms will depend on how much lung damage you have. If you keep smoking, the damage will occur faster than if you stop smoking.

Severe COPD can cause other symptoms, such as swelling in your ankles, feet, or legs; weight loss; and lower muscle endurance.

Some severe symptoms may require treatment in a hospital. You—or, if you are unable, family members or friends—should seek emergency care if you are experiencing the following:
• You are having a hard time catching your breath or talking.
• Your lips or fingernails turn blue or gray, a sign of a low oxygen level in your blood.
• People around you notice that you are not mentally alert.
• Your heartbeat is very fast.
• The recommended treatment for symptoms that are getting worse is not working.

Diagnosis

Your doctor will diagnose COPD based on your signs and symptoms, your medical and family histories, and test results.

Your doctor may ask whether you smoke or have had contact with lung irritants, such as secondhand smoke, air pollution, chemical fumes, or dusts.

If you have an ongoing cough, let your doctor know how long you've had it, how much you cough, and how much mucus comes up when you cough. Also, let your doctor know whether you have a family history of COPD.

Your doctor will examine you and use a stethoscope to listen for wheezing or other abnormal chest sounds. He or she also may recommend one or more tests to diagnose COPD.

■ Pulmonary Function Tests
Pulmonary function tests measure how much air you can breathe in and out, how fast you can breathe air out, and how well your lungs deliver oxygen to your blood.

The main test for COPD is spirometry. Other lung function tests, such as a lung diffusion capacity test, also might be used. Read Pulmonary Function Tests for more information. Spirometry

During this painless test, a technician will ask you to take a deep breath in. Then, you'll blow as hard as you can into a tube connected to a small machine. The machine is called a spirometer.

The machine measures how much air you breathe out. It also measures how fast you can blow air out.

Your doctor may have you inhale, or breathe in, medicine that helps open your airways and then blow into the tube again. He or she can then compare your test results before and after taking the medicine.

Spirometry can detect COPD before symptoms develop. Your doctor also might use the test results to find out how severe your COPD is and to help set your treatment goals.

The test results also may help find out whether another condition, such as asthma or heart failure, is causing your symptoms.

■ Other Tests
Your doctor may recommend other tests, such as:
• A chest x ray or chest CT scan. These tests create pictures of the structures inside your chest, such as your heart, lungs, and blood vessels. The pictures can show signs of COPD. They also may show whether another condition, such as heart failure, is causing your symptoms.
• An arterial blood gas test. This blood test measures the oxygen level in your blood using a sample of blood taken from an artery. The results from this test can show how severe your COPD is and whether you need oxygen therapy.

Treatment

COPD has no cure yet. However, lifestyle changes and treatments can help you feel better, stay more active, and slow the progress of the disease.

The goals of COPD treatment include:
• Relieving your symptoms
• Slowing the progress of the disease
• Improving your exercise tolerance or your ability to stay active
• Preventing and treating complications
• Improving your overall health

To assist with your treatment, your family doctor may advise you to see a pulmonologist. This is a doctor who specializes in treating lung disorders.

Lifestyle Changes
■ Quit Smoking and Avoid Lung Irritants
Quitting smoking is the most important step you can take to treat COPD. Talk with your doctor about programs and products that can help you quit.

If you have trouble quitting smoking on your own, consider joining a support group. Many hospitals, workplaces, and community groups offer classes to help people quit smoking. Ask your family members and friends to support you in your efforts to quit.

Also, try to avoid secondhand smoke and places with dusts, fumes, or other toxic substances that you may inhale.

For more information about how to quit smoking, read Smoking and Your Heart and the National Heart, Lung, and Blood Institute's Your Guide to a Healthy Heart. Although these resources focus on heart health, they include basic information about how to quit smoking. For free help and support to quit smoking, you may call the National Cancer Institute’s Smoking Quitline at 1-877-44U-QUIT (1-877-448-7848).

■ Other Lifestyle Changes
If you have COPD, especially more severe forms, you may have trouble eating enough because of symptoms such as shortness of breath and fatigue. As a result, you may not get all of the calories and nutrients you need, which can worsen your symptoms and raise your risk for infections.

Talk with your doctor about following an eating plan that will meet your nutritional needs. Your doctor may suggest eating smaller, more frequent meals; resting before eating; and taking vitamins or nutritional supplements.

Also, talk with your doctor about what types of activity are safe for you. You may find it hard to remain active with your symptoms. However, physical activity can strengthen the muscles that help you breathe and improve your overall wellness.

Medicines

■ Bronchodilators

Bronchodilators relax the muscles around your airways. This helps open your airways and makes breathing easier.

Depending on the severity of your COPD, your doctor may prescribe short-acting or long-acting bronchodilators. Short-acting bronchodilators last about 4–6 hours and should be used only when needed. Long-acting bronchodilators last about 12 hours or more and are used every day.

Most bronchodilators are taken using a device called an inhaler. This device allows the medicine to go straight to your lungs. Not all inhalers are used the same way. Ask your health care providers to show you the correct way to use your inhaler.

If your COPD is mild, your doctor may only prescribe a short-acting inhaled bronchodilator. In this case, you may use the medicine only when symptoms occur.

If your COPD is moderate or severe, your doctor may prescribe regular treatment with short- and long-acting bronchodilators.

• Combination Bronchodilators Plus Inhaled Glucocorticosteroids (Steroids)
In general, using inhaled steroids alone is not a preferred treatment. If your COPD is more severe, or if your symptoms flare up often, your doctor may prescribe a combination of medicines that includes a bronchodilator and an inhaled steroid. Steroids help reduce airway inflammation.

Your doctor may ask you to try inhaled steroids with the bronchodilator for a trial period of 6 weeks to 3 months to see whether the addition of the steroid helps relieve your breathing problems.

■ Vaccines
• Flu Shots
The flu, or influenza, can cause serious problems for people who have COPD. Flu shots can reduce your risk of getting the flu. Talk with your doctor about getting a yearly flu shot.

• Pneumococcal Vaccine
This vaccine lowers your risk for pneumococcal pneumonia and its complications. People who have COPD are at higher risk for pneumonia than people who do not have COPD. Talk with your doctor about whether you should get this vaccine.

■ Pulmonary Rehabilitation
Pulmonary rehabilitation or rehab is a broad program that helps improve the well-being of people who have chronic breathing problems.

Rehab may include an exercise program, disease management training, and nutritional and psychological counseling. The program's goal is to help you stay active and carry out your daily activities.

Your rehab team may include doctors, nurses, physical therapists, respiratory therapists, exercise specialists, and dietitians. These health professionals will create a program that meets your needs.

■ Oxygen Therapy
If you have severe COPD and low levels of oxygen in your blood, oxygen therapy can help you breathe better. For this treatment, oxygen is delivered through nasal prongs or a mask.

You may need extra oxygen all the time or only at certain times. For some people who have severe COPD, using extra oxygen for most of the day can help them:
• Do tasks or activities while experiencing fewer symptoms
• Protect their hearts and other organs from damage
• Sleep more during the night and improve alertness during the day
• Live longer

■ Surgery
Surgery may benefit some people who have COPD. Surgery usually is a last resort for people who have severe symptoms that have not improved from taking medicines.

Surgeries for people who have COPD that is mainly related to emphysema include bullectomy and lung volume reduction surgery (LVRS). A lung transplant might be an option for people who have very severe COPD.

• Bullectomy
When the walls of the air sacs are destroyed, larger air spaces called bullae form. These air spaces can become so large that they interfere with breathing. In a bullectomy, doctors remove one or more very large bullae from the lungs.

• Lung Volume Reduction Surgery
In LVRS, surgeons remove damaged tissue from the lungs. This helps the lungs work better. In carefully selected patients, LVRS can improve breathing and quality of life.

• Lung Transplant
During a lung transplant, doctors remove your damaged lung and replace it with a healthy lung from a donor.

A lung transplant can improve your lung function and quality of life. However, lung transplants have many risks, such as infections and rejection of the transplanted lung.

If you have very severe COPD, talk with your doctor about whether a lung transplant is an option. Ask your doctor about the benefits and risks of this type of surgery.

Managing Complications
COPD symptoms usually worsen slowly over time. However, they can worsen suddenly. For instance, a cold, flu, or lung infection may cause your symptoms to quickly worsen. You may have a much harder time catching your breath. You also may have chest tightness, more coughing, changes in the color or amount of your sputum or spit, and a fever.

Call your doctor right away if your symptoms worsen suddenly. He or she may prescribe antibiotics to treat the infection, along with other medicines, such as bronchodilators and inhaled steroids, to help you breathe.

Some severe symptoms may require treatment in a hospital. For more information, read Signs and Symptoms.

Living With COPD

COPD has no cure yet. However, you can take steps to manage your symptoms and slow the progression of the disease.

• Avoid lung irritants.
• Get ongoing care.
• Manage the disease and its symptoms.
• Prepare for emergencies.

■ Avoid Lung Irritants

If you smoke, quit. Smoking is the leading cause of COPD. Talk with your doctor about programs and products that can help you quit.

If you have trouble quitting smoking on your own, consider joining a support group. Many hospitals, workplaces, and community groups offer classes to help people quit smoking. Ask your family members and friends to support you in your efforts to quit.

For more information about how to quit smoking, go to the Health Topics Smoking and Your Heart article and the National Heart, Lung, and Blood Institute's Your Guide to a Healthy Heart. Although these resources focus on heart health, they include basic information about how to quit smoking. For free help and support to quit smoking, you may call the National Cancer Institute’s Smoking Quitline at 1-877-44U-QUIT (1-877-448-7848).

Also, try to avoid lung irritants that can contribute to COPD, such as air pollution, chemical fumes, dusts, and secondhand smoke, which is smoke in the air from other people smoking.

Keep these irritants out of your home. If you are getting your home painted or sprayed for insects, have it done when you can stay away for a while.

If possible, keep your windows closed and stay at home when there is a lot of air pollution or dusts outside.

■ Get Ongoing Care
If you have COPD, it is important to get ongoing medical care. Take all your medicines as your doctor prescribes. Make sure to refill your prescriptions before they run out. Bring a list of all the medicines you are taking when you have medical checkups.

Talk with your doctor about whether and when you should get flu, or influenza, and pneumonia vaccines. Also, ask him or her about other diseases for which COPD may increase your risk, such as heart disease, lung cancer, and pneumonia.

■ Manage COPD and Its Symptoms
You can do things to help manage COPD and its symptoms. For example:
• Do activities slowly.
• Put items you use often in one easy-to-reach place. Find simple ways to cook, clean, and do other chores. For example, you might want to use a small table or cart with wheels to move things around and a pole or tongs with long handles to reach things.
• Ask for help in making things more accessible in your house so that you won't need to climb stairs as often.
• Keep your clothes loose, and wear clothes and shoes that are easy to put on and take off.

Depending on how severe your disease is, you may want to ask your family and friends for help with daily tasks.

■ Prepare for Emergencies
If you have COPD, know when and where to seek help for your symptoms. You should get emergency care if you have severe symptoms, such as trouble catching your breath or talking. For more information on severe symptoms of COPD, read Signs and Symptoms.

Call your doctor if you notice that your symptoms are worsening or if you have signs of an infection, such as a fever. Your doctor may change or adjust your treatments to relieve and treat symptoms.

Keep phone numbers handy for your doctor, hospital, and someone who can take you for medical care. You also should have on hand directions to the doctor's office and hospital and a list of all the medicines you are taking.

■ Emotional Issues and Support
Living with COPD may cause fear, anxiety, depression, and stress. Talk about how you feel with your health care team. Talking to a professional counselor also might help. If you are depressed, your doctor may recommend medicines or other treatments that can improve your quality of life.

Joining a patient support group may help you adjust to living with COPD. You can see how other people who have the same symptoms have coped with them. Talk with your doctor about local support groups or check with an area medical center.

Support from family and friends also can help relieve stress and anxiety. Let your loved ones know how you feel and what they can do to help you.

How Is COPD Treated

When you are diagnosed with chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema, you likely will have many questions and the answers may not always be clear at first. Not all people with COPD have the same symptoms and treatment may differ from person to person.

COPD Medications
A variety of medicines are used to treat COPD and there is no "best" medicine for all people. Each person's COPD is different.

By taking the right medicine at the right time, you can:
• Breathe better
• Do more of the things you enjoy
• Have fewer flare-ups or exacerbations

Pulmonary Rehabilitation
If you from a chronic lung disease like COPD, there is hope for rebuilding strength and enjoying a fuller, more active life. Pulmonary rehabilitation programs typically combine education, exercise training, nutrition advice and counseling. Get answers to common questions about pulmonary rehabilitation.

Supplemental Oxygen
Your body needs oxygen to do everything from digesting food, daily household chores, to going to the grocery store. Sometimes with COPD, you require extra or supplemental oxygen (also called oxygen therapy).

Surgery
Some people with very severe COPD symptoms may have a hard time breathing all of the time. In some of these cases, doctors may suggest lung surgery to improve breathing. Not everyone is a candidate for lung surgery. Understand what should be considered before surgery and the different types of procedures.

Clinical Trials
Clinical trials are research studies that test how well new medical approaches work in people. Each study answers scientific questions and tries to find better ways to prevent, screen for, diagnose or treat a disease. People who take part in clinical trials for COPD have an opportunity to contribute to knowledge of and progress against COPD. They also receive up-to-date care from experts.

Complementary Therapies
Complementary therapies refer to the many therapies, philosophies and practices that are not considered conventional or standard in the United States. Some examples of complementary therapy included massage, yoga and acupuncture. These techniques can't treat COPD, but may be able to improve symptoms and quality of life.

Palliative Care and COPD
Palliative care is a specialty in medicine focused on treating the symptoms, pain and stress that accompany serious illnesses like COPD. It is available to you from the moment you are diagnosed and through the entire course of your illness. The goal of palliative care is to help you and your family, achieve the highest quality of life.

Managing Your COPD Medications

There are a range of treatment options to manage chronic obstructive pulmonary disease (COPD). Many are directed at aiding the airways to keep them open as much as possible, help with mucus clearance, and decrease inflammation. No single strategy or medicine is "best" for all people. Personalization is key to address each person’s COPD and devise the best plan for symptom control. This involves identifying the right medicine to take at the right time to ensure:
• Better breathing
• Participation in the activities you enjoy
• Fewer flare-ups

Managing COPD often requires many different types of medicine that need to be taken daily, and it can be confusing especially if you are taking other medicines for other health conditions. The goal is for you to be able to take the right medicine at the right time.

COPD medicines can be swallowed in pill form, inhaled using a metered-dose inhaler or a breath-actuated device.
Some patients with COPD will need to use a nebulizer instead of an inhaler.

Types of medicines often prescribed for COPD:

Bronchodilator
Bronchodilators relax the muscles around the airways which helps to keep them open and makes breathing easier. Most bronchodilators are often delivered through an inhaler or can be nebulized so you breathe the medicine straight into your lungs. Inhalers operate in different ways, so make sure to ask your healthcare team to show you how your specific inhaler works. This ensures you will get a full dose of medicine with each breath.

Bronchodilators can be short-acting or long-acting. Short-acting bronchodilators work quickly so that you get relief from symptoms fast, but they wear off in a few hours. Long-acting bronchodilators provide relief for many hours, but the effect may be slower. Short- and long-acting bronchodilators include beta2-agonists and anticholinergics.
• Beta2-Agonists are very potent at relaxing tightened muscles around your airways. This opens the airway and makes breathing easier. Short-acting beta-agonists work within minutes but last only 4-6 hours. Long-acting beta-agonists may be slow to start working but can last up to 12 to 24 hours so are used to maintain open airways throughout the day or the night.
• Anticholinergics prevent the muscles around your airways from tightening so keep the airways open and help clear mucus from your lungs. This combination allows your cough to expel mucus more easily. There are short-acting and long-acting anticholinergics.

Beta-agonists and anticholinergics can be delivered through an inhaler or a nebulizer.

Anti-Inflammatory
Decreasing inflammation leads to less swelling and mucus production in the airways and that makes it easier to breathe. These medicines are known as corticosteroids or steroids. They are usually inhaled with an inhaler device.

Corticosteroids can also be swallowed as a pill and are usually delivered for short periods of time in special circumstances when your symptoms are getting more severe. Steroids have serious side effects, such as weight gain, diabetes, osteoporosis, cataracts and increased risk of infection so they must be monitored carefully.

(Note: Rinse your mouth with water immediately after using a steroid inhaler to prevent thrush, a yeast infection of the throat.)

Combination Medicines
A corticosteroid, an anticholinergic and a beta-agonist can be combined into one inhaler or nebulizer solution. The most common combinations contain two or three of these medicines as a:
• Short-acting beta-agonist and short-acting anticholinergic
• Long-acting beta-agonist and corticosteroid
• Long-acting anticholinergic and corticosteroid
• Long-acting beta-agonist and long-acting anticholinergic
• Long-acting beta-agonist, long-acting anticholinergic and corticosteroid

Antibiotics
People with COPD do experience flare-ups with more coughing, more mucus and more shortness of breath. This is often caused by bacterial or viral infections. Your doctor may give you an antibiotic to keep on hand and fill for when you have an infection.

Make sure you take all of the antibiotic exactly as prescribed. You may start to feel better during the antibiotic course but make sure you take the antibiotic for the prescribed duration. Short cutting the antibiotic course may allow the infection to come back or become resistant to the antibiotic. Learn more about protecting your lungs to avoid an infection.

Vaccinations COPD increases your risk for infection with influenza (flu) and pneumonia. Vaccines are available to protect you against the flu and you should get immunized every year. You need a yearly flu shot because the influenza virus changes slightly every year and you must get the latest and newest vaccine.

Find where you can get vaccinated in your area. Pneumococcal pneumonia is a bacterial infection of the lung that often follows an influenza infection. There are two vaccines to protect against this infection. You only need to get vaccinated once but you need to get each one. Your doctor can provide these to you.

Vaccinations are very important for people living with COPD to prevent COPD flare-ups.

Symptoms

COPD symptoms often don't appear until significant lung damage has occurred, and they usually worsen over time, particularly if smoking exposure continues. For chronic bronchitis, the main symptom is a daily cough and mucus (sputum) production at least three months a year for two consecutive years.

Other signs and symptoms of COPD may include:
• Shortness of breath, especially during physical activities
• Wheezing
• Chest tightness
• Having to clear your throat first thing in the morning, due to excess mucus in your lungs
• A chronic cough that may produce mucus (sputum) that may be clear, white, yellow or greenish
• Blueness of the lips or fingernail beds (cyanosis)
• Frequent respiratory infections
• Lack of energy
• Unintended weight loss (in later stages)
• Swelling in ankles, feet or legs

People with COPD are also likely to experience episodes called exacerbations, during which their symptoms become worse than usual day-to-day variation and persist for at least several days.

Causes

The main cause of COPD in developed countries is tobacco smoking. In the developing world, COPD often occurs in people exposed to fumes from burning fuel for cooking and heating in poorly ventilated homes.

Only about 20 to 30 percent of chronic smokers may develop clinically apparent COPD, although many smokers with long smoking histories may develop reduced lung function. Some smokers develop less common lung conditions. They may be misdiagnosed as having COPD until a more thorough evaluation is performed.

How your lungs are affected
Air travels down your windpipe (trachea) and into your lungs through two large tubes (bronchi). Inside your lungs, these tubes divide many times — like the branches of a tree — into many smaller tubes (bronchioles) that end in clusters of tiny air sacs (alveoli).

The air sacs have very thin walls full of tiny blood vessels (capillaries). The oxygen in the air you inhale passes into these blood vessels and enters your bloodstream. At the same time, carbon dioxide — a gas that is a waste product of metabolism — is exhaled.

Your lungs rely on the natural elasticity of the bronchial tubes and air sacs to force air out of your body. COPD causes them to lose their elasticity and overexpand, which leaves some air trapped in your lungs when you exhale.

Causes of airway obstruction
Causes of airway obstruction include:
    • Emphysema. This lung disease causes destruction of the fragile walls and elastic fibers of the alveoli. Small airways collapse when you exhale, impairing airflow out of your lungs.
    • Chronic bronchitis. In this condition, your bronchial tubes become inflamed and narrowed and your lungs produce more mucus, which can further block the narrowed tubes. You develop a chronic cough trying to clear your airways.

Cigarette smoke and other irritants
In the vast majority of cases, the lung damage that leads to COPD is caused by long-term cigarette smoking. But there are likely other factors at play in the development of COPD, such as a genetic susceptibility to the disease, because only about 20 to 30 percent of smokers may develop COPD.

Other irritants can cause COPD, including cigar smoke, secondhand smoke, pipe smoke, air pollution and workplace exposure to dust, smoke or fumes.

Alpha-1-antitrypsin deficiency
In about 1 percent of people with COPD, the disease results from a genetic disorder that causes low levels of a protein called alpha-1-antitrypsin. Alpha-1-antitrypsin (AAt) is made in the liver and secreted into the bloodstream to help protect the lungs. Alpha-1-antitrypsin deficiency can affect the liver as well as the lungs. Damage to the lung can occur in infants and children, not only adults with long smoking histories.

For adults with COPD related to AAt deficiency, treatment options include those used for people with more-common types of COPD. In addition, some people can be treated by replacing the missing AAt protein, which may prevent further damage to the lungs.

Risk factors

Risk factors for COPD include:
• Exposure to tobacco smoke. The most significant risk factor for COPD is long-term cigarette smoking. The more years you smoke and the more packs you smoke, the greater your risk. Pipe smokers, cigar smokers and marijuana smokers also may be at risk, as well as people exposed to large amounts of secondhand smoke.
• People with asthma who smoke. The combination of asthma, a chronic inflammatory airway disease, and smoking increases the risk of COPD even more.
• Occupational exposure to dusts and chemicals. Long-term exposure to chemical fumes, vapors and dusts in the workplace can irritate and inflame your lungs.
• Exposure to fumes from burning fuel. In the developing world, people exposed to fumes from burning fuel for cooking and heating in poorly ventilated homes are at higher risk of developing COPD.
• Age. COPD develops slowly over years, so most people are at least 40 years old when symptoms begin.
• Genetics. The uncommon genetic disorder alpha-1-antitrypsin deficiency is the cause of some cases of COPD. Other genetic factors likely make certain smokers more susceptible to the disease.

Complications

COPD can cause many complications, including:
• Respiratory infections. People with COPD are more likely to catch colds, the flu and pneumonia. Any respiratory infection can make it much more difficult to breathe and could cause further damage to lung tissue. An annual flu vaccination and regular vaccination against pneumococcal pneumonia can prevent some infections.
• Heart problems. For reasons that aren't fully understood, COPD can increase your risk of heart disease, including heart attack. Quitting smoking may reduce this risk.
• Lung cancer. People with COPD have a higher risk of developing lung cancer. Quitting smoking may reduce this risk.
• High blood pressure in lung arteries. COPD may cause high blood pressure in the arteries that bring blood to your lungs (pulmonary hypertension).
• Depression. Difficulty breathing can keep you from doing activities that you enjoy. And dealing with serious illness can contribute to development of depression. Talk to your doctor if you feel sad or helpless or think that you may be experiencing depression.

Prevention

Unlike some diseases, COPD has a clear cause and a clear path of prevention. The majority of cases are directly related to cigarette smoking, and the best way to prevent COPD is to never smoke — or to stop smoking now.

If you're a longtime smoker, these simple statements may not seem so simple, especially if you've tried quitting — once, twice or many times before. But keep trying to quit. It's critical to find a tobacco cessation program that can help you quit for good. It's your best chance for preventing damage to your lungs.

Occupational exposure to chemical fumes and dust is another risk factor for COPD. If you work with this type of lung irritant, talk to your supervisor about the best ways to protect yourself, such as using respiratory protective equipment.

Diagnosis

COPD is commonly misdiagnosed — former smokers may sometimes be told they have COPD, when in reality they may have simple deconditioning or another less common lung condition. Likewise, many people who have COPD may not be diagnosed until the disease is advanced and interventions are less effective.

To diagnose your condition, your doctor will review your signs and symptoms, discuss your family and medical history, and discuss any exposure you've had to lung irritants — especially cigarette smoke. Your doctor may order several tests to diagnose your condition.

Tests may include:
• Lung (pulmonary) function tests. Pulmonary function tests measure the amount of air you can inhale and exhale, and if your lungs are delivering enough oxygen to your blood.

Spirometry is the most common lung function test. During this test, you'll be asked to blow into a large tube connected to a small machine called a spirometer. This machine measures how much air your lungs can hold and how fast you can blow the air out of your lungs.

Spirometry can detect COPD even before you have symptoms of the disease. It can also be used to track the progression of disease and to monitor how well treatment is working. Spirometry often includes measurement of the effect of bronchodilator administration. Other lung function tests include measurement of lung volumes, diffusing capacity and pulse oximetry.

• Chest X-ray. A chest X-ray can show emphysema, one of the main causes of COPD. An X-ray can also rule out other lung problems or heart failure.

• CT scan. A CT scan of your lungs can help detect emphysema and help determine if you might benefit from surgery for COPD. CT scans can also be used to screen for lung cancer.

• Arterial blood gas analysis. This blood test measures how well your lungs are bringing oxygen into your blood and removing carbon dioxide. • Laboratory tests. Laboratory tests aren't used to diagnose COPD, but they may be used to determine the cause of your symptoms or rule out other conditions. For example, laboratory tests may be used to determine if you have the genetic disorder alpha-1-antitrypsin (AAt) deficiency, which may be the cause of some cases of COPD. This test may be done if you have a family history of COPD and develop COPD at a young age, such as under age 45.

Treatment

A diagnosis of COPD is not the end of the world. Most people have mild forms of the disease for which little therapy is needed other than smoking cessation. Even for more advanced stages of disease, effective therapy is available that can control symptoms, reduce your risk of complications and exacerbations, and improve your ability to lead an active life.

Smoking cessation
The most essential step in any treatment plan for COPD is to stop all smoking. It's the only way to keep COPD from getting worse — which can eventually reduce your ability to breathe. But quitting smoking isn't easy. And this task may seem particularly daunting if you've tried to quit and have been unsuccessful.

Talk to your doctor about nicotine replacement products and medications that might help, as well as how to handle relapses. Your doctor may also recommend a support group for people who want to quit smoking. It's also a good idea to avoid secondhand smoke exposure whenever possible.

Medications
Doctors use several kinds of medications to treat the symptoms and complications of COPD. You may take some medications on a regular basis and others as needed.

• Bronchodilators
These medications — which usually come in an inhaler — relax the muscles around your airways. This can help relieve coughing and shortness of breath and make breathing easier. Depending on the severity of your disease, you may need a short-acting bronchodilator before activities, a long-acting bronchodilator that you use every day or both.

Short-acting bronchodilators include albuterol (ProAir HFA, Ventolin HFA, others), levalbuterol (Xopenex HFA), and ipratropium (Atrovent). The long-acting bronchodilators include tiotropium (Spiriva), salmeterol (Serevent), formoterol (Foradil, Perforomist), arformoterol (Brovana), indacaterol (Arcapta) and aclidinium (Tudorza).

• Inhaled steroids
Inhaled corticosteroid medications can reduce airway inflammation and help prevent exacerbations. Side effects may include bruising, oral infections and hoarseness. These medications are useful for people with frequent exacerbations of COPD. Fluticasone (Flovent HFA, Flonase, others) and budesonide (Pulmicort Flexhaler, Uceris, others) are examples of inhaled steroids.

• Combination inhalers
Some medications combine bronchodilators and inhaled steroids. Salmeterol and fluticasone (Advair) and formoterol and budesonide (Symbicort) are examples of combination inhalers.

• Oral steroids
For people who have a moderate or severe acute exacerbation, short courses (for example, five days) of oral corticosteroids prevent further worsening of COPD. However, long-term use of these medications can have serious side effects, such as weight gain, diabetes, osteoporosis, cataracts and an increased risk of infection.

• Phosphodiesterase-4 inhibitors
A new type of medication approved for people with severe COPD and symptoms of chronic bronchitis is roflumilast (Daliresp), a phosphodiesterase-4 inhibitor. This drug decreases airway inflammation and relaxes the airways. Common side effects include diarrhea and weight loss.

• Theophylline
This very inexpensive medication may help improve breathing and prevent exacerbations. Side effects may include nausea, headache, fast heartbeat and tremor. Side effects are dose related, and low doses are recommended.

• Antibiotics
Respiratory infections, such as acute bronchitis, pneumonia and influenza, can aggravate COPD symptoms. Antibiotics help treat acute exacerbations, but they aren't generally recommended for prevention. However, a recent study shows that the antibiotic azithromycin prevents exacerbations, but it isn't clear whether this is due to its antibiotic effect or its anti-inflammatory properties.

Lung therapies
Doctors often use these additional therapies for people with moderate or severe COPD:
• Oxygen therapy. If there isn't enough oxygen in your blood, you may need supplemental oxygen. There are several devices to deliver oxygen to your lungs, including lightweight, portable units that you can take with you to run errands and get around town.

Some people with COPD use oxygen only during activities or while sleeping. Others use oxygen all the time. Oxygen therapy can improve quality of life and is the only COPD therapy proven to extend life. Talk to your doctor about your needs and options.

• Pulmonary rehabilitation program. These programs generally combine education, exercise training, nutrition advice and counseling. You'll work with a variety of specialists, who can tailor your rehabilitation program to meet your needs.

Pulmonary rehabilitation may shorten hospitalizations, increase your ability to participate in everyday activities and improve your quality of life. Talk to your doctor about referral to a program.

Managing exacerbations
Even with ongoing treatment, you may experience times when symptoms become worse for days or weeks. This is called an acute exacerbation, and it may lead to lung failure if you don't receive prompt treatment.

Exacerbations may be caused by a respiratory infection, air pollution or other triggers of inflammation. Whatever the cause, it's important to seek prompt medical help if you notice a sustained increase in coughing, a change in your mucus or if you have a harder time breathing.

When exacerbations occur, you may need additional medications (such as antibiotics, steroids or both), supplemental oxygen or treatment in the hospital. Once symptoms improve, your doctor will talk with you about measures to prevent future exacerbations, such as quitting smoking, taking inhaled steroids, long-acting bronchodilators or other medications, getting your annual flu vaccine, and avoiding air pollution whenever possible.

Surgery
Surgery is an option for some people with some forms of severe emphysema who aren't helped sufficiently by medications alone. Surgical options include:
• Lung volume reduction surgery. In this surgery, your surgeon removes small wedges of damaged lung tissue from the upper lungs. This creates extra space in your chest cavity so that the remaining healthier lung tissue can expand and the diaphragm can work more efficiently. In some people, this surgery can improve quality of life and prolong survival.
• Lung transplant. Lung transplantation may be an option for certain people who meet specific criteria. Transplantation can improve your ability to breathe and to be active. However, it's a major operation that has significant risks, such as organ rejection, and it's necessary to take lifelong immune-suppressing medications.
• Bullectomy. Large air spaces (bullae) form in the lungs when the walls of the air sacs are destroyed. These bullae can become very large and cause breathing problems. In a bullectomy, doctors remove bullae from the lungs to help improve air flow.

Clinical trials
Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Lifestyle and home remedies
If you have COPD, you can take steps to feel better and slow the damage to your lungs:
• Control your breathing. Talk to your doctor or respiratory therapist about techniques for breathing more efficiently throughout the day. Also be sure to discuss breathing positions and relaxation techniques that you can use when you're short of breath.
• Clear your airways. With COPD, mucus tends to collect in your air passages and can be difficult to clear. Controlled coughing, drinking plenty of water and using a humidifier may help.
• Exercise regularly. It may seem difficult to exercise when you have trouble breathing, but regular exercise can improve your overall strength and endurance and strengthen your respiratory muscles. Discuss with your doctor which activities are appropriate for you.
• Eat healthy foods. A healthy diet can help you maintain your strength. If you're underweight, your doctor may recommend nutritional supplements. If you're overweight, losing weight can significantly help your breathing, especially during times of exertion.
• Avoid smoke and air pollution. In addition to quitting smoking, it's important to avoid places where others smoke. Secondhand smoke may contribute to further lung damage. Other types of air pollution also can irritate your lungs.
• See your doctor regularly. Stick to your appointment schedule, even if you're feeling fine. It's important to steadily monitor your lung function. And be sure to get your annual flu vaccine in the fall to help prevent infections that can worsen your COPD. Ask your doctor when you need the pneumococcal vaccine. Let your doctor know if you have worsening symptoms or you notice signs of infection.

Coping and support
Living with COPD can be a challenge — especially as it becomes harder to catch your breath. You may have to give up some activities you previously enjoyed. Your family and friends may have difficulty adjusting to some of the changes.

It can help to share your fears and feelings with your family, friends and doctor. You may also want to consider joining a support group for people with COPD. And you may benefit from counseling or medication if you feel depressed or overwhelmed.

1: Spirometry should be obtained to diagnose airflow obstruction in patients with respiratory symptoms (Grade: strong recommendation, moderate-quality evidence).
Spirometry should not be used to screen for airflow obstruction in individuals without respiratory symptoms (Grade: strong recommendation, moderate-quality evidence).
2: For stable COPD patients with respiratory symptoms and FEV1 between 60% and 80% predicted, treatment with inhaled bronchodilators may be used (Grade: weak recommendation, low-quality evidence).
3: For stable COPD patients with respiratory symptoms and FEV1<60% predicted, treatment with inhaled bronchodilators is recommended (Grade: strong recommendation, moderate-quality evidence).
4: Monotherapy using either long-acting inhaled anticholinergics or long-acting inhaled β-agonists is recommended for symptomatic patients with COPD and FEV1<60% predicted. (Grade: strong recommendation, moderate-quality evidence).
Clinicians should base the choice of specific monotherapy on patient preference, cost, and adverse effect profile.
5: Clinicians may administer combination inhaled therapies (long-acting inhaled anticholinergics, long-acting inhaled β-agonists, or inhaled corticosteroids) for symptomatic patients with stable COPD and FEV1<60% predicted (Grade: weak recommendation, moderate-quality evidence).
6: Clinicians should prescribe pulmonary rehabilitation for symptomatic patients with an FEV1<50% predicted (Grade: strong recommendation, moderate-quality evidence).
Clinicians may consider pulmonary rehabilitation for symptomatic or exercise-limited patients with an FEV1>50% predicted. (Grade: weak recommendation, moderate-quality evidence).
7: Clinicians should prescribe continuous oxygen therapy in patients with COPD who have severe resting hypoxemia (PaO2≤55 mm Hg or SpO2≤88%) (Grade: strong recommendation, moderate-quality evidence).

The key questions and scope of the guideline were:
1. What is the value of the history and physical examination for predicting airflow obstruction?
2. What is the value of spirometry for screening and diagnosis of adults who are asymptomatic and have risk factors for developing airflow obstruction, or who are COPD treatment candidates?
3. What management strategies are effective for treating COPD?
  a. mono- and combination inhaled therapies (anticholinergics, long-acting β-agonists, or corticosteroids;
  b. pulmonary rehabilitation programs; or
  c. supplemental long-term oxygen therapy (evidence not updated).

PREDICTION OF AIRFLOW OBSTRUCTION ON THE BASIS OF HISTORY AND PHYSICAL EXAMINATION
The evidence evaluated for the 2007 ACP guideline showed that findings on physical examination had high specificity (>90%) but poor sensitivity for airflow obstruction. The literature showed that combinations of findings in the history and clinical examination were more helpful than a single finding for predicting the presence or absence of airflow obstruction. A 70–pack-year history of smoking is the best predictor of airflow obstruction. The best combination to rule out airflow obstruction was absence of a smoking history and no evidence of wheezing on either history or physical examination.

This update indicated that the single best variable for identifying adults with airflow obstruction (typically defined as postbronchodilator FEV1–FVC ratio <0.70, with severity category based on the results of postbronchodilator FEV1 reported as a percent of the predicted value) is a history of greater than 40 pack-years of smoking (positive likelihood ratio [LR], 12 [95% CI, 2.7 to 50]).
A combination of findings was more helpful for diagnosing airflow obstruction than was any individual sign, symptom, or piece of historical information.
The combination of all 3 of the following items—patient-reported smoking history greater than 55 pack-years, wheezing on auscultation, and patient self-reported wheezing—almost assures the presence of airflow obstruction (LR, 156). In addition, the absence of all 3 items practically rules out airflow obstruction (LR, 0.02).

A physician’s “overall clinical impression” has been evaluated in only 2 studies with a total of 13 physicians.
Based on a standardized history and physical examination, the “overall clinical impression” was useful for diagnosing airflow obstruction in patients with moderate to severe disease (LR, 5.6 [CI, 3.1-10]) but was of limited value in ruling out airflow obstruction (LR, 0.59 [CI, 0.51-0.68]).
However, the sparseness of the data makes any conclusion about the value of “overall clinical impression” premature.

USING SPIROMETRY TO SCREEN FOR AIRFLOW OBSTRUCTION OR DIAGNOSE COPD
Spirometry is a pulmonary function test that measures the presence and severity of airflow obstruction.
In symptomatic patients, spirometry is helpful for determining whether the symptoms are due to respiratory disease or other conditions. Chronic obstructive pulmonary disease is diagnosed when spirometry demonstrates airflow obstruction that is not fully reversible.

As reported in the 2007 ACP guideline, regardless of exposure to COPD risk factors, our evidence update found no evidence of benefit of using spirometry to screen adults who have no respiratory symptoms.
What constitutes “asymptomatic” with respect to patients with airflow obstruction on spirometry is not precisely defined in the literature, although wheezing, shortness of breath, chronic cough, or limitations on exertion, when due to the respiratory system disease, in most cases would classify a patient as having symptomatic COPD.
Clinicians should be alert, however, that some patients may deny limitation on exertion because they have knowingly or unknowingly restricted their activities to those that do not cause symptoms. Patients with very low daily activities may be symptomatic if they tried to engage in the activities normal for someone of their age and health state.

Evidence for Treating At-Risk Asymptomatic Individuals With Mild to Moderate Airflow Obstruction (FEV1–FVC Ratio<0.70 and FEV1>50% Predicted) or Without Airflow Obstruction (FEV1–FVC Ratio>0.70) to Prevent the Development of Symptomatic Airflow Obstruction
The evidence reviewed for the 2007 ACP guideline showed no beneficial effect of treatment of asymptomatic persons, with or without risk factors for airflow obstruction, to prevent future respiratory symptoms or reduce subsequent decline in lung function.

In our guideline update, we identified 1 study that provided subgroup data comparing smoking cessation plus ipratropium, smoking cessation plus placebo, and usual care (the control group that received no intervention) in asymptomatic adult smokers with mild to moderate airflow obstruction.
In the smoking cessation plus ipratropium group, ipratropium did not prevent the development of symptoms, regardless of the presence of airflow obstruction at baseline.

No evidence from randomized, controlled trials (RCTs) has evaluated the effectiveness of long-acting inhaled bronchodilators (anticholinergics or β-agonists) or inhaled corticosteroids in at-risk asymptomatic persons who do not have airflow obstruction.

Thus, we reaffirm our 2007 guideline, which recommends against treating asymptomatic individuals with or without spirometric evidence of airflow obstruction, regardless of the presence or absence of risk factors for airflow obstruction.

Initiating, Monitoring, or Modifying Therapy in Symptomatic Patients on the Basis of Spirometric Findings
In the 2007 ACP clinical guideline, we did not find any evidence to support the use of routine periodic spirometry after initiation of therapy in order to monitor disease status or guide therapy modification.
In our guideline update, there is no new evidence to support the use of routine periodic spirometry after initiation of therapy to monitor disease status or to modify therapy in symptomatic patients.
Improvements in clinical symptoms do not necessarily correlate with spirometric responses to therapy or reduction of long-term decline in FEV1.
Spirometry is useful to identify symptomatic patients with airflow obstruction who may benefit from pharmacotherapy.
The evidence supports the initiation of inhaled bronchodilator treatment (anticholinergics, longacting β-agonists, or corticosteroids) in patients who have respiratory symptoms and FEV1 less than 60% predicted.
Because of the wide intraindividual variation, the spirometric decline of lung function cannot be used to measure individual long-term response to treatment.

Using Spirometry Results to Promote Smoking Cessation
In the 2007 ACP guideline, we did not find any highquality evidence that the use of spirometry or the communication of spirometry results to patients improved smoking cessation.
Updated evidence for this guideline supports our prior findings that obtaining and providing individuals with spirometry results does not independently improve smoking cessation or the likelihood of continued abstinence.

COPD MANAGEMENT STRATEGIES

The goals of COPD treatment are to reduce long-term lung function decline, prevent and treat exacerbations, reduce hospitalizations and mortality, relieve disabling dyspnea, and improve exercise tolerance and health-related quality of life.

Effect of Inhaled Therapies on Long-Term Decline in Lung Function
Pooled results from 9 long-term trials, some of which were not statistically significant, demonstrated that inhaled therapies (long-acting bronchodilators, inhaled corticosteroids, or combination bronchodilator and corticosteroid therapy) reduced the annual decline in mean FEV1 more than placebo did.
Monotherapy trials reported absolute decreases in the annual rate of FEV1 decline associated with use of tiotropium (40 mL/y), inhaled corticosteroids (44 mL/y), and long-acting β-agonists (42 mL/y). The mean differences in decline compared with placebo, were -2, -8 and -13 mL/y, respectively, and were not considered by most authorities to be clinically important differences.
Other studies have demonstrated that combinations of inhaled agents are not more effective than monotherapy for slowing declines in lung function.
Evidence is inadequate to predict in which patients inhaled therapies will have the greatest effect on long-term decline in lung function.

The largest clinically significant effect of combination therapy was observed in the TORCH (Towards a Revolution in COPD Health) trial, in which the mean annual decline in FEV1 associated with a long-acting β-agonist plus an inhaled corticosteroid was 39 mL/y compared with 55 mL/y for placebo (difference, -16 mL/y).
In the UPLIFT (Understanding the Potential Long-Term Impacts on Function with Tiotropium) trial, there was a nonsignificant difference in long-term lung function decline between long-term tiotropium plus usual care (in general, another inhaled therapy) and placebo plus usual care (40 mL/y and 42 mL/y, respectively).
Another trial of long-acting β-agonist plus inhaled corticosteroid compared with tiotropium alone showed no statistically significant mean change in FEV1 decline over 2 years. In comparison, the effect of smoking cessation on FEV1,as measured by the difference in mean FEV1 decline among sustained quitters (13 mL/y) versus continuing smokers (60 mL/y), was -47 mL/y.

Comparison of the Benefits of Inhaled Therapies According to Baseline FEV1
Updated evidence reconfirms our prior findings that the patients who benefit the most from inhaled therapies (anticholinergics, long-acting β-agonists, or corticosteroids) are those who have respiratory symptoms and airflow obstruction with FEV1 less than 60% predicted.

Effects of Monotherapy in COPD

• Exacerbations, Hospitalizations, and Mortality
Evidence reviewed in the 2007 ACP guideline showed that monotherapy with a long-acting inhaled β-agonist, a long-acting inhaled anticholinergic (tiotropium), or an inhaled corticosteroid was superior to placebo and shortacting anticholinergics in reducing exacerbations.
Annual rates of exacerbations with salmeterol and fluticasone were statistically significantly lower than with placebo.
Tiotropium (relative risk [RR], 0.84 [CI, 0.78 to 0.90]), long-acting β-agonists (RR, 0.87 [CI, 0.82 to 0.93]), and inhaled corticosteroids (RR, 0.85 [CI, 0.75 to 0.96]) reduced the RR for at least one exacerbation compared with placebo.
However, ipratropium, a short acting anticholinergic, was not superior to placebo (RR, 0.95 [CI, 0.78 to 1.15]).
In comparison studies, long-acting β-agonists were as effective in reducing exacerbations as ipratropium (RR, 0.89 [CI, 0.72 to 1.10]), inhaled corticosteroids (RR, 1.06 [CI, 0.84 to 1.34]), and the long-acting anticholinergic tiotropium (RR, 1.11 [CI, 0.93 to 1.33]).
Finally, tiotropium was more effective than ipratropium (RR, 0.77 [CI, 0.62 to 0.95]) in reducing exacerbations.

Tiotropium has been shown to statistically significantly reduce hospitalizations for COPD exacerbations compared with placebo (absolute risk difference, -2% [CI, -4% to -1%]) but not compared with ipratropium (absolute risk difference, -4% [CI, -10% to 1%]).

The Lung Health Study (trials 1 and 2) found no statistically significant differences in hospitalizations per 100 person-years of exposure between ipratropium and placebo or between inhaled corticosteroids and placebo.

The TORCH study found no difference in pulmonary-cause mortality with salmeterol, fluticasone, or the combination of these agents compared with placebo.
However, the annual hospitalization rate was 18% lower in the salmeterol group than the placebo group.

A meta-analysis by Salpeter and colleagues identified an increase in pulmonary-cause mortality associated with use of long-acting β-agonist (21 deaths among 1320 participants vs. 8 deaths per 1084 participants in the placebo group; RR, 2.47 [CI, 1.12 to 5.45]) and a 73% relative reduction in mortality associated with anticholinergics compared with placebo (2 deaths per 4036 participants vs. 12 deaths per 3845 participants, respectively; RR, 0.27 [CI, 0.09 to 0.82]).

In this guideline update, no new studies were identified during our initial search time frame that evaluated the effect of inhaled monotherapies (anticholinergics, longacting β-agonists, or corticosteroids) on exacerbations, hospitalizations, or mortality.
After the search date for the guideline had passed, a large randomized trial demonstrated that tiotropium compared with salmeterol reduced the time to first exacerbation (primary outcome), total number of exacerbations, and severe exacerbations in patients with moderate to very severe COPD (mean FEV1, 52%). Adverse effects were similar between groups.

• Health-Related Quality of Life and Dyspnea
One new trial of at least 2 years’ duration in addition to the 2 trials reviewed for the 2007 guideline provided information on respiratory health-related quality of life as measured by the St. George’s Respiratory Questionnaire. All 3 studies demonstrated a statistically significant improved quality of life with monotherapy (tiotropium, salmeterol, or fluticasone) compared with placebo, but the mean absolute difference did not achieve the threshold of a minimal important difference (defined as at least a 4-point difference in the symptom scale scores).

Studies infrequently reported dyspnea scores, and when these were reported, a small improvement with monotherapies was typically demonstrated.

• Adverse Effects
As reported in the 2007 guideline, potential adverse reactions include oropharyngeal candidiasis, dysphonia, and moderate to severe easy bruisability with inhaled corticosteroids; dry mouth with tiotropium; and increased cardiovascular events with long-acting inhaled β-agonists. On the basis of 2 RCTs, the incidence of fracture over 3 years was similar with inhaled corticosteroids and placebo (1.4% vs. 2.0%, respectively).
However, in the Lung Health Study, lumbar spine and femur bone densities were statistically significantly lower in the inhaled triamcinolone group.

Two recent meta-analyses published after the 2007 review reported on adverse effects.
One metaanalysis of 11 RCTs of greater than 6 months’ duration did not identify increased risks for pneumonia, 1-year mortality, or fracture associated with inhaled corticosteroids as monotherapy.
Another recent meta-analysis of RCTs found that short- or long-acting anticholinergics were associated with an increased risk for major cardiovascular events in 4 trials 48 weeks to 24 months in duration (RR, 2.12 [CI, 1.22 to 3.67]; absolute risk difference, 1.2) but not in 8 RCTs 6 weeks to 6 months in duration (RR, 0.82 [CI, 0.43 to 1.58]).
However, a panel convened by the U.S. Food and Drug Administration noted the limitations of that meta analysis, which included potentially biased study selection, lack of assessment of patient follow-up time, lack of information on adverse events in patients who withdrew from many of the included trials, lack of patientlevel data, and the combination of the trials on short-acting and long-acting anticholinergics in the main analysis.

• Evidence for Using Monotherapies in Patients With FEV1 Between 50% and 80% Predicted
Among symptomatic patients with FEV1 greater than 50% predicted but less than 80% predicted or those with normal airflow but who have chronic sputum production (at-risk individuals), 7 large studies of inhaled corticosteroids or short- or long-acting anticholinergics that lasted atleast 1 year (including 2 published since the 2007 review found little to no improvement in exacerbations, health-related quality of life, COPD hospitalizations, or mortality.

Effect of Combination Therapies for COPD

In the 2007 ACP guideline, the conclusion was that it cannot be clearly established when to use combination therapy instead of monotherapy. The evaluated evidence showed that combination therapies do not consistently demonstrate benefits over monotherapy.

This guideline update reprises the analysis of the 2007 ACP guideline by focusing on 9 trials of at least 2 years’ duration.
The outcome “exacerbations” was evaluated according to “rates” (exacerbations per patient-year in patients who had at least 1 exacerbation).
Two new large, long-term studies with data on combination therapy compared with monotherapy found a benefit of using combination therapy over monotherapy in symptomatic patients with an FEV1 less than 60% predicted, because combination therapy was associated with a higher percentage of patients with clinically noticeable improvement in respiratory symptoms.
However, results of other studies did not support this benefit; the average change in respiratory symptoms was below a clinically noticeable threshold, and adverse events were increased.
Because studies of various combination therapies are lacking, there is little evidence to support the identification of any preferred combination therapy.
A recent Cochrane review concluded that the relative efficacy and safety of combination inhalers remains uncertain because the authors found that the proportion of missing outcome data compared with the observed outcome data in the current studies may be sufficient to induce a clinically relevant bias in the intervention effect.

• Exacerbations, Hospitalizations, and Mortality
One study compared combination therapy (salmeterol plus fluticasone) with monotherapy (tiotropium) for 2 years in 1323 patients with a mean FEV1 of 39% predicted. The results for secondary end points showed that compared with monotherapy, combination therapy reduced overall mortality (hazard ratio [HR], 0.48 [CI, 0.27 to 0.85]) and increased the percentage of patients who had a clinically significant improvement in respiratory health status scores (32% with combination therapy vs. 27% with monotherapy at year 2).
The absolute risk difference in mortality was approximately 1%.
There were no differences between monotherapy and combination therapy in the overall rates of exacerbations, exacerbations requiring hospitalization, the percentage of patients who had at least 1 exacerbation, or mean change in FEV1 at 2 years.
In the TORCH trial, the mean FEV1 was 44% predicted among 6112 patients, and fewer than 15% of patients had an FEV1 greater than 60% predicted. Combination therapy (salmeterol plus fluticasone) reduced the annual rate of exacerbations compared with monotherapy (salmeterol alone, fluticasone alone, or placebo).
Although mortality with combination therapy was reduced in this trial compared with monotherapy, the reduction did not reach the predetermined level of statistical significance.
Another randomized trial showed that addition of fluticasone–salmeterol to tiotropium therapy compared with tiotropium plus placebo did not influence exacerbation rates but did improve lung function, health-related quality of life, and hospitalization in patients with moderate or severe COPD (postbronchodilator FEV1 <65% predicted).
The UPLIFT study included 5993 patients and compared tiotropium plus any other nonanticholinergic respiratory medications with placebo plus any other nonanticholinergic respiratory medications over 4 years.
This study was not a true comparison of combination versus placebo because more than 90% of the patients in the placebo group were using another (nonstudy) inhaled medication throughout the trial; approximately two thirds were receiving long-acting β-agonists, inhaled corticosteroids, or both agents).
Inclusion in the study required an FEV1 less than 70% predicted; the mean FEV1 of enrollees was 48% predicted.
The study authors concluded that in patients with severe symptomatic airflow obstruction the addition of tiotropium reduced the rate of exacerbations (HR, 0.86 [CI, 0.81 to 0.91]), increased the delay in time to first exacerbation (16.7 months vs. 12.5 months;P < 0.05), and reduced the incidence of respiratory failure compared with placebo.
The percentage of patients who experienced at least 1 exacerbation differed between study groups, although all patients experienced at least 1 exacerbation. Addition of tiotropium also prolonged the time to first hospitalization for exacerbations (HR, 0.86 [CI, 0.78 to 0.95]) but not the number of exacerbations per patient-year leading to hospitalization (RR, 0.94 [CI, 0.82 to 1.07]). There was no statistically significant difference in overall mortality (HR, 0.89 [CI, 0.79 to 1.02]).

• Health-Related Quality of Life and Dyspnea
Two trials of at least 2 years’ duration provided information on health-related quality of life as measured by the St. George’s Respiratory Questionnaire.
In a study published after the 2007 review, Wedzicha and colleagues noted a statistically significant improvement among symptomatic patients with severe airflow obstruction (mean FEV1, 39% predicted) who were assigned to receive inhaled combined long-acting β-agonist and corticosteroid therapy compared with tiotropium alone.
In the TORCH trial, the average change in score over 3 years was statistically significantly better in the combination therapy group than in the salmeterol-alone group, the fluticasone-alone group, and the placebo group (averaged over 3 years, the difference of the difference between combination and placebo group in the score for the St. George’s Respiratory Questionnaire was 3.1 units).
Two new studies provide an update to the 2007 review. The UPLIFT study assessed the effect of tiotropium on the incidence of dyspnea and found a decrease of 39% in patients receiving tiotropium compared with those receiving placebo (RR, 0.61 [CI, 0.40 to 0.94]; 0.38 vs. 0.62 per 100 patient-years, respectively). Lapperre and colleagues found that use of inhaled corticosteroids alone or in combination with a long-acting β-agonist was associated with a small, non–clinically significant improvement over baseline dyspnea compared with placebo (change in Medical Research Council dyspnea score of approximately 0.2 to 0.3).

• Adverse Effects
The 2007 literature was updated with 2 studies of the adverse effects of combination therapy.
One study of 2 years’ duration that included 1323 patients with a mean FEV1 39% predicted found that the percentage of patients with serious adverse events was greater with combination therapy (salmeterol–fluticasone) than with monotherapy (tiotropium) (30% vs. 24%;P = 0.02). Salmeterol–fluticasone therapy was also associated with more cases of patient- and investigator-reported pneumonia than was therapy with tiotropium alone (8% vs. 4%;P = 0.008).
In contrast, the UPLIFT trial (tiotropium plus any other nonanticholinergic respiratory medications compared with placebo plus any other nonanticholinergic respiratory medications) found a reduced risk for myocardial infarction with long-acting inhaler tiotropium compared with placebo (RR, 0.73 [CI, 0.53 to 1.00]) and no difference in risk for stroke.

• Evidence to Use Combination Therapy in Patients With FEV1 Between 50% and 80% Predicted
One study of patients with FEV1 between 50% and 80% predicted who were treated with the combination of a long-acting β-agonist and inhaled corticosteroid showed little improvement in exacerbations, mortality, or healthrelated quality of life compared with placebo recipients.
Subgroup data from another trial showed that the time to first exacerbation and the time to exacerbation resulting in hospital admission were longer in the tiotropium group than in the control group (HR, 0.82 [CI, 0.75 to 0.90] and 0.74 [CI, 0.62 to 0.88], respectively).

Pulmonary Rehabilitation

Results reported in the 2007 ACP guideline suggest that pulmonary rehabilitation programs provide improvements in respiratory symptoms, quality of life, and the 6-minute walk test, at least in the short term following the program, among persons with baseline respiratory symptoms and a mean FEV1 of approximately 50% predicted.
Most studies have historically enrolled patients with a mean FEV1 of 50% predicted or lower. Although the generalizability of these data to patients with less severe airflow obstruction is less clear, evidence reviewed in this guideline update suggests that patients with moderate COPD also experience benefit.
We found no new information on the effectiveness of pulmonary rehabilitation programs in severe COPD. However, a recently published RCT (outside our inclusion criteria) that included 252 patients with moderate to severe COPD who were monitored over 8 weeks compared outpatient hospital-based pulmonary rehabilitation with home-based pulmonary rehabilitation.
Study inclusion required a diagnosis of COPD and an FEV1 less than 70% predicted. The mean FEV1 was 43% predicted, and approximately one third of individuals had moderate COPD (Global Initiative for Chronic Obstructive Lung Disease stage II). More than 99% of patients had self-reported shortness of breath.
Results showed that both interventions produced similar improvements in the dyspnea domain of the Chronic Respiratory Questionnaire and total score on St. George’s Respiratory Questionnaire. The improvement in dyspnea from baseline in both groups was statistically significant and greater for both scale scores than the previously determined minimally important difference at 3 months. However, only the homebased program reached the minimum clinically important difference at 12 months. The main components of most reported pulmonary rehabilitation programs included endurance and exercise training, education, behavioral modification, and outcome assessment.
One study used a multidisciplinary pulmonary rehabilitation program that included a 4-month clinic-based program followed by 20 months of community-based maintenance among symptomatic adults, among whom approximately 68% had an FEV1 greater than 50%. Participants showed clinically significant benefits in St. George’s Respiratory Questionnaire scores at 4 months but not at 12 months. There were no statistically significant differences in moderate to severe exacerbations (coprimary outcome with St. George’s Respiratory Questionnaire score) at 4 or 12 months and no clinically important differences in the 6-minute walk test after 4 months or 2 years.
One small study showed that there were no differences in 18-month mortality between the outpatient rehabilitation group and the control group (P = 0.79).
Evidence reviewed by Puhan and colleagues from small studies of moderate-quality evidence showed that pulmonary rehabilitation is an effective intervention to reduce hospital readmissions and to improve health-related quality of life in patients with COPD after an exacerbation.
Another systematic review showed that inspiratory muscle training with targeted hyperventilation increases muscle strength and endurance, and it improves exercise capacity and decreases dyspnea for adults with stable COPD.

Supplemental Long-Term Oxygen Therapy

We did not update the search to evaluate the utility of long-term oxygen therapy because widespread consensus remains on this point.
To summarize the evidence presented in the 2007 ACP guideline, 2 trials showed that supplemental oxygen used 15 or more hours daily to maintain a PaO2 greater than 60 mm Hg reduced mortality in patients with COPD who have severe resting hypoxemia (mean resting PaO2 ≤ 55 mm Hg) (RR, 0.61 [CI, 0.46 to 0.82]).
Two other studies showed no effect on relative risk for mortality with use of supplemental oxygen (9 to 13 hours daily) during the day or at night in patients with similar severity of airflow obstruction but daytime PaO2 greater than 60 mm Hg. In addition, studies showed no effect of ambulatory oxygen on respiratory health-related quality of life measures. Physiologic indications for the use of long-term oxygen therapy include cor pulmonale or polycythemia with PaO2 between 55 and 59 mm Hg.

SUMMARY

Evidence shows that history and physical examination are poor predictors of airway obstruction and its severity.
However, combination of all 3 of the following findings in an individual—greater than 55–pack-year history of smoking, wheezing on auscultation, and patient self-reported wheezing—can be considered predictive of airflow obstruction, defined as postbronchodilator FEV1–FVC ratio less than 0.70.

Spirometry is a pulmonary function test that is useful to identify airflow obstruction in symptomatic patients who may benefit from pharmacotherapy, long-term oxygen, or pulmonary rehabilitation (or all of these strategies.
Symptomatic patients with FEV1 less than 60% predicted will benefit from inhaled treatments (anticholinergics long-acting β-agonists, or corticosteroids).
The evidence does not support treating asymptomatic persons, regardless of the presence or absence of airflow obstruction or risk factors for airflow obstruction.
Currently, evidence does not support the use of spirometry as a screening strategy for airflow obstruction in persons without respiratory symptoms, even in the presence of risk factors.
In addition, spirometry does not seem to have an independent influence on the likelihood of quitting smoking or maintaining abstinence.
The routine use of spirometry in asymptomatic patients in primary care settings may potentially lead to unnecessary testing, increased costs and resource utilization, unnecessary disease labeling, and the harms of long-term treatment with no known preventive effect on avoiding future symptoms.
Most trials that compared the efficacy or effectiveness of various inhaled monotherapies did not show any differences among these medications.
Monotherapy with a longacting inhaled agent (long-acting anticholinergic, longacting β-agonist, or corticosteroid) was superior to placebo or short-acting anticholinergic therapy in reducing exacerbations.
The evidence is not conclusive in linking inhaled monotherapies with reductions in hospitalizations or mortality.
In some studies, combination therapy with various inhaled agents (anticholinergics, long-acting β-agonists, or corticosteroids) was shown to reduce exacerbations, hospitalizations, mortality, and improve health-related quality of life compared with monotherapy.
Other studies have not identified these benefits, however, and a few studies have identified a modest increase in the risk for adverse events.
Finally, on the basis of studies that showed benefit, it remains unclear when combination therapy is preferred over monotherapy.

Pulmonary rehabilitation improves symptoms in patients with an FEV1 less than 50% predicted. However, the generalizability of pulmonary rehabilitation benefits to all patients is not clear. We did not update the search to evaluate the utility of long-term oxygen therapy. Evidence evaluated for our 2007 guideline showed a reduction in mortality associated with use of long-term supplemental oxygen therapy for patients with severe resting hypoxemia (PaO2 ≤ 55 mm Hg).

DIAGNOSIS AND ASSESSMENT OF COPD OVERALL

• COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease.

• Spirometry is required to make the diagnosis; the presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation.

• The goals of COPD assessment are to determine the severity of the disease, including the severity of airflow limitation, the impact of disease on the patient’s health status, and the risk of future events (such as exacerbations, hospital admissions, or death), in order to guide therapy.

• Concomitant chronic diseases occur frequently in COPD patients, including cardiovascular disease, skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression, anxiety, and lung cancer. These comorbidities should be actively sought and treated appropriately when present as they can influence mortality and hospitalizations independently.

Note: Alpha-1 antitrypsin deficiency (AATD) screening. The World Health Organization recommends that all patients with a diagnosis of COPD should be screened once especially in areas with high AATD prevalence.14 A low concentration (< 20% normal) is highly suggestive of homozygous deficiency. Family members should also be screened.

Differential Diagnosis of COPD

A major differential diagnosis is asthma. In some patients with chronic asthma, a clear distinction from COPD is not possible using current imaging and physiological testing techniques. In these patients, current management is similar to that of asthma. Other potential diagnoses are usually easier to distinguish from COPD (See Table 2.7.).

Table 2.7. Differential Diagnosis of COPD

  Differential Diagnosis       Suggestive Features

ASSESSMENT

The goals of COPD assessment are to determine the severity of airflow limitation, its impact on the patient’s health status and the risk of future events (such as exacerbations, hospital admissions or death), in order to, eventually, guide therapy. To achieve these goals, COPD assessment must consider the following aspects of the disease separately:
 The presence and severity of the spirometric abnormality
 Current nature and magnitude of the patient’s symptoms
 Exacerbation history and future risk
 Presence of comorbidities

Classification of severity of airflow obstruction
The classification of airflow limitation severity in COPD is shown in Table 2.4. Specific spirometric cut-points are used for purposes of simplicity. Spirometry should be performed after the administration of an adequate dose of at least one short-acting inhaled bronchodilator in order to minimize variability.

It should be noted that there is only a weak correlation between FEV1, symptoms and impairment of a patient’s health status.15,16 For this reason, formal symptomatic assessment is also required.

Assessment of symptoms
In the past, COPD was viewed as a disease largely characterized by breathlessness. A simple measure of breathlessness such as the Modified British Medical Research Council (mMRC) Questionnaire (Table 2.5) was considered adequate, as the mMRC relates well to other measures of health status and predicts future mortality risk.

However, it is now recognized that COPD impacts patients beyond just dyspnea.20 For this reason, a comprehensive assessment of symptoms is recommended using measures such as the COPD Assessment Test (CATTM)1 (Figure 2.3) and the COPD Control Questionnaire (The CCQ©) have been developed and are suitable.

Revised combined COPD assessment
An understanding of the impact of COPD on an individual patient combines the symptomatic assessment with the patient’s spirometric classification and/or risk of exacerbations.
The “ABCD” assessment tool of the 2011 GOLD update was a major advancement from the simple spirometric grading system of the earlier versions of GOLD because it incorporated patient-reported outcomes and highlighted the importance of exacerbation prevention in the management of COPD.
However, there were some important limitations. Firstly, the ABCD assessment tool performed no better than the spirometric grades for mortality prediction or other important health outcomes in COPD.
Moreover, ............

Commonly used maintainance medications in COPD

VACCINATIONS

Influenza vaccine
Influenza vaccination can reduce serious illness (such as lower respiratory tract infections requiring hospitalization) 32 and death in COPD patients.

Pneumococcal vaccine
Pneumococcal vaccinations, PCV13 and PPSV23, are recommended for all patients ≥ 65 years of age (Table 3.2). The PPSV23 is also recommended for younger COPD patients with significant comorbid conditions including chronic heart or lung disease. 37 PPSV23 has been shown to reduce the incidence of community-acquired pneumonia in COPD patients < 65 years, with an FEV 1 < 40% predicted, or comorbidities (especially cardiac comorbidities).

Table 3.2. Vaccination for stable COPD
• Influenza vaccination reduces serious illness and death in COPD patients (Evidence B).
• The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been shown to reduce the incidence of community- acquired pneumonia in COPD patients aged < 65 years with an FEV1 < 40% predicted and in those with comorbidities (Evidence B).
• In the general population of adults ≥ 65 years the 13-valent conjugated pneumococcal vaccine (PCV13) has demonstrated significant efficacy in reducing bacteremia and serious invasive pneumococcal disease (Evidence B).

PHARMACOLOGIC THERAPY FOR STABLE COPD

Pharmacologic therapy for COPD is used to reduce symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance and health status. To date, there is no conclusive clinical trial evidence that any existing medications for COPD modify the long-term decline in lung function.

The classes of medications commonly used to treat COPD are shown in Table 3.3.

Bronchodilators
Bronchodilators are medications that increase FEV 1 and/or change other spirometric variables. • Bronchodilator medications in COPD are most often given on a regular basis to prevent or reduce symptoms.
• Toxicity is also dose-related (Table 3.3).
• Use of short acting bronchodilators on a regular basis is not generally recommended.

■ Beta 2 -agonists
• The principal action of beta 2 -agonists is to relax airway smooth muscle by stimulating beta 2 - adrenergic receptors, which increases cyclic AMP and produces functional antagonism to bronchoconstriction.
• There are short-acting (SABA) and long-acting (LABA) beta 2 -agonists.
• Formoterol and salmeterol are twice-daily LABAs that significantly improve FEV 1 and lung volumes, dyspnea, health status, exacerbation rate and number of hospitalizations, but have no effect on mortality or rate of decline of lung function.
• Indacaterol is a once daily LABA that improves breathlessness, health status and exacerbation rate.
• Oladaterol and vilanterol are additional once daily LABAs that improve lung function and symptoms.
• Adverse effects. Stimulation of beta 2 -adrenergic receptors can produce resting sinus tachycardia and has the potential to precipitate cardiac rhythm disturbances in susceptible patients. Exaggerated somatic tremor is troublesome in some older patients treated with higher doses of beta 2 -agonists, regardless of route of administration.
■ Antimuscarinic drugs
• Antimuscarinic drugs block the bronchoconstrictor effects of acetylcholine on M3 muscarinic receptors expressed in airway smooth muscle.
• Short-acting antimuscarinics (SAMAs), namely ipratropium and oxitropium and long-acting antimuscarinic antagonists (LAMAs), such as tiotropium, aclidinium, glycopyrronium bromide and umeclidinium act on the receptors in different ways.
• A systematic review of RCTs found that ipratropium alone provided small benefits over short- acting beta 2 -agonist in terms of lung function, health status and requirement for oral steroids.
• Clinical trials have shown a greater effect on exacerbation rates for LAMA treatment (tiotropium) versus LABA treatment.
• Adverse effects. Inhaled anticholinergic drugs are poorly absorbed which limits the troublesome systemic effects observed with atropine. Extensive use of this class of agents in a wide range of doses and clinical settings has shown them to be very safe. The main side effect is dryness of mouth.

■ Methylxanthines
• Controversy remains about the exact effects of xanthine derivatives.
• Theophylline, the most commonly used methylxanthine, is metabolized by cytochrome P450 mixed function oxidases. Clearance of the drug declines with age.
• There is evidence for a modest bronchodilator effect compared with placebo in stable COPD. 56 • Addition of theophylline to salmeterol produces a greater improvement in FEV 1 and breathlessness than salmeterol alone.
• There is limited and contradictory evidence regarding the effect of low-dose theophylline on exacerbation rates.
• Adverse effects. Toxicity is dose-related, which is a particular problem with xanthine derivatives because their therapeutic ratio is small and most of the benefit occurs only when near-toxic doses are given.

■ Combination bronchodilator therapy
• Combining bronchodilators with different mechanisms and durations of action may increase the degree of bronchodilation with a lower risk of side-effects compared to increasing the dose of a single bronchodilator.
• Combinations of SABAs and SAMAs are superior compared to either medication alone in improving FEV 1 and symptoms.
• Treatment with formoterol and tiotropium in separate inhalers has a bigger impact on FEV 1 than either component alone.
• There are numerous combinations of a LABA and LAMA in a single inhaler available (Table 3.3).
• A lower dose, twice daily regimen for a combination LABA/LAMA has also been shown to improve symptoms and health status in COPD patients (Table 3.4).

Table 3.4. Bronchodilators in stable COPD
• Inhaled bronchodilators in COPD are central to symptom management and commonly given on a regular basis to prevent or reduce symptoms (Evidence A).
• Regular and as-needed use of SABA or SAMA improves FEV1 and symptoms (Evidence A).
• Combinations of SABA and SAMA are superior compared to either medication alone in improving FEV1 and symptoms (Evidence A).
• LABAs and LAMAs significantly improve lung function, dyspnea, health status, and reduce exacerbation rates (Evidence A).
• LAMAs have a greater effect on exacerbation reduction compared with LABAs (Evidence A) and decrease hospitalizations (Evidence B).
• Combination treatment with a LABA and LAMA increases FEV1 and reduces symptoms compared to monotherapy (Evidence A).
• Combination treatment with a LABA and LAMA reduces exacerbations compared to monotherapy (Evidence B) or ICS/LABA (Evidence B).
• Tiotropium improves the effectiveness of pulmonary rehabilitation in increasing exercise performance (Evidence B).
• Theophylline exerts a small bronchodilator effect in stable COPD (Evidence A) and that is associated with modest symptomatic benefits (Evidence B).

Anti-inflammatory agents • To date, exacerbations (e.g., exacerbation rate, patients with at least one exacerbation, time- to-first exacerbation) represent the main clinically relevant end-point used for efficacy assessment of drugs with anti-inflammatory effects (Table 3.5).

■ Inhaled corticosteroids (ICS)
• ICS in combination with long-acting bronchodilator therapy. In patients with moderate to very severe COPD and exacerbations, an ICS combined with a LABA is more effective than either component alone in improving lung function, health status and reducing exacerbations.
• Adverse effects. There is high quality evidence from randomized controlled trials (RCTs) that ICS use is associated with higher prevalence of oral candidiasis, hoarse voice, skin bruising and pneumonia.
• Withdrawal of ICS. Results from withdrawal studies provide equivocal results regarding consequences of withdrawal on lung function, symptoms and exacerbations. 69-73 Differences between studies may relate to differences in methodology, including the use of background long-acting bronchodilator medication(s) which may minimize any effect of ICS withdrawal.

Table 3.5. Anti-inflammatory therapy in stable COPD
■ Inhaled corticosteroids
• An ICS combined with a LABA is more effective than the individual components in improving lung function and health status and reducing exacerbations in patients with exacerbations and moderate to very severe COPD (Evidence A).
• Regular treatment with ICS increases the risk of pneumonia especially in those with severe disease (Evidence A).
• Triple inhaled therapy of ICS/LAMA/LABA improves lung function, symptoms and health status (Evidence A) and reduces exacerbations (Evidence B) compared to ICS/LABA or LAMA monotherapy.
■ Oral glucocorticoids
• Long-term use of oral glucocorticoids has numerous side effects (Evidence A) with no evidence of benefits (Evidence C).
■ PDE4 inhibitors
• In patients with chronic bronchitis, severe to very severe COPD and a history of exacerbations:
➢ A PDE4 inhibitor improves lung function and reduces moderate and severe exacerbations (Evidence A).
➢ A PDE4 inhibitor improves lung function and decreases exacerbations in patients who are on fixed-dose LABA/ICS combinations (Evidence B).
■ Antibiotics
• Long-term azithromycin and erythromycin therapy reduces exacerbations over one year (Evidence A).
• Treatment with azithromycin is associated with an increased incidence of bacterial resistance (Evidence A) and hearing test impairments (Evidence B).
■ Mucolytics/antioxidants
• Regular use of NAC and carbocysteine reduces the risk of exacerbations in select populations (Evidence B).
■ Other anti-inflammatory agents
• Simvastatin does not prevent exacerbations in COPD patients at increased risk of exacerbations and without indications for statin therapy (Evidence A). However, observational studies suggest that statins may have positive effects on some outcomes in patients with COPD who receive them for cardiovascular and metabolic indications (Evidence C).
• Leukotriene modifiers have not been tested adequately in COPD patients.

• Triple inhaled therapy
o The step up in inhaled treatment to LABA plus LAMA plus ICS (triple therapy) can occur by various approaches.
o This may improve lung function and patient reported outcomes.
o Adding a LAMA to existing LABA/ICS improves lung function and patient reported outcomes, in particular exacerbation risk.

o A RCT did not demonstrate any benefit of adding ICS to LABA plus LAMA on exacerbations.
o A double-blind, parallel group, RCT reported that treatment with extrafine fixed triple therapy had greater clinical benefits compared to tiotropium in patients with symptomatic COPD, FEV 1 <50%, and a history of exacerbations. Another double-blind RCT reported benefits of single- inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD.

• Oral glucocorticoids
o Oral glucocorticoids have numerous side effects, including steroid myopathy which can contribute to muscle weakness, decreased functionality, and respiratory failure in subjects with very severe COPD.
o While oral glucocorticoids play a role in the acute management of exacerbations, they have no role in the chronic daily treatment in COPD because of a lack of benefit balanced against a high rate of systemic complications.

• Phosphodiesterase-4 (PDE4) inhibitors
o Roflumilast reduces moderate and severe exacerbations treated with systemic corticosteroids in patients with chronic bronchitis, severe to very severe COPD, and a history of exacerbations.
o The beneficial effects of roflumilast have been reported to be greater in patients with a prior history of hospitalization for an acute exacerbation. There has been no study directly comparing roflumilast with an inhaled corticosteroid.
o Adverse effects. PDE4 inhibitors have more adverse effects than inhaled medications for COPD. The most frequent are nausea, reduced appetite, weight loss, abdominal pain, diarrhea, sleep disturbance, and headache.

• Antibiotics
o More recent studies have shown that regular use of macrolide antibiotics may reduce exacerbation rate.
o Azithromycin (250 mg/day or 500 mg three times per week) or erythromycin (500 mg two times per day) for one year in patients prone to exacerbations reduced the risk of exacerbations compared to usual care. 92-94 Azithromycin use was associated with an increased incidence of bacterial resistance and impaired hearing tests. A post-hoc analysis suggests lesser benefit in active smokers.
o There are no data showing the efficacy or safety of chronic azithromycin treatment to prevent COPD exacerbations beyond one-year of treatment.
• Mucolytic (mucokinetics, mucoregulators) and antioxidant agents (NAC, carbocysteine) o In COPD patients not receiving inhaled corticosteroids, regular treatment with mucolytics such as carbocysteine and N-acetylcysteine may reduce exacerbations and modestly improve health status.

Issues related to inhaled delivery
• Determinants of poor inhaler technique in asthma and COPD patients include: older age, use of multiple devices, and lack of previous education on inhaler technique.
• The main errors in delivery device use relate to problems with inhalation rate, inhalation duration, coordination, dose preparation, exhalation maneuver prior to inhalation and breath-holding following dose inhalation (Table 3.6).

Table 3.6. The inhaled route
• When a treatment is given by the inhaled route, the importance of education and training in inhaler device technique cannot be over-emphasized.
• The choice of inhaler device has to be individually tailored and will depend on access, cost, prescriber, and most importantly, patient’s ability and preference.
• It is essential to provide instructions and to demonstrate the proper inhalation technique when prescribing a device, to ensure that inhaler technique is adequate and re-check at each visit that patients continue to use their inhaler correctly.
• Inhaler technique (and adherence to therapy) should be assessed before concluding that the current therapy is insufficient.

Other pharmacologic treatments
Other pharmacologic treatments for COPD are summarized in Table 3.7.

Table 3.7. Other pharmacological treatments
Alpha-1 antitrypsin augmentation therapy
• Intravenous augmentation therapy may slow down the progression of emphysema (Evidence B).
Antitussives
• There is no conclusive evidence of a beneficial role of antitussives in patients with COPD (Evidence C).
Vasodilators
• Vasodilators do not improve outcomes and may worsen oxygenation (Evidence B).

BRONCHODILATORS

Apart from being effective in asthma, they also help improve the breathing of patients with lung diseases such as bronchitis, emphysema, pulmonary fibrosis, interstitial lung disease, pneumonia and bronchiolitis in young children.

Types of bronchodilators:
■ beta2-agonists
■ anticholinergics
■ theophyllines

β2 adrenergic receptor agonist

Beta 2 Agonists are a group of medications that act on special receptor called beta-2 adrenergic receptor, located predominantly on smooth muscle and mucous membrane in the lungs. They also act on cells called mast cells to prevent release of substances which play a role in asthma attacks. Additionally, they may help clear mucous from the lungs. As the airways dilate, any mucous present can move more freely and can be coughed out of the airways.

Inhaled beta2-agonists can be fast-acting (start to work within 3 to 5 minutes), or slow-acting (take 20 minutes to work). These medications can also be short- or long-lasting.
■ Short-lasting beta2-agonists - albuterol, pirbuterol, salbutamol, terbutaline - last for 4-6 hours.
■ Long-lasting - salmeterol (Serevent), formoterol (Foradil, Perforomist), arformoterol (Brovana), indacaterol (Arcapta) - can last for up to 12 hours,
■ Ultra-Long-lasting - indacaterol and vilanterol last up to 24 hours.

■ Short-lasting beta2-agonists
• albuterol (ProAir HFA, Ventolin HFA, others)
• Albuterol and terbutaline are available in both inhaled and pill forms or syrups. The pill form or syrups can cause more side effects than the inhaled form.
Beta2-agonists that are fast-acting are also known as reliever medicines because they bring quick relief for breathlessness, but do not last long enough to provide 24- hour relief.
Using your reliever medication before an activity that you know makes your breathing worse (exercise, showering, or going out into the cold air) may help lessen or prevent your breathing difficulty.

• levalbuterol (Xopenex HFA): levosalbutamol, also known as levalbuterol is a short-acting β2 adrenergic receptor agonist used in the treatment of asthma and COPD. Evidence does not show that levosalbutamol works better than salbutamol, thus there may not be sufficient justification for prescribing it.

■ Long-lasting beta2-agonists are taken every 12 to 24 hours, providing more convenient treatment of COPD than short acting drugs.
• salmeterol (Serevent), formoterol (Foradil, Perforomist), arformoterol (Brovana), indacaterol (Arcapta) ■ Ultra-long-acting beta-adrenoceptor agonist
• indacaterol is an ultra-long-acting beta-adrenoceptor agonist developed by Novartis. It was approved by the European Medicines Agency (EMA) under the trade name Onbrez Breezhaler on November 30, 2009, and by the United States Food and Drug Administration (FDA), under the trade name Arcapta Neohale.

• vilanterol is an ultra-long-acting β2 adrenoreceptor agonist, which was approved in May 2013 in combination with fluticasone furoate for sale as Breo Ellipta by GlaxoSmithKline for the treatment of chronic obstructive pulmonary disease (COPD).
vilanterol is available in following combinations:
    with inhaled corticosteroid fluticasone furoate — fluticasone furoate/vilanterol (trade names Breo Ellipta (U.S.), Relvar Ellipta (EU, RU, JPN))
    with muscarinic antagonist umeclidinium bromide — umeclidinium bromide/vilanterol (trade name Anoro Ellipta)

A common combination is to take a fast-acting bronchodilator with a long-lasting bronchidilator. This combination gives fast action and long-lasting relief.
You may be given a beta2-agonist with an anticholinergic because the two work better than just one alone.e.g., • Combivent (albuterol and Ipratropium bromide)

Anticholinergics

Anticholinergic bronchodilators are inhaled medicines. They can be short- or long-lasting.
The short-lasting form (ipatropium) works in about 15 minutes and lasts for 6–8 hours, and is usually taken 4 times a day.
The long-lasting forms take about 20 minutes to begin working and last 24 hours (tiotropium, umedclidinum) or 12 hours (aclidinium).
Because of the slower onset of action of anticholinergics, they are not to be used for quick relief (reliever medicine).

■ Short-acting muscarinic antagonists
• ipratropium (Atrovent)
■ Long-acting muscarinic antagonists
• aclidinium (Tudorza, Pressair)
■ Ultra-Long-acting muscarinic antagonists
• tiotropium (Spiriva)
• umedclidinum

There are several anticholinergic bronchodilators currently available —
ipratropium bromide (Atrovent® HFA), which is available as a metered dose inhaler and nebulizer solution, and
tiotropium bromide (Spiriva®), which is a dry powder inhaler.
Ipratropium is used four times per day. Tiotropium is used only once per day and lasts 24 hours. It should be used at the same time every day.
These are not quick-relief medications but they can add to the bronchodilator effect for certain asthmatics with difficult-to-control symptoms.
Side effects are minor; dry throat is the most common. If the medicine gets in your eyes, it might cause blurred vision for a short period of time.

Theophylline

Brand names include Uniphyl®, Elixophyllin®, Theochron and Theo-24®.
Theophylline is no longer commonly used for COPD in the U.S.
Theophylline is usually taken in tablet or capsule form, but a different version called aminophylline can be given intravenously for severe symptoms are. Inhaled forms of theophylline are not available.
It's unclear exactly how theophylline works, but it seems to reduce any inflammation in the airways, in addition to relaxing the muscles lining them.
The effect of theophylline is weaker than other bronchodilators and corticosteroids. It's also more likely to cause side effects, so is often only used alongside these medicines if they're not effective enough.
When taking theophylline, a blood test must be done to check your theophylline level. The amount of theophylline you take needs careful supervision since your theophylline blood level can change just by starting a new medicine or stopping smoking.
Common side effects are shakiness, but very serious side effects that may occur are severe nausea, vomiting, heart irregularities, and seizures.

Steroid

Steroids, also known as corticosteroids, are medications used to reduce swelling in the breathing tubes. These drugs are not the same as anabolic steroids (misused by athletes) to build muscles.
Steroids are usually taken by inhaler or pill.
The inhaled steroid may be combined with a bronchodilator.
Inhaled steroids can be given in small doses, resulting in fewer side effects. They do not work quickly, however, and may take a week or more before you notice the benefits.
Pills can act faster (within 24 hours) than inhaled steroids, but can cause more side effects.

Common side effects when taking steroid medications Side effects depend on the dose, length of use, and whether taken by pill or inhaled.
The most common side effects of inhaled steroids are a sore mouth, hoarse voice, and infections in the throat and mouth. You can avoid or reduce these side effects by rinsing your mouth after taking an inhaled steroid.
If using a spray inhaler, also use a spacer/chamber to reduce the amount of steroid landing in your mouth and throat.
Taking steroids by pill in high doses, or taking low doses for a long time, may cause problems including bruising of the skin, weight gain, weakening of the skin and bones (osteoporosis), cataracts, increased blood sugar, mood changes, muscle weakness, and swelling of the ankles or feet.

Patients who use inhaled steroids may have a higher risk of pneumonia. While many of these unwanted effects can be troublesome, not taking steroids when they are needed can lead to severe, life-threatening breathing problems. You should discuss any concerns about taking steroids with your health care provider.

■ Inhaled corticosteroid (ICS)
Inhaled corticosteroid medications can reduce airway inflammation and help prevent exacerbations. Side effects may include bruising, oral infections and hoarseness. These medications are useful for people with frequent exacerbations of COPD.
• fluticasone (Flovent HFA, Flonase, Cutivate)
• budesonide (Pulmicort, Flexhaler, Uceris, Entocort)

■ Oral corticosteroid
For people who have a moderate or severe acute exacerbation, short courses (for example, five days) of oral corticosteroids prevent further worsening of COPD.
However, long-term use of these medications can have serious side effects, such as weight gain, diabetes, osteoporosis, cataracts and an increased risk of infection.

Combination inhalers

Some medications combine bronchodilators and inhaled steroids.
• salmeterol and fluticasone (Advair)
• formoterol and budesonide (Symbicort)

Phosphodiesterase-4 inhibitors

A new type of medication approved for people with severe COPD and symptoms of chronic bronchitis is roflumilast (Daliresp), a phosphodiesterase-4 inhibitor.
This drug decreases airway inflammation and relaxes the airways. Common side effects include diarrhea and weight loss.

SABA: short-acting β₂-agonists
LABA: long-acting β₂-agonists
SAMA: short-acting muscarinic antagonists
LAMA: long-acting muscarinic antagonists

Examples of bronchodilator actions and common side effects:

Patients usually take bronchodilators using an inhaler or a nebulizer.
• Metered-dose inhalers (“MDIs” for short) deliver the medicine as a mist or spray that comes out of a canister and is inhaled by mouth.
• Dry-powdered inhalers (“DPIs” for short) deliver a dry powder through the inhaler, instead of a mist or spray.
• Nebulizers are special machines that change medicine from liquid form into a very fine mist that can be more easily absorbed in the lungs when inhaled.

Beta-2 agonists should be used with caution in people with:
• hyperthyroidism, • cardiovascular disease, • arrhythmia • hypertension • diabetes
Anticholinergics should be used with caution in people with:
• benign prostatic hyperplasia • a bladder outflow obstruction – any condition that affects the flow of urine out of the bladder, such as bladder stones or prostate cancer • glaucoma
Theophylline should be used with caution in people with:
• an overactive thyroid • cardiovascular disease • liver disease • hypertension • gastric ulcers • epilepsy
In people with liver problems, it can sometimes lead to a dangerous level of theophylline in the body.

What are the four stages of COPD?

One way to stage chronic obstructive pulmonary disease is the Global Initiative for Chronic Obstructive Lung Disease program (GOLD).
The staging is based on the results of a pulmonary function test. Specifically, the forced expiratory volume (how much air one can exhale forcibly) in one second (FEV1) of a standard predicted value is measured, based on the individual patient's physical parameters.
The staging of chronic obstructive pulmonary disease by this method is as follows:
• Stage I is FEV1 of equal or more than 80% of the predicted value
• Stage II is FEV1 of 50% to 79% of the predicted value
• Stage III is FEV1 of 30% to 49% of the predicted value
• Stage IV is FEV1 of less than 30% of predicted value or an FEV1 less than 50% of predicted value plus respiratory failure

What Bronchodilator Options Do We Have for COPD?

In a recent comprehensive review, the investigators analyzed the results of 18 trials that compared fixed combinations of a long-acting beta-agonist/long-acting muscarinic antagonist (LABA/LAMA) with LAMA monotherapy.

The LABAs included indacaterol, vilanterol, formoterol, salmeterol, or olodaterol;
the LAMAs included glycopyrronium, umeclidinium, tiotropium, or aclidinium.
Fluticasone was the inhaled corticosteroid (ICS) when a corticosteroid was a component.

The FEV1 as measured after 12-52 weeks was significantly greater with the LABA/LAMA combination than with LAMA monotherapy.
Similarly, the LABA/LAMA combination yielded greater improvements in lung function than a LABA/ICS combination.
In general, the improvements seen with fixed LABA/LAMA combinations were of meaningful magnitude, with the exception being those combinations that included aclidinium.

Other important outcomes, such as less need to take reliever medications for breakthrough symptoms and frequency of acute exacerbations, were significantly better with combination bronchodilators.
In addition, the adverse event rate was low in all treatment arms and did not differ between treatments.

Viewpoint
The guidelines for the management of COPD, the GOLD Guidelines, recommend that initial symptoms of COPD be treated with short-acting bronchodilators (SABAs) on an as-needed basis, moving to long-acting agents on a regular basis if symptoms are not adequately managed with a SABA. Either a LABA or a LAMA could be introduced on a 12- or 24-hour schedule. If symptoms deteriorate over time, as is common, a fixed combination, such as a LABA/LAMA, is appropriate.

one might expect, two bronchodilators that relax airways through different and separate receptors result in more bronchodilation than one. Before LABA/LAMAs became widely available, the combination would have most likely been a LABA/ICS fixed combination, but we now recognize that unless the patient has a component of asthma or is having acute exacerbations of COPD, an ICS is not appropriate and carries a risk for pneumonia.

If symptoms are still not adequately controlled with a LABA/LAMA fixed combination, one may consider adding an ICS to the LAMA/LABA prescription by adding an ICS to a LABA/LAMA combination or by prescribing a fixed combination of a LABA/ICS plus a LAMA monotherapy. No fixed LABA/LAMA/ICS triple combination is available at present, but several are in clinical trials.

Among the various long-term monotherapies and fixed combinations, there is little to choose; with very few exceptions, all the bronchodilator molecules mentioned above are effective and relatively safe. The 12-hour or 24-hour duration of action can be an issue, and the patient may have a preference.

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Inhaled therapy

Bronchodilators (short-acting β2 agonists [SABA] and short-acting muscarinic antagonists [SAMA]) should be the initial empirical treatment for the relief of breathlessness and exercise limitation.
ICS have potential adverse effects (including non-fatal pneumonia) in people with COPD.

Offer a once-daily LAMA in preference to four-times-daily SAMA to people with stable COPD who remain breathless or have exacerbations, despite using short-acting bronchodilators as required, and in whom a decision has been made to commence regular maintenance bronchodilator therapy with a muscarinic antagonist.

Most patients – whatever their age – are able to acquire and maintain an adequate inhaler technique.
Bronchodilators are usually best administered using a hand-held inhaler device (including a spacer device if appropriate).

Patients with distressing or disabling dyspnoea, despite maximal therapy using inhalers, should be considered for nebulizer therapy.
They should be offered a choice between a face mask and a mouthpiece to administer their nebulized therapy, unless the drug specifically requires a mouthpiece (for example, anticholinergic drugs).

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Bronchodilators

Aid to Diagnosis
Bronchodilator reversibility testing is still widely performed in many laboratories.
The principle is simple: Lung function, normally assessed as the FEV1, is measured before and at an appropriate interval after the inhalation of a bronchodilator. Any change greater than that expected by chance would represent a positive response, which has been defined operationally as a change greater than 12% of the baseline which also exceeds 200 mLs.
This information can be helpful as an adjunct to other diagnostic and clinical assessments but unfortunately cannot be relied on by itself as a guaranteed way of defining specific diseases.
In asthma, it is the within- and between-day variability in lung function that is more important than the acute response to a drug, although a return to normal lung function after a bronchodilator test on a day when lung function is impaired constitutes strong evidence for this diagnosis.
If the patient is tested when lung function is close to normal, however, the bronchodilator test result may be negative, but the diagnosis will still be asthma.
Similarly, in COPD, many patients show responses to drugs on some occasions but not others.
This inconsistency reflects the categorical nature of the response criteria and the fact that even in COPD, some physiologic variation in day-to-day lung function is typical.
In general, the likelihood of a response falls as the baseline lung function worsens, along with the degree of clinical emphysemas.
If more than one drug is used, then the chance of a positive response increases, so testing the combination of a β-agonist and an anticholinergic will produce a prevalence of disease different from that observed with use of a β-agonist alone. The latter drug has the advantage that only 15 minutes is required before the patient can be retested, explaining its popularity in many laboratories.

Chronic Obstructive Pulmonary Disease

Bronchodilators
Bronchodilator therapy is indicated in acute COPD exacerbations, even in patients without clinical wheezing.
Although intravenous bronchodilators are available (methylxanthines or in some countries β2-selective agonists), inhaled delivery of β2-selective agonists and ipratropium is the therapy of choice for acute exacerbations of COPD because of the advantageous benefit-to-toxicity ratio.

Bronchodilator treatment in acutely ill COPD patients has been shown to decrease inspiratory muscle loading, with an increase in FEV1 and a decrease in functional residual capacity and dynamic hyperinflation. In mechanically ventilated patients, a reduction in expiratory resistance and dynamic hyperinflation (measured as a decrease in intrinsic PEEP) has been described.

There is no strong evidence supporting use of one inhaled β2-selective agonist over another.
The widespread use of inhaled β-agonists has been accompanied by clinical concern of cardiac complications in elderly patients and patients with coronary artery disease.
In a study on clinically stable COPD or asthma patients with a history of myocardial ischemia, no ischemic events, arrhythmias, or tachycardias were observed, however, when commonly used doses of salbutamol were administered.
In high-risk cardiac patients, ipratropium may be preferred over β-agonists because of the decreased chance of cardiac side effects.
Although ipratropium bromide is widely used in stable COPD patients with improvement of pulmonary mechanics and essentially no toxicity, its use as the sole therapy in acute exacerbations is not recommended because it has a less predictable clinical response compared with β-agonists in this population.

Tiotropium bromide is a cholinolytic bronchodilator that antagonizes muscarinic receptors and dissociates more slowly from M1 and M3 than from M2 and subsequently has a long duration of action.
Tiotropium reduces the number of exacerbations, increases time to first exacerbation, and improves lung function significantly compared with ipratropium.
Tiotropium produces superior bronchodilation and improvements in dyspnea and health-related quality of life compared with ipratropium and salmeterol in patients with COPD.
The use of tiotropium is associated with sustained reduction of lung hyperinflation at rest and during exercise. Its benefits in acute exacerbation have not been fully shown, however.
Superiority of combination β-agonist and ipratropium bromide also is controversial, with some reports showing clinical improvement with combined use, and others showing no difference from the improvement achieved with inhaled β-agonist therapy alone.
In acute severe exacerbations of COPD, we recommend combination therapy.

Although parenteral use of theophylline compounds is not recommended as part of initial therapy of COPD exacerbation, it may be considered in admitted patients who are unresponsive to β-agonist, ipratropium, and steroid therapy.
Magnesium sulfate therapy, although reported in a few case reports to be temporarily associated with improvement,107 is not recommended as therapy in COPD exacerbation.